FIGURE

13.52 Colonoscopic appearance of sessile and pedunculated polyps. A. A sessile flat polyp with
Indigo carmine. B. Colon after resection of a sessile polyp. C. A large pedunculated polyp.

Many histological types of polyp are found in the colon (Box 13.31). However, adenomas
are the precursor lesions in most cases of colon cancer.

 Box 13.31
C la ssif ic a t io n o f c o lo re c t a l po lyps a nd po lypo sis syndro me s
 Histology Polyposis syndrome Defective gene Inheritance CRC risk
Hyperplastic Hyperplastic polyposis BRAF Yes
Hamartoma Juvenile polyposis MADH4 or BMPR1A AD 10–70%
Peutz–Jeghers syndrome STK11 AD Yes
Cowden syndrome PTEN AD 10%?
Lhermitte–Duclos disorder PTEN AD
Bannayan–Riley–Ruvalcaba syndrome PTEN AD
Inflammatory None None No
Lymphoid Benign lymphoid polyposis Unknown No
Adenoma FAP APC AD 100%
AFAP Yes
Gardner syndrome Yes
Turcot syndrome Yes
MYH-AP MYH-AP AR
Adenoma Lynch syndrome (HNPCC) Mismatch repair genes (MSH-2, MLH-1) AD 70–80%

AD, autosomal dominant; AFAP, attenuated FAP; APC, adenomatous polyposis coli; AR, autosomal recessive;
CRC, colorectal cancer; FAP, familial adenomatous polyposis; HNPCC, hereditary non-polyposis colorectal
cancer; MLH-1, MutL homologue 1; MSH-2, MutS homologue 2; MYH-AP, MUT Y homologue-associated polyposis;
PTEN, phosphatase and tensin homologue.

Classification of colorectal polyps

Classification is summarized in Box 13.31.

Sporadic adenomas
An adenoma is a benign, dysplastic tumour of columnar cells or glandular tissue. Adenomas
have tubular, tubulovillous or villous morphology. The vast majority of adenomas are not
inherited and are termed ‘sporadic’. Although many sporadic adenomas do not become
malignant in the patient's lifetime, they have a tendency to progress to cancer via increasing
grades of dysplasia due to progressive accumulation of genetic changes (adenoma–carcinoma
sequence). Factors favouring malignant transformation in colorectal polyps, and the relation
between adenoma size and likelihood of cancer, are shown in Box 13.32.

 Box 13.32
F a c t o rs a f f e c t ing risk o f ma lig na nt c ha ng e in a n a de no ma
 Factor Higher risk Lower risk
Size >1.5 cm <1 cm
Type Sessile or flat Pedunculated
Histology Severe dysplasia Mild dysplasia
Villous architecture Tubular architecture
Squamous metaplasia
Number Multiple polyps Single polyp

The progression from benign polyp to cancer is shown in Figure 17.2.

The likelihood of an adenoma being present increases with age; it is rare before the age of
30 years. By the age of 60–70, 5% of asymptomatic subjects will have a polyp of ≥1 cm, or
cancer with no symptoms, and up to 50% will have at least one small <1 cm adenoma.
Removal of polyps at colonoscopy and subsequent surveillance reduce the risk of development
of colon cancer by approximately 80%. Techniques such as chromoscopy, using dye spray or
narrow band imaging, are being used to assist in their detection (flat adenomas account for
approximately 12% of all adenomas).
Polyps in the rectum and sigmoid often present with rectal bleeding. More proximal lesions
rarely produce symptoms and most are diagnosed on barium enema, CT colonography or on
colonoscopy performed for screening or for other reasons. Large villous adenomas can present
with profuse diarrhoea with mucus and hypokalaemia.
Once a polyp has been found, it is almost always possible to remove it endoscopically.
Surveillance guidelines dictate the frequency of repeat investigations:
• at 5 years, if 1 or 2 adenomas <1 cm are found
• at 3 years, if there are 3–4 small adenomas or at least 1 that is >1 cm
• at 1 year, if there are ≥5 small adenomas or there are ≥3, at least 1 of which is >1 cm.
If any doubt exists about the completeness of excision of any polyp, then an earlier repeat
examination is suggested.

Sessile serrated adenomas

Serrated polyps form a heterogeneous group of colorectal lesions that includes the benign
hyperplastic polyps (HPs), and the pre-malignant sessile serrated adenoma (SSA) and
traditional serrated adenoma (TSA). They are characterized by the saw-tooth appearance of
the crypt epithelium. It is now recognized that approximately 30% of colorectal cancers
(particularly those in the right colon) originate from these lesions. Progression of serrated
polyps is thought to occur via a distinct pathway from the adenoma–carcinoma sequence, with
involvement of BRAF gene mutations and gene promoter hypermethylation (CpG island
methylator phenotype, or CIMP; see p. 423). Microsatellite instability can be detected in both
the adenoma–carcinoma and the serrated pathways. Endoscopic resection of SSAs and TSAs
with appropriate surveillance is recommended.
 Inherited polyposis syndromes
About 5% of colorectal cancers have a well-defined single-gene basis.

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant condition arising from
germline mutations of the APC gene, located on chromosome 5q21–q22. More than 825
different mutations have been identified. Penetrance is virtually 100%. It is characterized by
the presence of hundreds to thousands of colorectal and duodenal adenomas. The mean age of
adenoma development is 16 years; the average age at which colorectal cancer develops is 39 
years. Tracing and screening of relatives are essential, and affected individuals should be
offered a prophylactic colectomy. Surgical options include colectomy and ileorectal
anastomosis, which requires lifelong surveillance of the rectal stump, or a restorative
proctocolectomy or pouch procedure with complete removal of rectal mucosa.
Cystic gland polyps, predominantly in the proximal stomach, and duodenal adenomas are
frequently found in FAP, as well as other extraintestinal lesions such as osteomas, epidermoid
cysts and desmoid tumours. The duodenal adenomas may progress to cancer and are the most
common cause of death in colectomized patients with FAP. Congenital hypertrophy of the
retinal pigment epithelium (CHRPE) occurs in many families with FAP. Other cancers in FAP
include thyroid, pancreatic and hepatoblastomas.
APC gene mutations can be found in about 80% of families with FAP. Once the mutation has
been identified in an index case, other family members can be tested for the mutation, and
screening can then be directed at mutation carriers. If a mutation cannot be found in a known
FAP case, all family members should undergo clinical screening with regular colonoscopy.
Attenuated FAP may be missed as it presents later (average age 44 years) and has fewer
polyps (<100), which tend to occur on the right side of the colon rather than on the left. It may
be indistinguishable from sporadic cases but the gene mutation is in the APC germline.

MYH-associated polyposis
MUT Y homologue-associated polyposis (MYH-AP) is an autosomal recessive inherited
syndrome of multiple colorectal adenomas and cancer. MYH is a base-excision-repair gene
that corrects oxidative DNA damage. MYH-AP may account for 7–8% of families with the
FAP phenotype in whom APC mutations cannot be found. Subjects with multiple adenomas or
an FAP phenotype without APC mutations and with a family history compatible with a
recessive pattern of inheritance should be tested for MYH-AP.

Lynch syndrome
In Lynch syndrome (previously called hereditary non-polyposis colon cancer, HNPCC), polyps
are formed in the colon and may progress rapidly to colon cancer. It affects 1 : 5000 people,
causing 3–10% of colorectal cancer cases.
The disease is caused by a mutation in one of the DNA mismatch repair genes, usually
hMSH2 or hMLH1, although others (hMSH6, PMS1 and PMS) have been reported. Mismatch
repair genes are responsible for maintaining the stability of DNA during replication.
Inheritance is autosomal dominant. The defect in function of the mismatch repair mechanism
causes naturally occurring, highly repeated, short DNA sequences known as microsatellites to
be shorter or longer than normal, a phenomenon called microsatellite instability (MSI).
Onset of cancer is earlier than in sporadic cases, at age 40–50 or younger. Tumours have a
predilection for the right colon, in contrast to sporadic cases. In contrast to FAP, the lifetime
risk of colon cancer (penetrance of the gene) in mutation carriers is 70–80%. Other cancers are
also more common in Lynch syndrome: stomach, small intestine, bladder, skin, brain and
hepatobiliary system. Female patients are at risk for endometrial and ovarian cancer.
The diagnosis is made from the family history of colon cancer at a young age and the
presence of associated cancers in the family. These are formalized in the various editions of
the Amsterdam and the Bethesda criteria (Box 13.33).

 Box 13.33
D ia g no st ic c rit e ria f o r Lync h syndro me
Modified Amsterdam criteria
• One individual diagnosed with CRC (or extracolonic Lynch tumours) before age 50 years
• Two affected generations
• Three affected relatives, one a first-degree relative of the other two
• FAP excluded
• Tumours verified by pathological examination
Bethesda guidelines
• CRC diagnosed in patient who is younger than 50 years
• Presence of synchronous, metachronous CRC, or other Lynch tumours, irrespective of age
• CRC with the MSI-H histology diagnosed in a patient who is younger than 60 years
• CRC diagnosed in one or more first-degree relative with a Lynch-related tumour, with one
of the cancers being diagnosed under the age 50 years
• CRC diagnosed in two or more first- or second-degree relatives with Lynch-related
tumours, irrespective of age
CRC, colorectal cancer; MSI-H, microsatellite instability – high.

Turcot syndrome
This consists of FAP or Lynch syndrome (HNPCC) with brain tumours.

Gardner syndrome
This involves, in addition to FAP, desmoid tumours, osteomas of the skull and other lesions.

Hamartomatous polyps
These are commonly large and stalked. The inherited syndromes show autosomal dominant
inheritance and include:
• Juvenile polyps, which occur mainly in children and teenagers, and are found mainly in the
colon; histologically, they show mucus retention cysts. Most are sporadic, but a syndrome of
juvenile polyposis is defined as: >3–5 juvenile colonic polyps, juvenile polyps throughout
the gastrointestinal tract, or any number of polyps with a family history. This is an autosomal
dominant condition and the relevant gene has been identified (see Box 13.31). The polyps are
a cause of bleeding and intussusception in the first decade of life. There is also an increased
risk of colonic cancer (relative risk (RR) of 34), and surveillance and removal of polyps
must be undertaken.
• Peutz–Jeghers syndrome (see p. 403).
• PTEN hamartoma–tumour syndrome (PHTS), which includes Cowden syndrome,
Bannayan–Riley–Ruvalcaba syndrome and all syndromes caused by germline phosphatase
and tensin homologue (PTEN) mutations. Cowden (multiple hamartoma) syndrome is
associated with characteristic skin stigmata, and by intestinal polyps regarded as hamartomas
but with a mixture of cell types. These patients have an increased risk of various
extraintestinal malignancies (thyroid, breast, uterine and ovarian). These syndromes are
uncommon and together account for <1% of colon cancer cases.

Colorectal carcinoma
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most
common cause of cancer death in the UK.
Each year approximately, 40 000 new cases are diagnosed in England and Wales (68%
colon, 32% rectal cancer), and CRC is registered as the cause of death in about half this
number. The prevalence rate per 100 000 (at all ages) is 53.5 for men and 36.7 for women. The
incidence increases with age; the average age at diagnosis is 60–65 years. Approximately 20%
of patients in the UK have distant metastases at diagnosis. The disease is much more common
in westernized countries than in Asia or Africa.
Factors related to risk of colorectal cancer are shown in Box 13.34.

 Box 13.34
R isk f a c t o rs in c o lo re c t a l c a nc e r
Increased risk
• Increasing age
 • Animal fat (saturated) and red meat consumption
• Sugar consumption
• Colorectal polyps
• Family history of colon cancer or colonic polyps
• Chronic inflammatory bowel disease
• Obesity (body and abdominal)
• Smoking
• Acromegaly
• Abdominal radiotherapy
• Ureterosigmoidostomy
Decreased risk
• Vegetable, garlic, milk, calcium consumption
• Exercise (colon only)
• Aspirin (including low-dose) and other NSAIDs
NSAIDs, non-steroidal anti-inflammatory drugs.

Genetics
Most colorectal cancers develop as a result of progression from normal mucosa to adenoma to
invasive cancer. This progression is controlled by the accumulation of abnormalities in a
number of critical growth-regulating genes and can be divided into three main pathways:
• Chromosomal instability (CIN). CIN is the most common cause of conventional adenomas
throughout the colon. This pathway involves the sequential accumulation of genetic mutations
in tumour suppressor genes, usually initiated by a mutation in the gene encoding adenomatous
polyposis coli (APC).
• CpG island methylator phenotype. CpG island methylator phenotype (CIMP) tumours arise
via the serrated neoplasia pathway and have a marked predilection for the proximal colon.
Following an initiating genetic mutation in the genes encoding BRAF or KRAS, these lesions
progress via epigenetic silencing of tumour suppressor and mismatch repair (MMR) genes by
promoter methylation (p. 421). This pathway is epitomized by the serrated polyposis
syndrome.
• Microsatellite instability. Microsatellite instability (MSI) tumours are also more commonly
located in the proximal colon. They arise from defective DNA repair through inactivation of
mismatch repair genes, epitomised by the germline mutation of MMR genes seen in Lynch
syndrome (HNPCC).
This molecular classification can help to distinguish clinical characteristics, such as patient
demographics, tumour distribution, response to therapy and prognosis.
Cancer families
A family history of CRC confers an increased risk to relatives. Family history is, next to age,
the most common risk factor for CRC. FAP (Fig. 13.53) is the best-recognized syndrome
predisposing to CRC but represents less than 1% of all colorectal cancers. Lynch syndrome
(HNPCC) accounts for 3–10% of familial cancer (see p. 422).

FIGURE 13.53 Percentages of colon cancer according to family risk. FAP, familial adenomatous polyposis;
HNPCC, hereditary non-polyposis colorectal cancer (Lynch syndrome).

Additionally, some colon cancers arise, at least in part, from an inherited predisposition, so-
called familial risk (Box 13.35). Estimates of their frequency range from 10% to 30% of all
CRC but the genes involved have yet to be identified. The risk of CRC can be estimated from a
family history matched with empirical risk tables, so that appropriate advice regarding
screening can be offered.

 Box 13.35
Lif e t ime risk o f c o lo re c t a l c a nc e r ( C R C ) in f irst - de g re e
re la t ive s o f a C R C pa t ie nt
 Individuals affected Risk
Population risk 1 in 50
One first-degree relative affected (any age) 1 in 17
One first-degree and one second-degree relative affected 1 in 12
One first-degree relative affected (age <45) 1 in 10
Two first-degree relatives affected 1 in 6
Autosomal dominant pedigree 1 in 2

(From: Houlston RS, Murday V, Harocopos C et al. Screening and genetic counselling for relatives of patients with
colorectal cancer in a family cancer clinic. British Medical Journal 1990; 301:366–368.)

Most CRCs are, however, sporadic and occur in individuals without a strong family history.
Their distribution is shown in Figure 13.54.

FIGURE 13.54 Distribution of sporadic colorectal cancer. Only 60% are in the range of flexible
sigmoidoscopy.

Pathology
CRC, which usually takes the form of a polypoid mass with ulceration, spreads by direct
infiltration through the bowel wall. It involves lymphatics and blood vessels with subsequent
spread, most commonly to the liver and lung. Synchronous cancers are present in 2% of cases.
Histology is adenocarcinoma with variably differentiated glandular epithelium and mucin
production. ‘Signet ring’ cells, in which mucin displaces the nucleus to the side of the cell, are
relatively uncommon and generally have a poor prognosis.

Clinical features
Symptoms suggestive of colorectal cancer include change in bowel habit with looser and more
frequent stools, rectal bleeding, tenesmus and symptoms of anaemia. A rectal or abdominal
mass may be palpable. Cancers arising in the caecum and right colon are often asymptomatic
until they present as an iron deficiency anaemia. Cancer may present with intestinal
obstruction.
Patients aged over 35–40 years presenting with new large bowel symptoms should be
investigated. Digital examination of the rectum is essential and examination of the colon should
be performed in all cases.

Investigations
• Colonoscopy is the ‘gold standard’ for investigation and allows biopsy for histology. Biopsy
of the tumour is mandatory, usually at endoscopy (Fig. 13.55).

FIGURE 13.55 Carcinoma in the ascending colon. A. Colonoscopic appearance of a large irregular ulcer.
B. Histopathology showing an adenocarcinoma.

• Double-contrast barium enema can visualize the large bowel but has now been superseded
by CT colonography.
• Endoanal ultrasound and pelvic MRI are used for staging rectal cancer.
• Chest, abdominal and pelvic CT scanning evaluate tumour size, local spread, and liver and
lung metastases, contributing to tumour staging.
• PET scanning is useful for detecting occult metastases and for evaluation of suspicious
lesions found on CT or MRI.
• MRI is also useful for evaluating suspicious lesions found on CT or ultrasound, especially in
the liver.
• Serum carcinoembryonic antigen (CEA) is of little use for primary diagnosis and should
not be performed as a screening test. It is useful for follow-up; rising levels suggest
recurrence.
• Faecal occult blood (FOB) tests are used for mass population screening.

Management
Management should be undertaken by multidisciplinary teams working in specialist units.
About 80% of patients with CRC undergo surgery (often laparoscopically). The operative
procedure depends on the cancer site. Long-term survival relates to the stage of the primary
tumour and the presence of metastatic disease. There has been a gradual move from using
Dukes' classification to the TNM classification system (see Box 24.58). Long-term survival is
only likely when the cancer is completely removed by surgery with adequate clearance
margins and regional lymph node clearance.
• Total mesorectal excision (TME) is required for rectal cancers and removes the entire
package of mesorectal tissue surrounding the cancer. A low rectal anastomosis is then
performed. Abdomino-perineal excision, which requires a permanent colostomy, is reserved
for very low tumours within 5 cm of the anal margin. TME combined with preoperative
radiotherapy reduces local recurrence rates in rectal cancer to around 8% and improves
survival. Pre- or postoperative chemotherapy reduces local recurrence rates but had no effect
on survival in a recent study.
• Segmental resection and restorative anastomosis, with removal of the draining lymph nodes
as far as the root of the mesentery, is used for cancer elsewhere in the colon. Surgery in
patients with obstruction carries greater morbidity and mortality. Where technically possible,
preoperative decompression by endoscopic stenting with a mesh-metal stent relieves
obstruction, so surgery can be elective rather than emergency, and is probably associated with
a decrease in morbidity and mortality.
• Local transanal surgery is very occasionally used for early superficial rectal cancers.
• Surgical or ablative treatment of liver and lung metastases prolongs life where treatment
is technically feasible and the patient is fit enough to undergo the treatment.
• Radiotherapy is not helpful for colonic cancers proximal to the rectum because of
difficulties in delivering a sufficient dose to the tumour without excess toxicity to adjacent
structures, particularly the small bowel.
• Adjuvant postoperative chemotherapy improves disease-free survival and overall survival
in stage III colon cancer (see pp. 636–637). Those with stage II tumours and advanced
features such as vascular invasion may also benefit.
Management of advanced colorectal cancer is discussed on pages 636–637.

Follow-up
All patients who have surgery should have a total colonoscopy performed before surgery to
look for additional lesions. If total colonoscopy cannot be achieved before surgery, a second
‘clearance’ colonoscopy within 6 months of surgery is essential. Patients with stage II or III
disease should be followed up with regular colonoscopy and CEA measurements; rising levels
of CEA suggest recurrence. Annual CT scanning of the chest and abdomen to detect operable
liver metastases should be performed for up to 3 years post surgery.

Screening for CRC

• FOB tests have been studied as a screening test for colorectal cancer. Several large
randomized studies have demonstrated a reduction in cancer-related mortality of 15–33%.
Immunologically based FOB tests are superior to the conventional guaiac-based systems. The
disadvantage of screening with FOB is its relatively low sensitivity, which means many
negative colonoscopies. In FOB test screen-positive patients in the UK National Bowel
Cancer Screening Programme (NHS BCSP), about 10% have cancer, 40% have adenomas
and the colon is normal in 50%.
• Flexible sigmoidoscopy screening has been shown to reduce the mortality from CRC, but not
overall mortality.
• Colonoscopy is the ‘gold standard’ technique for examination of the colon and rectum and is
the investigation of choice for high-risk patients. Universal screening strategies have been
implemented in the UK for subjects between 60 and 69 who have a positive FOB. Cancer has
been detected in 8–12% of patients, 75% of which was located in the left colon; 72% of
detected cancers are at an ‘early’ stage (10% polyp cancer, 32% stage I and 30% stage II).
• CT colonography (‘virtual colonoscopy’; see Fig. 13.5 ) is increasingly being used.

F urt he r re a ding
Atkin WS, Edwards R, Kralj-Hans I et al and UK Flexible Sigmoidoscopy Trial
Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal
cancer: a multicentre randomised controlled trial. Lancet 2010; 375:1624–1633.
Camilleri M, Bharucha AE. Behavioural and new pharmacological treatments for
constipation: getting the balance right. Gut 2010; 59:1288–1296.
Cunningham D, Atkin W, Lenz HJ et al. Colorectal cancer. Lancet 2010; 375:1030.
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of
colorectal cancer. N Engl J Med 2009; 361:2449–2460.
Morris AM, Regenbogen SE, Hardiman KM et al. Sigmoid diverticulitis: a systematic
review. JAMA 2014; 311:287–297.
National Institute for Health and Care Excellence. NICE Clinical Guideline 49: Faecal
Incontinence: The Management of Faecal Incontinence. NICE 2007;
http://www.nice.org.uk/guidance/CG49.
Norton C. Treating faecal incontinence with bulking-agent injections. Lancet 2011;
377:971–972.
Tursi A. Diverticular disease: what is the best long-term treatment? Nature Reviews.
Gastroenterol Hepatol 2010; 7:77–78.
http://www.bsg.org.uk British Society of Gastroenterology.
Diarrhoea
Diarrhoea is a common clinical problem and yet there is no uniformly accepted definition.
Organic causes (stool weights >250 g/day) have to be distinguished from functional causes
such as irritable bowel syndrome. Sudden onset of bowel frequency associated with crampy
abdominal pains, and a fever, will point to an infective cause; bowel frequency with loose,
blood-stained stools to an inflammatory basis; and the passage of pale, offensive stools that
float, often accompanied by loss of appetite and weight loss, to steatorrhoea. Nocturnal bowel
frequency and urgency usually point to an organic cause. Passage of frequent, small-volume
stools (often formed) points to a functional cause (see pp. 428–432).

Pathophysiology

Osmotic diarrhoea
The gut mucosa acts as a semipermeable membrane and fluid enters the bowel if there are
large quantities of non-absorbed hypertonic substances in the lumen. This occurs because the
patient:
• has ingested a non-absorbable substance (e.g. a purgative, such as magnesium sulphate or
magnesium-containing antacid)
• has generalized malabsorption, so that high concentrations of solute (e.g. glucose) remain in
the lumen
• has a specific absorptive defect (e.g. disaccharidase deficiency or glucose-galactose
malabsorption).
The volume of diarrhoea produced by these mechanisms is reduced by the absorption of
fluid by the ileum and colon. The diarrhoea stops when the patient stops eating or the
malabsorptive substance is discontinued.

Secretory diarrhoea
In this disorder, there is both active intestinal secretion of fluid and electrolytes, and decreased
absorption. The mechanism of intestinal secretion is shown in Figure 13.56A.
 FIGURE 13.56 Mechanisms of diarrhoea. A. Small intestinal secretion of water and electrolytes. (a)
Cholera toxin binds to its receptor (monosialoganglioside Gi) via fimbria (toxin co-regulated pili) on its β-
subunit. This activates the αs subunit (of the Gs protein), which in turn dissociates and activates cyclic AMP
(cAMP). The increase in cAMP activates intermediates (e.g. protein kinase and Ca2+), which then act on the
apical membrane, causing Cl− secretion (with water) and inhibition of Na+ and Cl− absorption. Heat-labile E.
coli enterotoxin shares a receptor with cholera toxin. (b) Heat-stable (HS) E. coli toxin binds to its own
receptor and activates guanylate cyclase (cGMP), producing the same effect on secretion. (c) Clostridium
difficile activates the protein kinases via Ca2+/calmodulin (Ca2+/CM). (d) Zona occludens toxin is the product
of the ZOT gene, which loosens tight junctions and is required for function of the cholera toxin. It has
enterotoxic activity, producing secretion. Cholera and E. coli cause these effects without invasion of the
cell. B. Colonic mucosal cell. This demonstrates one of the mechanisms by which an invasive pathogen
(e.g. Shigella) acts. Following penetration, the pathogens generate cytotoxins, which leads to mucosal
ulceration and cell death. ATP, adenosine triphosphate; G, G protein consisting of subunits α, β, γ ; GC,
guanyl cyclase; GMP, guanosine monophosphate; GTP, guanosine triphosphate; i, inhibitory; PKC, protein
kinase C; s, stimulatory; VIP, vasoactive intestinal polypeptide.

Common causes of secretory diarrhoea are:

• enterotoxins (e.g. cholera, E. coli thermolabile or thermostable toxin, C. difficile toxin)
• hormones (e.g. vasoactive intestinal peptide in Verner–Morrison syndrome; see p. 512)
• bile salts (in the colon) following ileal resection
• fatty acids (in the colon) following ileal resection
• some laxatives (e.g. docusate sodium).

Inflammatory diarrhoea (mucosal destruction)

Diarrhoea occurs because of damage to the intestinal mucosal cell so that there is a loss of
fluid and blood (Fig. 13.56B). In addition, there is defective absorption of fluid and
electrolytes. Common causes are infective conditions (e.g. dysentery due to Shigella) and
inflammatory conditions (e.g. ulcerative colitis and Crohn's disease).

Abnormal motility
Diabetic, post-vagotomy and hyperthyroid diarrhoea are all due to abnormal motility of the
upper gut. Symptoms may be exacerbated by small bowel bacterial overgrowth.
Causes of diarrhoea are shown in Box 13.23. It should be noted that the irritable bowel
syndrome, colorectal cancer, diverticular disease and faecal impaction with overflow in the
elderly do not cause ‘true’ organic diarrhoea (i.e. >250 g/day), even though patients may
complain of diarrhoea. Worldwide, infection and infestation are major problems and these are
discussed under the causative organisms in Chapter 11.

Acute diarrhoea
Diarrhoea of sudden onset is very common, is often short-lived and requires no investigation
or treatment. Although dietary causes should be considered, diarrhoea due to viral agents may
also last 24–48 hours (see pp. 263–265). The causes of other infective diarrhoeas are shown
on pages 273–279. Travellers' diarrhoea, which affects people travelling outside their own
countries, particularly to developing countries, usually lasts 2–5 days; it is discussed on pages
277–279. Cholera is described on pages 288–289.

Clinical features
Clinical features associated with the acute diarrhoeas include fever, abdominal pain and
vomiting. If the diarrhoea is particularly severe, dehydration can be a problem; the very young
and very old are at special risk from this.

Investigations
Investigations are necessary if the diarrhoea has lasted more than 5–7 days. Stools (up to three)
should be sent immediately to the laboratory for culture and examination for ova, cysts and
parasites and for C. difficile toxin assay. If the diagnosis has still not been made, a
sigmoidoscopy and rectal biopsy should be performed, with colonoscopy if necessary. Viral
and bacterial infective diarrhoeas do not last more than 7–10 days; in this case, inflammatory
bowel disease as a cause of the diarrhoea is a more likely diagnosis.

Management
Oral fluid and electrolyte replacement is often necessary. Special oral rehydration solutions
(e.g. sodium chloride and glucose powder) are available for use in severe episodes of
diarrhoea, particularly in infants. Antidiarrhoeal drugs are thought to impair the clearance of
any pathogen from the bowel but may be necessary for short-term relief (e.g. codeine
phosphate 30 mg four times daily or loperamide 2 mg three times daily). Antibiotics are
occasionally necessary for infective gastroenteritis, depending on the organism.
 Chronic diarrhoea
This always needs investigation. The flow diagram in Figure 13.57 is illustrative; whether the
large or the small bowel is investigated first will depend on the clinical story of, for example,
bloody diarrhoea or steatorrhoea. The investigations and treatment are described in detail
under the individual diseases. Colonoscopy with ileoscopy is usually the first investigation if
stool cultures are negative and small bowel disease is not suspected.

FIGURE 13.57 Flow diagram for the investigation of chronic diarrhoea. Note: All patients should have had
stool cultures with toxin testing for Clostridium difficile. CT, computed tomography; FBC, full blood count;
Hb, haemoglobin; MCV, mean cell volume; MRCP, magnetic resonance cholangiopancreatography; MRI,
magnetic resonance imaging; SeHCAT, 75Selenium-homocholic acid taurine; US, ultrasound; VIP,
vasoactive intestinal polypeptide.

Clostridium difficile-associated diarrhoea (pseudomembranous colitis)

Pseudomembranous colitis (see p. 277) may develop following the use of any antibiotic.
Diarrhoea occurs in the first few days after taking the antibiotic or even up to 6 weeks after
stopping the drug. The causative agent is C. difficile (see p. 277).
Bile acid malabsorption
Bile acid malabsorption is an under-diagnosed cause of chronic diarrhoea and many patients
with this disorder are assumed to have the irritable bowel syndrome. Bile acid diarrhoea
occurs when the terminal ileum fails to reabsorb bile acids. When present in increased
concentrations in the colon, bile acids (particularly the dihydroxy bile acids: deoxycholate and
chenodeoxycholate) lead to diarrhoea by reducing absorption of water and electrolytes and, at
higher concentrations, inducing secretion as well as increasing colonic motility. A variety of
causes of bile acid malabsorption are recognized (Box 13.36).

 Box 13.36
C a use s o f bile a c id dia rrho e a
• Ileal resection
• Ileal disease, e.g. active or inactive Crohn's disease
• Primary bile acid diarrhoea
• Post-infective gastroenteritis
• Rapid small bowel transit
• Post-cholecystectomy

Bile acid malabsorption should be considered not only in patients with chronic diarrhoea of
unknown cause, but also in those with diarrhoea and associated disease who are not
responding to standard therapy (e.g. patients with terminal ileal Crohn's disease or
microscopic inflammatory colitis).
Diagnosis is made using the SeHCAT test, in which a radio-labelled bile acid analogue is
administered and percentage retention at 7 days calculated (<19% retention abnormal).
Treatment is with bile salt sequestrants such as colestyramine, a resin that binds and
inactivates the action of bile acids in the colon. The best treatment results are obtained in
patients with a SeHCAT retention of <5%.

Factitious diarrhoea
Factitious diarrhoea accounts for up to 4% of new patients with diarrhoea attending
gastroenterology clinics.

Purgative abuse
This is most commonly seen in females who surreptitiously take high-dose purgatives and are
often extensively investigated for chronic diarrhoea. The diarrhoea is usually of high volume
(>1 L daily) and patients may have a low serum potassium. Biochemical analysis of the stool
may help diagnose laxative abuse. Management is difficult, as most patients deny purgative
ingestion. Purgative abuse often occurs in association with eating disorders and patients may
need psychiatric help.

Dilutional diarrhoea
In this condition, raised stool weights occur as a consequence of patients deliberately diluting
their stool with urine or tap water. The diagnosis is made by measuring stool osmolality and
electrolyte concentrations in order to calculate the faecal osmolar gap.

Diarrhoea in patients with HIV infection

Chronic diarrhoea is a common symptom in HIV infection, but HIV's role in the pathogenesis
of diarrhoea is unclear. Cryptosporidium (see p. 350) is the pathogen most commonly isolated.
Isospora belli and microsporidia have also been found.
The cause of the diarrhoea is often not found and treatment is symptomatic. Box 13.19
shows the conditions affecting the gastrointestinal tract in patients with AIDS.

Functional Gastrointestinal Disorders

There is a large group of gastrointestinal disorders that are termed ‘functional’ because
symptoms occur in the absence of any demonstrable abnormalities in the digestion and
absorption of nutrients, fluid and electrolytes, and no structural abnormality can be identified
in the gastrointestinal tract, although there may be discernible abnormalities in neuromuscular
function, such as dysmotility and visceral hypersensitivity, which are not routinely
investigated.
Box 13.37 lists some of the symptoms that are suggestive of a functional gastrointestinal
disorder. Modern classification systems are based on the premise that, for each disorder, there
is a symptom cluster that ‘breeds true’ across clinical and population groups. There is
inevitably overlap, some symptoms being common to more than one disorder.

 Box 13.37
C hro nic g a st ro int e st ina l sympt o ms sug g e st ive o f a f unc t io na l
g a st ro int e st ina l diso rde r
• Nausea alone
• Vomiting alone
• Belching
• Chest pain unrelated to exercise
• Postprandial fullness
• Abdominal bloating
• Abdominal discomfort/pain (right or left iliac fossa)
• Passage of mucus per rectum
 • Frequent bowel actions with urgency first thing in morning

Box 13.38 lists the common functional gastrointestinal disorders, as defined by Rome III
criteria. These conditions are extremely common worldwide, comprising 80% of patients seen
in the gastroenterology clinic.

 Box 13.38
M o dif ie d R o me III f unc t io na l g a st ro int e st ina l diso rde rs
A. Functional oesophageal disorders:
– Heartburn
– Chest pain of presumed oesophageal origin
– Dysphagia
– Globus
B. Functional gastroduodenal disorders:
– Non-ulcer dyspepsia
– Belching disorders
– Nausea and vomiting disorders
– Rumination syndrome in adults
C. Functional bowel disorders:
– Irritable bowel syndrome
– Functional bloating
– Functional constipation
– Functional diarrhoea
– Unspecified functional bowel disorder
D. Functional abdominal pain syndrome
E. Functional gall bladder and sphincter of Oddi disorders

Pathophysiology and brain–gut interactions

People with functional gastrointestinal disorders (FGIDs) are characterized by having a
greater gastrointestinal motility response to life events than normal subjects. There is,
however, a poor association between measured gastrointestinal motility changes and symptoms
in many of the FGIDs. Patients with FGID have been shown to have abnormalities in visceral
sensation and to have a lower pain threshold when tested with balloon distension (visceral
hyperalgesia). Visceral hypersensitivity possibly relates to:
• altered receptor sensitivity at the viscus itself
• increased excitability of the spinal cord dorsal horn neurones
• altered central modulation of sensations.
 A systematic review of published studies suggests that 10% of patients who experience an
acute infective gastroenteritis develop a degree of FGID. It is not clear whether this is caused
by post-infectious bile salt malabsorption, alterations in the mucosal immune system or the use
of antibiotics to treat the index infection
The brain–gut axis describes a combination of intestinal motor, sensory and activities (Fig.
13.58). Thus, extrinsic (e.g. vision, smell) and intrinsic (e.g. emotion, thought) information can
affect gastro​intestinal sensation because of the neural connections from higher centres.
Conversely, viscerotropic events can affect central pain perception, mood and behaviour.

FIGURE 13.58 A biopsychosocial conceptualization of the pathogenesis and clinical expression of

functional gastrointestinal disorders (FGIDs). Genetic, environmental and psychological factors may
interact to cause dysregulation of brain–gut function. (Modified from Drossman DA. The functional gastrointestinal disorders and the
Rome III process. Gastroenterology 2006; 130:1377–1390, with permission from Elsevier.)

Psychological stress can exacerbate gastrointestinal symptoms, and psychological

disturbances are more common in patients with FGIDs. These disturbances alter attitude to
illness, promote healthcare seeking, and often lead to a poor clinical outcome. They have
psychosocial consequences with poor quality of life at home and work. Early in life, genetic
and environmental influences (e.g. family attitudes towards bowel training, verbal or sexual
abuse, exposure to an infection) may affect psychosocial development (susceptibility to life
stress, psychological state, coping skills, development of social support) or the development of
gut dysfunction (abnormal motility or visceral hypersensitivity). Therefore, FGID should be
regarded as a dysregulation of brain–gut function.

Functional oesophageal disorders

The criteria for diagnosis rest mainly on compatible symptoms. However, pathological gastro-
oesophageal reflux and eosinophilic oesophagitis may need to be excluded (see pp. 373–374).

Globus
This presents as:
• persistent or intermittent sensation of a lump or foreign body in the throat
• occurrence of the sensation between meals
• absence of dysphagia and pain on swallowing (odynophagia).
Management is with explanation and reassurance, and a trial of anti-reflux therapy.
Antidepressants may be tried.

Functional chest pain of presumed oesophageal origin

This is characterized by episodes of mainly midline chest pain, not burning in nature, that are
potentially of oesophageal origin and occur in the absence of a cardiological cause, gastro-
oesophageal reflux and achalasia.
More than half of patients will respond to high-dose acid-suppression therapy in the first
week; some will respond to nitrates and calcium-channel blockers.
Antidepressant therapy, e.g. amitriptyline or the selective serotonin reuptake inhibitor
(SSRI) citalopram, have been shown to be effective.

Functional gastroduodenal disorders

Functional dyspepsia
This is the second most common functional gastrointestinal disorder (after irritable bowel
syndrome). Patients can present with a spectrum of symptoms, including upper abdominal pain
or discomfort, fullness, early satiety, bloating and nausea.
These patients have no structural abnormality as an explanation for their symptoms.

Functional dyspepsia subgroups

Two subgroups, based on the predominant (or most bothersome) single symptom, are
suggested:
• Epigastric pain syndrome, with pain centred in the upper abdomen as the predominant (most
bothersome) symptom.
• Postprandial distress syndrome, with an unpleasant or troublesome, non-painful sensation
(discomfort) centred in the upper abdomen being the predominant symptom. This sensation
may be associated with upper abdominal fullness, early satiety, bloating and nausea.
There is considerable overlap between these two groups.
 Investigations
Helicobacter pylori infection should be excluded using a stool antigen test, but many young
patients (<50 years) require no further investigation. Older patients or those with alarm
symptoms require endoscopy. Gastroscopy often shows gastritis but it is doubtful whether this
is the cause of the symptoms.

Management
The range of therapies prescribed for functional dyspepsia reflects the uncertain pathogenesis
and the lack of satisfactory treatment options. Management is further confounded by high
placebo response rates (20–60%). A proportion of patients will respond satisfactorily to
reassurance, explanations and lifestyle changes. Proton pump inhibitors and prokinetic agents
are used for patients with epigastric pain syndrome and postprandial distress syndrome,
respectively. Reducing intake of fat, coffee and alcohol and stopping cigarette smoking help.
SSRI medication is tried in refractory cases.
H. pylori eradication therapy has been shown to be effective in some patients with
functional dyspepsia.

Aerophagia
Aerophagia refers to a repetitive pattern of swallowing or ingesting air and belching. It is
usually an unconscious act unrelated to meals. Usually, no investigation is required.
Explanation that the symptoms are due to swallowed air, and reassurance are necessary, as is
treatment of associated psychiatric disease.

Functional vomiting
Functional vomiting is a rare condition in clinical practice, although chronic nausea is a
frequent accompaniment in all functional gastrointestinal disorders. CNS pathology and
migrainous syndromes (cyclical vomiting syndrome) should be considered and treated.

Clinical features
Clinically, functional vomiting is characterized by:
• frequent episodes of vomiting, occurring on at least 1 day a week
• absence of criteria for an eating disorder, rumination or major psychiatric disease
• absence of self-induced and medication-induced vomiting
• absence of abnormalities in the gut or CNS and of metabolic disease to explain the recurrent
vomiting.
 Investigations
Investigation is often not required but non-gastrointestinal disorders should always be
excluded (see Box 13.1).

Management
Treatment is with anti-nausea drugs and antidepressants; behavioural therapy and
psychotherapy are helpful. Dietary changes occasionally help.

Cyclical vomiting syndrome

This syndrome is characterized by typical bouts of intense vomiting lasting for hours to days,
separated by periods with no symptoms. It can occur in children or adults. There is a link to
migraine headaches but the cause is not known. In some cases, provocative triggers can be
identified; for example, there is a specific syndrome associated with frequent cannabis use –
cannabinoid hyperemesis syndrome.
Diagnosis of cyclical vomiting syndrome is by recognition of the pattern of symptoms and
ruling out of other causes.

Management
Treatment is with antiemetics and intravenous rehydration and electrolyte replacement during
bouts, with avoidance of triggers where these are known. Prophylactic treatment of migraine,
when it coexists, may help.

Gastroparesis
Gastroparesis results when there is delayed gastric emptying. There are a number of known
associations, such as diabetes, but many cases are primary. Symptoms include nausea,
vomiting, early satiety, fullness, bloating and upper abdominal pain.
Management is directed at relief of symptoms and correction of nutritional deficiencies.
Improvement of gastric emptying can sometimes be achieved by medical or surgical treatments,
such as pro-motility agents or gastric pacemaker insertion. In diabetics, glycaemic control is
helpful.

Functional bowel disorders

Irritable bowel syndrome
Irritable bowel syndrome (IBS) is the most common FGID. In Western populations, up to 1 in 5
people report symptoms consistent with IBS. Approximately 50% will consult their doctors
and, of these, up to 30% will be referred by their doctor to a hospital specialist. Up to 40% of
all patients seen in specialist gastroenterology clinics will have IBS. Estimates in the UK put
the annual cost of IBS to healthcare resources as £45.6 million; in the USA, the cost is higher at
$8 billion. In the UK, approximately one-quarter of IBS patients take time off work for periods
ranging from 7 to 13 days each year.
The factors that determine whether an IBS sufferer in the community seeks medical advice
include higher illness attitude scores and higher anxiety and depression scores than non-
consulters. Consulters perceive that their symptoms are more severe than those of non-
consulters, and consulting behaviour may be determined by the number of presenting
symptoms. Female consulters outnumber male consulters by a factor of 2–3 to 1.

IBS – a multisystem disorder

IBS patients suffer from a number of non-intestinal symptoms (Box 13.39), which may be more
intrusive than the classical features. IBS coexists with chronic fatigue syndrome (see pp. 899–
900), fibromyalgia (see pp. 664–665) and temporomandibular joint dysfunction.

 Box 13.39
N o n- g a st ro int e st ina l f e a t ure s o f irrit a ble bo w e l syndro me
Gynaecological symptoms
• Painful periods (dysmenorrhoea)
• Pain following sexual intercourse (dyspareunia)
Urinary symptoms
• Frequency
• Urgency
• Passing urine at night (nocturia)
• Incomplete emptying of bladder
Other symptoms
• Joint hypermobility
• Back pain
• Headaches
• Bad breath, unpleasant taste in the mouth
• Poor sleeping
• Fatigue

The biopsychosocial conceptualization of the pathogenesis and clinical expression of FGIDs

(Fig. 13.58) is particularly relevant to IBS, and Box 13.40 lists some common factors that
have been shown to trigger IBS symptoms. Infectious diarrhoea precedes the onset of IBS
symptoms in 7–30% of patients. Whether this is a factor for all patients or just a small
subgroup remains controversial. Risk factors in these patients have been shown to include
female gender, severity and duration of diarrhoea, pre-existing adverse life events and high
hypochondriacal anxiety and neurotic scores at the time of the initial illness. Symptoms of
anxiety and depression are more common in IBS patients, and stress or adverse life events
often precede the onset of chronic bowel symptoms.

 Box 13.40
So me f a c t o rs t ha t c a n t rig g e r o nse t o f irrit a ble bo w e l
sympt o ms
• Affective disorders, e.g. depression, anxiety
• Psychological stress and trauma
• Gastrointestinal infection
• Antibiotic therapy
• Sexual, physical or verbal abuse
• Pelvic surgery
• Eating disorders

Diagnosis
Diagnostic criteria (Rome III 2006) state that, in the preceding 3 months, there should be at
least 3 days/month of recurrent abdominal pain or discomfort associated with two or more of
the following for at least 25% of the time:
1. improvement with defecation
2. onset associated with a change in frequency of stool
3. onset associated with a change in form (appearance) of stool.
These are useful for comparative studies.
Subgroups of IBS patients can be identified according to the criteria listed in Box 13.41.

 Box 13.41
Subt yping irrit a ble bo w e l syndro me by pre do mina nt st o o l
pa t t e rn
 Type Description
IBS with constipation (IBS-C) Hard lumpy stools >25% and loose (mushy) or watery stools <25% of bowel movements
IBS with diarrhoea (IBS-D) Loose (mushy) or watery stools >25% and hard or lumpy stools <25% of bowel movements
Mixed IBS (IBS-M) Hard or lumpy stools >25% and loose (mushy) or watery stools >25% of bowel movements
Unsubtyped IBS Insufficient abnormality of stool consistency to meet criteria for IBS-C, D or M

The decision as to whether to investigate and the choice of investigations should be based
on clinical judgement. Pointers to the need for thorough investigation are the presence of the
above symptoms in association with rectal bleeding, nocturnal pain, fever and weight loss, and
a clinical suspicion of organic diarrhoea. A raised stool calprotectin or lactoferrin would
suggest inflammation needing further investigation.

Management
Current strategies for the treatment of IBS include therapies that target central and end-organ
pathways (Box 13.42); these are not mutually exclusive.

 Box 13.42
Appro a c he s t o t he ma na g e me nt o f t he irrit a ble bo w e l
syndro me
 Treatment modality Action
End-organ treatment
Exploration of dietary triggers Refer to dietitian
High-fibre diet ± fibre supplements for constipation, low Refer to dietitian
FODMAP diet for bloating
Alteration of microbiota Rifaximin has shown short-term benefit in IBS patients without
constipation (target I and II trials)
Pro- and prebiotics
Anti-diarrhoeal drugs for bowel frequency Loperamide
Codeine phosphate
Co-phenotrope
Eluxadoline*
Constipation 5-HT4 receptor agonist, e.g. prucalopride
Smooth muscle relaxants for pain Mebeverine hydrochloride
Dicycloverine hydrochloride
Peppermint oil
Central treatment
Explanation of physiology and symptoms At consultation (leaflets with diagrams help)
Psychotherapy Refer to clinical psychologist (see p. 900)
Hypnotherapy
Cognitive behavioural therapy Refer to psychiatrist
Antidepressants Functional diarrhoea – clomipramine
Diarrhoea-predominant IBS – tricyclic group, e.g. amitriptyline
Constipation-predominant IBS – SSRI, e.g. paroxetine
a
Eluxadoline – a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist.
FODMAP, fermentable oligo-, di- and monosaccharides and polyols; SSRI, selective serotonin reuptake inhibitor.

Patients with IBS are often worried that their symptoms are due to a serious disease such as
cancer. A positive diagnosis of IBS with an explanation of the symptoms and reassurance is
often helpful and may require no further treatment. Box 13.42 shows the overall management
strategies used in IBS for those with severe and longstanding problems. Patients should be
treated sympathetically and some may require psychiatric support.

Pain/gas/bloat syndrome/midgut dysmotility

Disordered motility and visceral sensation that predominantly affects the small intestine or
midgut result in symptoms of pain and bloating without altered defecation. Other symptoms
include postprandial fullness, nausea and, on occasions, anorexia and weight loss.
Management of patients with pain/gas/bloat syndrome is not easy, and in some, pain can
be chronic and severe. Narcotics should always be avoided. Central and end-organ-targeted
treatment approaches should be combined: for example, the SSRI paroxetine combined with a
prokinetic agent, such as domperidone, or a smooth muscle relaxant, such as mebeverine.
Small bowel bacterial overgrowth can be a contributory feature that can be treated with non-
absorbed antibiotics such as rifaximin. Recent research has highlighted the benefit of altering
the fermentable components of the diet. A diet with reduced fermentable oligo-, di- and
monosaccharides and polyols (FODMAP) will exclude a range of food types, including garlic,
onions, specific beans, fructose-containing fruit, wheat-containing products, and certain natural
and synthetic sweeteners. Small sham-diet-controlled clinical trials have shown significant
benefit in patients with functional symptoms but long-term randomized controlled studies are
necessary.
Some patients with pain/gas/bloat syndrome have particularly severe and chronic symptoms,
which may be nocturnal. A small subgroup of these has been shown to have manometric
features consistent with a diagnosis of chronic idiopathic intestinal pseudo-obstruction
(CIIP), and specifically of an enteric neuropathy. Full-thickness small intestinal biopsies
confirm this diagnosis by showing a deficiency of α actin staining in the inner circular layer of
smooth muscle. More appropriately, these patients should be considered as having a
gastrointestinal neuromuscular disorder of the gut. About 10% of these individuals are
subsequently found to have an underlying autoimmune overlap disorder (see p. 699).
Management of patients with neuromuscular disorders of the gut requires a
multidisciplinary approach, with an emphasis on the management of pain, psychological state
and nutrition. Patients with underlying autoimmune inflammatory mixed connective tissue
disorders may benefit from primary treatment of these. Patients with intestinal failure as a
result of CIIP need long-term parenteral nutrition.

Functional diarrhoea
In this form of functional bowel disease, symptoms occur in the absence of abdominal pain.
They commonly include:
• the passage of several stools in rapid succession, usually first thing in the morning; no further
bowel action may occur that day, or defecation takes place only after meals
• a first stool of the day that is usually formed, the later ones being mushy, looser or watery
• urgency of defecation
• anxiety, and uncertainty about bowel function with restriction of movement (e.g. travelling)
• exhaustion after defecation.
Chronic diarrhoea without pain is caused by many diseases that are indistinguishable by
history from functional diarrhoea. Features that are atypical of a functional disorder (e.g. large-
volume stools, rectal bleeding, nutritional deficiency and weight loss) call for more extensive
investigations.
Treatment of functional diarrhoea is with loperamide, often combined with a tricyclic
antidepressant prescribed at night (e.g. clomipramine 10–30 mg).

F urt he r re a ding
Chang L. The role of stress on physiologic responses and clinical symptoms in irritable
bowel syndrome. Gastroenterology 2011; 140:761–765.
 Drossman DA. The functional gastrointestinal disorders and the Rome III process.
Gastroenterology 2006; 130:1377–1390.
Ford AC, Talley NJ. IBS in 2010: advances in pathophysiology, diagnosis and treatment.
Nat Rev Gastroenterol Hepatol 2011; 8:76–78.
Manabe N, Rao AS, Wong BS et al. Emerging pharmacologic therapies for irritable
bowel syndrome. Curr Gastroenterol Rep 2010; 12:8–16.
Moayyedi P, Ford AC, Talley NJ et al. The efficacy of probiotics in the treatment of
irritable bowel syndrome: a systematic review. Gut 2010; 59:325–332.
National Institute for Health and Care Excellence. NICE Clinical Guideline 61: Irritable
Bowel Syndrome in Adults: Diagnosis and Management of Irritable Bowel Syndrome in
Primary Care. NICE 2008; http://www.nice.org.uk/guidance/cg61.

The Acute Abdomen

This section deals with the acute abdominal conditions that cause the patient to be hospitalized
within a few hours of the onset of pain (Box 13.43). If they are recognized quickly as an
emergency, a reduction in morbidity and mortality can be achieved. Although a specific
diagnosis should be attempted, the immediate problem in management is to decide whether an
‘acute abdomen’ exists and whether surgery is required.

 Box 13.43
C o mmo n c a use s o f a c ut e a bdo mina l pa in

Diagnosis %a
Non-specific abdominal pain 35
Acute appendicitis 30
Gall bladder disease 10
Gynaecological disorders 5
Intestinal obstruction 5
Perforated ulcer/dyspepsia 5
Renal colic 2
Urinary tract infection 2
Diverticular disease 2
Other diagnoses 4
a
Percentages are approximate and vary in different communities.

Diagnosis
History
This should include previous operations, any gynaecological problems and presence of any
concurrent medical condition.

Pain
The onset, site, type and subsequent course of the pain should be determined as accurately as
possible. In general, the pain of an acute abdomen can be either constant (usually owing to
inflammation) or colicky (because of a blocked ‘tube’). The inflammatory nature of a constant
pain will be supported by a raised temperature, tachycardia and/or a raised white cell count. If
these are normal, then other causes (e.g. musculoskeletal, aortic aneurysm), even rare ones
(e.g. porphyria), should be considered. Colicky pain can be due to an obstruction of the gut,
biliary system, urogenital system or uterus. These cases will probably require conservative
management initially, along with analgesics. If a colicky pain becomes a constant pain, then
inflammation of the organ may have supervened (e.g. strangulated hernia, ascending cholangitis
or salpingitis).
A sudden onset of pain suggests:
• perforation (e.g. of a duodenal ulcer)
• rupture (e.g. of an ectopic pregnancy)
• torsion (e.g. of an ovarian cyst)
• acute pancreatitis
• infarction (e.g. mesenteric).
Back pain suggests:
• pancreatitis
• rupture of an aortic aneurysm
• renal tract disease.
Inflammatory conditions (e.g. appendicitis) produce a more gradual onset of pain. With
peritonitis, the pain is continuous and may be made worse by movement. Many inflammatory
conditions can progress to those listed as having a sudden onset due to complications.

Vomiting
Vomiting may accompany any acute abdominal pain but, if persistent, suggests an obstructive
lesion of the gut. The character of the vomit should be asked about. Does it contain blood, bile
or small bowel contents?

Other symptoms
Any change in bowel habit or of urinary frequency should be documented and, in females, a
gynaecological history, including last menstrual period, should be taken.

Physical examination
The general condition of the person should be noted. Does he or she look ill or shocked? Large
volumes of fluid may be lost from the vascular compartment into the peritoneal cavity or into
the lumen of the bowel, giving rise to hypovolaemia: that is, a pale, cold skin, a weak, rapid
pulse and hypotension.

The abdomen
• Inspection. Look for the presence of scars, distension or masses.
• Palpation. The abdomen should be examined gently for sites of tenderness and the presence
or absence of guarding. Guarding is involuntary spasm of the abdominal wall and indicates
peritonitis. This can be localized to one area or may be generalized, involving the whole
abdomen.
• Bowel sounds. Increased high-pitched, tinkling bowel sounds indicate fluid obstruction; this
occurs because of fluid movement within the dilated bowel lumen. Absent bowel sounds
suggest peritonitis. In an obstructed patient, absent bowel sounds may be due to strangulation,
ischaemia or ileus. It is essential for the hernial orifices to be examined if intestinal
obstruction is suspected.

Vaginal and rectal examination

Vaginal examination can be very helpful, particularly in diagnosing gynaecological causes of
an acute abdomen (e.g. a ruptured ectopic pregnancy). Rectal examination is less helpful, as
localized tenderness may be due to any cause; it may show blood on the glove.

Other observations
• Temperature. Fever is more common in acute inflammatory processes.
• Urine. Examine for:
– blood – suggests urinary tract infection or renal colic
– glucose and ketones – ketoacidosis can present with acute pain
– protein and white cells – to exclude acute pyelonephritis.
• Medical causes. These should be borne in mind (Box 13.44).

 Box 13.44
M e dic a l c a use s o f a c ut e a bdo me n
• Referred pain:
– Pneumonia
– Myocardial infarction
• Functional gastrointestinal disorders
• Renal causes:
– Pelviureteric colic
 – Acute pyelonephritis
• Metabolic causes:
– Diabetes mellitus
– Acute intermittent porphyria
– Lead poisoning
– Familial Mediterranean fever
• Haematological causes:
– Haemophilia and other bleeding disorders
– Henoch–Schönlein purpura
– Sickle cell crisis
– Polycythaemia vera
– Paroxysmal nocturnal haemoglobinaemia
• Vasculitis

Investigations
• Blood count. A raised white cell count occurs in inflammatory conditions.
• Serum amylase. High levels (more than five times normal) indicate acute pancreatitis.
Raised levels below this can occur in any acute abdomen and should not be considered
diagnostic of pancreatitis.
• Serum electrolytes. These are not particularly helpful for diagnosis but are useful for general
evaluation of the patient.
• Pregnancy test. A urine dipstick is used for women of childbearing age.
• X-rays. An erect chest X-ray is useful to detect air under the diaphragm caused by a
perforation (Fig. 13.59). Dilated loops of bowel or fluid levels are suggestive of obstruction
on abdominal X-ray (Fig. 13.60).
 FIGURE 13.59 X-ray showing air under the diaphragm (arrowed).

FIGURE 13.60 X-ray showing small bowel obstruction.

• Ultrasound. This is useful in the diagnosis of acute cholangitis, cholecystitis and aortic
aneurysm, and in expert hands is reliable in the diagnosis of acute appendicitis.
 Gynaecological and other pelvic causes of pain can be detected.
• CT scan. Spiral CT of the abdomen and pelvis is the most accurate investigation in most
acute emergencies. It should be used more often to avoid unnecessary laparotomies.
• Laparoscopy. This is used increasingly as a diagnostic tool prior to proceeding with surgery,
particularly in men and women over the age of 50 years. In addition, therapeutic manœuvres,
such as appendicectomy, can be performed.

Acute appendicitis
This is a common surgical emergency and affects all age groups. Appendicitis should always
be considered in the differential diagnosis if the appendix has not been removed.
Acute appendicitis mostly occurs when the lumen of the appendix becomes obstructed with a
faecolith; however, in some cases, there is only generalized acute inflammation. If the appendix
is not removed at this stage, gangrene occurs with perforation, leading to a localized abscess
or to generalized peritonitis.

Clinical features
Most patients present with abdominal pain; in many, it starts vaguely in the centre of the
abdomen, becoming localized to the right iliac fossa in the first few hours. Nausea, vomiting,
anorexia and occasional diarrhoea can occur.
Examination of the abdomen usually reveals tenderness in the right iliac fossa, with guarding
due to the localized peritonitis. There may be a tender mass in the right iliac fossa. Although
raised white cell counts, ESR and CRP are helpful, other laboratory tests can be less valuable.
An ultrasound scan can detect an inflamed appendix and can also indicate an appendix mass or
other localized lesion. CT is highly sensitive (98.5%) and specific (98% negative predictive
value; 99.5% positive predictive value), and reduces the incidence of removal of a ‘normal’
appendix. With the use of these investigations, the incidence of ‘normal’ appendix histology
has fallen to 15–20%.

Differential diagnosis
• Non-specific mesenteric lymphadenitis – may mimic appendicitis.
• Acute terminal ileitis due to Crohn's disease or Yersinia infection.
• Gynaecological causes:
– Inflamed Meckel's diverticulum
– Functional bowel disease.

Management
The appendix is removed by laparoscopic surgery. If an appendix mass is present, the patient
is usually treated conservatively with intravenous fluids and antibiotics. The pain subsides
over a few days and the mass usually disappears over a few weeks. Interval appendicectomy
is recommended at a later date to prevent further acute episodes.

Gynaecological causes of an acute abdomen

Ruptured ectopic pregnancy
The fallopian tube is the most common extrauterine site of implantation. Delayed diagnosis is
the major cause of morbidity. Most patients will present with recurrent low abdominal pain
associated with vaginal bleeding. Diagnosis is usually made with abdominal and transvaginal
ultrasound. Most patients can be managed by laparoscopic salpingostomy or salpingectomy.

Ovarian causes
• Rupture of ‘functional’ ovarian cysts in the middle of the cycle (Mittelschmerz).
• Torsion or rupture of ovarian cysts.

Acute salpingitis
Most cases are associated with sexually transmitted infection. Patients commonly present with
bilateral low abdominal pain, a fever and vaginal discharge. In the Fitz-Hugh–Curtis
syndrome, Chlamydia infection tracks up the right paracolic gutter to cause a perihepatitis.
Patients can present with acute right hypochondrial pain, fever and mildly abnormal liver
biochemistry.

Acute peritonitis
Localized peritonitis
There is virtually always some degree of localized peritonitis with all acute inflammatory
conditions of the gastrointestinal tract (e.g. acute appendicitis, acute cholecystitis). Pain and
tenderness are largely features of this localized peritonitis. The treatment is for the underlying
disease.

Generalized peritonitis
This is a serious condition, resulting from irritation of the peritoneum owing to infection (e.g.
perforated appendix) or from chemical irritation due to leakage of intestinal contents (e.g.
perforated ulcer). In the latter case, superadded infection gradually occurs; E. coli and
Bacteroides are the most common organisms.
The peritoneal cavity becomes acutely inflamed, with production of an inflammatory exudate
that spreads throughout the peritoneum, leading to intestinal dilatation and paralytic ileus.
 Clinical features
In perforation, the onset is sudden with acute, severe abdominal pain, followed by general
collapse and shock. The patient may improve temporarily, only to become worse later as
generalized toxaemia occurs.
When peritonitis is secondary to inflammatory disease, the onset is less rapid, the initial
features being those of the underlying disease.

Investigations
Investigations should always include an erect chest X-ray. X-ray is used to detect free air
under the diaphragm, and serum amylase is measured to diagnose acute pancreatitis, which is
treated conservatively. Imaging with ultrasound and/or CT should always be performed for
diagnosis.

Management
Peritonitis is treated surgically after adequate resuscitation and the re-establishment of a good
urinary output. This includes insertion of a nasogastric tube, intravenous fluids and antibiotics.
Surgery has a two-fold objective:
• peritoneal lavage of the abdominal cavity
• specific treatment of the underlying condition.

Complications
Any delay in the treatment of peritonitis produces more profound toxaemia and septicaemia,
which may lead to development of multiorgan failure (see p. 1155). Local abscess formation
can occur and should be suspected if a patient continues to remain unwell postoperatively, with
a swinging fever, high white cell count and continuing pain. Abscesses are commonly pelvic or
subphrenic, and can be localized and drained using ultrasound and CT scanning techniques.

Intestinal obstruction
Most intestinal obstruction is due to a mechanical block. Sometimes, the bowel does not
function, leading to a paralytic ileus. This occurs temporarily after most abdominal operations
and with peritonitis. Some causes of intestinal obstruction are shown in Box 13.45. The most
common cause in adults is adhesions.

 Box 13.45
C a use s o f int e st ina l o bst ruc t io n
 Small intestinal obstruction
• Adhesions (80% in adults)
• Hernias
• Crohn's disease
• Intussusception
• Obstruction due to extrinsic involvement by cancer
Colonic obstruction
• Carcinoma of the colon
• Sigmoid volvulus
• Diverticular disease

Obstruction of the bowel leads to bowel distension above the block, with increased
secretion of fluid into the distended bowel. Bacterial contamination takes place in the
distended stagnant bowel. In strangulation, the blood supply is impeded, leading to gangrene,
perforation and peritonitis unless urgent treatment of the condition is undertaken.

Clinical features
The patient complains of abdominal colic, vomiting and constipation without passage of wind.
In upper gut obstruction the vomiting is profuse, but in lower gut obstruction it may be absent.
Examination of the abdomen reveals distension with increased bowel sounds. Marked
tenderness suggests strangulation, and urgent surgery is necessary. Examination of the hernial
orifices and rectum must be performed. X-ray of the abdomen reveals distended loops of
bowel proximal to the obstruction. Fluid levels are seen in small bowel obstruction on an erect
film. In large bowel obstruction, the caecum and ascending colon are distended. An instant,
water-soluble Gastrografin enema without air insufflation may help to demonstrate the site of
the obstruction. CT can localize the lesion accurately and is the investigation of choice.

Management
Initial management is by resuscitation with intravenous fluids (mainly 0.9% saline with
potassium) and decompression. Many cases will settle on conservative management, but an
increasing temperature, raised pulse rate, increasing pain and a rising white cell count require
urgent scanning and possible exploratory laparotomy.
Laparotomy with removal of the obstruction will be necessary in some cases of small bowel
obstruction. If the bowel is gangrenous owing to strangulation, gut resection will be required.
A few patients (e.g. those with Crohn's disease) may have recurrent episodes of incomplete
intestinal obstruction that can be managed conservatively. In large bowel obstruction due to
malignancy, a self-expanding metal stent can be used, followed by elective surgery. In
critically ill patients, a defunctioning colostomy may be needed. Volvulus of the sigmoid colon
can be managed by the passage of a flexible sigmoidoscope or a rectal tube to un-kink and
deflate the bowel, but recurrent volvulus may require sigmoid resection.

Acute colonic pseudo-obstruction

A clinical picture mimicking mechanical obstruction may develop in patients who do not have
a mechanical cause. In more than 80% of cases, it complicates other clinical conditions, such
as:
• intra-abdominal trauma, pelvic, spinal and femoral fractures
• postoperative states (abdominal, pelvic, cardiothoracic, orthopaedic, neurosurgical)
• intra-abdominal sepsis
• pneumonia
• metabolic disorders (e.g. electrolyte disturbances, malnutrition, diabetes mellitus, Parkinson's
disease)
• drugs – opiates (particularly after orthopaedic surgery), antidepressants, antiparkinsonian
drugs.
Patients present with rapid and progressive abdominal distension and pain. X-ray shows a
gas-filled large bowel. Management is of the underlying problem (e.g. withdrawal of opiate
analgesia), together with a trial of intravenous neostigmine therapy. Patients should be
monitored and consideration should be given to surgery if the diameter of the caecum exceeds
14 cm.

The Peritoneum

Anatomy and physiology

The peritoneal cavity is a closed sac lined by mesothelial cells; these produce surfactant,
which acts as a lubricant within the peritoneal cavity. The cavity contains <100 mL of serous
fluid containing <30 g/L of protein.
The mesothelial cells lining the diaphragm have gaps that allow communication between the
peritoneum and the diaphragmatic lymphatics. Approximately one-third of fluid drains through
these lymphatics, the remainder through the parietal peritoneum. These mechanisms allow
particulate matter to be removed rapidly from the peritoneal cavity.
Complement activation is an early defence mechanism and is followed rapidly by
upregulation of the peritoneal mesothelial cells and migration of polymorphonuclear
neutrophils and macrophages into the peritoneum.
Mast cells release potent mediators of inflammation, including histamine and eicosanoids,
and interact with T cells to generate an immune response.
 The peritoneum-associated lymphoid tissue includes the omental milky spots, the
lymphocytes within the peritoneal cavity and the draining lymph nodes. B cells with a unique
CD5+ are common. This defence system plays a major role in localizing peritoneal infection.

Disorders affecting the peritoneum

Conditions that can affect the peritoneum are shown in Box 13.46.

 Box 13.46
D ise a se s o f t he pe rit o ne um
Infective (bacterial) peritonitis
• Secondary to gut disease, e.g. appendicitis
• Perforation of any organ
• Chronic peritoneal dialysis
• Spontaneous, usually in ascites with liver disease
• Tuberculosis
Neoplasia
• Secondary deposits (e.g. from ovary, stomach)
• Primary mesothelioma
Vasculitis
• Rheumatic autoimmune disease
• Polyserositis (e.g. familial Mediterranean fever)

Peritonitis can be acute or chronic, as seen in TB. Most cases of infective peritonitis are
secondary to gastrointestinal disease, but it occurs occasionally without intra-abdominal sepsis
in ascites due to liver disease. Very rarely, fungal and parasitic infections (e.g. amoebiasis,
candidiasis) can also cause primary peritonitis. Peritonitis is discussed further on pages 434-
435.
The peritoneum can be involved by secondary malignant deposits, and the most common
cause of ascites in a young to middle-aged woman is an ovarian carcinoma.
A subphrenic abscess is usually secondary to infection in the abdomen and is characterized
by fever, malaise, pain in the right or left hypochondrium and shoulder-tip pain. An erect chest
X-ray may show gas under the diaphragm, impaired movement of the diaphragm on screening
and/or a pleural effusion. Ultrasound is usually diagnostic. Percutaneous catheter drainage
inserted under CT or ultrasound guidance and antibiotics constitute highly successful therapy.
Ascites is associated with all diseases of the peritoneum. The fluid that collects is an
exudate with a high protein content. It is also seen in liver disease. The mechanism, causes and
investigation of ascites are discussed on pages 472–474.

Peritoneal adhesions
Adhesions form as a result of abdominal or pelvic surgery, or inflammation in the
abdominoperitoneal cavity. They cause a variety of conditions, including adhesive small
bowel obstruction (ASBO), chronic abdominal pain, complications during future surgery, and
female infertility when they involve the fallopian tubes or ovaries. There is no satisfactory
medical or surgical treatment and so surgical techniques have been developed to minimize
peritoneal injury,

Retroperitoneal fibrosis (peri-aortitis)

This is a rare condition, in which there is a marked fibrosis over the posterior abdominal wall
and retroperitoneum. It is associated with raised serum IgG4 levels (see p. 145) and is
described on pages 760–761.

Tuberculous peritonitis
This is the second most common form of abdominal TB. Three subgroups can be identified:
wet, dry and fibrous.
• In patients with the wet type, ascitic fluid should be examined for protein concentration
(>20 g/L) and tubercle bacilli (rarely found).
• In the dry form, patients present with subacute intestinal obstruction, which is due to
tuberculous small bowel adhesions.
• In the fibrous form, patients present with abdominal pain, distension and ill-defined,
irregular, tender abdominal masses.
The diagnosis of peritoneal TB can be supported by findings on ultrasound or CT screening
(mesenteric thickening and lymph node enlargement). A histological diagnosis is not always
required before instituting treatment. In some patients, careful laparoscopy (to avoid
perforation) may have to be performed, and rarely laparotomy.

Management
Drug treatment is similar to that for pulmonary TB (see pp. 1110–1113) and should be
supervised by chest physicians who have experience in dealing with contacts.

Bibliography
Feldman M, Friedman LS, Brandt LL. Sleisenger and Fordtran's Gastrointestinal and
 Liver Disease. 10th edn. WB Saunders: Philadelphia; 2015.

Significant websites
http://www.bsg.org.uk British Society of Gastroenterology.
http://www.coeliac.co.uk Coeliac UK.
http://www.corecharity.org.uk/Information.html Gastric ulcer and GORD.
http://www.nacc.org.uk UK Crohn's and Colitis UK.
14

Liver disease
Graham Foster, Alastair O'Brien

Introduction 437
Anatomy of the liver and biliary system 440
Functions of the liver 441
Clinical approach to the patient with liver disease 443
Investigations 443
Clinical features of liver disease 447
Jaundice 448
Hepatitis 451
Viral hepatitis 452
Acute hepatitis due to other infectious agents 461
Acute hepatic failure 462
Autoimmune hepatitis 463
Drug-induced chronic hepatitis 464
Non-alcoholic fatty liver disease 465
Chronic hepatitis of unknown cause 464
Cirrhosis 465
Liver transplantation 468
Complications and effects of cirrhosis 469
Types of cirrhosis 475
Alcoholic liver disease 480
Budd–Chiari syndrome 482
Hepatic sinusoidal obstruction syndrome 482
Fibropolycystic diseases 483
Liver abscess 483
Other infections of the liver 484
Liver tumours 485
Secondary liver tumours 485
Primary malignant tumours 485
Benign tumours 486
Miscellaneous conditions of the liver 486
Drugs and the liver 487
Drug metabolism 487
Drug hepatoxicity 487
Drug prescribing for patients with liver disease 488

Introduction
 The aetiology of liver disease differs from region to region. In the developed world, liver
inflammation is most often due to obesity, the metabolic syndrome (non-alcoholic fatty liver
disease, NAFLD), non-alcoholic steatohepatitis (NASH) and alcohol excess. In the developing
world, chronic viral infection with either hepatitis B or hepatitis C is the leading cause of liver
mortality. In England, liver disease is the fifth most common cause of premature mortality.
Globally, about half a billion people suffer from chronic viral hepatitis. Health education and
the improvement in public health, along with vaccination programmes, should help to stop the
spread of viral infections and reduce risk factors for the metabolic syndrome.
Cirrhosis represents the final common pathway for liver diseases and is characterized by
progressive fibrosis of the liver parenchyma, which leads to portal hypertension and
deterioration of liver function. In decompensated cirrhosis, the median overall survival is 2 
years, which is a far worse prognosis than for many cancers.
Imaging techniques enable the liver, biliary tree and pancreas to be visualized with
precision, resulting in earlier diagnosis. Liver transplantation is an established therapy for both
acute and chronic liver disease.

Anatomy of the Liver and Biliary System

The liver
The liver is the body's largest internal organ (1.2–1.5 kg) and is situated in the right
hypochondrium. A functional division into the larger right lobe (containing caudate and
quadrate lobes) and the left lobe is made by the middle hepatic vein. The liver is further
subdivided into eight segments (Fig. 14.1) by divisions of the right, middle and left hepatic
veins. Each segment has its own portal pedicle, permitting individual segment resection at
surgery.

FIGURE 14.1 Segmental anatomy of the liver. The eight hepatic segments are shown: I, caudate lobe; II–IV,
left hemiliver; V–VIII, right hemiliver.

The hepatic blood supply constitutes 25% of the resting cardiac output and is delivered via
two main vessels, entering via the liver hilum (porta hepatis):
• The hepatic artery, a branch of the coeliac axis, supplies 25% of the hepatic blood flow. The
hepatic artery autoregulates flow, ensuring a constant total blood flow.
• The portal vein drains most of the gastrointestinal tract and the spleen. It supplies 75% of
hepatic blood flow. The normal portal pressure is 5–8 mmHg; flow increases after meals.
The blood from these vessels is distributed to the segments and flows into the sinusoids via
the portal tracts.
Blood leaves the sinusoids, entering branches of the hepatic vein, which join into three main
branches before entering the inferior vena cava.
The caudate lobe is an autonomous segment, as it receives an independent blood supply
from the portal vein and hepatic artery, and its hepatic vein drains directly into the inferior
vena cava.
Lymph, formed mainly in the perisinusoidal space, is collected in lymphatics that are
present in the portal tracts. These small lymphatics enter larger vessels, which eventually drain
into the portal system.
The acinus is the functional hepatic unit. This consists of parenchyma supplied by the
smallest portal tracts containing portal vein radicles, hepatic arterioles and bile ductules (Fig.
14.2). The hepatocytes near this triad (zone 1) are well supplied with oxygenated blood and
are more resistant to damage than the cells nearer the terminal hepatic (central) veins (zone 3).

FIGURE 14.2 The acinus. Zones 1, 2 and 3 represent areas supplied by blood, with zone 1 being best
oxygenated. Zone 3 is supplied by blood remote from afferent vessels and is in the microcirculatory
periphery of the acinus. The perivascular area (the star-shaped green area around the terminal hepatic
venule (THV)) is formed by the most peripheral parts of zone 3 and is made up of several adjacent acini; it
is the least well oxygenated area. PT, portal triad.

The sinusoids lack a basement membrane and are loosely surrounded by specialist
fenestrated endothelial cells and Kupffer cells (phagocytic cells). Sinusoids are separated by
plates of liver cells (hepatocytes). The subendothelial space between the sinusoids and
hepatocytes is the space of Disse, which contains a matrix of basement membrane constituents
and stellate cells (see Fig. 14.21).
Stellate cells store retinoids in their resting state and contain the intermediate filament,
desmin. When activated (to myofibro​blasts), they are contractile and regulate sinusoidal blood
flow. Endothelin and nitric oxide play a major role in modulating stellate cell contractility.
Stellate cells are activated by a wide variety of inflammatory cytokines (such as tumour
necrosis factor-alpha, TNF-α); once activated, they generate extracellular matrix proteins,
including collagen, leading, eventually, to cirrhosis. Under appropriate conditions, stellate
cells can also produce proteases that degrade the extracellular matrix, leading to reversal of
fibrosis. The balance between collagen production and degradation is critical to the
progression of liver scarring and cirrhosis development/resolution (see p. 466).

The biliary system

Bile canaliculi form a network between the hepatocytes. These join to form thin bile ductules
near the portal tract, which, in turn, enter the bile ducts in the portal tracts. These then combine
to form the right and left hepatic ducts, which leave each liver lobe. The hepatic ducts join at
the porta hepatis to form the common hepatic duct. The cystic duct connects the gall bladder to
the lower end of the common hepatic duct. The gall bladder lies under the right lobe of the
liver and stores and concentrates hepatic bile; its capacity is approximately 50 mL. The
common bile duct is formed at the junction of the cystic and common hepatic ducts and is 8 mm
in diameter or less, passing through the head of the pancreas, and narrowing at its lower end to
pass into the duodenum. The common bile duct and pancreatic duct open into the second part of
the duodenum, most often through a common channel at the ampulla of Vater, which contains the
muscular sphincter of Oddi. This contracts rhythmically and prevents all of the bile from
entering the duodenum, by maintaining a higher pressure than the gall bladder in the fasting
state.

Functions of the Liver

Protein metabolism (see also page 186)

Synthesis and storage

The liver is the principal site of synthesis of all circulating proteins, apart from γ-globulins
(produced in the reticuloendothelial system). The liver receives amino acids from the intestine
and muscles and, by controlling the rate of gluconeogenesis and transamination, regulates
plasma levels. Plasma contains 60–80 g/L of protein, mainly albumin, globulin and fibrinogen.
Albumin has a half-life of 16–24 days, and 10–12 g is synthesized daily. Its main functions
are to maintain intravascular oncotic (colloid osmotic) pressure, and to transport water-
insoluble substances such as bilirubin, hormones, fatty acids and drugs. Reduced synthesis of
albumin over prolonged periods produces hypoalbumi​naemia and is seen in chronic liver
disease and malnutrition. Hypoalbuminaemia is also found in hypercatabolic states (e.g.
trauma, burns and sepsis) and in diseases associated with an excessive loss (e.g. nephrotic
syndrome or protein-losing enteropathy).
Transport or carrier proteins, such as transferrin and caeruloplasmin, acute phase and other
proteins (e.g. α1-antitrypsin and α-fetoprotein) are also produced in the liver.
The liver also synthesizes all coagulation factors (except for one-third of factor VIII) – that
is, fibrinogen, prothrombin, factors V, VII, IX, X and XIII, proteins C and S, and antithrombin
(see pp. 565–567), as well as components of the complement system. The liver stores large
amounts of certain vitamins, particularly A, D and B12, lesser amounts of others (vitamin K and
folate), and minerals – iron in ferritin and haemosiderin, and copper.

Degradation (nitrogen excretion)

Amino acids are degraded by transamination and oxidative deamination to produce ammonia,
which is then converted to urea and excreted by the kidneys. This is the major pathway for the
elimination of nitrogenous waste. Failure of this process occurs in severe liver disease.

Carbohydrate metabolism
Glucose homeostasis and maintenance of blood sugar are major functions of the liver. It stores
approximately 80 g of glycogen. In the immediate fasting state, blood glucose is maintained
either by glucose release from glycogen breakdown (glycogenolysis) or by synthesis of new
glucose (gluconeogenesis). Sources for gluconeogenesis are lactate, pyruvate, amino acids
from muscles (mainly alanine and glutamine), and glycerol from lipolysis of fat stores. In
prolonged starvation, ketone bodies and fatty acids are used as alternative sources of fuel as
body tissues adapt to a lower glucose requirement (see p. 190).

Lipid metabolism
Fats are insoluble in water and are transported in plasma as protein–lipid complexes
(lipoproteins). These are discussed in detail on pages 1277–1279.
The liver has a major role in the metabolism of lipoproteins. It synthesizes very-low-density
lipoproteins (VLDLs) and high-density lipoproteins (HDLs). HDLs are the substrate for
lecithin-cholesterol acyltransferase (LCAT), which catalyses the conversion of free cholesterol
to cholesterol ester (see below). Hepatic lipase removes triglyceride from intermediate-
density lipoproteins (IDLs) to produce low-density lipoproteins (LDLs) which are degraded
by the liver after uptake by specific cell-surface receptors (see Fig. 28.3).
Triglycerides are mainly of dietary origin but are also formed in the liver from circulating
free fatty acids (FFAs) and glycerol, and incorporated into VLDLs. Oxidation or de novo
synthesis of FFAs occurs in the liver, depending on availability of dietary fat.
Cholesterol may be of dietary origin but most is synthesized from acetyl-coenzyme A
(acetyl-CoA) in the liver, intestine, adrenal cortex and skin. It either occurs as free cholesterol
or is esterified with fatty acids; this reaction is catalysed by LCAT. This enzyme is reduced in
severe liver disease, increasing the ratio of free cholesterol to ester, which alters membrane
structures. One result of this is the red cell abnormalities (e.g. target cells) seen in chronic
liver disease. Phospholipids (e.g. lecithin) are synthesized in the liver. The complex
interrelationships between protein, carbohydrate and fat metabolism are shown in Figure 14.3.

FIGURE 14.3 Interrelationships of protein, carbohydrate and lipid metabolism in the liver.

Formation of bile

Bile secretion and bile acid metabolism

Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated
bilirubin. Two processes are involved in bile secretion across the canalicular membrane of the
hepatocyte – bile salt-dependent and bile salt-independent processes – each contributing
about 230 mL/day. Another 150 mL/day is produced by bile ductule epithelial cells.
Bile formation requires uptake of bile acids and other organic and inorganic ions across the
basolateral (sinusoidal) membranes by multiple transport proteins (sodium taurocholate co-
transporting polypeptide (NTCP) and sodium-independent organic anion-transporting
polypeptide 2 (OATP2); Fig. 14.4). This process is driven by sodium/potassium adenosine
triphosphatase (Na+/K+-ATPase) in the basolateral membranes. Intracellular transport across
hepatocytes is partly through microtubules and partly by cytosol transport proteins.
 FIGURE 14.4 Cholesterol synthesis and its conversion to primary and secondary bile acids. All bile acids
are normally conjugated with glycine or taurine. BSEP, bile salt export pump; FXR, nuclear farnesoid X
receptor; MDR3, multidrug-resistant protein 3; MRP2, multidrug-resistant protein 2; NTCP, sodium
taurocholate co-transporting polypeptide; OATP2, sodium-independent organic anion-transporting
polypeptide 2.

Bile acids are also synthesized in hepatocytes from cholesterol, the rate-limiting step being
those catalysed mainly by cholesterol-7α-hydroxylase and the P450 enzymes (CYP7A1 and
CYP8B1).
The bile acid receptor, farnesoid X, blocks bile acid formation from cholesterol and also
regulates the transport proteins (NTCP, OATP2) that increase bile acid uptake by the liver. It is
a target for a new class of therapeutic drugs, farnesoid X receptor (FXR) agonists (see pp.
442–443).
The canalicular membrane contains multispecific organic anion transporters, mainly
ATPase-dependent (ATP binding cassette), the multidrug-resistant protein 2 (MRP2),
multidrug-resistant protein 3 (MDR3) and the bile salt excretory pump (BSEP), which carry a
broad range of compounds including bilirubin diglucuronide, glucuronidated and sulphated
bile acids, and other organic anions against a concentration gradient into the biliary
canaliculus. Na+ and water follow the passage of bile salts by diffusion across the tight
junction between hepatocytes (a bile salt-dependent process). In the bile salt-independent
process, water flow is due to other osmotically active solutes such as glutathione and
bicarbonate.
Secretion of a bicarbonate-rich solution is stimulated mainly by secretin and inhibited by
somatostatin. This involves several membrane proteins, including the Cl−/HCO3− exchanger
and the cystic fibrosis transmembrane conductance regulator that controls Cl− secretion, and
water channels (aquaporins) in cholangiocyte membranes.
The bile acids are excreted into bile and pass via the common bile duct into the duodenum.
The two primary bile acids – cholic acid and chenodeoxycholic acid (Fig. 14.4) – are
conjugated with glycine or taurine, which increases their solubility. Intestinal bacteria convert
these acids into secondary bile acids, deoxycholic and lithocholic acid. Figure 14.5 shows the
enterohepatic circulation of bile acids.

FIGURE 14.5 Recirculation of bile acids. The bile salt pool is relatively small and the entire pool recycles
6–8 times via the enterohepatic circulation. Synthesis of new bile acids compensates for faecal loss.

The average total bile flow is 600 mL/day. When fasting, half flows into the duodenum and
half is diverted into the gall bladder. The gall bladder mucosa absorbs 80–90% of the water
and electrolytes, but is impermeable to bile acids and cholesterol. Following a meal, the I
cells of the duodenal mucosa secrete cholecystokinin, which stimulates contraction of the gall
bladder and relaxation of the sphincter of Oddi, allowing bile to enter the duodenum. An
adequate bile flow is dependent on bile salts being returned to the liver by the enterohepatic
circulation.
Bile acids act as detergents; their main function is lipid solubilization. Bile acid molecules
have both a hydrophilic and a hydrophobic end. In aqueous solutions they form micelles, with
their hydrophobic (lipid-soluble) ends in the centre. Micelles are expanded by cholesterol and
phospholipids (mainly lecithin), forming mixed micelles.
Bile acid receptors in liver disease
Bile acids have been identified as crucial cell signalling molecules that regulate multiple
biological processes. Bile acids are endogenous ligands for FXR and TGR5, a G-protein
coupled receptor. Gain- and loss-of-function studies have demonstrated that both are involved
in the regulation of lipid and carbohydrate metabolism and inflammatory responses. These
receptors may therefore be potential targets for treatment of non-alcoholic fatty liver disease
(NAFLD). Furthermore, recent experimental and phase II studies have shown that the FXR
agonist, obeticholic acid, may be beneficial in primary biliary cholangitis (PBC). Obeticholic
acid also improves portal hypertension in rodents. It is hoped that these experimental and
early-phase findings will translate into new treatments.

Bilirubin metabolism
Bilirubin is produced mainly from the breakdown of mature red cells by Kupffer cells in the
liver and reticuloendothelial system; 15% of bilirubin is formed from catabolism of other
haem-containing proteins, such as myoglobin, cytochromes and catalases.
Normally, 250–300 mg (425–510 mmol) of bilirubin are produced daily. The iron and
globin are removed from haem and reused. Biliverdin is formed from haem and reduced to
form bilirubin (see p. 521). The bilirubin produced is unconjugated and water-insoluble, due
to internal hydrogen bonding, and is transported to the liver attached to albumin. Bilirubin
dissociates from albumin and is taken up by hepatic cell membranes and transported to the
endoplasmic reticulum by cytoplasmic proteins, where it is conjugated with glucuronic acid
and excreted into bile. The microsomal enzyme, uridine diphosphoglucuronosyl transferase,
catalyses the formation of bilirubin monoglucuronide and then diglucuronide. This conjugated
bilirubin is water-soluble; it is actively secreted into biliary canaliculi and excreted into the
intestine within bile (see Fig. 16.5). It is not absorbed from the small intestine because of its
large molecular size. In the terminal ileum, bacterial enzymes hydrolyse the molec​ule,
releasing free bilirubin, which is then reduced to urobilinogen; some of this is excreted in the
stools as stercobilinogen. The remainder is absorbed by the terminal ileum, passes to the liver
via the enterohepatic circulation, and is re-excreted into bile. Urobilinogen bound to albumin
enters the circulation and is excreted in urine via the kidneys. When hepatic excretion of
conjugated bilirubin is impaired, a small amount is strongly bound to serum albumin and is not
excreted by the kidneys; it accounts for persisting hyperbilirubinaemia after cholestasis has
resolved.

Hormone and drug inactivation

The liver catabolizes hormones such as insulin, glucagon, oestrogens, growth hormone,
glucocorticoids and parathyroid hormone. It is also the prime target organ for many hormones
(e.g. insulin). It is the major site for the metabolism of drugs (see p. 487) and alcohol (see pp.
217–218). Fat-soluble drugs are converted to water-soluble substances that facilitate their
excretion in the bile or urine. Cholecalciferol is converted to 25-hydroxycholecalciferol.
Immunological function
The liver plays a key role in the innate immune response and acts as a ‘sieve’ for bacterial and
other antigens carried to it by the portal vein from the gastrointestinal tract (see p. 468).
Hepatocytes are responsible for biosynthesis of 80–90% of innate immune proteins,
including complement components and many secreted pattern-recognition receptors (PRRs)
expressed by host cells. Kupffer cells (KCs), which account for 80–90% of the total
population of fixed tissue macrophages, are a critical component of the mononuclear
phagocytic system and are central to both the hepatic and the systemic responses to pathogens.
Following stimulation by endotoxin, the Kupffer cells release interleukin (IL)-6, IL-8 and
TNF-α, and, in combination with liver sinusoidal cells, are responsible for the elimination of
molecular wastes from the body.
In addition, liver lymphocytes are rich in innate immune cells, including natural killer and T
cell receptor γδ T cells. Finally, non-parenchymal liver cells express high levels of
membrane-bound PRRs, such as Toll-like receptor cells (TLRs). Not only does innate
immunity in the liver play a key role in host defence against microbial infection and tumour
formation, but it also contributes to the pathogenesis of acute and chronic liver diseases,
including alcoholic liver disease (see pp. 480–482).

F urt he r re a ding
Dooley J, Lok A, Burroughs AK et al. Anatomy and function. In: Sherlock's Diseases of the
Liver and Biliary System, 12th edn. London: Wiley–Blackwell; 2011.
Li Y, Jadhav K, Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease.
Biochem Pharmacol 2013; 86:1517–1524.

Clinical Approach to the Patient with Liver Disease

Investigations
Investigative tests can be divided into:
• Blood tests:
– Liver ‘function’ tests: serum albumin and bilirubin; prothrombin time (PT)
– Liver biochemistry: serum aspartate (AST) and alanine aminotransferases (ALT) – an
increase reflects hepatocellular damage; serum alkaline phosphatase (ALP) and gamma-
glutamyl transpeptidase (γ-GT) – an increase reflects cholestasis; total protein.
– Viral markers.
– Additional blood investigations; haematological, biochemical, immunological, markers
of liver fibrosis and genetic analysis.
• Urine tests – for bilirubin and urobilinogen.
• Imaging techniques – to define gross anatomy.
• Liver biopsy – for histology.
 Blood tests ordered for ‘liver function’ are usually processed by an automated multichannel
analyser to produce serum levels of bilirubin, aminotransferases, alkaline phosphatase, γ-GT
and total proteins. These routine tests are markers of liver damage but not actual tests of
‘function’ per se. Subsequent investigations are often based on these tests.

Blood tests
Useful blood tests for certain liver diseases are shown in Box 14.1.

 Box 14.1
U se f ul blo o d a nd urine t e st s f o r c e rt a in live r dise a se s

Test Disease
Anti-mitochondrial antibody Primary biliary cholangitis
Anti-nuclear, smooth muscle (actin), liver/kidney microsomal antibody Autoimmune hepatitis
Raised serum immunoglobulins:
 IgG Autoimmune hepatitis
 IgG4 Autoimmune hepatitis/cholangiopathy and pancreatitis
 IgM Primary biliary cholangitis
Viral markers Hepatitis A, B, C, D, E and others
α-Fetoprotein Hepatocellular carcinoma
Serum iron, transferrin saturation, serum ferritin Hereditary haemochromatosis
Serum and urinary copper, serum caeruloplasmin Wilson's disease
α1-Antitrypsin α1-Antitrypsin deficiency (cirrhosis (± emphysema))
Anti-nuclear cytoplasmic antibodies (ANCA) Primary sclerosing cholangitis
Markers of liver fibrosis (p. 445) Non-alcoholic fatty liver disease
Hepatitis C
Genetic analyses e.g. HFE gene (hereditary haemochromatosis), α1-antitrypsin

Liver function tests

Serum albumin
This is a marker of synthetic function and is useful for gauging the severity of chronic liver
disease: a falling serum albumin is a bad prognostic sign. In acute liver disease, initial albumin
levels may be normal. Interpretation of a low albumin can be difficult when other causes of
hypoalbuminaemia (e.g. malnutrition, urinary protein loss or sepsis) are present.

Bilirubin
Serum bilirubin is normally almost all unconjugated. In liver disease, increased serum
bilirubin is usually accompanied by other abnormalities in liver biochemistry. Differentiation
between conjugated or unconjugated bilirubin is only necessary in congenital disorders of
bilirubin metabolism (see below) or to exclude haemolysis.

Prothrombin time
Prothrombin time (PT) is also a marker of synthetic function. Because of its short half-life, it is
a sensitive indicator of both acute and chronic liver disease. Vitamin K deficiency should be
excluded as the cause of a prolonged PT by giving an intravenous bolus (10 mg) of vitamin K.
Vitamin K deficiency commonly occurs in biliary obstruction, as the low intestinal
concentration of bile salts results in poor absorption of vitamin K.
Prothrombin times vary in different laboratories, depending upon the thromboplastin used in
the assay. The International Normalized Ratio (INR) was developed to standardize
anticoagulation with coumarin derivatives but is very variable in liver disease, and causes
large differences when included in prognostic scores for cirrhosis across different centres. A
rising INR in patients with liver disease that is not corrected by vitamin K is a poor prognostic
sign.

Liver biochemistry

Aminotransferases
These enzymes (often referred to as transaminases) are contained in hepatocytes and leak into
the blood with liver cell damage. Two enzymes are measured:
• Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme (80%; 20% in
cytoplasm) and is also present in heart, muscle, kidney and brain. High levels are seen in
hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure.
• Alanine aminotransferase (ALT) is a cytosol enzyme, more specific to the liver, so that a
rise only occurs with liver disease.
The ALT : AST ratio is a useful clinical indicator.
– In viral hepatitis, ALT is greater than AST unless cirrhosis is present, in which case AST is
greater than ALT.
– In alcoholic liver disease and steatohepatitis, the AST is often greater than the ALT.
– In patients with viral hepatitis, an AST : ALT ratio of more than 1 indicates cirrhosis.
– In patients with liver disease without cirrhosis, in whom AST is greater than ALT, alcohol or
obesity is the most likely aetiological agent.

Alkaline phosphatase
Alkaline phosphatase (ALP) is present in hepatic canalicular and sinusoidal membranes, and
also in bone, intestine and placenta. If necessary, its origin can be determined by
electrophoretic separation of isoenzymes or bone-specific monoclonal antibodies. In clinical
practice, if the γ-GT is also abnormal, the ALP is presumed to come from the liver.
Serum ALP is raised in both intrahepatic and extrahepatic cholestatic disease of any cause,
due to increased synthesis. In cholestatic jaundice, levels may be 4–6 times the normal limit.
Raised levels also occur with hepatic infiltrations (e.g. metastases) and in cirrhosis, frequently
in the absence of jaundice. The highest serum levels due to liver disease (>1000 IU/L) are seen
with hepatic metastases and PBC.

γ-Glutamyl transpeptidase
This is a microsomal enzyme present in liver, and also in many tissues. Its activity can be
induced by many drugs such as phenytoin, warfarin and rifampicin, and by alcohol. If the ALP
is normal, a raised serum γ-GT can be a useful guide to alcohol intake (see p. 921). However,
mild elevations of γ-GT are common, even with minimal alcohol consumption, and it is also
raised in fatty liver disease. In the absence of other liver function test abnormalities, a slightly
raised γ-GT can safely be ignored. In cholestasis, the γ-GT rises in parallel with the ALP, as it
has a similar pathway of excretion. This is also true of 5-nucleotidase, another microsomal
enzyme that can be measured in blood.

Total proteins and globulin fraction

The globulin fraction is often raised in autoimmune hepatitis; if it falls, it indicates successful
therapy.

Viral markers
Viruses are a major cause of liver disease. Virological studies have a key role in diagnosis;
markers are available for most common viruses that cause hepatitis.

Additional blood investigations

Haematological tests
A full blood count may show thrombocytopenia. Thrombocytopenia is a common finding in
cirrhosis and is often aggravated by alcohol-induced bone marrow suppression. A low platelet
count (below the lower limit of normal – 150 × 109/L) should be regarded as indicative of
cirrhosis, unless another cause can be found. In alcohol excess, red blood cells are often
macrocytic.

Biochemical tests
• α1-Antitrypsin enzyme deficiency can produce cirrhosis.
• α-Fetoprotein is normally produced by the fetal liver. Its reappearance in increasing and high
concentrations in adults indicates hepatocellular carcinoma. Increased concentrations in
pregnancy in blood and amniotic fluid suggest fetal neural tube defects. Blood levels are also
slightly raised with regenerative liver tissue in patients with hepatitis, chronic liver disease
and also teratomas.
• Urinary copper is raised, and serum copper and caeruloplasmin are low in Wilson's disease
(see p. 479).
Immunological tests

Serum immunoglobulins
Increased γ-globulins are thought to result from reduced phagocytosis by sinusoidal and
Kupffer cells of the gut-absorbed antigens. These antigens then stimulate antibody production
in the spleen, lymph nodes and portal tract lymphoid and plasma cell infiltrates. In PBC, the
predominant raised serum immunoglobulin is IgM, while in autoimmune hepatitis it is IgG.
IgG4 is raised in autoimmune pancreatitis/cholangitis (see p. 506 and Box 8.12 ).

Serum autoantibodies
• Anti-mitochondrial antibody (AMA) in serum is found in over 95% of patients with PBC
(see p. 475). Several different AMA subtypes are described, depending on their antigen
specificity, and are also found in autoimmune hepatitis and other autoimmune diseases. AMA
is demonstrated by an immunofluorescent technique and is neither organ- nor species-
specific. The M2 subtype is specific for PBC.
• Nucleic, smooth muscle (actin), liver/kidney microsomal antibodies can be found in
serum, often in high titre, in patients with autoimmune hepatitis. These serum antibodies are
also present in other autoimmune conditions and other liver diseases.
• Anti-nuclear cytoplasmic antibodies (ANCA) can be found in the serum of patients with
primary sclerosing cholangitis (see pp. 476–477).

Markers of liver fibrosis

Fibrosis plays a key role in the outcome of many chronic liver diseases, and accurate
assessment of fibrosis is critical for the appropriate management of many liver disorders. A
variety of different systems have been developed to assess the extent of liver fibrosis and these
range from algorithms of varying degrees of complexity that use standard haematological and
biochemical tests, to novel biomarkers. Simple algorithms include the APRI (aspartate
aminotransferase to platelet ratio index) score, while more complex commercial tests include
the fibrotest algorithm. Novel biomarker-based algorithms include those based on
measurements of hyaluronic acid, procollagen III amino terminal peptide and tissue inhibitor of
metalloproteinase I (TIMP-1), all combined in the enhanced liver fibrosis (ELF) test. In
general, these markers have been developed for chronic hepatitis C but they are often
successfully applied to other liver disorders. The current assays have a high
sensitivity/specificity for the detection or absence of cirrhosis but are less effective at
detecting intermediate levels of fibrosis. Combining mechanical non-invasive fibrosis tests,
such as transient elastography (see p. 446), with fibrosis markers allows many patients to
avoid a liver biopsy to assess fibrosis.

Genetic analysis
These tests are performed routinely for haemochromatosis (HFE gene) and for α1-antitrypsin
deficiency. Markers are also available for the most frequent abnormal genes in Wilson's
disease (see p. 479).

Urine tests
Dipstick tests are available for bilirubin and urobilinogen. Bilirubinuria is due to the
presence of conjugated (soluble) bilirubin; it is found in patients with jaundice due to
hepatobiliary disease, but is absent if unconjugated bilirubin is the major cause of jaundice.
The presence of urobilinogen in urine is of little value in practice but suggests haemolysis or
hepatic dysfunction.

Imaging techniques

Ultrasound examination
This is a non-invasive, safe and relatively cheap technique. It involves the analysis of the
reflected ultrasound beam detected by a probe moved across the abdomen. The normal liver
appears as a relatively homogeneous structure. The gall bladder, common bile duct, pancreas,
portal vein and other structures in the abdomen can be visualized. Abdominal ultrasound is
useful in:
• Detection of extrahepatic obstruction (the bile duct is usually dilated, particularly in
advanced disease). Note that opiates may cause biliary dilatation without obstruction, and so
scans in injecting drug users often show extrahepatic biliary dilatation.
• Assessment of a jaundiced patient (to exclude obstruction) (see p. 450).
• Assessment of hepatomegaly/splenomegaly.
• Detection of gallstones (see Fig. 15.2 ).
• Assessment of focal liver disease – lesions >1 cm.
• Assessment of portal and hepatic vein patency.
• Assessment of the hepatic parenchyma – diffuse fatty infiltration often leads to a ‘bright’
appearance on ultrasound but experience is required to distinguish this from normal variation.
• Identification of cirrhosis – in advanced cirrhosis, the liver edge is irregular and the spleen is
often enlarged. Note that a normal ultrasound does not exclude cirrhosis.
• Assessment of lymph node enlargement.
Other abdominal masses can be delineated and biopsies obtained under ultrasonic guidance.

Colour Doppler ultrasound

This will demonstrate vascularity within a lesion, and the direction of portal and hepatic vein
blood flow.

Ultrasound contrast agents

These are mostly based on the production of microbubbles within flowing blood. They enhance
the detection of vascularity, allowing the detection of abnormal circulation within liver
nodules, and giving a more specific diagnosis of hepatocellular carcinoma.

Hepatic stiffness (transient elastography)

Using an ultrasound transducer, a vibration of low frequency and amplitude is passed through
the liver, the velocity of which correlates with hepatic stiffness. Stiffness (measured in kPa)
increases with worsening liver fibrosis (sensitivity and specificity 80–95%, compared to liver
biopsy). Elastography can reliably exclude cirrhosis and there is some evidence to show that,
in cirrhosis, increasing liver stiffness is associated with a higher risk of complications.
Elastography is less effective for determining lesser degrees of fibrosis but, particularly when
combined with non-invasive fibrosis tests (see above), it can be used to exclude cirrhosis
reliably. It cannot be employed in the presence of ascites and morbid obesity, and is affected
by inflammatory tissue and congestion.
Acoustic radiation force impulse is incorporated into standard B mode ultrasonography and
has similar physical principles to transient elastography.

Computed tomography examination

Computed tomography (CT), during or immediately after intra​venous contrast, shows both
arterial and portal venous phases of enhancement, enabling more precise characterization of a
lesion and its vascular supply (Fig. 14.6). Retrospective analysis of data allows multiple
overlapping slices to be obtained with no increase in the radiation dose, providing excellent
visualization of the size, shape and density of the liver, pancreas, spleen, lymph nodes and
lesions in the porta hepatis. Multiplanar and three-dimensional reconstruction in the arterial
phase can create a CT angiogram, often making formal invasive angiography unnecessary. CT
also provides guidance for biopsy. It has advantages over ultrasound in detecting calcification
and is useful in obese subjects, although ultrasound is usually the imaging modality used first to
investigate liver disease.
 FIGURE 14.6 Use of contrast-enhanced spiral CT. A. Unenhanced. B. Arterial phase (note high-density
contrast in the aorta (thick arrow)). There is an irregular mass (thin arrow) in the posterior aspect of the
right lobe of the liver, which is only well seen on this early arterial phase enhanced scan. C. Portal venous
phase scan through the right lobe of the liver.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) produces cross-sectional images in any plane within the
body and does not involve radiation. It is the most sensitive investigation for focal liver
disease but can also assess fibrosis. Diffuse liver disease alters the T1 and T2 characteristics.
Other fat-suppression modes, such as short T1 inversion recovery (STIR), allow good
differentiation between haemangiomas and other lesions. Contrast agents such as intravenous
gadolinium, which allow further characterization of lesions, are suitable for those with iodine
allergy, and provide angiography and venography of the splanchnic circulation. Use of these
agents has superseded direct arteriography.

Magnetic resonance cholangiopancreatography

Magnetic resonance cholangiopancreatography (MRCP) involves the manipulation of data
acquired by MRI. A heavily T2-weighted sequence enhances visualization of the ‘water-filled’
bile ducts and pancreatic ducts to produce high-quality images of ductal anatomy. This non-
invasive technique is replacing diagnostic (but not therapeutic) endoscopic retrograde
cholangiopancreatography (see p. 501), and is usually the next test to be applied if a biliary
abnormality is present on ultrasound examination.

Plain X-rays of the abdomen

These are rarely requested but may show:
• gallstones – 10% contain enough calcium to be seen
• air in the biliary tree owing to its recent instrumentation, surgery, or a fistula between the
intestine and the gall bladder
• pancreatic calcification
• rarely, calcification of the gall bladder (porcelain gall bladder).

Radionuclide imaging – scintiscanning

In a 99mTc-IODIDA scan, technetium-labelled iododiethyl IDA is taken up by the hepatocytes
and excreted rapidly into the biliary system. Its main uses are in the diagnosis of:
• acute cholecystitis
• jaundice due to either biliary atresia or hepatitis in the neonatal period.

Endoscopy
Upper gastrointestinal endoscopy is used for diagnosis and treatment of varices, detection of
portal hypertensive gastropathy, and for detection of associated lesions such as peptic ulcers.
Colonoscopy may show portal hypertensive colopathy. Capsule endoscopy can identify small
intestinal varices.

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) outlines the biliary and pancreatic
ducts (see p. 501).

Angiography
This is performed by selective catheterization of the coeliac axis and hepatic artery. It outlines
the hepatic vasculature and the abnormal vasculature of hepatic tumours, but spiral CT and
MRI have replaced diagnostic angiography. The portal vein can be demonstrated with
increased definition using subtraction techniques that have replaced splenoportography (by
direct splenic puncture).
In digital vascular imaging (DVI), contrast given intravenously or intra-arterially can be
detected in the portal system using computerized subtraction analysis.
Hepatic venous cannulation allows abnormal hepatic veins to be diagnosed in patients
with Budd–Chiari syndrome and is also used to measure portal pressure indirectly. There is a
1 : 1 relationship of occluded (by balloon) hepatic venous pressure with portal pressure in
patients with alcoholic or viral-related cirrhosis. The height of portal pressure has prognostic
value for survival in cirrhosis: a difference of the occluded minus the free hepatic venous
pressure (hepatic venous pressure gradient, HVPG) of 20% or more from baseline values, or
<12 mmHg, has been associated with protection from rebleeding, and prevention of other
complications of cirrhosis.

Liver biopsy
Histological examination of the liver is valuable in the differential diagnosis of diffuse or
localized parenchymal disease and its severity. Liver biopsy can be performed on a day-case
basis. The indications and contraindications are shown in Box 14.2. The mortality rate is less
than 0.02% when the technique is performed by experienced operators.

 Box 14.2
Indic a t io ns f o r a nd c o nt ra indic a t io ns t o live r bio psy
Diagnosis
• Multiple parenchymal liver diseases
• Abnormal liver tests of unknown aetiology
• Fever of unknown origin
• Focal or diffuse abnormalities on imaging studies (rarely for HCC)
• Unexplained hepatomegaly
 • Drug-related liver disease
• Post liver transplant
Prognosis
• Staging of known parenchymal liver disease, e.g. hepatitis B/C, NAFLD, PBC, AIH, PSC
• Haemochromatosis and alcohol-induced liver disease
Management
• Development of treatment plans based on histological analysis
Usual contraindications to percutaneous needle biopsy
• Uncooperative patient
• Prolonged INR (>1.5)*
• Platelets <60 × 109/L*
• Ascites
• Extrahepatic cholestasis
AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; INR, International
Normalized Ratio; NAFLD, non-alcoholic fatty liver disease; PBC, primary biliary
cholangitis; PSC, primary sclerosing cholangitis.

Liver biopsy guided by ultrasound or CT is performed under a local anaesthetic via a

percutaneous approach in the right intercostal space. A transjugular approach is used when
liver histology is essential for management but coagulation abnormalities or ascites prevent the
percutaneous approach.
Most complications of liver biopsy occur within 24 hours (usually in the first 2 hours).
They are often minor, and include abdominal or shoulder pain that settles with analgesics.
Minor intraperitoneal bleeding can occur but this settles spontaneously. Rare complications
include major intraperitoneal bleeding, haemothorax and pleurisy, biliary peritonitis,
haemobilia and transient septicaemia. Haemobilia produces biliary colic, jaundice and
melaena within 3 days of the biopsy.

F urt he r re a ding
Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;
365:147–156.

Clinical features of liver disease

Symptoms

Acute liver disease

This may be asymptomatic and anicteric. Symptomatic disease, often viral, produces malaise,
anorexia and fever. Jaundice (see below) may appear as the illness progresses.

Chronic liver disease

Patients may be asymptomatic or experience non-specific symptoms, particularly weakness,
anorexia and fatigue. Specific symptoms include:
• right hypochondrial pain due to liver distension
• abdominal distension due to ascites
• ankle swelling due to fluid retention
• haematemesis and melaena from gastrointestinal haemorrhage
• pruritus due to cholestasis – often an early symptom of PBC
• gynaecomastia, loss of libido and amenorrhoea due to endocrine dysfunction
• confusion and drowsiness due to neuropsychiatric complications (portosystemic
encephalopathy).

Signs

Acute liver disease

There may be few signs, apart from jaundice and an enlarged liver. Jaundice is a yellow
discoloration of the skin and mucous membranes, and is best seen in the conjunctivae and
sclerae. In the cholestatic phase of the illness, pale stools and dark urine are present. Spider
naevi and palmar erythema usually indicate chronic disease but can occur in severe acute
disease.

Chronic liver disease

The physical signs are shown in Figure 14.7. However, physical examination is occasionally
normal in patients with advanced chronic liver disease.
 FIGURE 14.7 Physical signs in chronic liver disease.

The skin
The chest and upper body may show spider naevi. These are telangiectases that consist of a
central arteriole with radiating small vessels (resembling a spider's legs). They are found in
the distribution of the superior vena cava and more than five are diagnostic. They may also
occur in pregnancy.
In haemochromatosis, the skin may have a slate-grey appearance.
The hands may show palmar erythema, indicative of a hyperdynamic circulation; it is also
seen in pregnancy, thyrotoxicosis or rheumatoid arthritis. Clubbing occasionally occurs, and a
Dupuytren's contracture is often seen in alcoholic cirrhosis, though the association is with
alcohol consumption rather than liver disease itself.
Xanthomas (cholesterol deposits) are seen in the palmar creases or above the eyes in PBC.

The abdomen
Initial hepatomegaly will be followed by a small liver in well-established cirrhosis.
Splenomegaly occurs with portal hypertension.

The endocrine system

Gynaecomastia (occasionally unilateral) and testicular atrophy may be found in males.
Gynaecomastia is probably related to altered oestrogen metabolism, often combined with
spironolactone treatment.
Additional physical signs in decompensated cirrhosis are shown in Figure 14.7.

Jaundice
Jaundice (icterus) is detectable clinically when the serum bilirubin is >50 µmol/L (3 mg/dL). It
may be divided into:
• haemolytic jaundice – increased bilirubin load for the liver cells
• congenital hyperbilirubinaemias – defects in conjugation
• cholestatic jaundice – including hepatocellular (parenchymal) liver disease and large duct
obstruction.

Haemolytic jaundice
The increased breakdown of red cells (see p. 521) leads to an increase in production of
bilirubin. The resulting jaundice is usually mild (serum bilirubin of 68–102 µmol/L, or 4–6 
mg/dL), as normal liver function can easily manage the increased bilirubin. Unconjugated
bilirubin is not water-soluble and therefore does not pass into urine: hence ‘acholuric
jaundice’. Urinary urobilinogen is increased.
The causes are those of haemolytic anaemia (pp. 531–533), and clinical features of anaemia,
jaundice, splenomegaly, gallstones and leg ulcers may be seen.
Investigations show haemolysis (p. 532) and elevated unconjugated bilirubin, but normal
serum ALP, transferases and albumin. Serum haptoglobulins are low.

Congenital hyperbilirubinaemias (non-haemolytic)

Unconjugated types

Gilbert syndrome
This is the most common familial conjugated hyperbilirubinaemia and affects 2–7% of the
population. It is asymptomatic and usually detected incidentally with a raised bilirubin (17–
102 µmol/L, or 1–6 mg/dL). All other liver biochemistry is normal and there are no signs of
liver disease. There is a family history of jaundice in 5–15% of patients. Most patients have
reduced levels of UDP-glucuronosyl transferase (UGT-1) activity, the enzyme that conjugates
bilirubin with glucuronic acid.
Mutations occur in the gene (UGT1A1 promoter region) encoding this enzyme, with an
expanded nucleotide repeat consisting of two extra bases in the upstream 5′ promoter element.
This abnormality appears to be necessary for the syndrome, but is not in itself sufficient for
clinical manifestation (phenotypic expression).
 Establishing the diagnosis is necessary to provide reassurance and prevent unnecessary
investigations. The raised unconjugated bilirubin is diagnostic and rises on fasting and during
mild illness. The reticulocyte count is normal, excluding haemolysis, and no treatment is
necessary.

Crigler–Najjar syndrome
This is very rare. Only patients with type II (autosomal dominant) disease, with a decrease in
rather than absence (type I – autosomal recessive) of UGT survive into adult life. Liver
histology is normal. Transplantation is the only effective treatment.

Conjugated types

Dubin–Johnson and Rotor syndromes

Dubin–Johnson and Rotor syndromes (autosomal recessive) are due to defects in hepatic
bilirubin handling. The prognosis is good in both. In the Dubin–Johnson syndrome, the liver is
black owing to melanin deposition.

Benign recurrent intrahepatic cholestasis

This is rare and presents in early adulthood. Recurrent attacks of acute cholestasis occur
without progression to chronic liver disease. Jaundice, severe pruritus, steatorrhoea and
weight loss develop. Serum γ-GT is normal. Benign recurrent intrahepatic cholestasis may be
associated with intrahepatic cholestasis of pregnancy (see p. 1304).

Progressive familial intrahepatic cholestasis syndromes

Progressive familial intrahepatic cholestasis (PFIC) syndromes are a heterogeneous group of
autosomal recessive conditions defined by defective secretion of bile acids (see Figs 14.4 and
15.1).
• In type 1 (PFIC1), with cholestasis in the first weeks of life, the γ-GT is normal.
• In type 2 (PFIC2), there is frequently a non-specific giant cell hepatitis that progresses to
cholestasis; again, γ-GT is normal.
• In type 3 (PFIC3), deficient canalicular phosphatidylcholine transport and accumulation of
toxic bile acids cause liver damage, which can lead to cirrhosis.
Liver transplantation is the only cure for these syndromes.

Cholestatic jaundice (acquired)

This condition can be divided into extrahepatic and intrahepatic cholestasis. The causes are
shown in Figure 14.8.
• Extrahepatic cholestasis is due to large duct obstruction of bile flow at any point in the
biliary tract distal to the bile canaliculi.
• Intrahepatic cholestasis occurs because of failure of bile secretion, which may be caused by
intrinsic defects in bile secretion or inflammation in the intrahepatic ducts.

FIGURE 14.8 Causes of jaundice.

Clinically, in both types, there is jaundice with pale stools and dark urine, and the serum
bilirubin is conjugated. However, intrahepatic and extrahepatic cholestatic jaundice must be
differentiated, as their clinical management is entirely different.

Differential diagnosis of jaundice

Jaundice may occur in previously healthy people who have an acute hepatic illness or may
develop in patients with cirrhosis who have ‘decompensated’ (see p. 448). The management of
decompensated cirrhosis is described on page 467 but all patients with jaundice should be
questioned closely about risk factors for chronic liver disease to determine whether this is a
true acute presentation rather than an ‘acute on chronic’ illness. The history often gives a clue
to the diagnosis. Certain causes of jaundice are more likely in particular categories of people.
For example, a young person is more likely to have infectious hepatitis, so questions should be
asked about drug and alcohol misuse, and sexual behaviour. An elderly person with gross
weight loss is more likely to have a carcinoma. All patients may complain of malaise.
Abdominal pain occurs in patients with biliary obstruction by gallstones, and sometimes with
an enlarged liver there is pain resulting from distension of the capsule.
Questions should be appropriate to the particular situation, and the following aspects of the
history should be covered:
• Country of origin. The incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV)
infection is increased in many parts of the world (see pp. 454–455).
• Duration of illness. A history of jaundice with prolonged weight loss in an older patient
suggests malignancy. A short history, particularly with a prodromal illness of malaise,
suggests an infectious hepatitis.
• Recent outbreak of jaundice. An outbreak in the community suggests hepatitis A virus
(HAV).
• Intravenous drug use, or recent injections or tattoos. These all increase the chance of HBV
and HCV infection.
• Men having sex with men. This increases the chance of HBV and HCV infection.
• Female sex workers. This increases the chance of HBV infection.
• Medical treatment in the developing world. There is an increased risk of HBV and HCV
due to poorly sterilized equipment or administration of unscreened blood or blood products.
• Alcohol consumption. A history of drinking habits should be taken, although many patients
often understate their consumption.
• Drugs (particularly those taken in the previous 2–3 months). Many drugs, including over-
the-counter and herbal preparations, cause jaundice (see pp. 487–488).
• Travel. Certain areas have a high risk of hepatitis A virus (HAV) infection, as well as
hepatitis E virus (HEV), but HAV is common in the UK and HEV is common in travellers to
the Indian subcontinent.
• Family history. Patients with, for example, Gilbert's disease may have family members who
experience recurrent jaundice.
• Recent surgery. Surgery on the biliary tract or for carcinoma is relevant.
• Environment. People engaged in recreational activities in rural areas, as well as farm and
sewage workers, are at risk for leptospirosis, hepatitis E and exposure to chemicals.
• Fevers or rigors. These are suggestive of cholangitis or possibly a liver abscess.

Clinical features
The signs of acute and chronic liver disease should be looked for (see pp. 447–448). Certain
additional signs may be helpful:
• Hepatomegaly. A smooth, tender liver is seen in hepatitis and in extrahepatic obstruction, but
a knobbly, irregular liver suggests metastases or cirrhosis. Causes of hepatomegaly are shown
in Box 14.3.

 Box 14.3
C a use s o f he pa t o me g a ly
Apparent
 • Low-lying diaphragm
• Riedel's lobe
• Cirrhosis (early)
Inflammation
• Hepatitis
• Schistosomiasis
• Abscesses (pyogenic or amoebic)
Cysts
• Hydatid
• Polycystic
Metabolic
• Fatty liver
• Amyloid deposition
• Glycogen storage disease
Haematological
• Leukaemias
• Lymphoma
• Myeloproliferative disorders
• Thalassaemia
Tumours
• Primary and secondary carcinoma
Venous congestion
• Heart failure
• Constrictive pericarditis
• Hepatic vein occlusion
Biliary obstruction
• (Particularly extrahepatic)

• Splenomegaly. This indicates portal hypertension when signs of chronic liver disease are
present. The spleen can also be ‘tipped’ occasionally in viral hepatitis. In alcoholic cirrhosis,
in particular, the spleen may not be grossly enlarged and may not be palpable
• Ascites. This is found in cirrhosis but can also be due to other causes (see Box 14.19).
A palpable gall bladder occurs with a carcinoma of the pancreas obstructing the bile duct.
Generalized lymphadenopathy suggests a lymphoma.
Cold sores are often seen with a herpes simplex virus hepatitis.

Investigations
Jaundice is not itself a diagnosis and the cause should always be sought. The two most useful
tests are the viral markers for HAV, HBV and HCV, with an ultrasound examination. Liver
biochemistry confirms the jaundice and may help in the diagnosis.
An ultrasound examination should always be performed to exclude an extrahepatic
obstruction, and to diagnose any features compatible with chronic liver disease. Ultrasound
will demonstrate:
• the size of the bile ducts, which are dilated in extrahepatic obstruction (Fig. 14.9)

FIGURE 14.9 Liver ultrasound. A. Dilated intrahepatic bile ducts (arrowed). B. Common bile duct
(arrowed). The normal bile duct measures 6 mm at the porta hepatis.

• the level of the obstruction

• the cause of the obstruction in virtually all patients with tumours and in 75% of patients with
gallstones.
The pathological diagnosis of any mass lesion can be made by fine-needle aspiration
cytology (sensitivity approximately 60%) or by needle biopsy (sensitivity approximately
90%).
A flow diagram for the general investigation of the jaundiced patient is shown in Figure
14.10.
 FIGURE 14.10 Approach to the patient with jaundice. CBD, common bile duct; MRCP, magnetic resonance
cholangiopancreatography; US, ultrasound. *Proceed as in bottom left box (Re-check drug history …).

Liver biochemistry
In hepatitis, serum AST and ALT tend to be high early in the disease, with only a small rise in
serum ALP. Conversely, in extrahepatic obstruction, the ALP is high, with a smaller rise in
aminotransferases. However, these findings alone cannot be relied upon to make a diagnosis in
an individual case. The prothrombin time is often prolonged in longstanding liver disease, and
the serum albumin is also low.

Haematological tests
In haemolytic jaundice, the bilirubin is raised and the other liver biochemistry is normal. A
raised white cell count may indicate infection (e.g. cholangitis). A leucopenia often occurs in
viral hepatitis, while abnormal mononuclear cells suggest infectious mononuc​leosis and a
Monospot test should be performed.

Other blood tests

These include tests to confirm the presence of specific causes of acute or chronic liver disease,
e.g. anti-mitochondrial antibody (AMA) for PBC. HIV status should be established.

Hepatitis
• Acute parenchymal liver damage can be caused by many agents (Fig. 14.11).

FIGURE 14.11 Some causes of acute parenchymal damage.

• Chronic hepatitis is defined as any hepatitis lasting for 6 months or longer and is classified
according to the aetiology (Box 14.4). Chronic viral hepatitis is the principal cause of
chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide.

 Box 14.4
C a use s o f c hro nic he pa t it is
• Metabolic:
– Non-alcoholic fatty liver disease
• Alcohol-induced
• Viral:
– Hepatitis B ± hepatitis D
– Hepatitis C
– Hepatitis E (immunosuppressed)
• Drugs:
– (e.g. Methyldopa, isoniazid, ketoconazole, nitrofurantoin)
• Autoimmune
• Hereditary:
– Wilson's disease, haemochromatosis.
Unusual causes include infections (syphilis, tuberculosis, various tropical infections),
infiltrative diseases, including amyloidosis and lymphoma, and ingestion of toxins.
 Acute hepatitis

Pathology
Although some histological features are suggestive of the aetiological factor, most changes are
non-specific. Hepatocytes show degenerative changes (swelling, cytoplasmic granularity,
vacuolation) and undergo necrosis (becoming shrunken, containing eosinophilic Councilman
bodies). The distribution of these changes may vary with aetiology, but necrosis is usually
maximal in zone 3. The extent of the damage is very variable between individuals, even when
they are affected by the same agent; at one end of the spectrum, single and small groups of
hepatocytes die (spotty or focal necrosis), while at the other end, there is multiacinar necrosis
involving a substantial part of the liver (massive hepatic necrosis), resulting in acute hepatic
failure. Between these extremes, there is limited confluent necrosis with collapse of the
reticulin framework, leading to linking (bridging) between the central veins, between the
central veins and portal tracts, and between the portal tracts. The extent of the inflammatory
infiltrate is also variable, but portal tracts and lobules are infiltrated mainly by lymphocytes.
Other variable features include cholestasis in zone 3 and fatty change, the latter being
prominent in hepatitis that is due to alcohol or certain drugs.

Chronic hepatitis

Pathology
The pathological features are often diagnostic. Chronic inflammatory cell infiltrates,
comprising lymphocytes, plasma cells and sometimes lymphoid follicles, are usually present in
the portal tracts. The amount of inflammation varies from mild to severe. In addition, there may
be:
• loss of definition of the portal/periportal limiting plate – interface hepatitis (damage is due to
apoptosis rather than necrosis)
• lobular change, focal lytic necrosis, apoptosis and focal inflammation
• confluent necrosis
• fibrosis, which may be mild, bridging (across portal tracts) or severe cirrhosis.
The overall severity of the hepatitis is judged by the degree of hepatitis and inflammation
(grading), and the severity of fibrosis or cirrhosis (staging). In chronic viral hepatitis, there are
various scoring systems. For example, the Knodell Scoring System (histological activity
index) uses the sum of four factors (periportal or bridging necrosis, intralobular degeneration
and focal necrosis, portal inflammation and fibrosis). The Ishak score stages fibrosis from 0
(none) to 6 (cirrhosis). The METAVIR system has four stages. Scoring systems are used for
drug trials and for assessing progression of disease, but are not quantitative measures of
fibrosis and different systems may be used for different diseases (for example, the Brunt
scoring system is usually applied to NAFLD, and the METAVIR system is reserved for
hepatitis C).

Viral hepatitis
The differing features of the common forms of viral hepatitis are summarized in Box 14.5. Two
different patterns are recognized: acute hepatitis with rapid onset of infection and, usually,
rapid resolution; and chronic viral hepatitis, which is asymptomatic and often detected on
routine blood tests or during screening for infection. Hepatitis A always and E usually cause
acute infections whilst hepatitis B, C and D may cause acute or chronic disease.

 Box 14.5
So me f e a t ure s o f vira l he pa t it is
 A B C D E
Virus RNA DNA RNA RNA RNA
27 nm 42 nm Approx. 50 nm 36 nm (with 27–35 nm
HBsAg
coat)
Picorna Hepadna Flaviviridae Deltaviridae Hepeviridae virus
Spread
Faeco-oral Yes No No No Yes
Blood/blood Rare Yes Yes Yes No
products
Vertical No Yes Rare Occasional No
Saliva Yes Yes Yes ? No ?
Sexual Rare Yes Yes (rare) Rare No
Incubation Short (2–3 weeks) Long (1–5 months) Long Intermediate Short
Age Young Any Any Any Any
Carrier No Yes Yes ? No a
state
Chronic No Yes Yes Yes No a
liver
disease
Liver cancer No Yes Yes Yes No
Mortality <0.5% <1% <1% <1% 1–2% (pregnant
(acute) women 10–20%)
Immunizatio
n
Passive Normal immunoglobulin serum Hepatitis B No No No
i.m. (0.04–0.06 mL/kg) immunoglobulin
(HBIg)
Active Vaccine Vaccine HBV vaccine to No Vaccine
prevent co-
infection
a
Chronic hepatitis in immunosuppressed patients.
HBsAg, hepatitis B surface antigen.

Hepatitis A

Epidemiology
Hepatitis A is the most common acute viral hepatitis occurring worldwide, often in epidemics.
The disease is commonly seen in the autumn and affects children and young adults. Spread of
infection is mainly by the faeco-oral route and arises from the ingestion of contaminated food
or water (e.g. shellfish). Overcrowding and poor sanitation facilitate spread. There is no
carrier state. In the UK, it is a notifiable disease.
Hepatitis A virus (HAV)
Hepatitis A virus (HAV) is a picornavirus, having the structure shown in Figure 14.12. It has a
single serotype, as only one epitope is immunodominant. It replicates in the liver, is excreted in
bile, and then excreted in the faeces for about 2 weeks before the onset of clinical illness and
for up to 7 days after. The disease is maximally infectious just before the onset of jaundice.
HAV particles can be demonstrated in the faeces by electron microscopy.

FIGURE 14.12 Hepatitis A. A. The hepatitis A (HAV) virion consists of four polypeptides (VP1–VP4), which
form a tight protein shell, or capsid, containing the RNA. The major antigenic component is associated
with VP1. B. Arrangement of the HAV genome.

Clinical features
The viraemia causes the patient to feel unwell, with non-specific symptoms that include nausea
and anorexia. Many recover at this stage and remain anicteric. An anicteric infection is
common in children and leads to lifetime immunity. In the developing world, improvements in
hygiene have reduced early infection and, paradoxically, led to an increase in symptomatic
infection in exposed adults.
After 1 or 2 weeks, some patients become jaundiced and symptoms often improve.
Persistence of nausea, vomiting or any mental confusion warrants assessment in hospital. As
the jaundice deepens, the urine becomes dark and the stools pale, owing to intrahepatic
cholestasis. The liver is moderately enlarged and the spleen is palpable in about 10% of
patients. Occasionally, tender lymphadenopathy is seen, with a transient rash in some cases.
Thereafter, the jaundice lessens and, in the majority of cases, the illness is over within 3–6 
weeks. Extrahepatic complications are rare but include arthritis, vasculitis, myocarditis and
acute kidney injury. A biphasic illness occasionally occurs, with the return of jaundice and,
classically, a more severe ‘second phase’, which is cholestatic (cholestatic viral hepatitis)
with an increase in the alkaline phosphatase rather than the aminotransferases; thus, it runs a
prolonged course of 7–20 weeks. Rarely, the disease may be very severe with acute hepatitis,
liver coma and death; this is more common in the elderly. The typical sequence of events after
HAV exposure is shown in Figure 14.13.

FIGURE 14.13 Hepatitis A virus (HAV): sequence of events after exposure. ALT, alanine aminotransferase;
Ig, immunoglobulin.

Investigations

Liver biochemistry
• Prodromal stage: The serum bilirubin is usually normal. However, there is bilirubinuria and
increased urinary urobilinogen. A raised serum AST or ALT, which can sometimes be very
high, precedes the jaundice.
• Icteric stage: The serum bilirubin reflects the level of jaundice. Serum AST reaches a
 maximum 1–2 days after the appearance of jaundice, and may rise above 500 IU/L. Serum
ALP is usually less than 300 IU/L.
After the jaundice has subsided, the aminotransferases may remain elevated for some weeks
and occasionally for up to 6 months.

Haematological tests
There is leucopenia with a relative lymphocytosis. Very rarely, there is a Coombs'-positive
haemolytic anaemia or an associated aplastic anaemia. The prothrombin time is prolonged in
severe cases. The erythrocyte sedimentation rate (ESR) is raised.

Viral markers: antibodies to HAV

IgG antibodies are common in the general population over the age of 50 years, but an anti-HAV
IgM means an acute infection. In areas of high prevalence, most children have antibodies by the
age of 3 years following asymptomatic infection.

Other tests
Further tests are not necessary in the presence of an IgM antibody, but liver biochemistry must
be followed to establish a return to normal levels.

Differential diagnosis
Differentiation must be made from all other causes of jaundice, but in particular from other
types of viral and drug-induced hepatitis.

Prognosis
The prognosis is excellent, with most patients making a complete recovery. The mortality in
young adults is 0.1% but increases with age. Death is due to acute hepatic necrosis. During
convalescence, 5–15% of patients may suffer a relapse of the hepatitis but this settles
spontaneously.
There is no reason to stop alcohol consumption, other than for the few weeks when the
patient is ill. Patients may complain of debility for several months following resolution of the
symptoms and biochemical parameters. This is known as the post-hepatitis syndrome and
treatment is by reassurance. HAV hepatitis never progresses to chronic liver disease.

Management
There is no specific treatment, and rest and dietary measures are unhelpful. Corticosteroids
have no benefit. Admission to hospital is not usually necessary.

Prevention
Control of hepatitis depends on good hygiene. The virus is resistant to chlorination but is killed
by boiling water for 10 minutes.

Active immunization
A formaldehyde-inactivated HAV vaccine is given to people travelling frequently to endemic
areas, patients with chronic liver disease, those with haemophilia, and workers in frequent
contact with hepatitis cases (e.g. in residential institutions for patients with learning
difficulties). Community outbreaks can be interrupted by vaccination. A single dose produces
antibodies that persist for at least 1 year, with immunity lasting beyond 10 years. This obviates
the need for a booster injection in healthy individuals.

Passive immunization
Normal human immunoglobulin (0.02 mL/kg i.m.) is used if exposure to HAV is <2 weeks.
HAV vaccine should also be given.

Hepatitis B

Epidemiology
The hepatitis B virus (HBV) is present worldwide and there an estimated 220 million carriers.
The UK and the USA have a low carrier rate (0.5–2%), but this rises to 10–20% in parts of
Africa and the Middle and Far East.
Vertical transmission from mother to child, in utero, during parturition or soon after birth,
is the usual means of transmission worldwide, although in Africa transmission from other
infected children is very common during the early childhood years. HBV is not transmitted by
breast-feeding.
Horizontal transmission occurs, particularly in children, through minor abrasions or close
contact with other children, and HBV can survive on household articles, such as toys or
toothbrushes, for prolonged periods. Childhood chronic HBV is associated with very high
levels of viral replication (up to 1010 IU/mL), ensuring that high levels of virus are present in
minute amounts of blood and thus facilitating viral spread.
HBV spread also occurs by the intravenous route (e.g. by transfusion of infected blood or
blood products, or by contaminated needles used by drug users, tattooists or acupuncturists) or
by close personal contact, such as during sexual intercourse, particularly in men who have sex
with men. The virus can be found in semen and saliva.

Hepatitis B virus
The complete infective virion or Dane particle is a 42 nm particle comprising an inner core or
nucleocapsid (27 nm), surrounded by an outer envelope of surface protein (hepatitis B surface
antigen, HBsAg). This surface coat is produced in excess by the infected hepatocytes and can
exist separately from the whole virion in serum and body fluid as 22 nm particles or tubules.
 The hepatitis B virus (HBV) genome is variable, and genetic sequencing can be used to
define the different HBV genotypes, A to H. There is a strong correlation between genotypes
and geographical areas. Genotype A is found in north-west Europe, North America and
Central Africa; B in South-east Asia (including China, Taiwan and Japan); genotype C in
South-east Asia; D in southern Europe, India and the Middle East; E in West Africa; F in South
and Central America, in American Indians and in Polynesia; G in France and the USA; and H
in Central and South America. These genotypes may influence the chance of responding to
interferon treatment (A more than B; C more than D) but all genotypes respond equally well to
nucleoside analogues.
The core or nucleocapsid is formed of core protein (HBcAg), containing incompletely
double-stranded circular DNA and DNA polymerase/reverse transcriptase. One strand is
almost a complete circle and contains overlapping genes that encode both structural proteins
(pre-S, surface (S), core (C)) and replicative proteins (polymerase and X). The other strand is
variable in length. DR1 and DR2 are direct repeats necessary for HBV synthesis during viral
replication (Fig. 14.14).

FIGURE 14.14 Hepatitis B virus (HBV) genome. The viral DNA is partially double-stranded (red incomplete
circle and blue circle). The long strand (blue) encodes seven proteins from four overlapping reading
frames (S, surface (Pre-S1, Pre-S2, S); c, core (Pre-C, C); P, polymerase (P); and X gene (X)). EcoRI
restriction-enzyme-binding site is included as a reference point. DR, direct repeat; HBsAg, hepatitis B
surface antigen.

HBeAg is a protein formed via specific self-cleavage of the pre-core/core gene product,
which is secreted separately by the cell.

Hepatitis B mutants
Mutations occur in the various reading frames of the HBV genome (Fig. 14.14). These mutants
can emerge in patients with chronic HBV infection (escape mutants) or can be acquired by
infection.
HBsAg mutants are produced by alterations in the ‘a’ antigenic determinants of the HbsAg
proteins, usually with a substitution of glycine for arginine at position 145. This results in
changes in the antibody-binding domain and may confer resistance to the vaccine.
In patients with some HBV genotypes (particularly genotype D), a mutation in the pre-core
region, when a guanosine (G) to adenosine (A) change creates a stop codon (TAG), prevents
the production of HBeAg (the secreted form of HBcAG), but the synthesis of HBcAg is
unaffected. This mutation may be associated with HBeAg-negative disease but other mutations
in the core promoter region of the virus also give rise to HBeAg-negative disease. To detect
infectivity in HBeAg-negative disease, HBV DNA must always be measured, as no eAg will
be present.
DNA polymerase mutants occur, particularly following treatment with the first generation
of directly acting antiviral drugs, such as lamivudine.

Pathogenesis
Pre-S1 and pre-S2 regions are involved in attachment to the hepatocyte receptor, recently
identified as the sodium taurocholate co-transporting polypeptide (NTCP). After penetration
into the cell, the virus loses its coat and the virus core is transported to the nucleus without
processing. The transcription of HBV into messenger RNA takes place when the HBV DNA is
converted into a closed circular form (cccDNA), which acts as a template for RNA
transcription.
Translation into HBV proteins (Box 14.6), as well as replication of the genome, takes
place in the endoplasmic reticulum; the proteins are then packaged together and exported from
the cell. There is an excess production of non-infective HBsAg particles, which are extruded
into the circulation.

 Box 14.6
He pa t it is B virus ( HB V) pro t e ins
 The HBV is not usually directly cytopathic (although high replication levels in
immunosuppressed individuals can lead to direct toxicity) and liver damage is produced by the
host immune response.
HBV-specific cytotoxic CD8 T cells recognize the viral antigen via human leucocyte antigen
(HLA) class I molecules on the infected hepatocytes. However, suppressor or regulatory T
cells inhibit these cytotoxic cells, leading to viral persistence and chronic HBV infection. Th1
responses (IL-2, γ-interferon) are thought to be associated with viral clearance, and Th2 (IL-4,
5, 6, 10, 13) responses with the development of chronic infection and disease severity. Viral
persistence in patients with a very poor cell-mediated response leads to an asymptomatic,
inactive, chronic HBV infective state. However, a better response results in continuing
hepatocellular damage, with the development of chronic hepatitis.
Chronic HBV infection progresses through a series of four distinct phases (Fig. 14.15).
• Immunotolerant phase. The natural history of childhood-acquired HBV is shown in the
figure. In this first early phase, high-level viral replication, with HBeAg, is not associated
with an immune response and hence there is no damage to hepatocytes. Management is not
indicated but close follow-up is required. This phase matures into the next adolescent phase.
• Immunoactive phase. During adolescence, an immune response develops, leading to liver
damage with fluctuating raised transferases (ALT) in the presence of high levels of HBeAg-
positive infection. In some patients, this disease phase will progress to cirrhosis and therapy
is therefore indicated to reduce the development of fibrosis. Management in this phase may
lead to seroconversion from HBeAg-positive to HBeAg-negative.
• Immunosurveillance phase. In many, the immunoactive phase is followed by a period of
immune control (the ‘inactive carrier’ phase), when host immune responses suppress viral
replication, leading to low-level HBV DNA (<2000 IU/mL), absence of HBeAg and normal
ALTs. In some patients, the virus is eventually cleared with the loss of HBsAg.
• Immunoescape phase. A proportion of patients with inactive HBV will reactivate their
disease as they age, and this final phase of disease is characterized by high-level viral
replication (HBV DNA 105/106) but negative HBeAg and raised ALT. Note that, in this phase,
fluctuating ALT levels may lead to a misdiagnosis and so the liver function tests and HBV
DNA should be tested four times a year to establish the diagnosis in patients who are HBeAg-
 negative.

FIGURE 14.15 Natural history of childhood-acquired hepatitis B virus (HBV). Immunotolerant phase: Early
disease is characterized by high-level viraemia with HBeAg (the secreted form of HBcAg) and a minimal
immune response, leading to no significant liver damage. Immunoactive phase: Fluctuating liver function
tests (ALTs) and ongoing liver damage that may lead to cirrhosis. Treatment in this phase may lead to
seroconversion. In many, the immunoactive phase is followed by a period of immune control (the ‘inactive
carrier’ phase), when host immune responses suppress viral replication, leading to low-level HBV DNA
(<2000 IU/mL), absence of HBeAg and normal ALTs. In some patients, the virus is eventually cleared, with
the loss of HBsAg; in many, however, viral reactivation occurs with viral mutations, leading to HBeAg-
negative disease with high levels of viral replication (HBV DNA 105/106) and alanine aminotransferase (ALT)
in the absence of HBeAg. Note that, in this phase, fluctuating ALTs may lead to misdiagnosis, and so the
ALTs and HBV DNA should be tested four times a year to establish the diagnosis in patients who are
HBeAg-negative.

This disease phase is often associated with viral mutations (see above). Therapy for
HBeAg-negative disease is indicated to prevent disease progression
Hepatocellular carcinoma (HCC) can develop in patients at all stages of disease but is more
common in those with high levels of HBV DNA.
Immunosuppression, such as occurs during chemotherapy, aggravates all phases of HBV and
a particular problem is seen in patients with HBeAg-negative, inactive disease, where the
presence of normal liver biochemistry provides a false sense of security. HBV reactivation is
common in such patients and has a high mortality. It is essential that all patients who are due to
receive chemotherapy are screened for HBsAg, and those who have chronic HBV should
receive prophylactic antiviral therapy, such as tenofovir or entecavir.

Clinical features of acute hepatitis B infection

The sequence of events following acute HBV infection is shown in Figure 14.16. However, in
many, the infection is subclinical. When HBV infection is acquired perinatally, an acute
hepatitis does not usually occur and chronic infection develops. In adults, an acute infection is
common and the virus is cleared in approximately 99% of patients. The clinical picture is the
same as that found in HAV infection, although the illness may be more severe. In addition, a
serum sickness-like immunological syndrome may be seen. This consists of rashes (e.g.
urticaria or a maculopapular rash) and poly​arthritis affecting small joints occurring in up to
25% of cases in the prodromal period. Fever is usual. Extrahepatic immune complex-mediated
conditions, such as an arteritis or glomerulonephritis, are occasionally seen.

FIGURE 14.16 Time course of the events and serological changes seen following acute infection with
hepatitis B virus (HBV). Antigens: HBsAg appears in the blood from about 6 weeks to 3 months after an
acute infection and then disappears. HBeAg rises early and usually declines rapidly. Antibodies: Anti-HBs
appears late and indicates immunity. Anti-HBc is the first antibody to appear and high titres of IgM anti-
HBc suggest an acute and continuing viral replication. It persists for many months. IgM anti-HBc may be
the only serological indicator of recent HBV infection in a period when HBsAg has disappeared and anti-
HBs is not detectable in the serum. Anti-HBe appears after the anti-HBc and its appearance relates to a
decreased infectivity: that is, a low risk. ALT, alanine aminotransferase.

Investigations
These are generally the same as for hepatitis A.

Specific tests
The markers for HBV are shown in Box 14.7. HBsAg is looked for initially; if it is found, a
full viral profile is then performed. In acute infection, as HBsAg may be cleared rapidly and
anti-HBc IgM is diagnostic, patients must be tested for both HBsAg and anti-core antibodies if
HBV is suspected. HBV DNA is the most sensitive index of viral replication.

 Box 14.7
Sig nif ic a nc e o f vira l ma rke rs in he pa t it is B
 Marker Significance
Antigens
HBsAg Acute or chronic infection
HBeAg Acute hepatitis B
Persistence implies:
Continued infectious state
Development of chronicity
HBV DNA Implies viral replication
Found in serum and liver
Levels indicate response to antiviral treatment
Antibodies
Anti-HBs Immunity to HBV; previous exposure; vaccination
Anti-HBe Seroconversion
Anti-HBc
 IgM Acute hepatitis B (high titre)
Chronic hepatitis B (low titre)
 IgG Past exposure to hepatitis B (HBsAg-negative)

Prognosis
The majority of patients recover completely, acute hepatic failure occurring in up to 1%. Some
patients go on to develop chronic hepatitis and the outcome depends upon several factors,
chiefly the age of the patient.

Management of acute hepatitis

This is mainly symptomatic. However, patients should have their HBV markers monitored.
Several experts suggest that entecavir or tenofovir should be given for the persistent presence
of HbeAg beyond 12 weeks, and in some patients who are very ill.

Prevention
Prevention depends on vaccination. In countries that do not vaccinate all citizens, prevention
depends upon avoiding risk factors (see above). These include not sharing needles and having
safe sex. Vertical transmission is discussed below. Infectivity is highest in those with the e
antigen and/or HBV DNA in their blood.

Immunization
Vaccination is obligatory in most developed countries (but not the UK), as well as countries
with high endemicity. Vaccination has been shown to reduce mortality and morbidity. In
countries that do not have a universal vaccination policy, groups at high risk are vaccinated.
These include all healthcare personnel; members of emergency and rescue teams; morticians
and embalmers; children in high-risk areas; people with haemophilia; patients in some
psychiatric units; patients with chronic kidney disease/on dialysis units; long-term travellers;
men who have sex with men, bisexual men and sex workers; and intravenous drug users.
Active and passive (combined) prophylaxis with vaccination and immunoglobulin should be
given to: healthcare staff with accidental needlestick injury; all newborn babies of HBsAg-
positive mothers; and regular sexual partners of HBsAg-positive patients who have been found
to be HBV-negative.
For adults, a dose of 500 IU of specific hepatitis B immunoglobulin (HBIG) (200 IU to
newborns) is given; the vaccine (i.m.) is given at another site.

Active immunization
This is with a recombinant yeast vaccine, produced by insertion of a plasmid containing the
gene of HBsAg into a yeast.

Dosage regimen
Three injections (at 0, 1 and 6 months) are given into the deltoid muscle; this gives short-term
protection in over 90% of patients. People who are over 50 years of age or clinically ill and/or
immunocompromised (including those with human immunodeficiency virus (HIV) infection or
acquired immunodeficiency syndrome (AIDS)), have a poor antibody response; more frequent
and larger doses are required. Antibody levels should be measured at 7–9 months after the
initial dose in all at-risk groups. Antibody levels fall steadily after vaccination, and booster
doses may be required after approximately 3–5 years. It is not cost-effective to check antibody
levels prior to active immunization. There are few side-effects from the vaccine.

Chronic hepatitis B virus infection

Following an acute HBV infection, which may be subclinical, approximately 1–10% of
patients will not clear the virus and will develop a chronic HBV infection. The features are
described on pages 455–456.

Investigations
These may show a moderate rise in aminotransferases but infection with normal
aminotransferases is common. The serum bilirubin is often normal. HBsAg and HBV DNA are
found in the serum, sometimes with HBeAg.
Histologically, there is a full spectrum of changes, from near-normal with only a few
lymphocytes and interface hepatitis to a full-blown cirrhosis. HBsAg may lend a ‘ground-
glass’ appearance to the cytoplasm on haematoxylin and eosin staining, and this can be
confirmed on orcein staining or, more specifically, with immunohistochemical staining. HBcAg
can also be de​monstrated in hepatocytes by appropriate immunohistochemical staining.

Management of chronic hepatitis B

Indications for therapy are similar for HBeAg-positive and negative patients with chronic
hepatitis. Three criteria are used: serum HBV DNA levels, serum ALT levels and histological
grade and stage:
• Patients with moderate to severe active necroinflammation and/or fibrosis in the liver
biopsy, with HBV DNA above 2000 IU/mL (approximately 10 000 copies/mL) and/or ALT
above the upper limit of normal are usually offered therapy. Age and co-morbidities also
affect the decision to treat and the choice of agents.
• If cirrhosis is present, treatment should be given, independent of ALT or HBV DNA levels.
Patients with decompensated cirrhosis can also be treated with oral antiviral agents, but liver
transplantation may be required.
All patients, regardless of disease phase, need long-term follow-up, as transition to an
active phase is common; the lifetime risk of malignancy is increased in all patients who are
HBsAg-positive.

Aim of therapy
This is to prevent disease progression and, ideally, to eliminate HBsAg.
• Interferon is an immunostimulator that induces an immune response, leading to prolonged
remission after discontinuation of therapy.
• Oral nucleotides suppress viral replication and are used for prolonged periods of time.
In patients receiving long-term oral antiviral agents, liver fibrosis regresses. Even those
patients with cirrhosis may recover, and the liver may remodel and lose all traces of fibrosis.

Antiviral agents
Interferon, entecavir and tenofovir are the most commonly used drugs.
Pegylated interferon-alfa-2a (180 µg once a week s.c.) is most often used in patients who
are HBeAg-positive with active disease. Some patients (25–45%, depending on genotype – A
and B respond best) lose HBeAg and move to the ‘inactive’ HBeAg-negative phase of disease.
A proportion then goes on to lose HBsAg some years after treatment discontinuation. Patients
with higher serum amino​transferase values (three times the upper limit of normal), who are
younger, with viral loads <107 IU/mL, respond best to treatment. Patients with concomitant HIV
respond poorly and those with cirrhosis should not receive interferon. Response can be
assessed during therapy by measuring the serum levels of HBsAg: if these fall after 3 months,
then a favourable outcome is likely, and most doctors stop therapy after 3 months if the HBsAg
level remains unchanged. In patients with HBeAg-negative HBV, pegylated interferon-alfa-2a
is increasingly used, as it offers a finite duration of therapy. A proportion of patients with
active disease (high ALT, increased HBV DNA) convert to inactive disease, and response can
be assessed by an early decline in HBsAg.
Side-effects of treatment include an acute influenza-like illness occurring 6–8 hours after the
first injection. This usually disappears after subsequent injections but malaise, headaches and
myalgia are common; depression, reversible hair loss and bone marrow depression and
infection may also occur.
Oral antiviral therapy for HBV (entecavir, tenofovir and lamivudine) is very effective and
almost all compliant patients respond with a decrease in HBV DNA to undetectable levels and
a reduction in liver inflammation (Box 14.8). Both HBeAg-positive and HBeAg-negative
patients respond equally well. Long-term viral suppression has been shown to reverse fibrosis,
and even patients with cirrhosis respond with reversion of fibrosis. Resistance is rarely seen
with third-generation drugs, and older, more resistance-prone drugs, like lamivudine, are no
longer recommended. A small proportion of patients develop an immune response leading to
loss of HBeAg and, very rarely, loss of HBsAg. However, the majority of patients who
commence oral antiviral agents will require very prolonged treatment, perhaps life-long.
Studies to determine whether antiviral therapy can ever be safely discontinued are in progress.
Entecavir and tenofovir are the drugs of choice for HBV, and both agents are associated with
very few side-effects and an excellent response. Combination therapy has little benefit and a
single drug should be used.

 Box 14.8
F a c t o rs pre dic t ive o f a sust a ine d re spo nse t o t re a t me nt in
c hro nic he pa t it is B
Duration of disease
• Short
Liver biochemistry
• High serum aminotransferases
Histology
• Active liver disease (mild to moderate)
Viral levels
• Low HBV DNA levels
Other
• Absence of immunosuppression
• Female gender
• Adult-acquired
• Delta virus negative
• Rapidity of response to oral therapy

Prognosis
The clinical course of hepatitis B is very variable; treatments have improved survival, stopped
progression of fibrosis and enabled regression of fibrosis to occur. Established cirrhosis is
associated with a poor prognosis. Hepatocellular carcinoma (HCC) is a frequent association
and is one of the most common carcinomas in HBV-endemic areas such as the Far East.
Surveillance for HCC must continue, even when HBV DNA is negative in patients who have
HBsAg and are not treated, and also in these rendered negative by therapy. The incidence of
HCC is being reduced by routine HBV vaccination of all children.

Hepatitis D
This is caused by the hepatitis D virus (HDV or delta virus), which is an incomplete RNA
particle enclosed in a shell of HBsAg; it belongs to the Deltaviridae family. The virus is
unable to replicate on its own but is activated by the presence of HBV. It is common in some
parts of the world, including Eastern Europe (Romania, Bulgaria), North Africa and the
Brazilian rainforest. Hepatitis D viral infection can occur either as a co-infection or as a
superinfection.
• Co-infection of HDV and HBV is clinically indistinguishable from an acute icteric HBV
infection, but a biphasic rise of serum aminotransferases may be seen. Diagnosis is
confirmed by finding serum IgM anti-HDV in the presence of IgM anti-HBc. IgM anti-delta
appears at 1 week and disappears by 5–6 weeks (occasionally 12 weeks), when serum IgG
anti-delta is seen. The HDV RNA is an early marker of infection. The infection may be
transient but the clinical course is variable.
• Superinfection results in an acute flare-up of previously quiescent chronic HBV infection. A
rise in serum AST or ALT may be the only indication of infection. Diagnosis is made by
finding HDV RNA or serum IgM anti-HDV at the same time as IgG anti-HBc. Active HBV
DNA synthesis is reduced by delta superinfection and patients are usually negative for
HBeAg with low HBV DNA.
Acute hepatic failure can follow both types of infection but is more common after co-
infection. HDV RNA in the serum and liver can be measured and is found in acute and chronic
HDV infection.

Chronic hepatitis D
This is a relatively infrequent chronic hepatitis, but spontaneous resolution is rare. Between
60% and 70% of patients will develop cirrhosis, and more rapidly than with HBV infection
alone. In 15%, the disease is rapidly progressive, with development of cirrhosis in only a few
years. The diagnosis is made by finding anti-delta antibody in a patient with chronic liver
disease who is HBsAg-positive. It can be confirmed by finding HDV in the liver or HDV RNA
in the serum by reverse transcription polymerase chain reaction (PCR).
 Management
Treatment of patients with active liver disease (raised ALT levels and/or inflammation on
biopsy) is with pegylated interferon-alfa-2a for 12 months, although response rates are very
low.

Hepatitis C

Epidemiology
An estimated 240 million people are infected with this virus worldwide. The prevalence rate
of infection ranges from 0.4% in Europe, 1–3% in Southern Europe (possibly linked to
intramuscular injections of vaccines or other medicines) and 6% in Africa; in Egypt, the rates
are as high as 19% owing to parenteral antimony treatment for schistosomiasis. The virus is
transmitted by blood and blood products, and was common in people with haemophilia treated
before screening of blood products was introduced. The incidence in intravenous drug users is
high (50–60%). The low rate of hepatitis C virus infection in high-risk groups – such as men
who have sex with men, sex workers and attendees at sexually transmitted infection clinics –
suggests a limited role for sexual transmission. Vertical transmission from a healthy mother to
child can occur but is rare (approximately 5%). Other routes of community-acquired infection
(e.g. close contact) are extremely rare. In 20% of cases, the exact mode of transmission is
unknown.

Hepatitis C virus (HCV)

Hepatitis C virus (HCV) is a single-stranded RNA virus of the Flaviviridae family. The RNA
genome is approximately 10 kb in length, encoding a polyprotein product consisting of
structural (capsid and envelope) and non-structural viral proteins (Fig. 14.17). Comparisons
of subgenomic regions, such as E1, NS4 or NS5, have allowed variants to be classified into
six genotypes, which have differing geographical distributions. Variability is distributed
throughout the genome, with the non-structural gene of different genotypes showing 30–50%
nucleotide sequence disparity. Genotypes 1a and 1b account for 70% of cases in the USA and
50% in Europe. There is a rapid change in envelope proteins, making it difficult to develop a
vaccine. Antigens from the nucleocapsid regions have been used to develop enzyme-linked
immunosorbent assays (ELISAs). The current assay, ELISA-3, incorporates antigens NS3, NS4
and NS5 regions.
 FIGURE 14.17 Hepatitis C virus. A single-stranded RNA virus with viral proteins. Targets for recent drugs
are shown. C, core; E, envelope; NS, non-structural.

Clinical features
Most acute infections are asymptomatic, about 10% of patients having a mild influenza-like
illness with jaundice and a rise in serum aminotransferases. Most patients will not be
diagnosed until they present, years later, with evidence of abnormal transferase values at health
checks or with chronic liver disease.

Investigations
This is by evaluation of HCV, RNA and HCV antibodies; HCV RNA can be detected from 1 to
8 weeks after infection. Anti-HCV tests are usually positive 8 weeks from infection. Patients
with acute HCV infection should be tested on several occasions, as many have fluctuating
viraemia during the first few months of infection, with periods of undetectable HCV RNA
followed by virological relapse. Viral clearance is confirmed by multiple tests for HCV RNA
over a period of many months.

Management
In acute infection, most experts recommend a period of monitoring for a few weeks with serial
assessments of HCV RNA. If the viral load is falling, treatment may not be required, but the
patient should be observed for several months to confirm true viral clearance. If the HCV RNA
level does not decline, then therapy with interferon (with or without ribavirin) is indicated.
Needle-stick injuries must be followed and treated early, although the vast majority (>97%) do
not go on to develop viraemia. For treatment of patients with co-infection with HIV, see p. 351.
 Prognosis
Some 85–90% of asymptomatic patients develop chronic liver disease. A higher percentage of
symptomatic patients ‘clear’ the virus, with only 48–75% going on to chronic liver disease
(see pp. 447–448).

Chronic hepatitis C infection

Pathogenesis
As with hepatitis B infection, cytokines in the Th2 phenotypes are profibrotic and cause the
development of chronic infection. A dominant CD4 Th2 response, with a weak CD8 interferon-
gamma response, may lead to rapid fibrosis. Th1 cytokines are antifibrotic and thus a dominant
CD4 Th1 and CD8 cytolytic response may cause less fibrosis.

Clinical features
Patients with chronic HCV infection are usually asymptomatic, the disease only being
discovered following a routine biochemical test when mild elevations in the aminotransferases
(usually ALT) are noticed (50%). The elevation in ALT may be minimal and fluctuating (Fig.
14.18), and some patients have a persistently normal ALT (25%), the disease being detected by
checking HCV antibodies (e.g. in blood donors). Non-specific malaise and fatigue are common
in chronic infection and often reverse following viral clearance. Extrahepatic manifestations
are seen, including arthritis, cryoglobulinaemia with or without glomerulonephritis, and
porphyria cutanea tarda. There is a higher incidence of diabetes, and associations with lichen
planus, sicca syndrome and non-Hodgkin's lymphoma.
 FIGURE 14.18 Time course of the events and serological changes seen following infection with hepatitis
C virus. ALT, alanine aminotransferase.

Chronic HCV infection causes slowly progressive fibrosis that leads, over decades, to
cirrhosis. After 20 years of infection, 16% of patients have developed cirrhosis; the proportion
that will ultimately develop cirrhosis after a lifetime of infection remains unknown but is likely
to be higher than the proportions reported after short-term follow-up. Factors associated with
rapid progression of HCV fibrosis include excess alcohol consumption, co-infection with HIV,
obesity, diabetes and infection with genotype 3. Once cirrhosis has developed, some 3–4% per
year will develop decompensated cirrhosis and approximately 1% will develop liver cancer.
Unlike HBV infection, HCV does not cause liver cancer in the absence of cirrhosis. In most
parts of the world, HCV was spread (either by injection drug use, or by poorly sterilized
medical devices) in the 1970s. Given the slow development of cirrhosis, current mathematical
models of disease burden predict a massive increase in HCV-related end-stage liver disease
over the next decade.

Investigations
Diagnosis is made by finding HCV antibody in the serum using third-generation ELISA-3 tests.
A small proportion of patients with spontaneous clearance will have undetectable HCV RNA
in the serum (measured by PCR) but most individuals who are antibody-positive will be
viraemic. The level of viraemia varies from a few thousand to many millions of viral copies
per millilitre, although current practice is to present viral load measurements in international
units (IU). Disease progression is not influenced by the viral load, but treatment outcome is
modified in those with high levels of viraemia.
The HCV genotype should be characterized in patients who are to be given treatment (see
below), and assessment of fibrosis (by either liver biopsy or non-invasive methods) is
required in patients who would prefer to defer therapy. Cirrhosis should be excluded in all
patients who have been infected for more than 20 years and a liver biopsy or non-invasive
marker should be used.
 Management
The aim of treatment is to eliminate the HCV RNA from the serum in order to:
• stop the progression of active liver disease
• prevent the development of HCC.
A clinical cure is determined by a sustained virological response (SVR), defined by a
negative HCV RNA by PCR, 6 months after the end of therapy.

Antiviral agents
Treatment for HCV infection is undergoing a revolution, with treatments changing from
interferon-based regimes to all-oral combination regimes using directly acting antiviral agents.
The latter are expensive and currently are available and funded in a few countries only.
However, new, less costly, all-oral regimes are expected and it is to be hoped that, in the near
future, all patients can be cured without interferon, which is associated with numerous side-
effects. Therapy for HCV is critically dependent upon the genotype of the infecting virus;
current treatment algorithms are outlined below.
The direct-acting antiviral regimes for HCV target different viral replication enzymes, and
inhibitors of the NS3 protease enzyme, the NS5A replication complex initiator and the NS5B
polymerase are now available. NS5B polymerase can be inhibited by both nucleotide and non-
nucleotidic inhibitors.
The optimal therapy for patients with genotype 1 infection is with a combination of direct-
acting antiviral agents. Two regimes are available: one involves the nucleotide sofosbuvir,
which, when combined with either a protease inhibitor (simeprevir) or an NS5A inhibitor
(daclatasvir or ledipasvir), cures over 90% of patients. The preferred combination is likely to
be an 8-week regime involving a combined tablet containing sofosbuvir plus ledipasvir, which
showed SVR rates of 95% in clinical trials. Alternative regimes that do not involve a
nucleotide usually require three agents; regimes involving a protease inhibitor, an NS5A
inhibitor and a non-nucleotidic NS5B inhibitor have been shown to cure over 95% of patients
following 12 weeks of treatment. Both regimes are effective in patients with cirrhosis and there
is an on-going debate as to whether or not patients with cirrhosis should receive slightly longer
durations of therapy.
Alternative interferon-based regimes for patients with genotype 1 HCV involve at least 24 
weeks of a long-acting pegylated interferon (given by weekly injections), combined with the
oral agent ribavirin and a protease inhibitor. Older protease inhibitors (telaprevir and
boceprevir) are associated with high levels of anaemia but the newer protease inhibitors (such
as simeprevir) are better tolerated.
For patients with genotype 2 HCV, 12 weeks' therapy with sofosbuvir plus ribavirin cures
over 90% and compares favourably to 24 weeks' therapy with pegylated interferon and
ribavirin, which leads to an SVR in no more than 80% of individuals.
For genotype 3-infected patients, 24 weeks of sofosbuvir plus ribavirin are required to
achieve SVR rates of more than 80%; the cost of this regime has led many to suggest that
interferon and ribavirin for 24 weeks should be used, as the response rate, approaching 70–
80%, is not too dissimilar. Combining sofosbuvir with an NS5A inhibitor (such as ledipasvir
or daclatasvir) allows the duration of therapy to be shortened to 12 weeks, and response rates
approaching 90% are to be expected in patients without cirrhosis.
Patients with genotype 3 HCV and cirrhosis respond less well to current therapies;
pegylated interferon combined with ribavirin and sofosbuvir for 12 weeks may be preferred,
as response rates approaching 90% have been reported in large-scale clinical trials.
Interferon-free regimes – sofosbuvir plus daclatasvir or ledipasvir – are effective alternatives,
but ribavirin should be included in the regimen and therapy may need to be extended to 24
weeks. In the future, new drugs that are active against genotype 3 HCV may change this
approach and allow effective, all-oral com​bination therapy for patients with cirrhosis. Novel
NS5A inhibitors (5816) and protease inhibitors (grazoprevir) are expected in the near future
and results of phase III trials are awaited with interest.
Side-effects of interferon are described on page 458. Ribavirin is usually well tolerated but
side-effects include a dose-related haemolysis, pruritus and nasal congestion. Telaprevir
causes a rash and anaemia, and boceprevir causes dysgeusia and anaemia. Pregnancy must be
avoided with antiviral therapy. The new all-oral regimes are almost free of side-effects; they
have not yet been widely used, however, so their full side-effect profile has not been clearly
defined.

Hepatitis E
Hepatitis E virus (HEV) is an RNA virus (Hepeviridae virus; Fig. 14.19); it causes a hepatitis
that is clinically very similar to hepatitis A. It is enterally transmitted, usually by contaminated
water, with 30% of dogs, pigs and rodents carrying the virus. Epidemics have been seen in
many developing countries and sporadically in developed countries, in patients who have had
contact with farm animals or have travelled abroad. In some developing countries, zoonotic
infection from contaminated pork has led to acute HEV infection becoming relatively common.
It has a mortality from fulminant hepatic failure of 1–2%, which rises to 20% in pregnant
women. There is no carrier state and infection does not progress to chronic liver disease,
except in some immunosuppressed patients. An ELISA for IgG and IgM anti-HEV is available
for diagnosis. HEV RNA can be detected in the serum or stools by PCR. Prevention and
control depend on good sanitation and hygiene; a vaccine has been developed and used
successfully in China.
 FIGURE 14.19 Hepatitis E genome. A single-stranded RNA genome is shown with three open reading
frames (ORFs).

Hepatitis non-A–E
Approximately 10–15% of acute viral hepatitides cannot be typed and are described as
hepatitis non-A–E. GB agent (hepatitis G virus, HGV) and transfusion-transmitted virus (TTV)
agents have not been documented as causing disease in humans.

Acute hepatitis due to other infectious agents

Abnormal liver biochemistry is frequently found in a number of acute infections. The
abnormalities are usually mild and have no clinical significance.

Infectious mononucleosis
Infectious mononucleosis (see also p. 258) is due to the Epstein–Barr (EB) virus. Mild
jaundice, associated with minor abnormalities of liver biochemistry, is extremely common but
‘clinical’ hepatitis is rare. Hepatic histological changes occur within 5 days of onset; the
sinusoids and portal tracts are infiltrated with large mono​nuclear cells but the liver
architecture is preserved. A Paul–Bunnell or Monospot test is usually positive, and atypical
lymphocytes are present in the peripheral blood. Treatment is symptomatic.

Cytomegalovirus
Cytomegalovirus (CMV; see also pp. 258–259) can cause acute hepatitis, usually a ‘glandular
fever-type syndrome’, in healthy individuals, but is more severe in those with an impaired
immune response. Only the latter need treatment with valganciclovir or ganciclovir (see pp.
258–259).
CMV DNA is positive in blood; CMV IgM is also positive, but there are false-positive
reactions. Liver biopsy shows intranuclear inclusions and giant cells.

Herpes simplex
Very occasionally, the herpes simplex virus (see also pp. 247–249) causes a generalized acute
infection, particularly in the immunosuppressed patient, and occasionally in pregnancy.
Aminotransferases are usually massively elevated. Liver biopsy shows extensive necrosis.
Aciclovir is used for treatment.

Toxoplasmosis
The clinical picture in toxoplasmosis (see also p. 305) is similar to that of infectious
mononucleosis, with abnormal liver biochemistry, but the Paul–Bunnell test is negative.

Yellow fever
Yellow fever (see also pp. 265–266) is a viral infection carried by the mosquito Aedes
aegypti; it can cause acute hepatic necrosis. There is no specific treatment.

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European Association for the Study of the Liver. EASL Clinical Practice Guidelines:
Management of chronic hepatitis B infection. J Hepatol 2012; 57:167–185.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines:
Management of hepatitis C virus infection. J Hepatol 2014; 60:392–420.
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet 2011; 378:73–85.
National Institute for Health and Care Excellence. NICE Clinical Guideline 165:
Hepatitis B (Chronic): Diagnosis and Management of Chronic Hepatitis B in Children,
Young People and Adults. NICE 2013; https://www.nice.org.uk/guidance/cg165.
Nelson PK, Mathers BM, Cowie B et al. Global epidemiology of hepatitis B and hepatitis
C in people who inject drugs: results of systematic reviews. Lancet 2011; 378:578–583.
Razavi H, Waked I, Sarrazin C et al. The present and future disease burden of hepatitis C
virus (HCV) infection with today's treatment paradigm. J Viral Hepatitis 2014;
21(Supplement S1):34–59.
Visvanathan K, Dusheiko G, Giles M et al. Managing HBV in pregnancy. Gut 2016;
65:340–350.
 Wedemeyer H, Yurdaydìn C, Dalekos GN et al, for the HIDIT Study Group. Peginterferon
plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364:322–331.
Zeuzem S. Decade in review – HCV: hepatitis C therapy – a fast and competitive race.
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Lancet 2010; 376:895–902.
http://www.easl.eu/_clinical-practice-guideline European Association for the Study of
the Liver: Clinical Practice Guidelines on viral hepatitis.

Acute Hepatic Failure

Acute liver failure is defined as acute liver injury with encephalopathy and dearranged
coagulation (INR > 1.5) in a patient with a previously normal liver. The time intervals are
variable. The development of jaundice to encephalopathy varies from 7 days (hyper-acute), 8–
28 days (acute), and sub-acute (>21 and <26 weeks). Occasionally, patients may have previous
liver damage: for example, D virus superinfection in a previous carrier of HBsAg, Budd–
Chiari syndrome or Wilson's disease).
AHF is a rare but often life-threatening syndrome that is due to acute hepatitis from many
causes (Box 14.9). These causes vary throughout the world; most cases are due to viral
hepatitis, but paracetamol overdose is common in the UK (50% of cases). HCV does not
usually cause acute hepatic failure, although exceptional cases have been reported from Japan
and India.

 Box 14.9
C a use s o f a c ut e he pa t ic f a ilure
Viruses
• HAV, HBV, (HDV), HEV; rarely, HCV
• Cytomegalovirus
• Haemorrhagic fever viruses
• Herpes simplex virus
• Paramyxovirus
• Epstein–Barr virus
Drugs (examples)
• Paracetamol (acetaminophen)
• Antibiotics (ampicillin-clavulanate, ciprofloxacin, doxycycline, erythromycin, isoniazid,
nitrofurantoin, tetracycline)
• Antidepressants (amitriptyline, nortriptyline)
• Antiepileptics (phenytoin, valproate)
• Anaesthetic agents (halothane)
• Lipid-lowering medications (atorvastatin, lovastatin, simvastatin)
• Immunosuppressive agents (cyclophosphamide, methotrexate)
• NSAIDs
• Salicylates (as a result of Reye syndrome, p. 483)
• Disulfiram, flutamide, gold, propylthiouracil
• Illicit drugs (e.g. ‘ecstasy’ or cocaine)
• Herbal/alternative medicines (ginseng, pennyroyal oil, Teucrium polium chaparral or
germander tea, kawa kawa)
Toxins
• Amanita phalloides mushroom toxin
• Bacillus cereus toxin
• Cyanobacteria toxin
• Organic solvents (e.g. carbon tetrachloride)
• Yellow phosphorus
Hepatic failure in pregnancy
• Acute fatty liver of pregnancy (AFLP)
• HELLP (haemolysis, elevated liver enzymes, low platelets)
Vascular causes
• Ischaemic hepatitis
• Budd–Chiari syndrome
• Hepatic sinusoidal obstruction syndrome
• Portal vein thrombosis
• Hepatic arterial thrombosis (consider post transplant)
Metabolic causes
• α1-antitrypsin deficiency
• Fructose intolerance
• Galactosaemia
• Lecithin–cholesterol acyltransferase deficiency
• Reye syndrome
• Tyrosinaemia
• Wilson's disease
 Malignancies
• Primary (usually HCC, rarely cholangiocarcinoma)
• Secondary (extensive hepatic metastases or infiltration)
Miscellaneous
• Adult-onset Still's disease
• Heatstroke
• Primary graft non-function in liver transplant
HAV/HBV/HCV/HDV/HEV, hepatitis A/B/C/D/E virus; HCC, hepatocellular carcinoma;
NSAIDs, non-steroidal anti-inflammatory drugs.

Histologically, there is multiacinar necrosis involving a substantial part of the liver. Severe
fatty change is seen in pregnancy (see p. 1304) and Reye's syndrome (p. 486), or following
intravenous tetracycline administration.

Clinical features
Examination shows a jaundiced patient with a small liver and signs of hepatic encephalopathy.
The mental state varies from slight drowsiness, confusion and disorientation (grades I and II)
to unresponsive coma (grade IV) with convulsions. Fetor hepaticus is common, but ascites and
splenomegaly are rare. Fever, vomiting, hypotension and hypoglycaemia occur. Neurological
examination shows spasticity and hyper-reflexia; plantar responses remain flexor until late.
Cerebral oedema develops in 80% of patients with AHF but is far less common with subacute
failure and its consequences of intracranial hypertension and brain herniation account for about
25% of the causes of death. Other complications include bacterial and fungal infections,
gastrointestinal bleeding, respiratory arrest, kidney injury (hepatorenal syndrome and acute
tubular necrosis) and pancreatitis.

Investigations
• Routine tests (see pp. 443–447)
• There is hyperbilirubinaemia, high serum aminotransferases and low levels of coagulation
factors, including prothrombin and factor V. Aminotransferases are not useful indicators of the
course of the disease, as they tend to fall along with the albumin with progressive liver
damage.
• An electroencephalogram (EEG) is sometimes helpful in grading the encephalopathy.
• Ultrasound will define liver size and may indicate underlying liver pathology.

Management
There is no specific treatment but patients should be managed in a specialized unit. Transfer
criteria to such units are shown in Box 14.10. Supportive therapy as for hepatic
encephalopathy is necessary (see p. 474). When signs of raised intracranial pressure (which is
sometimes measured directly) are present, 20% mannitol (1 g/kg body weight) should be
infused intravenously; this dose may need to be repeated. Dexamethasone is of no value.
Hypoglycaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia and hypocalcaemia
should be anticipated and corrected with a 10% glucose infusion (checked by 2-hourly dipstick
testing) and with potassium, calcium, phosphate and magnesium supplements. Hyponatraemia
should be corrected with hypertonic saline (see p. 161). Coagulopathy is managed with
intravenous vitamin K, platelets, blood or fresh frozen plasma. Haemorrhage may be a problem
and patients are given a proton pump inhibitor (PPI) to prevent gastro​intestinal bleeding.
Prophylaxis against bacterial and fungal infection is routine, as infection is a frequent cause of
death and may preclude liver transplantation. Suspected infection should be treated
immediately with suitable antibiotics. Renal and respiratory failure should be treated as
necessary. Liver transplantation has been a major advance for patients with AHF. It is difficult
to judge the timing or the necessity for transplantation, but there are guidelines based on
validated prognostic indices of survival (see below).

 Box 14.10
Tra nsf e r c rit e ria t o spe c ia lize d unit s f o r pa t ie nt s w it h a c ut e
live r injury
• INR >3.0
• Presence of hepatic encephalopathy
• Hypotension after resuscitation with fluid
• Metabolic acidosis
• Prothrombin time (seconds) > interval (hours) from overdose (paracetamol cases)
INR, International Normalized Ratio.

Prognosis
In mild cases (grades I and II encephalopathy with drowsiness and confusion), two-thirds of
the patients will survive. The outcome of severe cases (grades III and IV encephalopathy with
stupor or deep coma) is related to the aetiology. In special units, 70% of patients with
paracetamol overdosage and grade IV coma survive, as do 30–40% patients with HAV or HBV
hepatitis. Poor prognostic variables indicating a need to transplant the liver are shown in Box
14.11.

F urt he r re a ding
 Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369:2525–2534.

 Box 14.11
P o o r pro g no st ic va ria ble s in a c ut e he pa t ic f a ilure indic a t ing
live r t ra nspla nt a t io n
Non-paracetamol (acetaminophen) causes
Three of following five:
• Drug or non-A, non-B hepatitis
• Age <10 and >40 years
• Interval from onset of jaundice to encephalopathy >7 days
• Serum bilirubin >300 µmol/L
• Prothrombin time >50 s (or >100 s in isolation)
Paracetamol overdose
• Arterial pH <7.3 (after resuscitation, 7.25 on acetylcysteine)
or
• Serum creatinine >300 µmol/L and
• Prothrombin time >100 s and
• Grade III–IV encephalopathy

Autoimmune Hepatitis
Autoimmune hepatitis (AIH) is a progressive inflammatory liver condition with a 75% female
preponderance. Approximately 40% of AIH patients have a family history of autoimmune
disease (e.g. pernicious anaemia, thyroiditis or coeliac disease), and at least 20% have
concomitant autoimmune diseases or develop them during follow-up.

Pathogenesis
The pathogenesis of AIH is incompletely understood, although increasingly evidence
demonstrates that genetic susceptibility, molecular mimicry and impaired immunoregulatory
networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage
is thought to be mediated primarily by T cell-mediated events (CD4+ T cells) against liver
antigens, producing a progressive necroinflammatory process that leads to fibrosis and
cirrhosis. However, no clear trigger mechanism has been found.

Clinical features
There are two peaks in presentation. In the peri- and postmenopausal group, patients may be
asymptomatic, or present with fatigue and abnormalities in liver biochemistry or the presence
of chronic liver disease on examination. In the teens and early twenties, the disease (often type
II) presents as an acute hepatitis with jaundice and very high aminotransferases, which do not
improve with time. This age group often has clinical features of cirrhosis and patients who are
ill may also have features of an autoimmune disease, such as fever, migratory polyarthritis,
glomerulonephritis, pleurisy, pulmonary infiltration or lung fibrosis.
There are rare overlap syndromes with primary biliary cholangitis and primary sclerosing
cholangitis, existing concomitantly or developing consecutively.

Investigations

Liver biochemistry
The serum aminotransferases are high, with lesser elevations in the ALP and bilirubin. The
serum γ-globulins are high: frequently twice normal, particularly the IgG. The biochemical
pattern is similar in both types.

Haematology
A mild normochromic normocytic anaemia with thrombocytopenia and leucopenia is present,
even before portal hypertension and splenomegaly. The prothrombin time is often high.

Autoantibodies
Two types of autoimmune hepatitis have been recognized:
• Type I with antibodies (titres >1 : 80):
– anti-nuclear (ANA)
– anti-smooth muscle (anti-actin).
• Type II with antibodies: anti-liver/kidney microsomal (anti-LKM1). The main target is
cytochrome P4502D6 (CYP2D6) on liver cell plasma membranes.
• A third type of AIH (AIH-3) was proposed, positive for anti-soluble liver antigen (SLA) and
negative for conventional autoantibodies. However, subsequent studies showed that anti-SLA
is also present in typical cases of AIH-1 and AIH-2. Patients positive for anti-SLA only, and
therefore having bona fide AIH-3, are rare.
Approximately 13% of patients lack the autoantibodies listed above.

Liver biopsy
Since transferases and IgG levels do not reflect disease activity, liver biopsy is mandatory to
confirm the diagnosis and evaluate disease severity. The biopsy (Fig. 14.20) commonly shows
chronic active hepatitis with inflammation and interface hepatitis. This reflects the changes of
chronic hepatitis described on page 452. The amount of interface hepatitis is variable, but
tends to be high in untreated patients. Lymphoid follicles are less often seen than in hepatitis C,
and plasma cell infiltration is frequent. Fibrosis is present in all but the mildest forms of the
disease and approximately one-third of patients have cirrhosis at presentation.

FIGURE 14.20 Chronic active hepatitis. Note the inflammation with interface hepatitis (×10).

Management
Prednisolone 30 mg is given daily for at least 2 weeks, followed by slow reduction to a
maintenance dose of 5–15 mg daily. Azathioprine should be added, 1–2 mg/kg daily, as a
steroid-sparing agent and, in some, as sole long-term maintenance therapy. Levels of thiopurine
methyltransferase (TPMT) should be obtained before treatment is started (see p. 411). Other
agents that have been used in resistant cases include budesonide (in non-cirrhotic patients),
mycophenolate, ciclosporin and tacrolimus.

Prognosis
Steroid and azathioprine therapy induce remission in over 80%; indeed, this response forms
part of the diagnostic criteria. Treatment is life-long in most, although withdrawal may be
considered after 2–3 years of biochemical remission. Those with initial cirrhosis are more
likely to relapse following withdrawal and require indefinite therapy. Liver transplantation is
performed if treatment fails, although the disease may recur. HCC occurs less frequently than
with viral-induced cirrhosis. The risk of malignancy associated with chronic low-dose
azathioprine therapy has been reported to be 1.4 times normal.

F urt he r re a ding
Liberal R, Grant CR, Longhi MS et al. Diagnostic criteria of autoimmune hepatitis.
Autoimmun Rev 2014; 13:435–440.
Liberal R, Grant CR, Mieli-Vergani G et al. Autoimmune hepatitis: a comprehensive
 review. J Autoimmun 2013; 41:126–139.

Drug-Induced Chronic Hepatitis

Several drugs can cause a chronic hepatitis similar to autoimmune hepatitis (see Box 14.23).
Patients are often female, present with jaundice and hepatomegaly, and have raised serum
aminotransferases and globulin levels. Improvement follows drug withdrawal but
exacerbations can occur with re-introduction. Isoniazid, amiodarone and methotrexate can
cause chronic histological changes. With rare exceptions, patients with pre-existing chronic
liver disease are not more susceptible to drug injury.

Chronic Hepatitis of Unknown Cause

As increasing numbers undergo routine blood tests, mild elevations in serum aminotransferases
and γ-GT are commonly found. Many will have no symptoms or signs of liver disease. All
known aetiological agents should be excluded, risk factors for NAFLD evaluated, and tests
carried out to exclude liver diseases. Liver biopsy should be performed if the elevation in
aminotransferases (>100 IU/L) persists for over a year, but often only non-specific changes are
found.

Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver
disease in many developed countries. It is often detected on routine abdominal ultrasound
examination, and steatosis is found in up to one-third of these patients. Traditionally, it was
considered that the 10–30% of patients with non-alcoholic steatohepatitis (NASH) were
considerably more likely than those with simple steatosis to develop cirrhosis, but a recent
large study demonstrated no difference in liver-related adverse events between definite NASH
and severe steatosis. However, patients with advanced fibrosis at presentation were much
more likely to progress than those without. In this cohort, complications of cirrhosis were the
third most common cause of death, following cardiovascular events and non-hepatic
malignancies.
Risk factors for NAFLD are obesity, hypertension, type 2 diabetes and hyperlipidaemia,
such that NAFLD is considered to be the liver component of the metabolic syndrome (see p.
209). Most patients are asymptomatic; hepatomegaly may be present. Mild increases in serum
aminotransferases and/or γ-GT (with ALT greater than AST) are frequently the sole liver
biochemical abnormality.

Pathogenesis
Histological changes follow a spectrum similar to those of alcohol-induced hepatic injury,
and range from simple fatty change to fat and inflammation (NASH), fibrosis and cirrhosis.
 Oxidative stress injury and other factors lead to lipid peroxidation in the presence of fatty
infiltration and inflammation. Fibrosis may then occur, enhanced by insulin resistance, which
induces connective tissue growth factor.

Investigations
• Diagnosis is usually by ultrasound demonstration of steatosis in the absence of other
injurious causes, such as alcohol.
• Liver biopsy allows staging of the disease. Although no definitive guidelines exist, many
clinicians perform a biopsy if a diagnosis of NASH or advanced fibrosis is considered likely.
• Elastography (see p. 446) is used to evaluate the degree of fibrosis but may not be
technically possible in the morbidly obese.

Management
• All NAFLD patients require lifestyle advice aimed at weight loss, increased physical
activity, and attention to cardiovascular risk factors. Calorie restriction is recommended,
aimed at losing 0.5–1 kg per week until target weight is achieved. A reduction of more than
7–9% in body weight has been associated with reduced steatosis, hepatocellular injury and
hepatic inflammation.
• Orlistat, an enteric lipase inhibitor causing malabsorption of dietary fat, is used with a low-
fat diet as an adjunct in subjects with a body mass index (BMI) of more than 30 kg/m2. Only
those achieving a loss of body weight of more than 5% in 3 months should continue orlistat,
and then for only 1 year, as fat-soluble vitamin deficiency may occur.
• Pioglitazone or vitamin E may be used for those with biopsy-proven NASH, in whom
lifestyle intervention has failed. Meta-analysis data demonstrated that pioglitazone
significantly improved liver steatosis, inflammation and, to a lesser degree, fibrosis.
However, it is associated with weight gain and reports of congestive cardiac failure, bladder
cancer and reduced bone density. Conversely, pioglitazone reduces death, myocardial
infarction and stroke in diabetes patients. The risks and benefits to each patient should be
evaluated accordingly.
• Vitamin E (800 IU/day) is an antioxidant that improves steatohepatitis. However, a meta-
analysis showed an increase in all-cause mortality at doses over 400 IU/day, and an increased
risk of haemorrhagic stroke and prostate cancer has also been reported.
• Weight loss following bariatric surgery leads to reduced steatosis, steatohepatitis and
fibrosis. The optimum technique is unknown and long-term data are lacking, although initial
concerns about worsening fibrosis do not appear to have been borne out. Bariatric surgery
should be avoided in those with advanced cirrhosis and portal hypertension, but gastric
bypass and sleeve gastrectomy (pp. 210–211) have been shown to achieve weight loss and
improve obesity-related co-morbidities in Child–Pugh A cirrhotic patients.
Hepatocellular carcinoma
The yearly cumulative incidence of HCC is 2.6% in patients with NASH cirrhosis, and
ultrasound surveillance should therefore be performed 6-monthly. Hyperinsulinaemia and
obesity are risk factors for many malignancies. Metformin and statin treatment may reduce the
risk of HCC in patients with type 2 diabetes.

Liver transplantation
NASH cirrhosis is now the third most common indication for liver transplantation in the USA.
Survival is comparable to that in other indications, and although recurrence occurs post
transplant (4–25%), it does not appear to have an impact on graft survival. Patients frequently
have multiple cardiovascular risk factors that should be managed aggressively. UK guidelines
suggest that bariatric surgery could be considered at transplantation for the morbidly obese.
 F urt he r re a ding
Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical
approach to treatment. Frontline Gastroenterol 2014; 5:277–286.
Gawrieh S, Chalasani N. NAFLD fibrosis score: is it ready for wider use in clinical
practice and for clinical trials? Gastroenterology 2013; 145:717–719.
Newsome PN, Allison ME, Andrews PA et al. Guidelines for liver transplantation for
patients with non-alcoholic steatohepatitis. Gut 2012; 61:484–500.

Cirrhosis
In cirrhosis, the liver architecture is diffusely abnormal and interferes with liver blood flow
and function; this leads to the clinical manifestations of portal hypertension and liver failure.

Aetiology
Causes of cirrhosis are shown in Box 14.12. Alcohol is currently the most common cause in
the West, but likely to be superseded by NAFLD; viral infection the most common worldwide.
Young patients with cirrhosis must be investigated to exclude treatable causes (e.g. Wilson's
disease).

 Box 14.12
C a use s o f c irrho sis
Common
• Alcohol
• Hepatitis B ± D
• Hepatitis C
• Non-alcoholic fatty liver disease (NAFLD)
Others
• Primary biliary cholangitis
• Secondary biliary cirrhosis
• Autoimmune hepatitis
• Hereditary haemochromatosis
• Hepatic venous congestion
• Budd–Chiari syndrome
• Wilson's disease
 • Drugs (e.g. methotrexate)
• α1-Antitrypsin deficiency
• Cystic fibrosis
• Galactosaemia
• Glycogen storage disease
• Veno-occlusive disease
• Idiopathic (cryptogenic)
• ? Other viruses

Pathogenesis
Although the liver has a remarkable capacity to adapt to injury through tissue repair, chronic
injury results in inflammation, matrix deposition, necrosis and angiogenesis, all of which lead
to fibrosis (Fig. 14.21). Liver injury causes necrosis and apoptosis, releasing cell contents and
reactive oxygen species (ROS). This activates hepatic stellate cells and tissue macrophages
through the CC-chemokine ligand 2–CC-chemokine receptor 2 (CCL2–CCR2) axis (see p.
440). These cells phagocytose necrotic and apoptotic cells and secrete pro-inflammatory
mediators, including transforming growth factor-beta (TGF-β); this leads to transdifferentiation
of stellate cells to myofibro​blasts and platelet-derived growth factor (PDGF), which
stimulates myofibroblast proliferation. Macrophages degrade scar matrix by secretion of
matrix metalloproteinases (MMPs), but this is inhibited by concurrent myofibroblast and
macrophage production of tissue inhibitors of metalloproteinases (TIMPs). This results in
progressive matrix deposition and scar accumulation. Increased gut permeability and hepatic
lipopolysaccharide–Toll-like receptor 4 (LPS–TLR4) signalling also promotes fibrogenesis.
Repetitive or chronic injury and inflammation perpetuate this process.
 FIGURE 14.21 Pathogenesis of fibrosis. The normal liver is shown on the left. Activation of the stellate cell
is followed by proliferation of fibroblasts and the deposition of collagen.

If the cause of fibrosis is eliminated (e.g. treatment of viral hepatitis), resolution (complete
reversal to near-normal liver architecture) of early fibrosis can occur. In cirrhosis, regression
(improvement, not reversal) occurs, which improves clinical outcomes. Antifibrotic therapies
are emerging (including stem cell transplant strategies) but currently liver transplantation is the
only available treatment for liver failure.

Pathology
The characteristic features of cirrhosis are regenerating nodules separated by fibrous septa,
and loss of lobular architecture within the nodules (Fig. 14.22A–C). Two types are described:
• Micronodular cirrhosis. Regenerating nodules are usually <3 mm in size with uniform
involvement of the liver; often caused by alcohol or biliary tract disease.
• Macronodular cirrhosis. The nodules are of variable size and normal acini may be seen
within larger nodules; often caused by chronic viral hepatitis.
 FIGURE 14.22 Pathology of cirrhosis. A. Haematoxylin and eosin histological view (×10). B. Histological
appearance (Giemsa stain), showing nodules of liver tissue of varying size, surrounded by fibrosis. C.
Picrosirius red stain of collagen used for morphometric evaluation of fibrosis. D. CT scan showing an
irregular lobulated liver. There is splenomegaly and enlargement of collateral vessels beneath the anterior
abdominal wall (arrowed), caused by portal hypertension. E. CT image showing cirrhosis, with a patent
portal vein and no space-occupying lesion.

A mixed picture with small and large nodules occurs occasionally.

Symptoms and signs are described on pages 447–448.

Investigations
Investigations aim to assess the severity and type of liver disease.

Severity
• Liver function. Serum albumin and prothrombin time are the best indicators of liver function;
the outlook is poor if the albumin level is <28 g/L. The degree to which the prothrombin time
is prolonged is commensurate with disease severity.
• Liver biochemistry. This may be normal, depending on the severity of disease. In most cases,
there is a slight elevation in the serum ALP and serum aminotransferases. In decompensated
cirrhosis, all biochemistry is deranged.
• Serum electrolytes. A low sodium indicates severe liver disease due to a defect in free
water clearance or excess diuretic therapy.
• Serum creatinine. An elevated concentration >130 µmol/L is a marker of poor prognosis.
• Biomarkers. In the Enhanced Liver Fibrosis (ELF™) test, which assesses fibrosis, a value of
<7.7 indicates none to mild, 7.7–9.8 moderate, and ≥9.8 severe.
In addition, a serum α-fetoprotein of >200 ng/mL is strongly suggestive of HCC.
Type
This can be determined by:
• viral markers
• serum autoantibodies
• serum immunoglobulins
• iron indices and ferritin
• copper and caeruloplasmin (see p. 479)
• α1-antitrypsin (see pp. 479–480).
• genetic markers.
Serum copper and serum α1-antitrypsin should always be measured in young cirrhotics.
Total iron-binding capacity (TIBC) and ferritin should be measured to exclude hereditary
haemochromatosis; genetic markers are also available (see pp. 477–479).

Imaging
• Ultrasound examination can demonstrate changes in the size and shape of the liver. Fatty
change and fibrosis produce a diffusely increased echogenicity. In established cirrhosis, there
may be marginal nodularity of the liver surface and distortion of the arterial vascular
architecture. The patency of the portal and hepatic veins can be evaluated. Ultrasound is
useful for detecting HCC.
• Transient elastography is increasingly used to avoid liver biopsy (see p. 446). Technical
limitations preclude its use in patients with ascites or morbid obesity, but it is suitable for
most.
• CT scanning (see p. 446) is also helpful. Figure 14.22D–E show hepatosplenomegaly and
the dilated collaterals seen in chronic liver disease. Arterial phase-contrast-enhanced scans
are useful for detecting of HCC.
• Endoscopy is performed for the detection and treatment of varices and portal hypertensive
gastropathy. Colonoscopy is occasionally carried out for colopathy.
• MRI scanning is useful in the diagnosis of both malignant and benign tumours such as
haemangiomas. MR angiography can demonstrate the vascular anatomy, and MR
cholangiography the biliary tree.

Liver biopsy
This remains the ‘gold standard’ for confirming the type and severity of liver disease.
Adequate samples, in terms of length and number of complete portal tracts, are necessary for
diagnosis and staging/grading of chronic viral hepatitis; in macronodular cirrhosis, the core of
liver may fragment, causing sampling errors. Immunocytochemical stains can identify viruses,
bile ducts, angiogenic structures and oncogenic markers. Chemical measurement of iron and
copper is necessary to confirm a diagnosis of iron overload or Wilson's disease. Digital image
analysis of Picrosirius red staining can be used to quantitate collagen in biopsy specimens
(Fig. 14.22C).

Management
Management is that of the complications of decompensated cirrhosis. Patients should undergo
6-monthly ultrasound to screen for the early development of HCC (see p. 485), as all
therapeutic strat​egies work best with small, single tumours.
Treatment of the underlying cause may arrest or reverse cirrhosis. Patients with
compensated cirrhosis should lead a normal life. Those at risk should receive hepatitis A and
B vaccination. The only dietary restriction is to reduce salt intake (≤2 g sodium per day).
Alcohol should be avoided, as should aspirin and non-steroidal anti-inflammatory drugs
(NSAIDs), which may precipitate gastro​intestinal bleeding or renal impairment.

Prognosis
Prognosis is extremely variable. In general, the 5-year survival rate is approximately 50%,
depending on the stage at which diagnosis is made. Poor prognostic indicators are shown in
Box 14.13. Development of any complication usually worsens the prognosis.

 Box 14.13
P o o r pro g no st ic indic a t o rs in c irrho sis
Blood tests
• Low albumin (<28 g/L)
• Low serum sodium (<125 mmol/L)
• Prolonged prothrombin time >6 s above normal value
• Raised creatinine >130 µmol/L
Clinical
• Persistent jaundice
• Failure of response to therapy
• Ascites
• Haemorrhage from varices, particularly with poor liver function
• Neuropsychiatric complications developing with progressive liver failure
• Small liver
• Persistent hypotension
• Aetiology (e.g. alcoholic cirrhosis, if the patient continues drinking)
 There are a number of prognostic classifications based on modifications of Child's grading
(A, B and C; Box 14.14) and the Model for End-stage Liver Disease (MELD; Box 14.15),
based on serum bilirubin, creatinine and INR, which is widely used as a predictor of mortality
in patients awaiting liver transplantation. Modifications of the MELD score (e.g. UKELD) are
used in some countries.

 Box 14.14
Sc o ring syst e ms in c irrho sis: mo dif ie d C hild– P ug h
c la ssif ic a t io n

Score 1 2 3
Ascites None Mild Moderate/severe
Encephalopathy None Mild Marked
Bilirubin (µmol/L) <34 34–50 >50
Albumin (g/L) >35 28–35 <28
Prothrombin time (seconds over normal) <4 4–6 >6
Add above scores for your patient for survival figures below:
Child's A (<7): 82% survival at 1 year, 45% at 5 years, 25% at 10 years
Child's B (7–9): 62% survival at 1 year, 20% at 5 years, 7% at 10 years
Child's C (10+): 42% survival at 1 year, 20% at 5 years, 0% at 10 years

 Box 14.15
Sc o ring syst e ms in c irrho sis
Model of End-stage Liver Disease (MELD)

3.8 × LN (bilirubin in mg/dL) + 9.6 × LN (creatinine in mg/dL) + 11.2 × LN (INR) + 6.4*

To convert:
• bilirubin from µmol/L to mg/dL, divide by 17
• creatinine from µmol/L to mg/dL, divide by 88.4
MELD scores (with no complications):
• Score <10: 97% survival at 1 year
• Score 30–40: 70% at 1 year
INR, International Normalized Ratio; LN, natural logarithm.
*Check online

Acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) refers to the condition of patients hospitalized for an
acute complication of cirrhosis accompanied by organ failure(s); it has a high short-term
mortality. ACLF is believed to be distinct from traditional decompensated cirrhosis, based not
only on the presence of organ failure(s) and high mortality rate, but also on younger age,
alcohol aetiology, higher prevalence of certain precipitating events (e.g. bacterial infections or
active alcohol excess), and a higher level of systemic inflammation. It is estimated to occur in
31% of patients hospitalized with an acute complication of cirrhosis.

Liver assist devices

As the liver has great potential to regenerate, extracorporeal liver support devices may allow
patients with liver failure to be bridged to recovery or even liver transplantation. Current
approaches include the use of biological devices that contain hepatocytes and those that
function as detoxification devices, and artificial liver support systems. However, no device is
currently available routinely.

Gut–liver axis
The liver is exposed to gut-derived bacterial components that have little consequence in health,
as an effective gut barrier limits the amount of bacterial components transported to the liver. In
advanced liver disease, the intestinal barrier function is compromised due to changes in gut
motility, an increase in intestinal permeability, and suppression of gut immunological functions.
This leads to bacteria and components entering the portal circulation and being transported to
the liver, activating Toll-like receptors and producing an inflammatory response. This cross-
talk between the intestinal microbiota and the liver is referred to as the gut–liver axis; it is
seen as a key pathophysiological mechanism in the progression of liver disease and
development of the complications of cirrhosis. Antibiotics and non-selective β-blockers
intercept the gut–liver axis by blocking bacterial translocation, which is likely to account for
their beneficial effects in reducing portal pressure, variceal haemorrhage and spontaneous
bacterial peritonitis. However, absorbable antibiotics will lead to the selection of resistant
bacteria. Rifaximin, a poorly absorbed antibiotic used for encephalopathy, specifically affects
the gut flora and has a low risk for inducing resistance; it may therefore have a role in this
indication.

F urt he r re a ding
Leckie P, Davenport A, Jalan R. Extracorporeal liver support. Blood Purif 2012; 34:158–
163.
Madsen BS, Havelund T, Krag A. Targeting the gut–liver axis in cirrhosis: antibiotics and
non-selective β-blockers. Adv Ther 2013; 30:659–670.
Moreau R, Jalan R, Gines P et al and the CANONIC Study Investigators of the EASL–
CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in
patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144:1426–1437.
Pellicoro A, Ramachandran P, Iredale JP et al. Liver fibrosis and repair: immune
regulation of wound healing in a solid organ. Nat Rev Immunol 2014; 14:181–194.
Liver transplantation
This is the only established treatment for advanced liver disease. Shortage of donors is a major
problem in all developed countries and in some, such as Japan or South Korea, living related
donors form the majority.

Indications
These include:
• Acute liver disease: acute hepatic failure of any cause (see p. 463).
• Chronic liver disease: usually for complications of cirrhosis that are no longer responsive to
therapy.
The timing of transplantation depends on donor availability. All patients with end-stage
cirrhosis (Child's grade C; MELD score ≥20; UKELD score ≥49) and those with debilitating
symptoms should be referred to a transplant centre. In addition, specific extrahepatic
complications of cirrhosis, even with preserved liver function, such as hepatopulmonary
syndrome and porto-pulmonary hypertension, can be reversed by transplantation.
• Primary biliary cholangitis. Patients should be transplanted when their serum bilirubin is
persistently >100 µmol/L or when they have symptoms such as intractable pruritus.
• Chronic hepatitis B if HBV DNA-negative or levels are falling with therapy. Following
transplantation, recurrence of hepatitis is prevented by hepatitis B immunoglobulin and
nucleoside analogues in combination (see pp. 243–244).
• Chronic hepatitis C. This is the most common indication. Universal HCV re-infection occurs
with varying severity and cirrhosis occurs in 10–20% at 5 years. The new antiviral drugs are
highly likely to improve these figures greatly.
• Autoimmune hepatitis. In patients who have failed to respond to medical treatment, the
disease can recur.
• Alcoholic liver disease. Well-motivated patients who have stopped drinking without
improvement of liver disease are offered a transplant, with frequent counselling. It has been
shown that transplantation may represent life-saving treatment in patients with severe
alcoholic hepatitis who are not responding to medical therapy. However, further studies are
awaited.
• Primary metabolic disorders. Examples are Wilson's disease, hereditary haemochromatosis
and α1-antitrypsin deficiency.
• NASH cirrhosis. Now one of the most common causes of chronic liver disease in developed
countries, this is likely to become the most frequent indication for transplantation.
• Other conditions, such as primary sclerosing cholangitis (PSC), polycystic liver disease,
and metabolic diseases such as primary oxaluria.

Contraindications
Absolute contraindications include active sepsis outside the hepatobiliary tree, malignancy
outside the liver, liver metastases (except neuroendocrine), and a lack of psychological
commitment on the part of the patient.
Relative contraindications are mainly anatomical considerations that make surgery more
difficult, such as extensive splanchnic venous thrombosis. With exceptions, patients aged 70 
years or over are not usually given a transplant. In HCC, the recurrence rate is high, unless
there are fewer than three small (<3 cm) lesions or a solitary nodule of <5 cm (Milan criteria).

Preparation for surgery

Pre-transplant work-up includes confirmation of the diagnosis, ultrasound and cross-sectional
imaging, and radiological demonstration of the hepatic arterial and biliary trees, as well as
assessment of cardiorespiratory and renal status. In view of the ethical and financial
implications of transplantation, regular psychosocial, and possibly psychiatric, support is vital.
The donor should be ABO-compatible (HLA matching is not necessary) and have no
evidence of active sepsis, malignancy, or HIV, HBV or HCV infection. Younger donors (<50 
years) experience better graft function. The donor liver is cooled and stored on ice; its
preservation time may be up to 20 hours. The recipient operation takes approximately 8 hours
and rarely requires a large blood transfusion. Cadaveric donor livers (from heart-beating or
non-heart-beating donors) may consist of whole graft, split grafts (for two recipients) or
reduced grafts. Live donors may be healthy individuals or patients with, for example, familial
amyloid polyneuropathy, whose livers can be transplanted into others (domino transplant). The
mortality of right lobe donors is between 1 in 200 and 1 in 400.
The operative mortality is low and most postoperative deaths occur in the first 3 months.
Sepsis and haemorrhage can be serious complications. Opportunistic infections occur owing to
immunosuppression. Various immunosuppressive agents have been used, but tacrolimus –
alone or in combination with azathioprine or mycophenolate mofetil, steroids, sirolimus and
microemulsified ciclosporin are the most common.

Rejection
• Acute or cellular rejection usually occurs 5–10 days post transplant; it can be asymptomatic
or there may be a fever. On biopsy, a pleomorphic portal infiltrate is seen with prominent
eosinophils, bile duct damage and endothelialitis of the blood vessels. This responds well to
immunosuppressive therapy.
• Chronic ductopenic rejection is seen between 6 weeks and 9 months post transplant, with
disappearing bile ducts (vanishing bile duct syndrome, VBDS), and an arteriopathy with
narrowing and occlusion of the arteries. Early ductopenic rejection is rarely reversed by
immunosuppression and often requires retransplantation.
• Graft-versus-host disease is extremely rare.

Prognosis
Elective liver transplantation in low-risk patients has a 90% 1-year survival and a 70–85% 5-
year survival. Patients require life-long immunosuppression, although doses can be reduced
over time without significant problems. Future strategies to reduce immunosuppression
requirements after transplant may include infusion of autologous regulatory T cells. HCV
cirrhosis, PSC and HCC are conditions in which long-term survival after transplantation is
compromised by disease recurrence.

F urt he r re a ding
Lucey MR. Liver transplantation for alcoholic liver diseases. Nat Rev Gastroenterol
Hepatol 2014; 11:300–307.

Complications and effects of cirrhosis

These are shown in Box 14.16.

 Box 14.16
C o mplic a t io ns a nd e f f e c t s o f c irrho sis
• Portal hypertension and gastrointestinal haemorrhage
• Ascites
• Portosystemic encephalopathy
• Hepatocellular carcinoma
• Bacteraemias, infections
• Renal failure
• Hepatopulmonary syndrome

Portal hypertension
The portal vein is formed by the union of the superior mesenteric and splenic veins. Normal
pressure is 5–8 mmHg with only a small gradient across the liver to the hepatic vein, in which
blood is returned to the heart via the inferior vena cava. Portal hypertension is classified
according to the site of obstruction:
• Prehepatic – blockage of the portal vein before the liver
• Intrahepatic – distortion of the liver architecture, either pre-sinusoidal (e.g. schistosomiasis)
or post-sinusoidal (e.g. cirrhosis)
• Post-hepatic – venous blockage outside the liver (rare).
As portal pressure rises above 10–12 mmHg, the compliant venous system dilates and
collaterals form within the systemic venous system. The main sites of collaterals are the
gastro-oesophageal junction, rectum, left renal vein, diaphragm, retroperitoneum and the
anterior abdominal wall via the umbilical vein.
The collaterals at the gastro-oesophageal junction (varices) are superficial and tend to
rupture. Portosystemic anastomoses at other sites rarely cause symptoms. Rectal varices are
found frequently (30%) if looked for and can be differentiated from haemorrhoids, which are
lower in the anal canal. The microvasculature of the gut becomes congested, giving rise to
portal hypertensive gastropathy and colopathy, in which there is punctate erythema and
erosions, which can bleed.

Pathophysiology
Following liver injury and fibrogenesis, the contraction of activated myofibroblasts (mediated
by endothelin, nitric oxide and prostaglandins) contributes to increased resistance to blood
flow. This increased resistance leads to portal hypertension and opening of portosystemic
anastomoses in both pre-cirrhotic and cirrhotic livers. Neoangiogenesis also occurs. The
hyperdynamic circulation of cirrhosis (caused by nitric oxide, cannabinoids and glucagon)
leads to peripheral and splanchnic vasodilatation. This, combined with plasma volume
expansion due to sodium retention (see ‘Ascites’, pp. 472–473), has a significant effect in
maintaining portal hypertension.

Aetiology
The most common cause is cirrhosis (Box 14.17). Others are described below.

 Box 14.17
C a use s o f po rt a l hype rt e nsio n
Prehepatic
• Portal vein thrombosis
Intrahepatic
• Pre-sinusoidal
– Schistosomiasis; sarcoidosis
– Primary biliary cholangitis
• Sinusoidal
– Cirrhosis (e.g. alcoholic)
– Partial nodular transformation
– Congenital hepatic fibrosis
• Post-sinusoidal
– Veno-occlusive disease
– Budd–Chiari syndrome
 Post-hepatic
• Right heart failure (rare)
• Constrictive pericarditis
• Inferior vena cava obstruction

Prehepatic causes
Extrahepatic blockage due to portal vein thrombosis can be caused by congenital portal venous
abnormalities, neonatal sepsis of the umbilical vein, or inherited prothrombotic conditions,
such as factor V Leiden or primary myeloproliferative disorders with or without JAK2
mutations (see p. 97).
Patients present with gastrointestinal bleeding, often at a young age. They have normal liver
function, and prognosis following bleeding is therefore excellent.
The portal vein blockage can be identified by ultrasound with Doppler imaging; CT and MR
angiography are also used.
Treatment for variceal bleeding is usually repeated endoscopic therapy or non-selective
beta-blockade. Splenectomy is only performed if there is isolated splenic vein thrombosis.
Anticoagulation prevents further thrombosis and intestinal infarction, and does not increase the
risk of bleeding.

Intrahepatic causes
Cirrhosis is by far the most common cause but others include:
• Non-cirrhotic portal hypertension is characterized by mild portal tract fibrosis on liver
histology. The aetiology is unknown, but arsenic, vinyl chloride, antiretroviral therapy and
other toxins have been implicated. A similar disease is frequently found in India. The liver
lesion does not progress and prognosis is good.
• Schistosomiasis with extensive pipe-stem fibrosis in endemic areas such as Egypt and
Brazil. Often, there is concomitant liver disease, such as HCV infection, which was
transmitted by non-sterile equipment.
• Other causes include congenital hepatic fibrosis, and nodular regenerative hyperplasia and
partial nodular transformation.

Post-hepatic causes
Prolonged severe heart failure with tricuspid incompetence or constrictive pericarditis can
cause portal hypertension. The Budd–Chiari syndrome is described on page 482.

Clinical features
Patients are often asymptomatic, the only clinical evidence being splenomegaly, although
features of chronic liver disease may exist (see pp. 447–448).
 Variceal haemorrhage
Approximately 90% of patients with cirrhosis will develop gastro-oesophageal varices over
10 years, but only one-third of these will bleed. Bleeding is likely to occur with large varices,
or those with red signs at endoscopy, and in severe liver disease.

Management
Management can be divided into:
• the active bleeding episode
• prevention of rebleeding
• prophylactic measures to prevent the first haemorrhage.
Despite the therapeutic techniques available, prognosis ultimately depends on the severity of
the underlying liver disease; overall 6-week mortality from variceal haemorrhage is 15–25%,
reaching 50% in Child's grade C.

Initial management of acute variceal bleeding

See Figure 14.23, and also the general management of gastrointestinal haemorrhage on page
385.

FIGURE 14.23 Management of gastrointestinal haemorrhage due to oesophageal varices. TIPS,

transjugular intrahepatic portosystemic shunt.

Resuscitation
• Assess the patient: pulse, blood pressure and conscious state.
• Insert a large-bore intravenous line and obtain blood for group and crossmatching,
haemoglobin, prothrombin time/INR, urea, electrolytes, creatinine, liver biochemistry and
blood cultures.
• Restore blood volume with plasma expanders or, if possible, blood transfusion. See the
treatment of shock for more detail (pp. 1156–1161). Prompt correction, but not over-
correction, of hypovolaemia is necessary in cirrhosis patients, as their baroreceptor reflexes
are diminished. A target haemoglobin of 80 g/L is sufficient and this lessens the likelihood of
early rebleeding.
• Carry out an ascitic tap.
• Monitor for alcohol withdrawal. Give intravenous thiamine.
• Start prophylactic antibiotics. These treat and prevent infection, and reduce early rebleeding
and mortality.

Urgent endoscopy
Endoscopy (Fig. 14.24) should be performed to confirm the diagnosis and to exclude bleeding
from other sites (e.g. gastric ulceration) and portal hypertensive gastropathy/gastric antral
vascular ectasia (GAVE). The latter describes chronic gastric congestion, punctate erythema
and gastric erosions, which may contribute to chronic anaemia. Portal hypertensive gastropathy
and GAVE are distinct entities; management of portal hypertensive gastropathy is centred on
reduction in portal pressures with β-blockers, whereas treatment of GAVE is endoscopic and
uses various ablative techniques.
 FIGURE 14.24 Endoscopic views of oesophageal varices. A. Gross varices. B. Blood spurting from a varix.
C. Following a recent bleed. D. Varices with a band in place (arrowed). (A, C and D Courtesy of Dr Peter Fairclough.)

Variceal banding or injection sclerotherapy

Banding of oesophageal varices is performed by mounting a band on the tip of the endoscope,
sucking the varix into the end of the scope, and dislodging the band over the varix using a trip-
wire mechanism.
Between 15% and 20% of bleeding comes from gastric varices, which are associated with a
greater mortality (up to 40%); endoscopic injection of cyanoacrylate is the best treatment.
Overall, haemostasis is achieved in 80–90% of patients. Best practice is to perform the
endoscopy with the patient under general anaesthetic and to provide appropriate airway
support.
Injection sclerotherapy is now rarely performed for oesophageal varices.

Other measures

Vasoconstrictor therapy
This is used to restrict portal inflow by splanchnic arterial constriction and has shown benefit
when used in combination with endoscopic techniques.
• Terlipressin. This is the only vasoconstrictor proven to reduce mortality. The dose is 2 mg 6-
hourly, reducing to 1 mg 4-hourly after 48 h if a prolonged regimen is required (up to 5 days).
Terlipressin should not be given to patients with ischaemic heart disease. The patient may
complain of abdominal colic, and may defecate and have facial pallor owing to generalized
 vasoconstriction. If haemostasis has been achieved at endoscopy, there is probably little
added benefit with this therapy and treatment should be tapered accordingly.
• Somatostatin. This has few side-effects. An infusion of 250–500 µg/h reduces bleeding and
is reserved for patients with contraindications to terlipressin. A recent prospective,
multicentre study showed that haemostatic effects and safety at day 5 of treatment did not
differ significantly between terlipressin, somatostatin and octreotide when utilized as
adjuvants to endoscopic treatment.

Balloon tamponade
Balloon tamponade is used if endoscopic therapy has failed or if there is exsanguinating
haemorrhage. The usual balloon tube is a four-lumen Sengstaken–Blakemore, which should be
left in place for no more than 12 hours and removed in the endoscopy room prior to endoscopy.
The tube is passed into the stomach and the gastric balloon inflated with air and pulled back. It
should be positioned in close apposition to the gastro-oesophageal junction to prevent the
cephalad variceal blood flow to the bleeding point. The oesophageal balloon should only be
inflated if bleeding is not controlled by the gastric balloon alone.
Haemostasis is achieved in up to 90%. However, the balloon may cause serious
complications, such as aspiration pneumonia, oesophageal rupture and mucosal ulceration. The
procedure is also very unpleasant for the patient.
A self-expanding covered metal stent (Danis), which has a wire loop to enable removal, and
is introduced orally or endoscopically, can be placed over the varices. This is effective and
has the advantages that it does not impair swallowing, cannot be removed by uncooperative
patients, and allows post-endoscopic investigation. The stent is removed 7 days after insertion.
It is currently only used in specialist centres but early results are encouraging.

Additional management of the acute episode

• Measures to prevent encephalopathy. Portosystemic encephalopathy (PSE) can be
precipitated by a large bleed (blood contains protein). Management is as outlined on page
474.
• Nursing. Patients require high-dependency/intensive care nursing. They should remain nil by
mouth until bleeding has stopped.
• Reduction in acid secretion. Ranitidine may be preferable to PPIs, as it lessens the risk of
Clostridium difficile infection; PPIs are widely used, however. Sucralfate 1 g four times
daily can reduce oesophageal ulceration following endoscopic therapy.

Management of an acute rebleed

Rebleeding occurs in about 15–20% within 5 days. The source should be established by
endoscopy and is sometimes due to ulceration or slippage of a ligation band. Endoscopy
should be performed once only to control rebleeding. If haemostasis cannot be achieved, then
transjugular intrahepatic portocaval shunting will be necessary.
Transjugular intrahepatic portocaval shunt
Transjugular intrahepatic portocaval shunt (TIPS) is used when bleeding cannot be controlled
either acutely or following a rebleed. Under X-ray guidance, a guidewire is passed from the
jugular vein into the liver and the portal vein. After balloon expansion of the tract between the
hepatic and portal veins, an expandable, covered metal shunt is placed over the wire to form a
channel between the systemic and portal venous systems. It reduces the hepatic sinusoidal and
portal vein pressure by creating a total shunt. There is an increased risk of portal systemic
encephalopathy. Stent stenosis or thrombosis is far less frequent with ‘covered’, compared to
‘bare’, stents. Collaterals arising from the splenic or portal veins can be selectively
embolized. These reduce rebleeding rates compared to endoscopic techniques, but do not
improve survival and increase encephalopathy.

Emergency surgery
This is performed rarely when other measures fail or if TIPS is not available. Oesophageal
transection and ligation of the feeding vessels to the bleeding varices is most commonly
performed; an alternative is acute portosystemic shunt surgery.

Prevention of recurrent variceal bleeding (secondary prophylaxis)

The risk of bleeding recurring without prophylaxis is 60–80% over a 2-year period, with an
approximate mortality of 20% per episode.

Prophylactic long-term measures

Non-selective beta-blockade
Oral propranolol or carvedilol to reduce the resting pulse rate by 25% decreases portal
pressure. Portal inflow is reduced by a decrease in cardiac output (β1) and by blockade of β2
vasodilator receptors on the splanchnic arteries, leaving an unopposed vasoconstrictor effect.
Significant reduction of hepatic venous pressure gradient (HVPG; measured by hepatic vein
catheterization) is associated with very low rates of rebleeding, particularly if <12 mmHg.
Data have emerged demonstrating that additional α1-adrenergic blockade, causing
vasodilatation with carvedilol, may increase the number of patients with a reduction in hepatic
venous pressure gradient compared to propranolol.

Endoscopic treatment
Repeated courses of banding at 2-weekly intervals lead to obliteration of varices. This
markedly reduces rebleeding, most instances occurring before the varices have been fully
obliterated. Between 30% and 40% of varices return per year, so follow-up endoscopy should
be performed at 1–3 months after obliteration and then every 6–12 months. Complications of
banding include oesophageal ulceration, mediastinitis and, rarely, strictures.
Combination therapy reduces overall bleeding compared to endoscopic therapy alone but
with no overall improvement in mortality. A pragmatic approach is therefore to give
combination therapy to those who can tolerate beta-blockade, and band ligation alone to those
who cannot.

Surgery
• Surgical portosystemic shunting is associated with an extremely low risk of rebleeding and
is used if TIPS is not available. Hepatic encephalopathy is a significant complication. The
‘shunts’ are usually an end-to-side portocaval anastomosis or a selective distal splenorenal
shunt (Warren shunt).
• Devascularization procedures, including oesophageal transection, do not produce
encephalopathy, and can be used when there is splanchnic venous thrombosis.
• Liver transplantation (see pp. 468–469) is the best option when there is poor liver function.

Prophylactic measures (primary prophylaxis)

Patients with cirrhosis and significant varices that have not bled should be prescribed non-
selective β-blockers. This reduces the chances of upper gastrointestinal bleeding by
approximately 50%, may increase survival, and is cost-effective. If there are contraindications,
variceal banding is an option.

Ascites
Ascites, fluid within the peritoneal cavity, is a common complication of cirrhosis. Several
factors underlie its pathogenesis:
• Sodium and water retention results from peripheral arterial vasodilatation (secondary to
nitric oxide, atrial natriuretic peptide and prostaglandins), which causes a reduction in the
effective blood volume. This reduction activates the sympathetic nervous system and the
renin–angiotensin system, promoting salt and water retention (see Fig. 9.3).
• Portal hypertension exerts a local hydrostatic pressure, leading to increased hepatic and
splanchnic production of lymph, and transudation of fluid into the peritoneal cavity.
• Low serum albumin (due to poor liver function) may further contribute by reducing plasma
oncotic pressure.
In patients with ascites, urine sodium excretion rarely exceeds 5 mmol in 24 hours. Loss of
sodium from extrarenal sites accounts for approximately 30 mmol in 24 hours. Under these
circumstances, a normal daily sodium intake of 120–200 mmol results in a positive sodium
balance of approximately 90–170 mmol in 24 hours (equivalent to 600–1300 mL of fluid
retained).

Clinical features
Abdominal swelling may develop over days or several weeks. Precipitating factors include a
high-sodium diet or development of an HCC or splanchnic vein thrombosis. Mild abdominal
pain and discomfort are common but, if more severe, should raise the suspicion of spontaneous
bacterial peritonitis (see below). Respiratory distress and difficulty eating accompany tense
ascites.
The presence of fluid is confirmed clinically by demonstrating shifting dullness. Many
patients also have peripheral oedema. A pleural effusion (usually right-sided) may infrequently
be found and arises from the passage of ascites through congenital diaphragmatic defects.

Investigations
A diagnostic aspiration of 10–20 mL of fluid should be obtained for:
• Cell count. A neutrophil count >250 cells/mm3 is indicative of an underlying (usually
spontaneous) bacterial peritonitis.
• Gram stain and culture.
• Protein measurement. A high serum–ascites albumin gradient of >11 g/L suggests portal
hypertension, and a low gradient <11 g/L is associated with non-liver disease-related
abnormalities of the peritoneum, such as neoplasia (Box 14.18).

 Box 14.18
The se rum– a sc it e s a lbumin g ra die nt
High serum–ascites albumin gradient (>11 g/L)
• Portal hypertension, e.g. hepatic cirrhosis
• Hepatic outflow obstruction
• Budd–Chiari syndrome
• Hepatic veno-occlusive disease
• Tricuspid regurgitation
• Constrictive pericarditis
• Right-sided heart failure
Low serum–ascites albumin gradient (<11 g/L)
• Peritoneal carcinomatosis
• Peritoneal tuberculosis
• Pancreatitis
• Nephrotic syndrome
(Modified from Chung RT, Iafrate AJ, Amrein PC et al. Case records of the Massachusetts General Hospital. New England
Journal of Medicine 2006; 354:2166–2175.)