Gangguan/Penyakit pada Hepar

dan Bilier (Hepatitis A, B, C,

Sirosis Hepatitis, Abses Liver)

Prof. Dr. dr. Djoni Djunaedi, SpPD, KPTI FINASM

 Apa fungsi Organ Hati?
➢ Menyaring darah
➢ Membuat empedu, suatu zat yang membantu pencernaan lemak
➢ Memproses dan mengikat lemak pada pengangkutnya (protein) termasuk kolestrol
➢ Menyimpan gula dan membantu tubuh untuk mengangkut dan menghemat energi
➢ Membuat protein-protein, seperti kebanyakan yang terlibat pada pembekuan darah
➢ Metabolisme banyak obat-obatan seperti barbiturates, sedatives, dan amphetamines
➢ Menyimpan besi, tembaga, vitamin A, D, dan beberapa dari vitamin B
➢ Membuat protein-protein penting seperti albumin yang mengatur pengakutan cairan
didalam darah dan ginjal
➢ Membantu mengurai dan mendaurulang sel-sel darah merah
Acute Hepatitis Virus Infection
(A, B, C)
Adapted from Harrison’s Manual of Medicine; Fauci AS, Braunwald E, Kasper DL, et al. eds. 2009;
New York, NY: The McGraw Hill Companies; 1264 pgs. Table 161-1
 The
differences
among
hepatitis A,
B, C, D, and
E

https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.hepb.org%2Fblog%2Fknow-your-abcs%2F&psig=AOvVaw0kY7Hfw2w3k_UlHJTe3Lri&ust=1656750927035000&source=images&cd=vfe&ved=0CA0QjhxqFwoTCOjiuaek1_gCFQAAAAAdAAAAABAU
Comparative
Features :
Hep A,
Hep B,
Hep C
 Medical History/Physical Examination
• HAV:
Viral Hepatitis
• The presence and severity of symptoms with HAV infection is related with the patient’s age, including nonspecific and flu-like
symptoms, persistent fever, severe pruritus, jaundice, diarrhea, and weight loss. Chronic infection does not occur with HAV.
• HBV:
• The symptoms of acute HBV infection are nonspecific and include fatigue, poor appetite, nausea, vomiting, abdominal pain, low-grade
fever, jaundice, and dark urine.15
• Clinical signs include liver tenderness, hepatomegaly, and splenomegaly.
• Acute HBV infection typically lasts for 2–4 months.
• Approximately 30–50% of children 5 years and older and adults are symptomatic; infants, children younger than 5 years, and
immunosuppressed adults are more likely to be asymptomatic.16
• In adults with healthy immune systems, approximately 95% of acute infections are self-limited, with patients recovering and developing
immunity.17
• Fewer than 5% of adults acutely infected with HBV progress to chronic infection, defined as disease lasting longer than 6 months.
• A small number (1%) develop acute hepatic failure and may die or require immediate liver transplantation.18
• HCV:
• The majority of acute and chronic HCV cases are asymptomatic, and patients rarely know when they acquired the infection. 10
• Nonspecific symptoms such as fatigue, vague right upper quadrant discomfort, and pruritus may be noted. HCV infection may progress
to cirrhosis with the consequent development of complications such as bleeding, hepatocellular carcinoma, and liver failure.
• Extrahepatic manifestations of HCV are uncommon and include renal disease, lichen planus, seronegative arthritis, and some
neurological conditions.19
Scheme of typical clinical and laboratory
features of HAV

https://doctorlib.info/medical/harrisons-manual-medicine/163.html
Scheme of typical clinical and laboratory
features of HBV.

https://doctorlib.info/medical/harrisons-manual-medicine/163.html
 Scheme of typical laboratory features during acute hepatitis C progressing to
chronicity.
HCV RNA is the first detectable event, preceding alanine aminotransferase (ALT)
elevation and the appearance of anti-HCV

https://doctorlib.info/medical/harrisons-manual-medicine/163.html
Hepatitis A
 Definition

• Acute inflammatory condition of the liver caused by hepatitis A

virus and characterized by constitutional symptoms including
anorexia, fatigue and weight loss, and jaundice.

Francisco Averhoff, ... Beth P. Bell, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015
HEPATITIS B
 Objectives :
• Describe the epidemiology of hepatitis B.
• Outline the common blood tests for the diagnosis of hepatitis B
infection.
• Review the complications of hepatitis B infection.
 Introduction
• Hepatitis B viral infection is a serious global healthcare problem.
• It is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV).
• It is often transmitted via body fluids like blood, semen, and vaginal secretions.
• The majority (more than 95%) of immunocompetent adults infected with HBV can clear the infection spontaneously.
• Patients can present with acute symptomatic disease or have an asymptomatic infection that is identified during
screening for HBV.
• The clinical manifestations of HBV infection vary in both acute and chronic diseases.
• During the acute infection, patients can have subclinical or anicteric hepatitis, icteric hepatitis, or less commonly
fulminant hepatitis.
• In chronic infection, patients can have an asymptomatic carrier state, chronic hepatitis, cirrhosis, and hepatocellular
carcinoma.
• Initial symptoms are nonspecific and may include anorexia, nausea, vomiting, abdominal pain, and jaundice.
• In cases of severe liver damage, patients can develop jaundice, hepatic encephalopathy, ascites, gastrointestinal
bleeding secondary to esophageal varices, coagulopathy, or infections.
• Diagnosis is based on serologic blood tests in patients with suspected signs and symptoms and associated risk
factors for viral hepatitis.
 Etiology
• Major modes of transmission for hepatitis B are as follows:
• 1. Horizontal transmission:
• It involves the transmission of hepatitis B through sexual contact or mucosal surface contact.
• Unprotected sex and injection drug use are major modes of transmission in low to intermediate
prevalence areas.[1]
• Sexual contact includes unprotected intercourse (vaginal, oral, or anal) and mucosal contact
involves any contact involving an infected patient’s saliva, vaginal secretion, semen, and blood.

• 2. Vertical transmission:
• Vertical transmission involves the maternal-to-newborn perinatal transmission of the virus.[2]
• It is the predominant mode of transmission in high-prevalence areas.
 Epidemiology
• HBV infection has the potential for progression to a chronic state and thus presents as a
global public health threat for its associated morbidity and mortality. While hepatitis B
vaccines are available, limited access to healthcare and lack of proper health education
contributes to the increasing global prevalence of hepatitis B.
• Worldwide Statistics
• 350-400 million of the world population has chronic hepatitis B.[6]
• Higher prevalence: Asian Pacific Islanders, Alaskan Eskimos, and Australian aborigines.[6]
• The prevalence of hepatitis B is reduced after the initiation of the hepatitis B vaccination program.
• 10 genotypes (A-J) of hepatitis B have been identified.[7]
• A majority of the global HBV disease burden is primarily through vertical transmission.

• Hepatitis in Indonesia
• Hepatitis B : Based on Risekadas 2013, the proportion of HBsAg positive was 7.1%, with the most cases in the 40-44 years age
group

• Prevalence areas are based on the percentage of the population with hepatitis B surface
antigen (HBsAg) positivity with greater than or equal to 8% representing high
prevalence areas, 2-7% representing low to intermediate prevalence areas, and less
than 2% representing low prevalence areas.[3]
 Possible
pathogenesis
of HBV
infection and
liver disease.

• secreted serine protease inhibitor

Kazal (SPIK)

https://www.semanticscholar.org/paper/Pathogenesis-of-Hepatitis-B-Virus-(HBV)-Mediated-Lu/ea7e186bcc3d4fcf0ae65ee39dc32a461f1f152d/figure/1
Cont..

https://els-jbs-prod-cdn.jbs.elsevierhealth.com/cms/attachment/e63dd3e1-6a12-4675-a133-3e7a540031b5/gr1_lrg.jpg
 Cont..

https://els-jbs-prod-cdn.jbs.elsevierhealth.com/cms/attachment/ed93d5fc-58d5-40e8-8f32-27535a615c28/fx1.jpg
• Hepatitis B virus is transmitted via
• Percutaneous inoculation or through mucosal exposure with infectious bodily fluids.
• Oral-fecal transmission is possible but considerably rare.
• The incubation period of HBV infection is typically between 30 and 180 days,
• Recovery is common in immunocompetent patients,
• A small percentage can progress to a chronic state, serologically defined as the
presence of HBsAg for greater than six months.
• HBsAg is transmitted via blood contact or body secretions,
• The risk of acquiring hepatitis B is considerably higher in individuals with close
contact with HBsAg-positive patients.
• The pathogenesis of liver disease in HBV infection is
• mainly immune-mediated,
• direct cytotoxic injury to the liver.
• Promote T cells-induced cellular lysis of HBV-infected cells.
• Cytotoxic T cell response to HBV-infected hepatocytes is relatively
ineffective
• The immune response may not be the sole etiology behind hepatic
injury in hepatitis B patients.
 DIAGNOSIS
• Diagnosis of Hepatitis B is based on proper history taking, physical
examination, laboratory works, and imaging.
• Initial symptoms are nonspecific and can include anorexia, nausea,
vomiting, abdominal pain, dark urine, clay-colored stool, and jaundice.
• In cases of severe liver damage, advanced findings specific to liver damage
are common :
• hepatic encephalopathy, confusion, coma, ascites, gastrointestinal bleeding,
coagulopathy, or infections.
• In cases of chronic hepatitis B, patients can have
• a chronic inactive infection
• or develop findings of acute hepatitis known as chronic active hepatitis.
 Cont……
• Viral serology of hepatitis B is usually detectable 1-12 weeks after initial infection (HBsAg +).
• The period of time between the disappearance of HBsAg and the appearance of Anti-HBsAg is termed “the
window period” or “serological gap.”
• During the window period, other viral serology could also be undetectable.
• HBsAg is the first virological marker to be detected
• Immune-mediated destruction of the nucleocapsid allows exposure of core antigen (HBcAg) or e antigen
(HBeAg) with subsequent antibody development.
• Liver enzymes are typically elevated within the latter part of the replicative phase on infection
• Liver transaminases should not be a sole guide to diagnosing suspected hepatitis B infection.
 Differential Diagnosis
• Broad due to the presence of non-specific symptoms • Alcoholic hepatitis
such as fatigue, abdominal pain, nausea, and • Autoimmune hepatitis
vomiting. • Cirrhosis
• Other etiologies of hepatitis (i.e., hepatitis A, • Drug-induced liver injury
hepatitis C, hepatitis E, alcoholic hepatitis, and • Hemochromatosis
autoimmune hepatitis) should be considered • Hepatitis A
• Hepatitis C
• Iron overload (hemochromatosis) can be associated • Hepatitis D
with abdominal tenderness and abnormal liver • Hepatitis E
transaminase levels. • Hepatocellular carcinoma
• Pertinent findings that favor a diagnosis of • Human immunodeficiency virus (HIV)
hemochromatosis compared to hepatitis B include • Wilson disease
diffuse skin discoloration (bronze diabetes) and
impaired glucose tolerance.
• Wilson disease, Laboratory evaluation that favors a
diagnosis of Wilson disease includes low serum
ceruloplasmin levels and elevated urinary copper
 Following groups of people should be screened for
hepatitis B :
• Persons born in high or intermediate endemic • Persons with chronic liver disease and HIV.
areas (HBsAg prevalence of greater than or • Close contacts of HBsAg-positive persons,
equal to 2%). such as household, sexual, or needle-sharing.
• The unvaccinated citizens whose parents were • Persons requesting evaluation or treatment
born in high prevalence areas. for sexually transmitted infections.
• History of illicit intravenous drug use. • Health care workers or public safety workers
• Men who have sex with men. who are at risk for occupational exposure to
blood or blood-contaminated body fluids.
• Persons on immunosuppressive therapy. • Residents and staff at facilities for
• Persons with elevated ALT or AST of unknown developmentally disabled persons.
origin. • Travelers to countries with an intermediate or
• Blood, plasma, organ, tissues, or semen donors. high prevalence of Hepatitis B virus infection.
• Persons with end-stage renal disease. • 19-59-year-old persons with diabetes who
have not been vaccinated for Hepatitis B.
• All pregnant women and infants born to HBsAg-
positive mothers.
 Interpretation of Serologic Markers
• Serologic markers : Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B surface
antigen (anti-HBs), Hepatitis B core Ab (Anti-HBc) IgM, Hepatitis B core Ab (Anti-HBc)
IgG, Hepatitis B e antigen (HBeAg), and Hepatitis B e antibody (anti-HBe).[10]
• HBsAg: Acute infection (less than 6 months) or chronic infection (more than 6 months).
• Anti-HBs: Recovery from acute infection or immunity from vaccination.
• HBeAg: Mostly associated with high viral load.
• Anti-HBe: Low replicative phase.
• Anti-HBc IgM: Acute infection, an only marker present in the window period, can be
present during exacerbation of chronic infection.
• Other markers are: Hepatitis B viral DNA is for detection of viral load.
• Hepatitis B genotype provides input about disease progression and response to
interferons.[11]
 Treatment / Management
• Prevention
• Preventive measures constitute a major component of the management of hepatitis B
(single-antigen hepatitis B vaccines or combination vaccines).
• Management
• Acute hepatitis B infection is self cleared in 95% of healthy adults.
• Management is supportive in a majority of patients.
• Severe acute disease need antiviral treatment.
• Management of chronic hepatitis B should include identification of HIV, hepatitis C, and
hepatitis D coinfection, hepatitis B virus replication status, and severity of the
disease.[10]
• The severity of the disease is based on clinical assessment, blood counts, liver enzymes,
and liver histology.[10]
• While non-invasive tests are useful (blood test, imaging to measure liver stiffness) for
chronic hepatitis B with normal alanine transferase, for patients with elevated or
fluctuating alanine transferase, liver biopsy is necessary to identify if they need antiviral
treatment.[10]
 ANTIVIRAL THERAPY
• FDA-approved medications for chronic hepatitis B include
• interferons (peginterferon alfa-2a, interferon alfa-2b),
• nucleoside analogs (entecavir, lamivudine, telbivudine),
• nucleotide analogs (adefovir, tenofovir).

• Entecavir and tenofovir are preferred for acute HBV infection if treatment is warranted, due to their relatively
higher barrier to resistance.
• Entecavir combination drugs have been developed.
• That entecavir combination drugs were no more effective than entecavir monotherapy.[12]
 Appropriate treatment response is indicated
by the following findings:[10]
• Blood tests: normalization of ALT
• Undetectable hepatitis B viral DNA
• Loss of HBsAg and HBeAg with seroconversion to anti-HBs and anti-
HBe
• Reduced inflammation on liver biopsy with no worsening of fibrosis
 RECOMMENDATION
• The counseling of patients on the prevention of transmission is
extremely valuable.
• Lifestyle modifications include reducing intake of agents with
potential for liver damage such as alcohol, hepatotoxic medications,
herbal medications, and herbal supplements.
• The goals of antiviral therapy are:[10]
• Suppression of hepatitis B virus replication
• Reduction of liver inflammation
• Prevention of progression to liver cirrhosis and hepatocellular carcinoma
Liver Abscess
 Objectives:
• Identify the different methods of classifying a liver abscess.
• Describe clinical symptoms consistent with a liver abscess.
• Explain how to systemically and non-invasively evaluate liver abscess.
 Introduction
• A liver abscess is defined as a pus-filled mass in the liver that can develop from injury to the liver or an
intraabdominal infection disseminated from the portal circulation.
• The majority of these abscesses are categorized into pyogenic or amoebic, although a minority is caused by
parasites and fungi.
• Most amoebic infections are caused by Entamoeba histolytica.
• The pyogenic abscesses are usually polymicrobial, such
as E.coli, Klebsiella, Streptococcus, Staphylococcus, and anaerobes.
• Abscess formation is that there is leakage from the bowel in the abdomen that travels to the liver through
the portal vein.
• Many cases have an infected biliary tract that causes an abscess via direct contact.
• One is by location in the liver. 50% of solitary liver abscesses occur in the right lobe of the liver (a more
significant part with more blood supply), less commonly in the left liver lobe or caudate lobe.
• Another method is by considering the source: If the cause is infectious
• The majority of liver abscesses can be classified into bacterial (including amebic) and parasitic sources
(including hydatiform cyst).
https://www.ncbi.nlm.nih.gov/books/NBK538230/#:~:text=A%20liver%20abscess%20is%20defined,caused%20by%20parasites%20and%20fun
gi.
 Etiology
• Appendicitis used to be the main reason why people develop a liver abscess, but that has decreased to less than 10%
since better diagnosis and management of the disease has become available. Nowadays, biliary tract disease (biliary
stone, strictures, malignancy, and congenital anomalies) are the major causes of pyogenic liver abscesses.
• The most common organisms include E.coli, Klebsiella, Streptococcus, Staphylococcus, and anaerobic organisms but are
generally polymicrobial.
• If strep or staph is isolated solely, the focus should be on finding another source of infection (endocarditis) that has
hematogenously spread to the liver.
• Klebsiella pneumoniae is a prominent etiology in Southeast Asia and is thought to be related to or associated
with colorectal cancer there as well.
• If the source is an anaerobe, the most common organism is Entamoeba histolytica. It affects the liver by first causing
amebic colitis, then seeding the portal system and migrating to the liver and causing an amebic liver abscess.
• Another rare but important parasitic organism is Echinococcus granulosus, which causes a hydatid cyst of the liver.
Infection is caused by the metacestode stage of the tapeworm Echinococcus which is part of the Taeniidae family.
Patients typically present with symptoms that include abdominal pain, diarrhea, and hepatomegaly. Hydatid cysts are
acquired from dogs and can take a while to cause symptoms in the host. Most cases are discovered in the late stages
and incidentally.
 Epidemiology
• The annual incidence rate is about 2.3 cases per 100,000 people.
• Males are more frequently affected.
• People aged 40-60 years are more vulnerable to developing liver
abscess.
• A significant number of liver abscesses are reported to be pyogenic. (Abbas
et al) due to Klebsiella pneumonia.

• The incidence in Taiwan seems to be very high (17.6 per 100,000).

• Pyogenic hepatic abscess constitutes about half of all visceral abscesses
 Pathophysiology
• The liver is developed in the septum transversum, which is enclosed by the ventral
mesentery.
• The liver receives its blood circulation from the systemic and portal circulations, it is
more susceptible to getting infections and abscesses from the bloodstream.
• Proximity to gall bladder is another risk factor for the liver.
• On the other hand, since Kupfer cells surrounding the liver are protective of the
parenchyma, getting infections or abscess formation might not happen that frequently
or as quickly as expected either.
• The usual pathophysiology for pyogenic liver abscesses is bowel content leakage and
peritonitis.
 History and Physical
• Certain risk factors promote the development of liver abscesses, such as diabetes, cirrhosis, male gender,
elderly, immunocompromised states, and people with proton pump inhibitor usage.
• Patients may complain of the following symptoms: fever, chills, night sweats, malaise, nausea or vomiting,
right shoulder pain (due to phrenic nerve irritation), right upper quadrant pain, cough, dyspnea, anorexia, or
recent unexplained weight loss. Fever is present in 90% and abdominal pain in about 50-75% of patients. Dark
urine is present, much like it is present in other forms of hepatitis.
• On physical examination, a patient can have hepatomegaly with an enlarged mass and jaundice. Although
Charcot triad (right upper quadrant pain, jaundice, and fever) is a sign of cholangitis, the physician will need to
consider liver abscess as a differential. A small number of patients with hepatic abscesses may present in
distress or even overt shock (septic shock or anaphylactic shock in the case of the hydatiform mole rupture).
• The usual rate of cyst progression is 1 to 5 centimeters in a year. The liver is affected in two-thirds of cases of
Echinococcus infection. Symptoms of compression usually start when the diameter is 10 cm and include biliary
colic, cholangitis, obstructive jaundice, portal and venous obstruction, Budd-Chiari syndrome, bronchial fistula,
If it ruptures, overt peritonitis or anaphylaxis will be present
 DIAGNOSIS
• Laboratory tests include a complete blood count with differential, tests for hepatocellular injury (liver enzymes that are usually
elevated in half the cases), liver synthetic function tests (Prealbumin and INR), alkaline phosphatase (elevated in around 90% of
patients), C-reactive protein, erythrocyte sedimentation rate, and blood cultures to rule out bacteremia.
• If an amebic abscess is suspected (such as in residents or travelers from Southeast Asia, Africa, etc.), stool test or serology for
Entamoeba histolytica should be performed. Enzyme-linked immunosorbent assay (ELISA) seems to be the most sensitive and specific
for Echinococcus. After initial screening with ELISA, confirmatory tests with immunoelectrophoresis and immunoblotting are needed.
Serology positivity is dependant on the size and site of the cysts.
• The initial test of choice is an abdominal ultrasound (US), which shows hyper or hypoechoic lesions with occasional debris or
septation.
• Computed tomography (CT) with contrast is the next step, and slightly more sensitive.
• The US or CT is followed by needle aspiration under guidance to identify the exact causative organism, which is essential for
diagnostic as well as therapeutic purposes (small cysts).
• Technetium scan is another test with an 80% sensitivity (less than CT), which is 50-80% for gallium and 90% for indium. If inner cyst
walls are in-folded
• Stains and cultures should be obtained from the direct aspirate. Drains that are in place will get contaminated with skin flora and are
not accurate for cultural purposes. Stains and cultures should be done for aerobes and anaerobes (special handling might be
needed), but occasionally more specific cultures need to be done, such as fungi, Mycobacterium, Entamoeba histolytica, and
parasites.
 Treatment / Management
• Drainage of the abscess and antibiotic treatment are the cornerstones of treatment.
• Drainage is needed and can be done under the US or CT. Needle aspiration (at times repeatedly) might be all that is
required for abscesses less than 5 cm, but a catheter placement might be warranted if the diameter is more significant than
that.
• Laparoscopic drainage is also used at times.
• Surgery should be done for peritonitis, thick wall abscesses, ruptured abscess, multiple large abscesses, and previously
failed drainage procedures.
• When previous biliary procedures have been done, endoscopic retrograde cholangiopancreatography (ERCP) drainage
might be used. Undrained liver abscesses may cause sepsis, peritonitis, and empyema.
• Empiric antibiotic coverage is essential when the organism is unknown. The antibiotics should cover Enterobacteriaceae,
anaerobes, streptococci, enterococci, and Entamoeba histolytica.
• Such antibiotic regimens include cephalosporins plus metronidazole, Beta-lactam Beta-Lactamase inhibitor plus
metronidazole, or synthetic penicillins plus aminoglycosides and metronidazole. Alternatively, fluoroquinolones or
carbapenems can be substituted for cephalosporins or penicillins in case of allergy or unavailability.
• Metronidazole should cover Entamoeba histolytica. The duration of treatment varies but is usually from two to six weeks.
After initial intravenous treatment, the oral route can be used safely in most cases to complete the course.
• Culture results help narrow down the organism, so empiric treatment is no longer needed, as it can lead to antibiotic
resistance.
• Empiric antifungal treatment is crucial in immunosuppressed patients with a risk for chronic disseminated fungemia.
 Differential Diagnosis
• Liver abscess manifests with right upper quadrant pain, fever, and
hepatitis. Therefore many liver and non-liver ailments are in its
differential diagnoses, such as:
• Viral hepatitis
• Cholecystitis
• Cholangitis
• Right lower lobe pneumonia
• Appendicitis
• Necrotic liver masses
• Other causes of hepatitis such as autoimmune, drug-induced and
acetaminophen toxicity can be mistaken although they are usually not
painful.
CHRONIC LIVER DISEASE
(CLD)
 Objectives:
• Identify the etiology of chronic liver disease.
• Outline the appropriate evaluation of chronic liver disease.
• Review the treatment options available for chronic liver disease.

https://www.ncbi.nlm.nih.gov/books/NBK554597/
 Introduction
• Progressive deterioration of liver functions for more than six months, which includes
synthesis of clotting factors, other proteins, detoxification of harmful products of
metabolism, and excretion of bile.
• CLD is a continuous process of inflammation, destruction, and regeneration of liver
parenchyma, which leads to fibrosis and cirrhosis.
• The spectrum of etiologies is broad for chronic liver disease, which includes toxins, alcohol
abuse for a prolonged time, infection, autoimmune diseases, genetic and metabolic
disorders.
• Cirrhosis is a final stage of chronic liver disease that results in disruption of liver
architecture, the formation of widespread nodules, vascular reorganization, neo-
angiogenesis, and deposition of an extracellular matrix.
• The underlying mechanism of fibrosis and cirrhosis at a cellular level is the recruitment of
stellate cells and fibroblasts, resulting in fibrosis, while parenchymal regeneration relies on
hepatic stem cells.
 Etiology
• Alcoholic Liver Disease
• Alcoholic liver disease is a spectrum of disease which includes alcoholic fatty liver with or without hepatitis,
alcohol hepatitis (reversible because of acute ingestion) to cirrhosis (irreversible). Patients with severe
alcohol use disorder mostly develop chronic liver disease; this is the most frequent cause of CLD.
• Non-alcoholic Fatty Liver Disease (NAFLD/NASH)
• NAFLD has an association with metabolic syndrome (obesity, hyperlipidemia, and diabetes mellitus). Some
of these patients develop non-alcoholic steatohepatitis, which leads to fibrosis of the liver. All the risk
factors of metabolic syndrome can aggravate the disease process.
• Chronic Viral Hepatitis
• Chronic hepatitis B, C, and D infections are the most common causes of chronic liver disease in East Asia and
Sub-Saharan Africa. There are various genotypes of hepatitis C. In Europe and North America, genotype 1a
and 1b are more prevalent, while in Southeast Asia, genotype 3 is more common. A molecular
epidemiological study revealed a high prevalence of HCV genotype 4, subtype 4a among Egyptian patients
living in Sharkia governorate, Egypt. Chronic hepatitis C, if not treated, may lead to hepatocellular
carcinoma.
Cont….
• Genetic Causes :
• Alpha-1 antitrypsin deficiency:
• Hereditary hemochromatosis:
• Wilson disease:
• Autoimmune Causes :
• Autoimmune hepatitis is a rare disease in which there is the destruction of liver parenchyma by
autoantibodies. Most of the patients who present with this disease have already developed
cirrhosis. Females are more commonly affected than males.
• Primary biliary cirrhosis (PBC)
• Primary Sclerosing Cholangitis (PSC)
• Autoimmune hepatitis (AIH)
• Other Causes of Chronic Liver Disease
• Drugs - amiodarone, isoniazid, methotrexate, phenytoin, nitrofurantoin.
• Vascular. Budd-Chiari syndrome.
• Idiopathic/cryptogenic, around 15%
 Epidemiology
• Chronic liver disease is one of the frequent causes of death, especially
in the developing world.
• The increasing prevalence of chronic liver disease has been noted in
recent times.
• The majority of chronic liver diseases in the developed world include
alcoholic liver disease, chronic viral hepatitis, including hepatitis B and
C, non-alcoholic fatty liver disease (NAFLD), and hemochromatosis.
 Pathophysiology
• Chronic liver disease represents a continuous and progressive process of hepatic fibrosis, liver tissue
architectural distortion, and regeneration nodule formation. While fibrosis is usually irreversible, but it
can be reversible in the initial stage of development. The transition time point of reversible fibrosis to
irreversible fibrosis is still not completely understood.
• In chronic liver disease, if not treated, the endpoint is usually irreversible fibrosis, regeneration nodule
formation, and development of cirrhosis liver. The development rate of fibrosis is dependent on the
underlying etiologies, environmental, and host factors.
• Hepatic fibrosis is the deposition of extracellular matrix (ECM) in response to chronic liver injury by any
etiology. The common pathway is initiated by hepatic stellate cells (HSC), which usually are vitamin A
storing dormant cells found in space between sinusoids and hepatocytes.
• In response to chronic liver injury, HSC gets activated into proliferative fibrogenic myofibroblast and
upregulates the expression of inflammatory receptors such as chemokine receptors, ICAM-1, and other
inflammatory mediators by releasing chemokines and other leukocyte chemoattractants.
• The pro-inflammatory phase or initiation phase also changes gene and phenotypic expression of the liver
cells, making them more responsive to these inflammatory cytokines, and perpetuation of activated HSC
cells results in the accumulation of ECM and progressive fibrosis.
Etiology & Complications of cirrhosis

http://www.pathophys.org/cirrhosis/
Pathophysiology
of acute-on-
chronic liver
failure (ACLF)

https://europepmc.org/article/pmc/pmc5548989
 History and Physical
• Clinical Manifestations
Signs and symptoms of CLD can be nonspecific, such as fatigue, anorexia, weight loss, or depend upon the complication
that the patient has developed.
• The three significant complications are because of portal hypertension (esophageal varices,
ascites), hepatocellular insufficiency (e.g., jaundice, hepatic encephalopathy), and
hepatocellular carcinoma.
• Portal Hypertension
• Portal hypertension is a result of resistance to portal blood flow because of cirrhotic and noncirrhotic etiology. A portal venous pressure above seven mmHg is
considered portal hypertension; however, clinical features or complications do not develop until portal pressure is higher than 12 mmHg. Portal hypertension causes can
divide into prehepatic (e.g., portal vein thrombosis), hepatic (e.g., cirrhosis), and post hepatic (e.g., Budd Chiari syndrome). Cirrhosis and hepatic schistosomiasis remain
the most common cause of portal hypertension, with cirrhosis being more common in developed countries. The following are the consequences of long-standing portal
hypertension.
➢ Esophageal varices:
It presents with melena or upper GI bleed. Cirrhosis of the liver leads to raised portal pressure, which can cause esophageal or gastric varices. Esophageal variceal bleeding is the most
common life-threatening complication of CLD.
➢ Caput medusae
➢ Rectal hemorrhoids
➢ Ascites:
It is an accumulation of fluid in the peritoneal cavity because of raised portal pressure (increased hydrostatic pressure), decreased albumin (reduced oncotic pressure), and splanchnic
vasodilation (due to the release of nitric oxide). Most of the patients develop ascites in the later stages of cirrhosis. Clinical findings in such patients are abdominal distension, shifting
dullness, and a fluid wave. Tense ascites can lead to shortness of breath or early satiety.
➢ Spontaneous Bacterial Peritonitis (SBP)

It is one of the acute and painful complications of chronic liver disease. Bacteria (E. coli, Klebsiella, Streptococcus pneumonia) seep through the gastrointestinal tract and infect the ascitic
fluid. The infection spread through the fluid to the peritoneal membrane, causing inflammation. SBP presents with fever, generalized abdominal pain, tenderness, and absent bowel sounds.
According to AASLD guidelines, depending upon the severity of
the disease, there are different grades of hepatic
encephalopathy
• Grade 0/Minimal: Subclinical, normal mental status with minimal changes in
memory, coordination, intellectual function, concentration.
• Grade 1: Trivial lack of awareness, euphoria or anxiety, shortened attention span,
impairment of addition or subtraction, altered sleep rhythm.
• Grade 2: Lethargy or apathy, disorientation to time, personality change,
inappropriate behavior, dyspraxia, asterixis.
• Grade 3: Somnolence to semi-stupor, responsive to stimuli, confused, gross
disorientation, bizarre behavior.
• Grade 4: Coma
The patient can present in any of these symptoms. Most of the patients with
hepatic encephalopathy present with altered sensorium. Infections, GI bleed,
hyperkalemia, TIPS, sedating agents, and alkalosis can aggravate hepatic
encephalopathy.
Cont…
• Hepatocellular Insufficiency
• Hepatic Encephalopathy
This is a neuropsychiatric syndrome caused by hepatic dysfunction. Detoxification of harmful products of metabolism, e.g.,
ammonia, occurs in the liver. In a patient with cirrhosis, the removal of these substances from the body is impaired, leading
to an increased level of ammonia. Raised levels of ammonia can impair consciousness. Almost 50% of patients with DCLD can
develop hepatic encephalopathy.
According to AASLD guidelines, depending upon the severity of the disease, there are different grades of hepatic
encephalopathy.
• Jaundice
Jaundice is a yellowish discoloration of the eyes, skin, and mucous membrane because of overproduction or under clearance
of bilirubin. Metabolism of hemoglobin or myoglobin produces bilirubin in the spleen. Bilirubin then circulates in the body,
bound to albumin. The liver dissociates this complex and converts unconjugated bilirubin to conjugated bilirubin. Jaundice is
clinically visible when total bilirubin is greater than 2 mg/dl. As in chronic liver disease, there is the destruction of liver
parenchyma, and it does not conjugate bilirubin, which deposits in various tissues of the body. There is pruritus because of
the accumulation of bile salts.
• Hyperestrinism
In chronic liver disease, the catabolism of estrogen becomes impaired, resulting in excess estrogen in the body. This
manifests as palmar erythema, spider angiomas (dilated cutaneous arterioles with a central red spot and red extensions that
radiate outward like a spider's web in the territory of SVC), gynecomastia (enlarged tender subareolar tissue), and testicular
atrophy.
Cont….
• Hepatorenal Syndrome (HRS)
Hepatorenal syndrome is a functional renal failure as kidneys are normal, where there
is a gradual loss of renal function. It is a diagnosis of exclusion. Vasoconstrictors are
released in CLD, which is responsible for the narrowing of renal vessels. The following
criteria have been described:
• Chronic liver disease with portal hypertension or advanced liver failure
• Continuous rising in creatinine, usually more than 0.3 mg/dl within 48 hours or doubling from
baseline within seven days.
• Oliguria with the absence or minimal proteinuria
• Urine sodium less than 10 meq/L
• Failure to improve with volume expansion and stopping the diuretics.
• Absence of shock
• No recent use of the nephrotoxic drug
• Absence of renal parenchymal disease
Cont….
• Coagulopathy
The liver produces clotting factors, so the patients with CLD have
coagulopathies and manifest or contribute to easy bruising and
bleeding per gastrointestinal tracts. Hence, PT/INR (intrinsic pathway)
and APTT (extrinsic pathways) are prolonged.
 DIAGNOSIS
• The diagnosis of chronic liver disease depends upon the etiology and complications of
the disease. An outline regarding the diagnosis for various CLD appears below.
• Viral hepatitis B and C: Serology, PCR (quantitative and qualitative) with genotype
• Alcoholic liver disease: Elevated levels of AST>ALT with a history of chronic alcohol
intake. Usually, AST: ALT ratio is 2 to 1 in alcoholic liver disease.
• Non-alcoholic fatty liver disease: Diagnosis of exclusion and ALT>AST. Ultrasonography of
the liver is informative.
• Autoimmune hepatitis: Raised ANA, ASMA, and LKM-1
• Alpha 1 antitrypsin deficiency: Decreased levels of alpha one antitrypsin
• Primary biliary cirrhosis: Markedly raised alkaline phosphatase levels with an
antimitochondrial antibody
• Budd-Chiari and veno-occlusive disease: CBC, clotting profile, and imaging studies like
ultrasound doppler or computed tomography with contrast study
 Laboratory Findings
• In chronic liver disease, there is inflammation and destruction of hepatocytes that leads to the release of aspartate
aminotransferase (AST) and alanine aminotransferase (ALT), hence the high levels of these markers in the blood. Other
parameters (ALP and GGT) of LFTs also appear elevated in cholestatic conditions like PBC. AST and ALT are usually elevated
two to three times of normal limit, but normal levels of these markers do not rule out cirrhosis. As in compensated CLD LFTs
may be normal in cirrhosis. Bilirubin (unconjugated> conjugated) levels are elevated in jaundice. There is reduced
production of clotting factors leading to raised PT/INR and APTT.
• Because of hepatocellular insufficiency in cirrhosis, albumin level drops, and ammonia raises, causing ascites and hepatic
encephalopathy. The increased concentration of ammonia, tryptophan metabolites, short-chain fatty acids, octopamine,
mercaptans, increased oxidative stress, and increase intracellular osmolality are among many which have been proposed as
the mechanism of developing hepatic encephalopathy. In the case of ascites, diagnostic paracentesis is an investigation of
choice to see whether ascites are because of raised portal pressure or another cause. By doing a biochemical and cytological
analysis of ascitic fluid, we calculate the serum ascites albumin gradient (serum albumin-ascitic fluid albumin). If this
gradient is greater than 1.1, then portal hypertension is a likely cause, but if it is less than 1.1, portal hypertension is unlikely.
WBC greater than 500/microliter or PMN greater than 250/microliter and fluid cultures will be positive in patients with
SBP. Ultrasound of the abdomen and serum AFP levels can help diagnose the presence of hepatocellular carcinoma. In
hepatorenal syndrome, creatinine usually is elevated to more than1.5 g/dl. Thrombocytopenia is an indirect measure of
splenomegaly, which occurs in CLD because of raised portal pressure.
 Cont…
• Radiologic Investigations
It includes an abdominal ultrasound, CT scan, fibro scan, hepatic wedge pressure, endoscopy, EEG, TIPS, triphasic CT, and Doppler scan.

• Ultrasound abdomen
is one of the most common and affordable imaging studies in the case of chronic liver disease. Ultrasound detects the size, echogenicity nodularity of the liver, thereby diagnosing liver cirrhosis.
Other benefits of ultrasound in CLD include measurement of portal vein diameter as portal vein diameter increases in portal HTN and assessment of a clot in the hepatic vein (Budd-Chari) and portal
vein in portal vein thrombosis.

• Computed tomography
scan can show a lesion in the liver or obstruction of biliary channels in a more precise way, but triphasic CT is the test of choice in diagnosing hepatocellular carcinoma.

• Transient elastography (TE)

detects early stages of cirrhosis. It can also detect cardiovascular damage in patients with NAFLD.[15] It works on two physical principles; strain displacement and shear wave imaging and
quantification. The latter includes point shear wave elastography. It measures the velocity of low frequency (50 Hz) elastic shear waves propagating through the liver. The stiffer the tissue, the faster
the elastic shear wave propagates. It can easily work on an ultrasound machine. According to the European association of study for the Liver (EASL), TE is the most effective approach to diagnose
cirrhosis in chronic liver disease.

• Wedge hepatic venous pressure measures portal venous pressure in CLD.

• Doppler scan can help in diagnosing Budd-Chiari and portal vein thrombosis.
• EEG shows delta waves in hepatic encephalopathy.
• An upper endoscopy can diagnose and treat esophageal varices. On endoscopy, we can measure the size of varices.
Small varices are less than 5 mm, and large varices are greater than 5 mm.
• A liver biopsy can confirm the diagnosis of chronic liver disease. Various techniques to perform a liver biopsy are by
laparoscope, transjugular, or percutaneously.
 Treatment / Management
• Treatment and Prophylaxis
• The treatment goal is to stop the progression of the disease and complications and require a multidisciplinary approach. The principle of management is
mainly underlying cause correction, Portal hypertension management, and specific treatments for individual disease. A brief outline regarding treatment
for various CLD and related complications is given below. For more comprehensive details, please see individual topics in the Statpearls glossary.

• General Management
• Patients with chronic liver disease mostly present with one of the complications.
• Esophageal varices - Varices related bleeding are one of the deadly complications, and the treatment includes aggressive fluid resuscitation, vasopressors
(octreotide, terlipressin), and endoscopy. Endoscopic band ligation and injection sclerotherapy are the usual modalities to treat variceal bleed in an
emergency. In some patients, early transjugular intrahepatic portosystemic shunt (TIPS) can increase the survival rate. Propranolol is used for primary and
secondary prophylaxis for esophageal varices. Diuretics (furosemide, spironolactone) and sodium restriction are essential treatment options for ascites.
For tense ascites, therapeutic paracentesis is done. Albumin infusion can also be considered. Initially, broad-spectrum antibiotics are the treatment of
choice for SBP and then specific antibiotics after culture.
• Hepatic encephalopathy - The basic principle of treatment is to address the precipitating factors. Patients with hepatic encephalopathy usually improve
with precipitating cause correction along with rifaximin and lactulose. Lactulose acts by converting ammonia to ammonium ions and decreases its
absorption from the gastrointestinal tract. Lactulose also relieves constipation through its osmotic effect, which further helps to ease the symptoms of
hepatic encephalopathy. Rifaximin is used to decrease ammonia production by gut flora. Liver transplant is a curative treatment in patients with
hepatorenal syndrome.
• Hepatorenal syndrome - HRS based on severity divided into two categories. HRS 1 is more severe compared to HRS 2 (less severe). The primary goal is to
correct underlying cause correction to reverse acute kidney injury. Treatment modalities depend on the severity and location of the patient. Treatment
modalities include norepinephrine or terlipressin with albumin infusion or midodrine, octreotide with albumin infusion. TIPS procedure in some patients
can help and liver transplantation the only definite treatment in the patient who fails to respond to all other treatments.
• Hepatocellular carcinoma (HCC) - Treatment is based on the Barcelona clinic liver cancer staging system in the management of HCC:
• Initial stage (single HCC lesion): Resection and ablation.
• Intermediate stage: Transarterial chemoembolization and radio-embolization.
• Metastatic disease: Sorafenib
Differential Diagnosis Staging
• Constrictive pericarditis • Stages of liver disease
• Cor-pulmonale • Hepatitis or steatosis or
• Dilated cardiomyopathy hepatosteatosis
• Inferior vena cava thrombosis • Fibrosis
• Nodular regenerative • Cirrhosis
hyperplasia • Hepatocellular carcinoma (HCC)
• Sarcoidosis
• Schistosomiasis
Thank you - どうも有難うございます