3 The kidneys

Renal glomerular function 37 Nephritic syndrome 49

Renal tubular function 37 Diagnosis of renal dysfunction 49
Water reabsorption: urinary concentration and dilution 38 Urinary sodium and osmolality 52
Biochemistry of renal disorders 42 Biochemical principles of the treatment of renal
Syndromes reflecting predominant tubular damage – dysfunction 53
renal tubular acidosis 49 Renal calculi 54
Nephrotic syndrome 49

In this chapter kidney function and how it can be membranes into the glomerular spaces (Bowman’s
altered in disease states is discussed. It is best read in capsules).
conjunction with Chapters 2, 4 and 5. Interpretation The proximal convoluted tubules, also in the cortex,
of renal function tests is also discussed. receive filtrate from the glomerular spaces. Convolution
The kidneys excrete metabolic waste products, increases the tubular length and therefore contact
and have an essential homeostatic function in that between the luminal fluid and the proximal tubular
they control the body solute and water status and cells.
the acid–base balance. There are about one million The loops of Henle extend down into the renal
nephrons per kidney, each of which is made up of medulla and ascend again after forming the loop.
five main functional segments (Fig. 3.1). The distal convoluted tubules, situated in the
The glomeruli, in the cortex of the kidney, are cortex, are important for fine adjustment of luminal
invaginated and surround a capillary network of fluid. They lie near the afferent arterioles, with the
blood vessels derived from the afferent, and draining juxtaglomerular apparatus between them. The enzyme
into the efferent, arterioles. Small molecules and renin is produced by the latter and its release is
water are passively filtered during the passage of controlled by local blood flow.
blood through these capillaries, the ultrafiltrate The collecting ducts start as the distal tubules lead
passing through the vessel walls and the glomerular down into the medulla and end by opening into the

Efferent arteriole
Glomerulus
Juxtaglomerular
apparatus
Distal tubule
Afferent arteriole
Proximal tubule

CORTEX

MEDULLA

Loop of Henle Collecting duct

Figure 3.1 The anatomical relation between the nephron and the juxtaglomerular apparatus.
 Renal tubular function 37

renal pelvis. The modified fluid from the original filtrate The filtrate contains diffusible constituents at
flows from the collecting ducts into the renal tract. almost the same concentrations as in plasma. About
Normal function of the kidneys depends on the 30 000 mmol of sodium, 800 mmol of potassium,
following: 800 mmol of urea, 300 mmol of free ionized calcium
and 1000 mmol of glucose are filtered daily. Proteins
● an adequate blood supply, which under normal
(mainly low-molecular-weight proteins) and protein-
circumstances is about 20 per cent of the cardiac
bound substances are filtered in only small amounts by
output, flowing through the kidneys,
normal glomeruli and most are reabsorbed. The huge
● normal secretion and feedback control of hormones
volume of filtrate allows adequate elimination of waste
acting on the kidney,
products such as urea; death from water and electrolyte
● the integrity of the glomeruli and the tubular cells.
depletion would occur within a few hours were the bulk
In addition to the excretory function and acid– of this water containing essential solutes not reclaimed.
base control, the kidneys have important endocrine
functions, including: RENAL TUBULAR FUNCTION

● production of 1,25-dihydroxyvitamin D, the active Changes in filtration rate alter the total amount of water
metabolite of vitamin D, which is produced following and solute filtered, but not the composition of the filtrate.
hepatic hydroxylation of 25-hydroxyvitamin by the From the 200 L of plasma filtered daily, only about 2 L
renal enzyme 1-hydroxylase, of urine are formed. The composition of urine differs
● production of erythropoietin, which stimulates markedly from that of plasma, and therefore of the
erythropoiesis. filtrate. The tubular cells use adenosine triphosphate-
dependent active transport, sometimes selectively, against
RENAL GLOMERULAR FUNCTION physicochemical gradients. Transport of charged ions
About 200 L of plasma ultrafiltrate usually enter the tends to produce an electrochemical gradient that inhibits
tubular lumina daily, mainly by glomerular filtration further transport. This is minimized by two processes.
into glomerular capsules but also through the spaces Isosmotic transport This occurs mainly in the
between cells lining the tubules (tight junctions). proximal tubules and reclaims the bulk of filtered
Production of ultrafiltrate depends on the blood essential constituents. Active transport of one ion leads
flow through normal glomeruli and on the difference to passive movement of an ion of the opposite charge in
between the hydrostatic pressure gradient and the the same direction, along the electrochemical gradient.
plasma effective colloid osmotic (oncotic) pressure The movement of sodium (Na+) depends on the
gradient across the membranes (Fig. 3.2) and tight availability of diffusible negatively charged ions, such
junctions. The colloid osmotic effect is weak relative as chloride (Cl–). The process is ‘isosmotic’ because the
to the hydrostatic gradient but does facilitate some active transport of solute causes equivalent movement
reabsorption of fluid from the proximal renal tubules. of water reabsorption in the same direction. Isosmotic
transport also occurs to a lesser extent in the distal part
of the nephron.
Ion exchange This occurs mainly in the more
Afferent Efferent
arteriole arteriole distal parts of the nephrons and is important for fine
adjustment after bulk reabsorption has taken place.
Ions of the same charge, usually cations, are exchanged
Blood
flow and neither electrochemical nor osmotic gradients are
created.
COLLOID Therefore, during cation exchange there is
OSMOTIC insignificant net movement of anions or water. For
HYDROSTATIC PRESSURE
PRESSURE example, Na+ may be reabsorbed in exchange for
Bowman’s potassium (K+) or hydrogen (H+) ions. Na+ and H+
capsule exchange also occurs proximally, but at that site it is
Figure 3.2 The relationship between flow of blood through more important for bicarbonate reclamation than for
the glomerulus and the factors that affect the rate of fine adjustment of solute reabsorption (see Chapter 4).
filtration across the glomerular basement membrane. In the cells lining the renal tubules, the intestine and
38 The kidneys

many secretory organs, the pumps are located on the to produce this gradient (see also Chapter 2). Two main
membrane on one side of the cell only and therefore processes are involved in water reabsorption:
solute flows in one direction.
● Isosmotic reabsorption of water from the proximal
Other substances, such as phosphate and urate, are
tubules. The nephrons reabsorb 99 per cent of the
secreted into, as well as reabsorbed from, the tubular
filtered water, about 70–80 per cent (140–160 L/day)
lumen. The tubular cells do not deal actively with waste
of which is returned to the body from the proximal
products such as urea and creatinine to any significant
tubules. Active solute reabsorption from the filtrate
degree. Most filtered urea is passed in urine (which
is accompanied by passive reabsorption of an
accounts for most of the urine’s osmolality), but some
osmotically equivalent amount of water. Therefore,
diffuses back passively from the collecting ducts with
fluid entering the lumina of the loops of Henle,
water; by contrast, some creatinine is secreted into the
although much reduced in volume, is still almost
tubular lumen.
isosmotic.
Reclamation of solute from the proximal ● Dissociation of water reabsorption from that of
tubule solute in the loops of Henle, distal tubules and
Almost all the potassium is actively reabsorbed from collecting ducts. Normally between 40 and 60 L of
the proximal tubules, as is more than 70 per cent water enter the loops of Henle daily. This volume
of the filtered sodium, free ionized calcium and is reduced to about 2 L as varying amounts of
magnesium. Some free ionized calcium is reabsorbed water are reabsorbed, helping to correct for
at more distal sites, possibly from the loops of Henle. changes in extracellular osmolality. At extremes
This reabsorption may be stimulated by parathyroid of water intake, urinary osmolality can vary from
hormone (PTH) and inhibited by loop diuretics such about 40 to 1400 mmol/kg. The proximal tubules
as furosemide. Only about 2 per cent of filtered calcium cannot dissociate water and solute reabsorption,
appears in the urine. and the adjustment must occur between the
Many inorganic anions follow an electrochemical end of the proximal tubule and the end of the
gradient; the reabsorption of sodium is limited by the collecting duct.
availability of chloride, the most abundant diffusible Two mechanisms are involved:
anion in the filtrate. Bicarbonate is almost completely
recovered following exchange of sodium and hydrogen ● Countercurrent multiplication is an active process
ions (see Chapters 2 and 4). Specific active transport occurring in the loops of Henle, whereby a high
mechanisms result in the almost complete reabsorption osmolality is created in the renal medulla and
of glucose, urate and amino acids. Some urate is secreted urinary osmolality is reduced. This can occur in the
into the lumina, mainly in the proximal tubules, but absence of antidiuretic hormone (ADH), also called
most of this is reabsorbed. arginine vasopressin or vasopressin, and a dilute
Phosphate reabsorption is incomplete; phosphate hypo-osmolal urine is produced.
in tubular fluid is important for buffering hydrogen ● Countercurrent exchange is a passive process,
ions. Inhibition of phosphate reabsorption by PTH occurring only in the presence of ADH. Water
occurs in both the proximal and the distal convoluted without solute is reabsorbed from the collecting
tubules, and accounts for the hypophosphataemia of ducts into the ascending vasa recta along the osmotic
PTH excess. Thus almost all the reusable nutrients and gradient created by countercurrent multiplication
the bulk of electrolytes are reclaimed from the proximal and by the high osmolality in the medulla, producing
tubules, with fine homeostatic adjustment taking place a concentrated urine.
more distally. Almost all the filtered metabolic waste
products, such as urea and creatinine, which cannot be Countercurrent multiplication
reused by the body, remain in the luminal fluid. This occurs in the loops of Henle. It depends on the
close apposition of the descending and ascending
WATER REABSORPTION: URINARY limbs of the loops to the vasa recta. The vasa recta
CONCENTRATION AND DILUTION make up a capillary network derived from the efferent
Water is always reabsorbed passively along an osmotic arterioles and, like the loops of Henle, pass deep into
gradient. However, active solute transport is necessary the medulla.
 Water reabsorption: urinary concentration and dilution 39

The descending limbs are permeable to water but the the loops and the adjacent medullary tissue would be
thick ascending limbs are impermeable to water and about 300 mmol/kg (Fig. 3.3a).
solute. Chloride is actively pumped from the thick Suppose the fluid column remained stationary and
ascending to the descending limbs as fluid flows through 1 mmol of solute per kilogram were pumped from the
the lumina of the loops; positively charged sodium ions ascending into the descending limb, the result would be
follow along the electrochemical gradient. Thus, the as in Figure 3.3b. If this pumping continued and there
osmolality progressively increases in the descending were no flow, the fluid in the descending limb would
limbs and renal medullary interstitium; it decreases in become hyperosmolal and that in the ascending limb
the ascending limbs, but, as these are impermeable to correspondingly hypo-osmolal.
water, this change is not transmitted to the interstitium. Suppose that the fluid flowed so that each figure ‘moved
The almost isosmolal fluid enters the descending limbs two places’ (Fig. 3.3c). As this happened, more solute
having the same osmolality as the plasma, just under would be pumped from the ascending to the descending
300 mmol/kg. If the fluid in the loops was stationary and limbs (Fig. 3.3d). If the fluid again flowed ‘two places’, the
no pumping had taken place, the osmolality throughout situation would be as shown in Figure 3.3e.

D A D A
Cortex Impermeable Cortex
300 300 to water 300 300

Medulla
300 300
Medulla
301 ¨ 299
300 300 301 ¨ 299
300 300 301 ¨ 299
300 300 301 ¨ 299
300 300 301 ¨ 299

(a) (b)

D A D A
Cortex Cortex
300 299 300 299

Medulla
300 299
Medulla
301 ¨ 298
300 299 301 ¨ 298
301 299 302 ¨ 298
301 301 302 ¨ 300
301 301 302 ¨ 300

(c) (d)

D A D A
Cortex Cortex
300 298 300 200

300 298 300 200

Medulla Medulla
300 300 550 475

301 300 800 750

301 302 1050 1025

302 302 1300 1300

(e) (f)

Figure 3.3 The renal counter-regulatory system. D, descending loop of Henle; A, ascending loop of Henle.
40 The kidneys

If these steps occurred simultaneously and then moves passively along the osmotic gradient
continuously, the consequences would be as follows: created by multiplication. Consequently luminal fluid
is concentrated as the collecting ducts pass into the
● Increasing osmolality in the tips of the loops of
increasingly hyperosmolal medulla.
Henle Because the walls of most of the loops are
The increasing concentration of the fluid would
permeable to water and solute, osmotic equilibrium
reduce the osmotic gradient as it passes down the
would be reached with the surrounding tissues in the
ducts if it did not meet even more concentrated plasma
deeper layers of the medulla, including the plasma
flowing in the opposite (countercurrent) direction.
within the vasa recta.
The gradient is thus maintained, and water continues
● Hypo-osmolal fluid leaving the ascending limbs
to be reabsorbed until the fluid reaches the deepest
(Fig. 3.3f) In the absence of ADH, the walls of the
layers, where the osmolality is about four or five times
collecting ducts are impermeable to water, and
that of plasma (Fig. 3.3f). The low capillary hydrostatic
therefore no further change in osmolality occurs,
pressure at this site and the osmotic effect of plasma
and hypo-osmolal urine would be passed.
proteins ensure that much of the reabsorbed water
within the interstitium enters the vascular lumina.
Countercurrent exchange (Fig. 3.4) The diluted blood is carried towards the cortex and
Countercurrent exchange is essential, together ultimately enters the general circulation and helps to
with multiplication, for regulating the osmolal dilute the extracellular fluid.
concentration of urine. It can only occur in the presence The osmotic action of urea in the medullary
of ADH and depends on the ‘random’ apposition interstitium may potentiate the countercurrent
of the collecting ducts and the ascending vasa recta. multiplication. As water is reabsorbed from the
Antidiuretic hormone increases the permeability of collecting ducts under the influence of ADH, the
the cell membranes (via the aquaporins) lining the luminal urea concentration increases. Because the distal
distal parts of the collecting ducts to water, which collecting ducts are permeable to urea, it enters the

Afferent blood Loop of Henle Efferent blood

to vasa recta from vasa recta
Site of


MULTIPLICATION
Urine from


Isosmotic zone


proximal tubule



  



 
Distal tubule




 

  

 Ascending vessel


+ –
NaCl Increasing
osmolality


Descending vessel


 
H2O


+ – 
NaCl 

H2O


Site of action of


+ –
  ADH EXCHANGE
NaCl 

H2O
 

Collecting duct

  To renal pelvis
  Hyperosmotic zone


Connecting capillary

Blood
 Direction of flow of blood or urine
Direction of movement of solute (multiplication)


Direction of movement of water (exchange)



Figure 3.4 The countercurrent mechanism, showing the relationship between the renal tubules and the vasa
recta. ADH, antidiuretic hormone.
 Water reabsorption: urinary concentration and dilution 41

deeper layers of the medullary interstitium, increasing Thus, not only is more water than usual lost in the
the osmolality and drawing water from the lower parts urine, more solute is ‘reclaimed’. Because medullary
of the descending limbs of the loops. The amount of hyperosmolality, and therefore the ability to concentrate
urea reabsorbed depends on: the urine maximally, is dependent on medullary blood
flow, under normal circumstances urinary osmolality
● the amount filtered,
will be fully restored only several days after a prolonged
● the rate of flow of tubular fluid: as much as
water load has stopped (see Chapter 2).
50 per cent of filtered urea may be reabsorbed when
flow is significantly reduced. Osmotic diuresis
In summary, both concentration and dilution An excess of filtered solute in the proximal tubular
of urine depend on active processes, which may be lumina impairs the bulk water reabsorption from
impaired if tubules are damaged. this site by its osmotic effect. Unabsorbed solute
concentration rises progressively as water is reabsorbed
Renal homeostatic control of water excretion with other solute during passage through the proximal
In this section, the mechanisms involved in the normal tubules, and this opposes further water reabsorption.
homeostatic control of urinary water excretion in Thus a larger volume than usual reaches the loops of
the extremes of water intake are discussed. It may be Henle. Moreover, fluid leaving the proximal tubules,
helpful to read it in conjunction with Chapter 2, which although still isosmotic with plasma, has a lower
deals with sodium and water balance. sodium concentration than plasma. The relative lack
of the major cation (sodium) to accompany the anion
Water restriction chloride along the electrochemical gradient inhibits
By increasing the plasma osmolality, water restriction the pump in the loops. The resulting impairment of
increases ADH secretion and allows countercurrent build-up of medullary osmolality inhibits distal water
exchange with enhanced water reabsorption. Reduced reabsorption, under the influence of ADH from the
circulatory volume results in a sluggish blood flow in the collecting ducts, resulting in a diuresis (see Chapter 2).
vasa recta and increased urea reabsorption, allowing a Normally most filtered water leaves the proximal
build-up of the medullary hyperosmolality produced by tubular lumina with reabsorbed solute. For example,
multiplication. This potentiates water reabsorption in glucose (with an active transport system) and urea
the presence of ADH. The reduced capillary hydrostatic (which diffuses back passively) are sometimes filtered
pressure and increased colloid osmotic pressure, due to at high enough concentration to exceed the proximal
the haemoconcentration following non-protein fluid tubular reabsorptive capacity. They can then act as
loss, ensure that much of the reabsorbed water enters osmotic diuretics and cause water depletion. This
the vascular compartment. is important, for example, in diabetes mellitus or in
uraemia.
Water load The most effective osmotic diuretics are substances
A high water intake dilutes the extracellular fluid, and that cannot cross cell membranes to any significant
the consequent fall in plasma osmolality reduces ADH degree; therefore, they must be infused, as they cannot
secretion. The walls of the collecting ducts therefore be absorbed from the gut. One example is mannitol, a
remain impermeable to water and the countercurrent sugar alcohol, which is sometimes used therapeutically
multiplication produces a dilute urine and a high as a diuretic.
osmolality within the medulla and medullary vessels.
Blood from the latter flows into the general circulation, Homeostatic solute adjustment in the distal
so helping to correct the fall in systemic osmolality. tubule and collecting duct
During maximal water diuresis the osmolality at Sodium reabsorption in exchange for hydrogen ions
the tips of the medullary loops may be 600 mmol/kg occurs throughout the nephrons. In the proximal
or less, rather than the maximum of about 1400 mmol/ tubules the main effect of this exchange is on
kg. Increasing the circulating volume increases renal reclamation of filtered bicarbonate. In the distal
blood flow; the rapid flow in the vasa recta ‘washes tubules and collecting ducts, the exchange process is
out’ medullary hyperosmolality, returning some of usually associated with net generation of bicarbonate
the solute, without extra water, to the circulation. to replace that lost in extracellular buffering. Potassium
42 The kidneys

and hydrogen ions compete for secretion in exchange ● reduced hydrogen ion secretion throughout the
for sodium ions. The possible mechanism stimulated nephron: bicarbonate can be reclaimed only if
by aldosterone is discussed in Chapter 2. The most hydrogen ions are secreted; plasma bicarbonate
important stimulus to aldosterone secretion is mediated concentrations will fall,
by the effect of renal blood flow on the release of renin ● reduced potassium secretion in the distal tubule,
from the juxtaglomerular apparatus; this method of with potassium retention (potassium can still be
reabsorption is part of the homeostatic mechanism reabsorbed proximally).
controlling sodium and water balance.
If there is a low GFR accompanied by a low renal
BIOCHEMISTRY OF RENAL DISORDERS blood flow:
Pathophysiology ● Systemic aldosterone secretion will be maximal: in
Different parts of the nephrons are in close anatomical such cases, any sodium reaching the distal tubule will
association and are dependent on a common blood be almost completely reabsorbed in exchange for H+
supply. Renal dysfunction of any kind affects all parts of and K+, and the urinary sodium concentration will
the nephrons to some extent, although sometimes either be low.
glomerular or tubular dysfunction is predominant. The ● ADH secretion will be increased: ADH acting on
net effect of renal disease on plasma and urine depends the collecting ducts allows water to be reabsorbed
on the proportion of glomeruli to tubules affected and in excess of solute, further reducing urinary volume
on the number of nephrons involved. and increasing urinary osmolality well above that of
To understand the consequences of renal disease it plasma and reducing plasma sodium concentration.
may be useful to consider the hypothetical individual This high urinary osmolality is mainly due to
nephrons, first with a low glomerular filtration rate substances not actively dealt with by the tubules. For
(GFR) and normal tubular function, and then with example, the urinary urea concentration will be well
tubular damage but a normal GFR. It should be above that of plasma. This distal response will occur
emphasized that these are hypothetical examples, as only in the presence of ADH; in its absence, normal
in clinical reality a combination of varying degree may nephrons will form a dilute urine.
exist. If the capacity of the proximal tubular cells to
Uraemia is the term used to describe a raised plasma reabsorb solute, and therefore water, is normal, a larger
urea concentration and is almost always accompanied proportion than usual of the reduced filtered volume
by an elevated creatinine concentration: in North will be reclaimed by isosmotic processes, thus further
America this is usually referred to as azotaemia (a raised reducing urinary volume.
nitrogen concentration). In summary, the findings in venous plasma and
urine from the affected nephrons will be as follows.
Reduced glomerular filtration rate with normal tubular
function
Plasma
The total amounts of urea and creatinine excreted
are affected by the GFR. If the rate of filtration fails ● High urea (uraemia) and creatinine concentrations.
to balance that of production, plasma concentrations ● Low bicarbonate concentration, with low pH
will rise. (acidosis).
Phosphate and urate are released during cell ● Hyperkalaemia.
breakdown. Plasma concentrations rise because less ● Hyperuricaemia and hyperphosphataemia.
than normal is filtered. Most of the reduced amount
reaching the proximal tubule can be reabsorbed, and Urine
the capacity for secretion is impaired if the filtered ● Reduced volume (oliguria).
volume is too low to accept the ions; these factors ● Low (appropriate) sodium concentration – only
further contribute to high plasma concentrations. if renal blood flow is low, stimulating aldosterone
A large proportion of the reduced amount of filtered secretion.
sodium is reabsorbed by isosmotic mechanisms; less ● High (appropriate) urea concentration and
than usual is then available for exchange with hydrogen therefore a high osmolality – only if ADH secretion
and potassium ions distally. This has two main outcomes: is stimulated.
 Biochemistry of renal disorders 43

Reduced tubular function with normal glomerular There may also be tubular proteinuria, which
filtration rate usually refers to low-molecular-weight proteins that
Damage to tubular cells impairs adjustment of the are normally produced in the body, filtered across the
composition and volume of the urine. Impaired solute glomerular membrane and reabsorbed in the proximal
reabsorption from proximal tubules reduces isosmotic tubule, but appear in the urine as a result of proximal
water reabsorption. Countercurrent multiplication tubular damage, for example a1-microglobulin and
may also be affected, and therefore the ability of the retinol binding protein. However, tubular proteinuria
collecting ducts to respond to ADH is reduced. A large also occurs when proximal tubular enzymes and
volume of inappropriately dilute urine is produced. proteins, such as N-acetyl-b-D-glucosaminidase
The tubules cannot secrete hydrogen ions and (NAG), are released into the urine due to tubular cell
therefore cannot reabsorb bicarbonate normally injury. See Chapter 19.
or acidify the urine. The response to aldosterone
and therefore the exchange mechanisms involving Clinical and biochemical features of renal
disease
reabsorption of sodium are impaired; the urine contains
an inappropriately high concentration of sodium for The biochemical findings and urine output in renal
the renal blood flow. Potassium reabsorption from the disease depend on the relative contributions of
proximal tubule is impaired and plasma potassium glomerular and tubular dysfunction. When the GFR
concentrations may be low. Reabsorption of glucose, falls, substances that are little affected by tubular action
phosphate, magnesium, urate and amino acids is (such as urea and creatinine) are retained. Although
impaired. Plasma phosphate, magnesium and urate their plasma concentrations start rising above the
concentrations may be low. baseline for that individual soon after the GFR falls,
Thus, the findings in venous plasma and urine from they seldom rise above the reference range for the
the affected nephrons will be as follows. population until the GFR is below about 60 per cent
of normal, although in individual patients they do rise
Plasma
above baseline.
● Normal urea and creatinine concentrations (normal Plasma concentrations of urea and creatinine
glomerular function). depend largely on glomerular function (Fig. 3.5). By
● Due to proximal or distal tubular failure: contrast, urinary concentrations depend almost entirely
– low bicarbonate concentration and low pH, on tubular function. However little is filtered at the
– hypokalaemia. glomeruli, the concentrations of substances in the initial
● Due to proximal tubular failure: filtrate are those of a plasma ultrafiltrate. Any difference
– hypophosphataemia, hypomagnesaemia and between these concentrations and those in the urine is
hypouricaemia. due to tubular activity. The more the tubular function is
Urine impaired, the nearer the plasma concentrations will be
● Due to proximal and/or distal tubular failure: to those of urine. Urinary concentrations inappropriate
– increased volume, to the state of hydration suggest tubular damage,
– pH inappropriately high compared with that in whatever the degree of glomerular dysfunction.
plasma. The plasma sodium concentration is not primarily
● Due to proximal tubular failure: affected by renal disease. The urinary volume depends
– generalized amino aciduria, on the balance between the volume filtered and the
– phosphaturia, proportion reabsorbed by the tubules. As 99 per cent
– glycosuria. of filtered water is normally reabsorbed, a very small
● Due to distal tubular failure: impairment of reabsorption causes a large increase in
– even if renal blood flow is low, an urine volume. Consequently, if tubular dysfunction
inappropriately high sodium concentration predominates, impairment of water reabsorption
(inability to respond to aldosterone), causes polyuria, even though glomerular filtration is
– even if ADH secretion is stimulated, an reduced (see Chapter 2).
inappropriately low urea concentration and The degree of potassium, phosphate and urate
therefore osmolality (inability of the collecting retention depends on the balance between the degree of
ducts to respond to ADH). glomerular retention and the loss as a result of a reduced
44 The kidneys

Glomerular permeability reduced Normal nephron Predominant tubular damage

Reduced filtration with high osmotic load Reduced reabsorptive capacity

Urea and water retained Increased urea and Normal urea load
normal water load

Oliguria Polyuria due to Polyuria due to

osmotic diuresis tubular impairment

Figure 3.5 The effects of glomerular and tubular dysfunction on urinary output and on plasma concentrations of
retained ‘waste’ products of metabolism, the volume depending on the proportion of nephrons involved.

proximal tubular reabsorptive capacity. If glomerular CASE 1

dysfunction predominates, so little is filtered that plasma
concentrations rise, despite the failure of reabsorption. A 17-year-old man was involved in a road traffic
Conversely, if tubular dysfunction predominates, accident. Both femurs were fractured and his spleen
glomerular retention is more than balanced by impaired was ruptured. Two days after surgery and transfusion
reabsorption of filtered potassium, urate and phosphate, of 16 units of blood, the following results were found:
and therefore plasma concentrations may be normal Plasma
or even low. A low plasma bicarbonate concentration Sodium 136 mmol/L (135–145)
is found in association with metabolic acidosis, which Potassium 6.1 mmol/L (3.5–5.0)
may worsen the hyperkalaemia. Urea 20.9 mmol/L (2.5–7.0)
Acute kidney injury Creatinine 190 µmol/L (70–110)
Albumin-adjusted calcium 2.40 mmol/L (2.15–2.55)
This was previously known as acute renal failure. In
Phosphate 2.8 mmol/L (0.80–1.35)
adults, oliguria is defined as a urine output of less than
Bicarbonate 17 mmol/L (24–32)
400 mL/day, or less than 15 mL/h; it usually indicates
a low GFR and a rapid decline in renal function over The patient was producing only 10 mL of urine per
hours to weeks, with retention of creatinine and hour and a spot urinary sodium was 8 mmol/L.
nitrogenous waste products. Oliguria may be caused by DISCUSSION
the factors discussed below. The results are compatible with pre-renal acute
Acute oliguria with reduced GFR (pre-renal) kidney injury (AKI), secondary to massive blood loss.
This is caused by factors that reduce the hydrostatic Note the oliguria, low urinary sodium concentration,
pressure gradient between the renal capillaries and hyperkalaemia, hyperphosphataemia and also low
the tubular lumen. A low intracapillary pressure is the plasma bicarbonate concentration, suggestive of a
metabolic acidosis.
 Biochemistry of renal disorders 45

most common cause. It is known as renal circulatory in an inappropriately dilute urine for the degree of
insufficiency (‘pre-renal uraemia’) and may be due to: hypovolaemia. Fluid must be given with caution, and
only until volume depletion has been corrected; there is
● intravascular depletion of whole blood
a danger of overloading the circulation.
(haemorrhage) or plasma volume (usually due to
During recovery, oliguria is followed by polyuria.
gastrointestinal loss), or reduced intake,
When cortical blood flow increases, and as tubular
● reduced pressure as a result of the vascular dilatation
oedema resolves, glomerular function recovers before
caused by ‘shock’, causes of which include myocardial
that of the tubules. The biochemical findings gradually
infarction, cardiac failure and intravascular haemolysis,
progress to those of tubular dysfunction until they
including that due to mismatched blood transfusion.
approximate those for ‘pure’ tubular lesions. Urinary
The patient is usually hypotensive and clinically output is further increased by the osmotic diuretic effect
volume depleted. If renal blood flow is restored within of the high load of urea. The polyuria may cause water
a few hours, the condition is reversible, but, the longer it and electrolyte depletion. The initial hyperkalaemia may
persists, the greater the danger of intrinsic renal damage. be followed by hypokalaemia. Mild acidosis (common to
As most glomeruli are involved and tubular function is both glomerular and tubular disorders) persists until late.
relatively normal, the biochemical findings in plasma and Recovery of the tubules may restore full renal function.
urine are those described earlier. Uraemia due to renal
dysfunction may be aggravated if there is increased protein Acute oliguria due to renal outflow obstruction (post-
breakdown as a result of tissue damage, a large haematoma renal)
or the presence of blood in the gastrointestinal lumen. Oliguria or anuria (absence of urine) may occur in
Intravenous amino acid infusion may have the same post-renal failure. The cause is usually, but not always,
effect because the urea is derived, by hepatic metabolism, clinically obvious and may be due to the following:
from the amino groups of amino acids. Increased
● Intrarenal obstruction, with blockage of the tubular
tissue breakdown may also aggravate hyperkalaemia,
lumina by haemoglobin, myoglobin and, very rarely,
hyperuricaemia and hyperphosphataemia.
urate or calcium. Obstruction caused by casts and
Acute oliguria due to intrinsic renal damage oedema of tubular cells is usually the result of true
renal damage.
This may be due to:
● Extrarenal obstruction, due to calculi, neoplasms,
● prolonged renal circulatory insufficiency, for example prostate or cervix, urethral strictures
● acute glomerulonephritis, usually in children – the or prostatic hypertrophy, any of which may cause
history of a sore throat and the finding of red cells in sudden obstruction. The finding of a palpable
the urine usually make the diagnosis obvious, bladder indicates urethral obstruction, and in males
● septicaemia, which should be considered when the is most likely to be due to prostatic hypertrophy,
cause of oliguria is obscure, although there are other, rarer, causes.
● ingestion of a variety of poisons or drugs,
Early correction of outflow obstruction may rapidly
● myoglobulinuria (see Chapters 18 and 19),
increase the urine output. The longer it remains
● Bence Jones proteinuria (see Chapter 19).
untreated, the greater the danger of ischaemic or
One problem in the differential diagnosis of acute pressure damage to renal tissue. Imaging studies such
oliguria is distinguishing between renal circulatory as renal tract ultrasound may be useful to confirm post-
insufficiency and intrinsic renal damage that may have renal obstruction (Box 3.1).
followed it. Acute oliguric renal dysfunction often
follows a period of reduced GFR and renal circulatory Investigation of acute kidney injury
insufficiency. ● A careful clinical history, especially of taking
The oliguria is due to reduced cortical blood flow nephrotoxic drugs, and examination may give
with glomerular damage, aggravated by back-pressure clues to the cause of acute kidney injury (AKI). It
on the glomeruli due to obstruction to tubular flow is essential to exclude reversible causes of pre-renal
by oedema. At this stage, the concentrations of many failure, including hypovolaemia or hypotension,
constituents in plasma, such as urea and creatinine, and also post-renal urinary tract obstruction (renal
are raised with hyperkalaemia; tubular damage results tract imaging may be useful, such as abdominal
46 The kidneys

Box 3.1 Some causes of acute kidney CASE 2

injury (AKI)
A 56-year-old man attended the renal out-patient
Pre-renal clinic because of polycystic kidneys, which had been
Hypotension diagnosed 20 years previously. He was hypertensive
Hypovolaemia and the following blood results were returned:
Decreased cardiac output Plasma
Renal artery stenosis + angiotensin-converting
Sodium 136 mmol/L (135–145)
enzyme inhibitor
Potassium 6.2 mmol/L (3.5–5.0)
Hepatorenal syndrome
Urea 23.7 mmol/L (2.5–7.0)
Renal or intrinsic renal disease
Creatinine 360 µmol/L (70–110)
Acute tubular necrosis, e.g. hypotension, toxins,
contrast media, myoglobinuria, sepsis, drugs,
Estimated glomerular filtration rate (eGFR) 14 mL/
sustained pre-renal oliguria min per 1.73 m2
Vasculitis Albumin-adjusted calcium 1.80 mmol/L (2.15–2.55)
Glomerulonephritis Phosphate 2.6 mmol/L (0.80–1.35)
Drugs that are nephrotoxic, e.g non-steroidal anti- Bicarbonate 13 mmol/L (24–32)
inflammatory drugs
Sepsis DISCUSSION
Thrombotic microangiopathy or thromboembolism These results are typical of a patient with chronic
Atheroembolism kidney disease (CKD) with raised plasma urea
Bence Jones proteinuria and creatinine concentrations. The patient has
Interstitial nephritis hyperkalaemia and a low plasma bicarbonate
Infiltration, e.g. lymphoma concentration, suggestive of a metabolic acidosis. The
Severe hypercalcaemia hypocalcaemia and hyperphosphataemia are also in
Severe hyperuricaemia keeping with CKD stage 5.
Post-renal
Calculi
Table 3.1 Some laboratory tests used to investigate
Retroperitoneal fibrosis
acute kidney injury
Prostate hypertrophy/malignancy
Carcinoma of cervix or bladder Pre-renal failure Intrinsic renal failure/
acute tubular necrosis
Urine sodium <20 >20
(mmol/L)
FENa% <1 >1
radiograph if calculi are suspected, and renal tract
ultrasound); see Box 3.1). Urine to plasma >40 <20
creatinine ratio
● Monitor urine output, plasma urea and creatinine
and electrolytes, as well as acid–base status. Urine to plasma >1.2 <1.2
osmolality ratio
● Hyperkalaemia, hypermagnesaemia, hyperphos-
phataemia, hyperuricaemia and metabolic acidosis Urine to plasma >10 <10
urea ratio
may occur in the oliguric phase of AKI.
● Urine microscopy may show granular casts Note that in post-renal failure there is usually anuria.
FENa%, fractional excretion of sodium.
supportive of the diagnosis of acute tubular necrosis.
● The urinary to plasma urea ratio can be useful,
and when more than 10:1 is suggestive of pre-renal urine [sodium] plasma [creatinine]
FENa% = ¥ ¥ 100%
problems. The urinary to plasma creatinine or plasma [sodium] urine [creatinine]
osmolality ratio may also be useful (Table 3.1). (3.1)
● The fractional excretion of sodium (FENa%) is also
useful diagnostically and can be measured using ● An FENa% of less than 1 per cent is typical of pre-
a simultaneous blood sample and spot urine (see renal failure, as is a urinary sodium concentration
above and Fig. 3.6). more than 20 mmol/L.
 Biochemistry of renal disorders 47

Recent elevated plasma urea

and/or creatinine

Anuria present?

Yes No

Consider Measure the patient’s

post-renal failure FENa%

FENa% 1% FENa% 1%

Consider pre-renal Consider acute

failure tubular necrosis

Figure 3.6 Algorithm for the investigation of acute kidney injury (AKI). FENa%, fractional excretion of sodium.

● Blood may be necessary for full blood count,

coagulation screen and blood cultures. Also exclude Box 3.2 Some causes of chronic kidney
myeloma, and look for Bence Jones proteinuria disease
and cryoglobulins. Autoantibody screen, including
Diabetes mellitus
antineutrophil cytoplasmic antibody (ANCA),
Nephrotoxic drugs
antinuclear antibody (ANA), extractable nuclear Hypertension
antigen (ENA) antibody, complement, antiglomerular Glomerulonephritis
basement membrane antibodies and double- Chronic pyelonephritis
stranded deoxyribonucleic acid (DNA), myoglobin, Polycystic kidneys
plasma creatine kinase and plasma calcium, may also Urinary tract obstruction
be indicated, depending on the clinical situation. Severe urinary infections
● In obscure cases, renal biopsy may be necessary to Amyloid and paraproteins
establish a diagnosis. Progression from acute kidney injury
● Recently, urine neutrophil gelatinase-associated Severe hypothyroidism (rare)
lipocalin (NGAL) has been suggested as a marker of
renal injury and predictor of AKI.
is an increase in plasma creatinine of about 20 per cent
and/or a decrease in eGFR of about 15 per cent soon
Chronic kidney disease after initiation of the drug.
Chronic renal dysfunction [defined as being reduced eGFR In most cases of acute oliguric renal disease there
(estimated GFR), proteinuria, haematuria and/or renal is diffuse damage involving the majority of nephrons.
structural abnormalities of more than 90 days’ duration] A patient who survives long enough to develop
is usually the end result of conditions such as diabetes chronic renal disease must have some functioning
mellitus, hypertension, primary glomerulonephritis, nephrons.
autoimmune disease, obstructive uropathy, polycystic Histological examination shows that not all
disease, renal artery stenosis, infections and tubular nephrons are equally affected: some may be
dysfunction and the use of nephrotoxic drugs (Box completely destroyed and others almost normal. Also,
3.2). It is common, perhaps affecting about 13 per cent some segments of the nephrons may be more affected
of the population. Acute or chronic renal dysfunction than others. The effects of chronic renal disease can
can occur when angiotensin-converting enzyme (ACE) be explained by this patchy distribution of damage;
inhibitors or angiotensin II receptor blockers (ARBs) are acute renal disease may sometimes show the same
given to patients with renal artery stenosis; a clue to this picture.
48 The kidneys

In chronic kidney disease (CKD) the functional Other abnormal findings in chronic kidney
adaptive effects can be divided into three main disease
categories: diminished renal reserve, renal insufficiency, Apart from uraemia, hyperkalaemia and metabolic
and end-stage uraemia. The loss of 75 per cent of renal acidosis, other abnormalities that may occur in CKD
tissue produces a fall in GFR of 50 per cent. Although include the following:
there is a loss of renal function, homeostasis is initially
preserved at the expense of various adaptations ● Plasma phosphate concentrations rise and
such as glomerulotubular changes and secondary plasma total calcium concentrations fall. The
hyperparathyroidism. increased hydrogen ion concentration increases
Chronic renal dysfunction may pass through two the proportion of free ionized calcium, the plasma
main phases: concentration of which does not fall in parallel with
the fall in total calcium concentration. Impaired
● an initially polyuric phase,
renal tubular function and the raised phosphate
● subsequent oliguria or anuria, sometimes needing
concentration inhibit the conversion of vitamin D
dialysis or renal transplantation.
to the active metabolite and this contributes to
the fall in plasma calcium concentration. Usually,
Polyuric phase
hypocalcaemia should be treated only after correction
At first, glomerular function may be adequate to of hyperphosphataemia. After several years of CKD,
maintain plasma urea and creatinine concentrations secondary hyperparathyroidism (see Chapter 6)
within the reference range. As more glomeruli are may cause decalcification of bone, with a rise in
involved, the rate of urea excretion falls and the plasma the plasma alkaline phosphatase activity. Some
concentration rises. This causes an osmotic diuresis in of these features of CKD can also evoke renal
functioning nephrons; in other nephrons the tubules osteodystrophy, associated with painful bones. The
may be damaged out of proportion to the glomeruli. increase in plasma PTH occurs early when the GFR
Both tubular dysfunction in nephrons with functioning falls below 60 mL/min per 1.73 m2.
glomeruli and the osmotic diuresis through intact ● Plasma urate concentrations rise in parallel with
nephrons contribute to the polyuria, other causes of plasma urea. A high plasma concentration does not
which should be excluded (see Chapter 2). necessarily indicate primary hyperuricaemia; clinical
During the polyuric phase, the plasma concentration gout is rare unless hyperuricaemia is the cause of the
of many substances, other than urea and creatinine, renal damage (see Chapter 20).
may be anywhere between the glomerular and tubular ● Hypermagnesaemia can also occur (see Chapter 6).
ends of the spectrum, although metabolic acidosis is ● Normochromic, normocytic anaemia due to
usually present. erythropoietin deficiency is common and, because
haemopoiesis is impaired, does not respond to
Oliguric phase iron therapy; this can be treated with recombinant
If nephron destruction continues, the findings become erythropoietin.
more like those of pure glomerular dysfunction. ● One of the commonest causes of death in patients
Glomerular filtration decreases significantly and urine with CKD is cardiovascular disease, in part
output falls; oliguria precipitates a steep rise in plasma explained by hypertension and a dyslipidaemia
urea, creatinine and potassium concentrations; and the of hypertriglyceridaemia and low high-density
metabolic acidosis becomes more severe. lipoprotein cholesterol. Some of these effects may be
The diagnosis of CKD is usually obvious. In due to reduced lipoprotein lipase activity.
the early phase, before plasma urea and creatinine ● Abnormal endocrine function, such as
concentrations have risen significantly, there may hyperprolactinaemia, insulin resistance, low plasma
be microscopic haematuria or proteinuria. However, testosterone and abnormal thyroid function, may
haematuria may originate from either the kidney also be seen in chronic renal dysfunction.
or the urinary tract, and may therefore indicate ● Some of the features of CKD may be explained by the
the presence of other conditions, such as urinary presence of ‘middle molecules’ – compounds that the
tract infections, renal calculi or tumours (see Box kidneys would normally excrete. These compounds,
3.2).
 Diagnosis of renal dysfunction 49

of relatively small molecular weights, can exert toxic NEPHROTIC SYNDROME

effects upon body tissues. The nephrotic syndrome is caused by increased
● The presence of increasing proteinuria may be the glomerular basement membrane permeability, resulting
best single predictor of disease progression. in protein loss, usually more than 3 g a day (or a urine
Irreversible but potentially modifiable complications protein to creatinine ratio of > 300 mg/mmol), with
such as anaemia, metabolic bone disease, under- consequent hypoproteinaemia, hypoalbuminaemia
nutrition and cardiovascular disease occur early in the and peripheral oedema. All but the highest molecular
course of CKD. A summary of the clinical features of weight plasma proteins can pass through the glomerular
chronic kidney disease is shown in Table 3.2. basement membrane. The main effects are on plasma
proteins and are associated with hyperlipidaemia and
SYNDROMES REFLECTING hyperfibrinoginaemia. (This is discussed more fully in
PREDOMINANT TUBULAR DAMAGE – Chapter 19.) Uraemia occurs only in late stages of the
RENAL TUBULAR ACIDOSIS
disorder, when many glomeruli have ceased to function.
There is a group of conditions that primarily affect
tubular function more than the function of the NEPHRITIC SYNDROME
glomeruli. However, scarring involving whole nephrons This comprises reduced eGFR, oedema, hypertension
may eventually cause chronic renal dysfunction. and proteinuria with significant haematuria. It is
Impaired function may involve a single transport usually associated with systemic disease such as post-
system, particularly disorders associated with amino infectious glomerulonephritis, e.g. post-streptococcal
acid or phosphate transport, or may affect multiple or immunoglobulin A (IgA) nephropathy, ANCA-
transport systems. Conditions associated with multiple associated vasculitis, e.g. Wegener’s granulomatosis or
transport defects may cause renal tubular acidoses microscopic polyarteritis, or antiglomerular basement
– renal tubular disorders associated with a systemic membrane disease (Goodpasture’s disease).
metabolic acidosis because of impaired reclamation of
bicarbonate or excretion of H+ (see Chapter 4). DIAGNOSIS OF RENAL DYSFUNCTION
Disorders affecting the urine-concentrating Glomerular function tests
mechanism and causing nephrogenic diabetes insipidus As glomerular function deteriorates, substances that
but which rarely in themselves cause a metabolic are normally cleared by the kidneys, such as urea and
acidosis are discussed elsewhere (see Chapter 2). creatinine, accumulate in plasma.

Table 3.2 Stages of renal dysfunction (chronic kidney disease)a

Stage Description GFR (mL/min per 1.73 m2) Metabolic features

1 Presence of kidney damage with normal or raised GFR b
>90 Usually normal
2 Presence of kidney damage with mildly reduced GFR 60–89 Plasma urea and creatinine rise
PTH starts to rise
3 Moderately reduced GFR 30–59 Calcium absorption decreased
Lipoprotein lipase decreased
Anaemia – erythropoietin decreased
4 Severely reduced GFR (pre-end stage) 15–29 Dyslipidaemia
Hyperphosphataemia
Metabolic acidosis
Hyperkalaemia and hyperuricaemia
5 End-stage kidney disease (may need dialysis or transplant) <15 Marked elevation of urea (uraemia) and creatinine
Note that a suffix of ‘p’ with staging can be used if proteinuria is present.
a
National Kidney Foundation.
b
Such as proteinuria or haematuria.
GFR, glomerular filtration rate; PTH, parathyroid hormone.
50 The kidneys

Measurement of plasma concentrations of urea and If the plasma concentration of either urea or
creatinine creatinine is significantly raised, and especially if it is
Urea is derived in the liver from amino acids and rising, impaired glomerular function is likely. Serial
therefore from protein, whether originating from the changes may be used to monitor changes in the GFR
diet or from tissues. The normal kidney can excrete and changes greater than 10–15 per cent are likely to be
large amounts of urea. If the rate of production exceeds clinically significant.
the rate of clearance, plasma concentrations rise. The With a reduced GFR, plasma urea concentrations
rate of production is accelerated by: tend to rise faster than those of creatinine and tend to
be disproportionately higher with respect to the upper
● a high-protein diet,
reference limit. The rate at which urea is reabsorbed
● absorption of amino acids and peptides from digested
from the collecting ducts is dependent on the amount
blood after haemorrhage into the gastrointestinal
filtered by the glomerulus and by the rate of luminal
lumen or soft tissues,
fluid flow (see Table 3.2).
● increased catabolism due to starvation, tissue
damage, sepsis or steroid treatment. Clearance as an assessment of glomerular filtration
In catabolic states, glomerular function is often rate (Fig. 3.7)
impaired due to circulatory factors and this contributes For a substance (S) that is filtered by the glomerulus,
more to the uraemia than does increased production. but not reabsorbed from or secreted into the tubules,
Conversely, the plasma urea concentration may be the amount filtered (GFR ¥ plasma[S]) must equal the
lower than 1.0 mmol/L, the causes of which include the amount excreted in the urine (urinary[S] ¥ volume per
following: unit time):
● those due to increased GFR or haemodilution GFR ¥ plasma[S]
(common): = urinary[S] ¥ urine volume per unit time (3.2)
– pregnancy (the commonest cause in young Thus, rearranging gives:
women),
– overenthusiastic intravenous infusion (the urinary[S] ¥ urine volume per unit time
GFR = (3.3)
commonest cause in hospital patients), plasma[S]
– ‘inappropriate’ ADH secretion (syndrome of
inappropriate ADH secretion, SIADH).
● those due to decreased synthesis:
400
– use of amino acids for protein anabolism
during growth, especially in children,
– low protein intake,
– very severe liver disease (low amino acid 300
Plasma creatinine (µmol/L)

deamination),
– inborn errors of the urea cycle are rare and
usually only occur in infants.
200
Creatinine is largely derived from endogenous sources
by muscle creatine breakdown. Plasma creatinine usually
correlates with muscle mass, with 95 per cent of creatine
occurring in skeletal muscle. The plasma creatinine 100

concentration varies more than that of urea during the

day owing to creatine intake in meals. However, sustained
high-protein diets and catabolic states probably affect the
plasma concentration of creatinine less than that of urea. 30 60 90 120
Creatinine concentration is used to assess renal function; Creatinine clearance (mL/min)
however, its assay may be less precise than that of urea, Figure 3.7 The inverse relationship between plasma
and can be prone to analytical interference by substances creatinine and creatinine clearance. (Shaded area is
such as bilirubin, ketone bodies and certain drugs. approximate 95 per cent confidence intervals.)
 Diagnosis of renal dysfunction 51

The GFR thus measured is referred to as the clearance Creatinine clearance is higher than inulin clearance
– the volume of plasma that could theoretically be because some creatinine is secreted by the tubules.
completely cleared of a substance in 1 min. Only Urea clearance is lower than inulin clearance as some
substances freely filtered by glomeruli and not acted on urea is reabsorbed into the tubules (urea and inulin
by the tubules can be used to give true measurement clearance are now essentially obsolete in clinical
of GFR. There is no such endogenous substance, but practice).
inulin, a polysaccharide, fulfils the criteria closely. However, there are various factors that make the
Inulin is not produced by the body; it must be given measurement of creatinine clearance inaccurate:
either by constant infusion in order to maintain steady
● All laboratory assays have an inherent imprecision.
plasma concentrations during the period of the test, or
The combined imprecision of two assays is greater
by a single injection followed by serial blood sampling
than that of one. Urine as well as plasma is assayed
to enable the concentration at the midpoint of the
for clearance measurements.
collection to be calculated.
● The most significant error of any method depending
Radiochromium-labelled ethylenediamine tetra-
on a timed urine collection is in the measurement
acetic acid (EDTA) is another exogenous compound
of urine volume. Inaccurate urine collection
that some consider the ‘gold standard’ for calculating
may yield misleading results. The difficulties are
patient GFR, although this requires the use of nuclear
increased in infants and young children, and in
medicine tests and is rarely used.
patients who have difficulty in bladder emptying
For endogenously produced substances such as
or are incontinent.
creatinine, with its relatively constant production, the
● Both creatinine and urea may be partly destroyed by
following equation can be used to calculate a clearance
bacterial action in infected or old urine.
that acts as an approximation for GFR:
For an individual patient, plasma creatinine
Creatinine clearance (mL/min)
concentrations may rise above the baseline level but
urinary [creatinine] ¥ urine volume (mL)
= remain within the population reference range despite a
plasma [creatinine] ¥ urine collection period (min)
deterioration in glomerular function. The reciprocal of
(3.4)
the plasma creatinine concentration is called the renal
The modification of diet in renal disease (MDRD) index.
formula can be used to estimate GFR (eGFR) and The plasma creatinine concentration may not
has generally superseded the need to use creatinine exceed the upper limit of the reference range until the
clearances in clinical practice and is also used to titrate GFR, and therefore the creatinine clearance, has been
drug dosing in patients with renal impairment. This is reduced by approximately 60 per cent (see Fig. 3.7).
calculated by the isotope dilution mass spectrometry Thus the measurement of creatinine clearance should
(IDMS) traceable MDRD equation recommended be a more sensitive but less accurate indicator of early
in the UK as: 175 ¥ ([plasma creatinine]/88.4)–1.154 ¥ glomerular dysfunction than of plasma creatinine
(age)–0.203 ¥ (0.742 if female) ¥ (1.210 if black). concentration.
The equation has not been validated in the following Clearance values will be low whether the reduced
groups: those under 18 years old, those acutely ill, GFR is due to renal circulatory insufficiency, intrinsic
patients with limb amputations, pregnant women, renal damage or ‘post-renal’ causes, and it cannot
the very elderly and the obese and malnourished. In distinguish among them. Creatinine clearance has
some of these situations there may be differences in been said to be useful in deciding the dose of a renally
muscle mass and hence in creatine concentrations and excreted drug.
ultimately creatinine. Those with muscle breakdown
may show higher plasma creatinine concentration Cystatin C
and the converse may be seen in those with reduced Another endogenous substance that can be used as a
muscle bulk. There may be increased muscle bulk in marker of GFR is plasma cystatin C (Cys C), and its
black compared with white people. Individuals taking use may alleviate some of the problems associated
creatine supplements for body building may show with creatinine clearance determinations. This is a
increased plasma creatinine and also plasma creatine 13-kDa protein that is a member of the family of
kinase (CK). cystine proteinase inhibitors. Unlike other endogenous
52 The kidneys

compounds such as creatinine, Cys C is not secreted are increased in the urine because of reduced tubular
by the renal tubules and does not return to the reabsorption and increased renal tubular secretion. If
bloodstream after glomerular filtration. It has been there is detectable glycosuria, phosphaturia and non-
suggested that plasma Cys C may approximate to selective amino aciduria, the condition is known as
the ‘ideal’ endogenous marker for GFR, as blood Fanconi’s syndrome.
concentrations are independent of patient age and sex,
although currently this test is not routinely available in Distal tubular function tests
most laboratories. Impaired distal tubular function primarily affects
urine acidification, with a failure to excrete hydrogen
Renal tubular function tests
ions; the urinary pH rarely falls below 5.5. There
Reduced tubular function, with normal glomerular is an impaired response to aldosterone involving
function, impairs the adjustment of the composition and reabsorption of sodium, and the urine contains an
volume of the urine with minimal effect on the plasma inappropriately high concentration of sodium for the
urea or creatinine concentration. The investigations renal blood flow. The associated findings may include
used to diagnose tubular disorders can be divided into the following.
those that predominantly identify proximal tubular
dysfunction and those that predominantly identify Plasma
distal tubular dysfunction. ● Low bicarbonate and high chloride concentration with
low pH (hyperchloraemic acidosis), hypokalaemia.
Proximal tubular function tests
Urine
Impaired solute reabsorption from the proximal tubules
● Increased volume.
reduces isosmotic water reabsorption. Countercurrent
● pH inappropriately high.
multiplication may also be affected, and hence the
● An inappropriately high sodium concentration, even
ability to respond to ADH is reduced. A large volume of
if renal blood flow is low (inability to respond to
inappropriately dilute urine is produced.
aldosterone).
The tubules cannot secrete hydrogen ions and so
● An inappropriately low urea concentration, and
cannot reabsorb bicarbonate normally and therefore
therefore osmolality, even if ADH secretion is
the urine is inappropriately alkaline for the degree of
stimulated.
acidosis in the blood.
The reabsorption of potassium, phosphate, The ability to form concentrated urine in response
magnesium, urate, glucose and amino acids is impaired. to fluid deprivation depends on normal tubular
The following findings may be present, and measurement function (countercurrent multiplication) and on
may occasionally be useful. the presence of ADH. Failure of this ability is usually
Plasma
due to renal disease, or cranial diabetes insipidus (see
Chapter 2 for discussion of the fluid deprivation test).
● Normal urea and creatinine concentrations (normal The investigation of renal tubular acidosis is covered in
glomerular function). Chapter 4.
● Low bicarbonate concentration with low pH
(metabolic acidosis). URINARY SODIUM AND OSMOLALITY
● Hypokalaemia, hypophosphataemia, hypomagnes- Urinary sodium estimation
aemia and hypouricaemia.
Urinary sodium estimation may be used to differentiate
Urine
acute oliguria due to renal damage from that due to
renal circulatory insufficiency. Aldosterone secretion
● Increased volume (polyuria). will be maximal only if renal blood flow is reduced;
● pH may be inappropriately high. in such circumstances, functioning tubules respond
● Phosphaturia, glycosuria, uricosuria. appropriately by selectively reabsorbing sodium by
● Generalized amino aciduria. distal tubular exchange mechanisms. A urinary sodium
Tubular proteinuria can be diagnosed by measuring concentration of less than about 20 mmol/L is usually
specific low-molecular-weight proteins such as retinol- taken to indicate that tubular function is not significantly
binding protein, NAG or a1-microglobulin, which impaired.
 Biochemical principles of the treatment of renal dysfunction 53

Measurement of urinary osmolality Control of blood pressure, lipids and, if present,

Measurement of urinary osmolality or other indicators diabetes mellitus (optimization of glycaemic control) is
of selective water reabsorption, such as urinary urea important and may help slow decline of eGFR and reduce
or creatinine concentrations, is less valuable than cardiovascular risk, which is common in these patients.
assaying urinary sodium concentration, as ADH Angiotensin-converting enzyme inhibitors may slow
secretion is stimulated for many other causes (see the decline in renal function, although patients should
Table 3.1). be monitored for hyperkalaemia. Dietary modification
with increased caloric intake along with reduced dietary
BIOCHEMICAL PRINCIPLES OF THE
protein intake may slow the decline in GFR by reducing
TREATMENT OF RENAL DYSFUNCTION protein catabolism. Nevertheless, it is also important to
ensure that the patient is well nourished.
Acute kidney injury
Tissue precipitation of calcium to phosphate
Pre-renal AKI can sometimes be reversed by careful may occur early in renal disease and is related to
control of fluid balance and prompt treatment hyperphosphataemia and the calcium phosphate
of hypovolaemia. Sometimes furosemide with product (calcium concentration ¥ phosphate
mannitol or dopamine infusion may re-establish concentration). This precipitation can be reduced by
normal urine flow. If oliguria is due to parenchymal/ adequate fluid intake. Dietary phosphate restriction is
intrinsic damage, some clinicians may restrict fluid used in the early stages of chronic renal dysfunction.
and sodium intake, giving only enough fluid to If the plasma phosphate concentration is raised,
replace losses and provide an adequate low-protein phosphate-binding agents such as calcium acetate
energy intake to minimize aggravation of uraemia. or carbonate may be indicated. When GFR is below
If possible, the cause of the intrinsic renal failure 60 mL/min per 1.73 m2, secondary hyperparathyroidism
should be treated. Careful attention should be given with elevated PTH concentration occurs. Giving
to nephrotoxic drugs in AKI. In post-renal failure, small doses of active vitamin D, such as calcitriol or
prompt relief of the obstruction may reverse the alfacalcidol, reduces the serum PTH, and improves
situation. bone histology, and leads to increased bone mineral
A polyuric phase may occur, particularly on relief density and helps avoid renal osteodystrophy,
of urinary obstruction with excretion of potassium hypocalcaemia and tertiary hyperparathyroidism (see
and magnesium, and this can result in hypovolaemia, Chapter 6).
hypokalaemia and hypomagnesaemia, which may need Recombinant erythropoietin and iron therapy may
correcting. be indicated to treat anaemia when haemoglobin is
Renal replacement therapy (RRT) such as dialysis less than 11 g/dL; this may slow progression of chronic
or haemofiltration may improve fluid and electrolyte renal disease.
imbalances (see below). RRT is important to prevent Dialysis removes urea and other toxic substances
dangerous hyperkalaemia or if resistant pulmonary from the plasma and corrects electrolyte balance by
oedema is present. Other indications for RRT include dialysing the patient’s blood against fluid containing
severe acidosis of pH less than 7.1, encephalopathy and no urea and appropriate concentrations of electrolytes,
uraemic pericarditis. free ionized calcium and other plasma constituents.
Chronic kidney disease The following are the principal forms of dialysis:
Careful control of fluid and electrolyte balance is ● Haemofiltration is a form of haemodialysis in which
important; water intake is usually only restricted if large volumes of fluid and solute can be removed
the plasma sodium concentration is not maintained. through a highly permeable membrane; dialysis
Similarly, sodium intake should be unrestricted unless is dependent primarily on the blood pressure.
contraindications such as hypertension or oedema Haemofiltration is mainly used for AKI whereas the
exist. Plasma potassium monitoring is essential and following forms of dialysis are mainly for CKD.
potassium restriction may become necessary (and ● In haemodialysis, blood is passed through an
avoidance of potassium-retaining medication) if there extracorporeal circulation and dialysed across an
is hyperkalaemia, which may need specific therapy and artificial membrane with a solution of low solute
can be life threatening (see Chapter 5). concentration before being returned to the body.
54 The kidneys

Negative pressure on the dialysate side of the membrane – a high rate of excretion of the metabolic
can be varied to adjust the amount of water removed. product forming the stone, due either to
● In intermittent and continuous ambulatory high plasma and therefore filtrate levels or to
peritoneal dialysis, the folds of the peritoneum are impairment of normal tubular reabsorption
used as the dialysing membrane with capillaries from the filtrate.
on one side, and an appropriate fluid of higher ● Changes in pH of the urine, often due to bacterial
osmolality is infused into the peritoneal cavity on the infection, which favour precipitation of different
other. After a suitable time to allow for equilibration salts at different hydrogen ion concentrations.
of diffusible solutes, depending on the type of ● Urinary stagnation due to obstruction to urinary
peritoneal dialysis, the peritoneal cavity is drained outflow or renal tract structural abnormality.
and the cycle is repeated. ● Lack of normal inhibitors: urine normally contains
inhibitors, such as citrate, pyrophosphate and
Dialysis is used in some cases of acute kidney injury
glycoproteins, which inhibit the growth of calcium
until renal function improves, or as a regularly repeated
phosphate and calcium oxalate crystals respectively.
procedure in suitable cases of end-stage kidney disease.
Hypocitraturia may partly explain the renal calculi
It may also be used to prepare patients for renal
found in distal or type 1 renal tubular acidosis (see
transplantation.
Chapter 4).
RENAL CALCULI
Renal calculi are usually composed of products of Constituents of urinary calculi
metabolism present in normal glomerular filtrate, often at Renal calculi may consist of the following (Box 3.3):
concentrations near their maximum solubility (Fig. 3.8).
● calcium-containing salts:
Conditions favouring renal calculus – calcium oxalate,
formation – calcium phosphate,
● A high urinary concentration of one or more ● urate,
constituents of the glomerular filtrate, due to: ● cystine,
– a low urinary volume with normal renal ● xanthine.
function, because of restricted fluid intake or
excessive fluid loss over a long period of time Calculi composed of calcium salts
(particularly common in hot climates) – this About 80 per cent of all renal stones contain calcium.
favours formation of most types of calculi, Precipitation is favoured by hypercalciuria, and the type
especially if one of the other conditions listed of salt depends on urinary pH and on the availability
below is also present, of oxalate. Any patient presenting with calcium-
containing calculi should have plasma calcium and
phosphate estimations performed, and, if the results are
normal, they should be repeated at regular intervals to
exclude primary hyperparathyroidism.
Hypercalcaemia causes hypercalciuria if glomerular
function is normal. The causes and differential

Box 3.3 Some causes of renal calculi

cm Calcium phosphate or oxalate
Triple phosphate stones
1 Urate
Cystine
Figure 3.8 A renal calculus. Reproduced with Complex/mixture stones
permission from Nyhan WL and Barshop BA. Atlas of Rarities, e.g. xanthine, dihydroxyadenine or indinavir
Inherited Metabolic Diseases, 3rd edition. London: Artefacts, e.g. fibrin/clots/Munchausen’s syndrome
Hodder Arnold, 2012.
 Renal calculi 55

diagnosis of hypercalcaemia are discussed in Chapter ● by treating hypercalcaemia if present,

6. In many subjects with calcium-containing renal ● if this is not possible, by reducing dietary calcium
calculi the plasma calcium concentration is normal. (although this alone may exacerbate hyperoxaluria)
Any increased release of calcium from bone (as and oxalate intake,
in actively progressing osteoporosis, in which loss ● by maintaining a high fluid intake, unless there is
of matrix causes secondary decalcification, or in glomerular failure.
prolonged acidosis, in which ionization of calcium
Thiazide diuretics reduce urinary calcium excretion,
is increased) causes hypercalciuria; hypercalcaemia
and treatment of urinary tract infection may reduce the
is unusual in such cases. In distal renal tubular
risk of calculi formation.
acidosis there is an increased calcium load and,
because of the relative alkalinity of the urine, calcium Struvite (magnesium ammonium phosphate)
precipitation in the kidney and renal tract may occur
These stones (about 10 per cent of all renal calculi)
– nephrocalcinosis.
are associated with chronic urinary tract infections by
Hypercalciuria has been defined as a daily urinary
organisms such as Proteus species capable of splitting
calcium excretion of more than 6.2 mmol in adult
ammonium. The urinary pH is usually greater than 7.
females and 7.5 mmol in adult males.
These urease-containing bacteria convert urea to
A significant proportion of cases remain in which
ammonia and bicarbonate.
there is no apparent cause for calcium precipitation.
A common cause is hypercalciuria despite Uric acid stones
normocalcaemia (see Chapter 6). About 8 per cent of renal calculi contain uric acid; these
Hyperoxaluria favours the formation of the very are sometimes associated with hyperuricaemia, with or
poorly soluble calcium oxalate, even if calcium without clinical gout. In most cases, no predisposing
excretion is normal. The source of the oxalate may be cause can be found. Precipitation is favoured in an acid
derived exogenously from the diet. Oxalate absorption urine. Uric acid stones are usually small, friable and
is increased by fat malabsorption: calcium in the bowel yellowish brown, but can occasionally be large enough
is bound to fat instead of precipitating with oxalate, to form ‘staghorn’ calculi. They are radiolucent but
which is then free to be absorbed. Foods rich in oxalate may be visualized by ultrasound or by an intravenous
include rhubarb, chocolate, beetroot, spinach, nuts pyelogram.
and tea. The treatment of hyperuricaemia is discussed
Primary hyperoxaluria, a rare inborn error, should in Chapter 20. If the plasma urate concentration is
be considered if renal calculi occur in childhood. normal, fluid intake should be kept high and the urine
There are two main types, 1 and 2, the former being alkalinized. A low-purine diet may help to reduce urate
more common. Type 1 is due to deficiency of alanine production and excretion.
glyoxylate aminotransferase, and type 2 is due to
deficient D-glycerate dehydrogenase. Hyperoxaluria Cystine stones
(urinary oxalate greater than 400 µmol/24 h) is a more
Cystine stones are rare. In normal subjects the
important risk factor for formation of renal stones than
concentration of cystine in urine is soluble, but in
is hypercalciuria.
homozygous cystinuria this may be exceeded and the
Calcium-containing calculi are usually hard, white
patient may present with radio-opaque renal calculi.
and radio-opaque. Calcium phosphate may form
Like urate, cystine is more soluble in alkaline than in
‘staghorn’ calculi in the renal pelvis, while calcium
acidic urine; the principles of treatment are the same as
oxalate stones tend to be smaller and to lodge in the
for uric acid stones. Penicillamine can also be used to
ureters, where they are compressed into a fusiform
treat the condition (see Chapter 27).
shape. Alkaline conditions favouring calcium phosphate
precipitation and stone formation are particularly
common in patients with chronic renal infection. Miscellaneous stones
The treatment of calcium-containing calculi depends Xanthine stones
on the cause. Urinary calcium concentration should be Xanthine stones are very uncommon and may be the
reduced: result of the rare inborn error xanthinuria.
56 The kidneys

Indinavir stones ● Exclude hypercalcaemia (see Chapter 6) and

These are seen in patients with human immuno- hyperuricaemia (see Chapter 20).
deficiency virus (HIV) infection who have been treated ● Collect a 24-h specimen of urine for urinary volume,
with the protease inhibitor indinavir. The stones are calcium and oxalate estimations. These tests will help
composed of pure protease inhibitor. to detect hypercalciuria or hyperoxaluria.
● If all these tests are negative, and especially if there
Other stones is a family history of calculi, screen the urine for
Other rare stones may consist of dihydroxyadenine (due cystine. If the qualitative test is positive, the 24-h
to adenine phosphoribosyltransferase deficiency) or excretion of cystine and basic amino acids should be
poorly calcified mucoproteinaceous material associated estimated.
with chronically infected kidneys (matrix stone). Some ● If fresh uninfected urine is alkaline despite a
stones may be factitious, as sometimes found in patients systemic metabolic acidosis, the diagnosis of renal
with Munchausen’s syndrome, who may add ‘stones’ to tubular acidosis is likely (see Chapter 4). A pH more
their urine. than 7 is suggestive of a urinary infection with a
urea-splitting organism such as Proteus vulgaris, in
Investigation of a patient with renal calculi
which case consider struvite calculi. A midstream
● If the stone is available, send it to the laboratory for urine specimen is useful to exclude infection before
analysis (Fig. 3.9). diagnosing renal tubular acidosis.

Evidence of renal calculi

Is stone fragment available for analysis?

Yes No

Evidence of hyperuricaemia?

Yes No

Evidence of hypercalcaemia and/or hypercalciuria?

Yes No

Assess 24-h
urine oxalate

High Low/normal

Hyperoxaluria Measure
urine cystine

High Low/normal

Cystinuria Consider
rare calculi
(see Box 3.3)

Figure 3.9 Algorithm for the investigation of renal calculi.

 Renal calculi 57

Low plasma urate and high urinary xanthine

CASE 3
●

concentrations suggest xanthinuria, particularly in

A 21-year-old man presented to the urology out- a child.
patient clinic because of renal calculi. There was also ● Determination of urinary citrate (an inhibitor of
a family history of renal calculi. some renal calculi) concentrations may sometimes
be useful, as low concentrations may be found.
Plasma
● If the cause is still unclear, consider the rare causes of
Sodium 137 mmol/L (135–145)
renal calculi shown in Box 3.3.
Potassium 4.2 mmol/L (3.5–5.0)
● Renal tract imaging techniques to clarify the anatomy,
Urea 5.9 mmol/L (2.5–7.0)
such as ultrasound or intravenous pyelogram, may
Creatinine 108 µmol/L (70–110)
also be necessary.
Estimated glomerular filtration rate (eGFR) > 90 mL/
min per 1.73m2 Treatment of renal calculi
Albumin-adjusted calcium 2.43 mmol/L (2.15–2.55)
Phosphate 1.1 mmol/L (0.80–1.35) Apart from specific treatments (see above), patients
Bicarbonate 27 mmol/L (24–32) with a tendency to form calculi are generally advised
Urate 0.33 mmol/L (0.20–0.43) to drink more water. The aim is usually to increase
the urinary volume to about 2–3 L in 24 h. Reducing
Urinary excretion of both calcium and oxalate fell calcium intake may not be advisable, as it may increase
within the laboratory reference ranges. However, oxalate absorption and excretion. Calculi removal
cystine was detected in the urine. by fragmentation using extracorporeal shock wave
DISCUSSION lithotripsy has in some cases reduced the need for
In conjunction with the family history and relatively surgical intervention.
young age of presentation, the results are suggestive
of cystinuria manifesting cystine stones. This is one
of the most common amino acidurias, although a
rare cause of renal calculi, and is treated by increasing
fluid intake and alkalinizing the urine.

SUMMARY
● The kidneys are vital organs for the excretion and, as renal reserve declines, there is further
of various waste products as well as for acid– hyperkalaemia, hyperphosphataemia, metabolic
base balance, fluid volume control, hormone acidosis, hypocalcaemia and anaemia. This may
production and metabolic function, such as necessitate renal support such as dialysis.
calcium homeostasis. ● Renal calculi can be the result of urinary stasis or
● Plasma creatinine determination is a useful test of infection associated with urinary supersaturation.
renal function, but plasma creatinine concentration The commonest calculi are calcium containing.
can still remain within the reference range in the ● Nephrotic syndrome is defined as gross proteinuria
presence of a significant decline in renal function. associated with oedema and hypoproteinaemia
● Acute kidney injury (AKI) can be due to pre-renal, (discussed further in Chapter 19). This is a disorder
renal or post-renal causes. Raised plasma urea of the renal glomerular membrane.
and creatinine concentrations occur along with ● Renal tubular disease can result in Fanconi’s
fluid retention, anuria or oliguria, hyperkalaemia, syndrome associated with acid–base and
hyperphosphataemia and metabolic acidosis. potassium disturbance, glycosuria, amino aciduria,
● End-stage chronic kidney disease (CKD5) implies hypouricaemia and hypophosphataemia.
slow, irreversible renal disease. Raised plasma ● Renal replacement therapy, such as dialysis
urea and creatinine concentrations occur initially (Fig. 3.10), may be indicated in AKI and CKD5.
58 The kidneys

Figure 3.10 A renal dialysis machine used to give renal replacement therapy in some patients with end-stage
chronic kidney disease (CKD5). Reproduced with kind permission of Pemed.
 17 Liver disorders and gallstones

Functions of the liver 252 Jaundice 263

Biochemical tests for liver disease 255 Bile and gallstones 264
Diseases of the liver 257 Investigation of suspected liver disease 266

This chapter looks at the chemical pathology of liver lobule are the portal tracts that contain branches of
and gall bladder disorders. These are common in the hepatic artery, the portal vein and bile ducts. Blood
clinical practice, and liver function tests constitute one flows from the portal tracts towards the central hepatic
of the most frequently requested clinical biochemistry vein. Therefore:
laboratory profiles.
● Hypoxia and toxins that are metabolized in the liver
FUNCTIONS OF THE LIVER cause damage to the centrilobular area first.
The liver has essential synthetic and excretory functions ● Toxins that do not depend on hepatic metabolism
and can be thought of as a large ‘metabolic factory’. It also primarily affect the periphery of the lobule.
detoxifies and, like the kidneys, excretes the end products Almost all nutrients from the gastrointestinal tract
of metabolism. The main blood supply to the liver is via pass through the sinusoidal spaces prior to entering the
the portal vein. The liver is made up of hexagonal lobules systemic circulation. The hepatic architecture may be
of cells (Fig. 17.1). Rows of hepatocytes radiate from disturbed in cirrhosis (fibrosis).
the central hepatic vein and are separated by sinusoidal
spaces, along the walls of which are interspersed hepatic General metabolic functions
macrophages, the Kupffer cells. These phagocytic cells When the glucose concentration is high in the portal
are part of the reticuloendothelial system and have an vein, it is converted to glycogen and the carbon skeletons
important detoxifying function. At the corners of each of fatty acids, which are transported to adipose tissue as
very low-density lipoprotein (VLDL). During fasting,
the systemic plasma glucose concentration is maintained
by the breakdown of glycogen (glycogenolysis) or by the
Hepatic artery
Portal vein
Bile duct synthesis of glucose from substrates such as glycerol,
lactate and amino acids (gluconeogenesis). Fatty acids
reaching the liver from fat stores may be metabolized
in the tricarboxylic acid cycle, converted to ketones or
incorporated into triglycerides (see Chapter 13).
Central
hepatic Synthetic functions
vein
Hepatocytes synthesize:
● plasma proteins, excluding immunoglobulins and
complement,
● most coagulation factors, including fibrinogen and
Portal tract factors II (prothrombin), V, VII, IX, X, XI, XII and
XIII – of these, prothrombin (II) and factors VII, IX
Figure 17.1 Diagrammatic representation of a cross- and X cannot be synthesized without vitamin K,
section of a hepatic lobule showing the relation between ● primary bile acids,
the central hepatic vein and the portal tracts. Blood flows ● the lipoproteins, such as VLDL and high-density
towards the central vein, as indicated by the arrows. lipoprotein (HDL) (see Chapter 13).
 Functions of the liver 253

The liver has a very large functional reserve. ● Many drugs – which are metabolized and inactivated
Deficiencies in synthetic function can be detected only if by enzymes of the endoplasmic reticulum system;
liver disease is extensive. Before a fall in plasma albumin some are excreted in the bile.
concentration is attributed to advanced liver disease, ● Toxins – the reticuloendothelial Kupffer cells in
extrahepatic causes must be excluded, such as the loss the hepatic sinusoids are well placed to extract
of protein through the kidney, gut or skin, or across toxic substances that have been absorbed from the
capillary membranes into the interstitial space, as in gastrointestinal tract.
even mild inflammation or infection (see Chapter 19).
Efficient excretion of the end products of metabolism
Prothrombin levels, assessed by measuring the
and of bilirubin depends on:
prothrombin time, may be reduced because of impaired
hepatic synthesis, whether due to failure to absorb ● normally functioning liver cells,
vitamin K or to hepatocellular damage. If hepatocellular ● normal blood flow through the liver,
function is adequate, parenteral administration of ● patent biliary ducts.
vitamin K may reverse the abnormality.
Formation and excretion of bilirubin (Fig. 17.2)
Excretion and detoxification
At the end of their lifespan, red blood cells are broken
The excretion of bilirubin is considered in more detail
down by the reticuloendothelial system, mainly in the
below. Other substances that are inactivated and
spleen. The released haemoglobin is split into globin,
excreted by the liver include the following:
which enters the general protein pool, and haem, which
● Cholesterol – excreted in the bile either unchanged or is converted to bilirubin after the removal of iron,
after conversion to bile acids. which is reused (see Chapter 21).
● Amino acids – which are deaminated in the liver. About 80 per cent of bilirubin is derived from haem
Amino groups, and the ammonia produced by within the reticuloendothelial system. Other sources
intestinal bacterial action and absorbed into the include the breakdown of immature red cells in the
portal vein, are converted to urea. bone marrow and of compounds chemically related to
● Steroid hormones – which are metabolized and haemoglobin, such as myoglobin and the cytochromes.
inactivated by conjugation with glucuronate and Less than 300 µmol of bilirubin is produced daily from
sulphate and excreted in the urine in these water- the breakdown of erythrocytes, while the normal
soluble forms. liver is able to conjugate up to about 1 mmol/day, and
SITE METABOLISM EXCRETION

Reticuloendothelial Haem
system

Circulation Bilirubin + albumin

Urine less than 7 µmol/day

Uptake by
ligandin

Liver Conjugation

Bile Excretion Stercobilinogen

(urobilinogen)

Intestinal tract
Faeces 170–300 µmol/day
Bacterial action

Figure 17.2 Metabolism and excretion of bilirubin.

254 Liver disorders and gallstones

therefore hyperbilirubinaemia is an insensitive index of Retention of bilirubin in plasma: jaundice

parenchymal hepatic disease. Unconjugated hyperbilirubinaemia occurs if there is:
Bilirubin is normally transported to the liver bound
to albumin. In this form it is called unconjugated ● a marked increase in the bilirubin load as a result of
bilirubin, which is lipid soluble and therefore, if not haemolysis, or of the breakdown of large amounts
protein bound, can cross cell membranes, including of blood after haemorrhage into the gastrointestinal
those forming the blood–brain barrier. In this form tract or, for example, under the skin due to extensive
it is potentially toxic; however, at physiological bruising; in cases of haemolysis, plasma bilirubin
concentrations it is all protein bound. rarely exceeds 75µmol/L,
In the adult, about 300 µmol per day of bilirubin ● impaired binding of bilirubin to ligandin or impaired
reaches the liver, where it is transferred from plasma conjugation with glucuronate in the liver.
albumin, through the permeable vascular sinusoidal
membrane. The hepatocytes can process a much In some pathological conditions, plasma
greater load than this. Bilirubin is bound to ligandin unconjugated bilirubin levels may increase so much
(Y protein). From there it is actively transported to the that they exceed the protein-binding capacity. The
smooth endoplasmic reticulum, where it is conjugated lipid-soluble, unbound bilirubin damages brain cells
with glucuronate by a process catalysed by uridine (kernicterus). This is most likely to occur in newborn,
diphosphate glucuronyl transferase. particularly premature, infants in whom the hepatic
Bilirubin monoglucuronide passes to the canalicular conjugating mechanisms are immature. In addition,
surfaces of the hepatocytes, where, after the addition of the proportion of unbound, unconjugated bilirubin,
a second glucuronate molecule, it is secreted by active and therefore the risk of cerebral damage, increases if:
processes into the bile canaliculi. This process is largely
● plasma albumin concentration is low,
dependent on the active secretion of bile acids from
● unconjugated bilirubin is displaced from binding
hepatocytes. These energy-dependent steps are the ones
sites, for example by high levels of free fatty acids or
most likely to be impaired by liver damage (hypoxia and
drugs such as salicylates or sulphonamides.
septicaemia) and by increased pressure in the biliary tract.
Other anions, including drugs, may compete for bind- Unconjugated bilirubin is normally all protein
ing to ligandin, thus impairing bilirubin conjugation and bound and is not water soluble and therefore cannot
excretion. Novobiocin inhibits glucuronyl transferase, be excreted in the urine. Patients with unconjugated
thus exacerbating unconjugated hyperbilirubinaemia. hyperbilirubinaemia do not have bilirubinuria
Bilirubin is often assayed by the Van den Bergh reaction, (‘acholuric jaundice’) such as Gilbert’s syndrome.
which allows conjugated (direct-reacting) and unconju- Conjugated bilirubinaemia is one of the earliest signs
gated (indirect-reacting) bilirubin to be distinguished. of impaired hepatic excretion. In most cases of jaundice
Bilirubin metabolism and jaundice in adults, both conjugated and unconjugated fractions
of bilirubin are increased in plasma but conjugated
Jaundice usually becomes clinically apparent when the
bilirubin predominates. Conjugated bilirubin is water
plasma bilirubin concentration reaches about 50 µmol/L
soluble and is less strongly protein bound than the
(hyperbilirubinaemia), about twice the upper reference
unconjugated form, and therefore can be excreted in the
limit. It occurs when bilirubin production exceeds the
urine. Bilirubinuria is always pathological. Dark urine
hepatic capacity to excrete it. This may be because:
may be an early sign of some forms of hepatobiliary
● An increased rate of bilirubin production exceeds disease.
normal excretory capacity of the liver (prehepatic Conjugated bilirubin enters the gut lumen in bile; it
jaundice). is broken down by bacteria in the distal ileum and the
● The normal load of bilirubin cannot be conjugated colon into a group of products known as stercobilinogen
and/or excreted by damaged liver cells (hepatic (faecal urobilinogen). Some is absorbed into the
jaundice). portal circulation, most of which is re-excreted in bile
● The biliary flow is obstructed, so that conjugated (enterohepatic circulation). A small amount enters
bilirubin cannot be excreted into the intestine and the systemic circulation and is excreted in the urine
is regurgitated into the systemic circulation (post- as urobilinogen, which can be oxidized to a coloured
hepatic jaundice). pigment, urobilin.
 Biochemical tests for liver disease 255

Urobilinogen a relatively greater increase in plasma ALT than AST

Urobilinogen, unlike bilirubin, is often detectable in activities.
the urine of normal people by testing with commercial In infiltrative disorders in which there is damage to
strip tests, particularly if the urine, and therefore the both mitochondrial and cytoplasmic membranes, there
urobilinogen, is concentrated. Urinary urobilinogen is a proportionally greater increase in plasma AST than
concentration is increased in the following situations. ALT activity.
The relative plasma activities of ALT and AST may
● When haemolysis is very severe: large amounts help to indicate the type of cell damage. The former is
of bilirubin enter the intestinal lumen and are more specific for hepatic disease; AST may be present in
converted to stercobilinogen. An increased amount skeletal muscle and is more sensitive than ALT. A plasma
of urobilinogen is formed and absorbed. If the AST:ALT ratio of > 2 is suggestive but not diagnostic of
hepatic capacity to re-secrete it is exceeded, it is alcoholic liver disease and a ratio < 1 suggests chronic
passed in the urine. viral hepatitis or hepatic steatosis (see Chapter 18).
● When liver damage impairs re-excretion of normal
amounts of urobilinogen into the bile. Hepatic synthetic function
The colourless, unabsorbed stercobilinogen is The measurement of plasma albumin and prothrombin
oxidized to stercobilin, a pigment that contributes to time may be used to assess function. The hepatic
the brown colour of faeces. Pale stools may, therefore, synthetic and secretory capacities are large; only
suggest biliary obstruction associated with an absence severe and usually prolonged liver disease, for
of urinary urobilinogen. example cirrhosis, demonstrably impairs albumin and
prothrombin synthesis.
BIOCHEMICAL TESTS FOR LIVER
DISEASE Albumin
Several biochemical tests constitute what are called the Hypoalbuminaemia is such a common finding in
‘liver function tests’. Different tests can give different many severe illnesses that it is a less specific indicator
information about hepatic dysfunction. of impaired synthetic capacity than a prolonged
prothrombin time. A plasma albumin concentration
Hepatocyte damage below the lower reference limit may imply hepatic
Strictly speaking, changes in plasma enzyme activity disease chronicity. However, there are many other
generally indicate liver cell membrane damage rather causes of a low plasma albumin concentration that are
than hepatic function capacity. Because these enzymes not due to hepatic disease (see Chapter 19).
are also present in other tissues, changes in plasma
activities may reflect damage to those tissues rather Prothrombin time
than to the liver (see Chapter 18). The prothrombin time may be prolonged by cholestasis:
fat-soluble vitamin K cannot be absorbed normally
Aminotransferases (alanine and aspartate) if fat absorption is impaired due to intestinal bile
A rise in plasma aminotransferase activities is a salt deficiency. The abnormality is then corrected by
sensitive indicator of damage to cytoplasmic and/ parenteral administration of the vitamin. A prolonged
or mitochondrial membranes. Plasma enzyme prothrombin time may also result from severe
activities rise when the membranes of only very few impairment of synthetic ability if the liver cell mass
cells are damaged. Liver cells contain more aspartate is greatly reduced; in such cases it is not corrected by
aminotransferase (AST) than alanine aminotransferase parenteral administration of vitamin K.
(ALT), but ALT is confined to the cytoplasm, in which
its concentration is higher than that of AST. Raised Hepatic excretory function
plasma transaminase concentrations are indicative of A high plasma conjugated bilirubin concentration
hepatocyte damage, but do not necessarily reveal its indicates impaired hepatic excretory function but
mechanism. as this is also raised in hepatocellular disease it is not
In inflammatory or infective conditions, such as specific for cholestasis. This may be accompanied by a
viral hepatitis, the cytoplasmic membrane sustains the high plasma alkaline phosphatase (ALP) activity, as we
main damage; leakage of cytoplasmic contents causes will now see. Jaundice has been described above.
256 Liver disorders and gallstones

Other tests for liver disease ● Reduced mass of hepatocytes, if considerable,

Alkaline phosphatase is characterized by a reduction in albumin and
Alkaline phosphatase is derived from a number of prothrombin synthesis. The plasma albumin
different tissues, including the liver, the osteoblasts concentration is reduced and the prothrombin time
in bone and the placenta. Plasma activities rise in is prolonged.
cholestatic liver disease because ALP synthesis is Urine tests useful in suspected hepatic
increased and the enzyme within the biliary tract is disease
regurgitated into plasma. A raised ALP concentration Fresh urine analysis may confirm the presence of
in the presence of a raised g-glutamyl transferase bilirubin (conjugated hyperbilirubinaemia) and
(GGT) concentration implies that the ALP is of hepatic urobilinogen
origin. Urine Multistix include stabilized, diazotized
2,4-dichloraniline, which reacts with bilirubin to form
g-Glutamyl transferase azobilirubin. The test will detect about 3 µmol/L of
g-Glutamyl transferase is an enzyme derived from the bilirubin. Drugs, such as large doses of chlorpromazine,
endoplasmic reticulum of the cells of the hepatobiliary may give false-positive results.
tract. As this reticulum proliferates, for example in Urine Multistix also include paradimethylamino-
response to the prolonged intake of alcohol and of drugs benzaldehyde, which reacts with urobilinogen. Urine
such as phenobarbital and phenytoin, synthesis of the Multistix do not react with porphobilinogen. This test
enzyme is induced and plasma GGT activity increases. will detect urobilinogen in urine from some normal
Therefore, raised plasma activities do not necessarily individuals. False-positive results may occur after
indicate hepatocellular damage, but may reflect enzyme taking drugs such as para-aminosalicylic acid and some
induction or cholestasis. sulphonamides.
Biochemical tests can be used to investigate hepatic
Bile acid measurement in obstetric
disorders, the mechanisms underlying which can be
cholestasis
divided into three main groups; these often coexist, but
one usually predominates in any particular condition Raised total plasma bile acid concentrations in the
(Table 17.1). third trimester of pregnancy associated with pruritus
are suggestive of obstetric cholestasis, which can lead
● Liver-cell damage is characterized by the release of to both maternal and fetal morbidity and mortality.
enzymes (AST and ALT) from damaged hepatocytes. Elevation of plasma ALT concentration may follow the
Plasma ALT and AST activities are increased. increase in the concentration of plasma bile salts (see
● Cholestasis is characterized by retention of Chapter 10).
conjugated bilirubin and of ALP, and by increased
ALP synthesis at the sinusoidal surface. Plasma New hepatic function tests
conjugated bilirubin levels and ALP activities are Owing to the very large hepatic reserve, tests for
increased. impairment of metabolic (including synthetic and

Table 17.1 Typical biochemical features of certain hepatic disorders

Plasma albumin Bilirubin ALT ALP GGT

Acute alcoholic hepatitis – ≠ ≠ ≠ ≠≠
Acute viral hepatitis – ≠≠ ≠≠ ≠ ≠≠
Chronic viral hepatitis – or Ø ≠ or – ≠ ≠ or – ≠
Cirrhosis Ø ≠ or – ≠ ≠ ≠
Gilbert’s syndrome – ≠ – – –
Primary biliary cirrhosis – or Ø ≠≠ ≠ ≠≠ ≠≠
Tumour secondaries – ≠ or – ≠ ≠≠ ≠≠
≠, raised; –, normal; Ø, reduced.
ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, g-glutamyl transferase.
 Diseases of the liver 257

secretory) function are relatively insensitive indicators Patients with prolonged and more widespread
of liver disease. There are a number of new tests that are cholestasis may present with severe jaundice and
being devised to improve the accuracy of the diagnosis pruritus due to the deposition of retained bile salts in
of hepatic disorders. Tests of hepatocellular activity have the skin; the plasma bilirubin concentration may be
been proposed, such as galactose elimination capacity, more than 800 µmol/L. More rarely, there is bleeding
the aminopyrine breath test, indocyanine green due to malabsorption of vitamin K, with consequent
clearance, and monoethylglycinexylidide (MEGX) prothrombin deficiency. Cholesterol retention may
production. All these tests are indirect measures of cause hypercholesterolaemia. Dark urine and pale
hepatic activity that rely on measuring compounds or stools suggest biliary retention of conjugated bilirubin.
their metabolites after they have been acted on by the The jaundice caused by extrahepatic obstruction due
liver. As yet, they do not have a place in routine clinical to malignant tissue is typically painless and progressive,
diagnosis. but there may be a history of vague persistent back pain
and weight loss. By contrast, intraluminal obstruction
DISEASES OF THE LIVER by a gallstone may cause severe pain, which, like the
Cholestasis jaundice, is often intermittent. Gallstones may not
Cholestasis may be either: always cause such symptoms. If a large stone lodges in
the lower end of the common bile duct, the picture may
● intrahepatic, in which bile secretion from the
be indistinguishable from that of malignant obstruction.
hepatocytes into the canaliculi is impaired, due to:
Although most of the findings are directly
– viral hepatitis,
attributable to cholestasis, biliary back pressure may
– drugs such as chlorpromazine or toxins such as
damage hepatocytes, and plasma aminotransferase
alcohol,
activities may increase. Unless the cause is clinically
– inflammation of the biliary tract (cholangitis),
obvious, evidence of dilated ducts due to extrahepatic
– autoimmune disease (primary biliary
obstruction should be sought using tests such as
cirrhosis),
ultrasound, computerized tomography (CT) scanning
– cystic fibrosis,
or cholangiography.
● extrahepatic, due to obstruction to the flow of bile

through the biliary tract by: Primary biliary cirrhosis

– biliary stones,
This is a rare autoimmune disorder that occurs most
– inflammation of the biliary tract,
commonly in middle-aged women. Destruction and
– pressure on the tract from outside by malignant
proliferation of the bile ducts produce a predominantly
tissue, usually of the head of the pancreas,
cholestatic picture, with pruritus and a plasma ALP
– biliary atresia (rare).
activity that may be very high. Jaundice develops late in
It is essential to distinguish between intrahepatic
most patients. Mitochondrial antibodies are detectable
and extrahepatic causes of cholestasis, as surgery may
in the plasma of more than 90 per cent of cases; the
be indicated for the latter but is usually contraindicated
plasma immmunoglobulin M (IgM) concentration
for intrahepatic lesions. The biochemical findings may
is usually raised. Patients may also manifest
be similar:
hypercholesterolaemia, xanthelasma (see Chapter 13),
● Bilirubin concentrations in plasma may be normal other autoimmune disorders and osteoporosis.
if only part of the biliary system is involved by
intrahepatic lesions such as cholangitis, early Parenteral nutrition
primary biliary cirrhosis or primary or secondary Prolonged parenteral nutrition may be associated
tumours. The unaffected areas can secrete with a progressive increase in plasma ALP activity
bilirubin. and a subsequent rise in the plasma aminotransferase
● Alkaline phosphatase activity is a sensitive test concentrations. The cause is not known, although
for cholestasis. Increased synthesis of ALP in the biliary sludging may occur and the biochemical changes
affected ducts increases the activity of this enzyme in may return to normal when the parenteral feeding is
plasma. If this is the only abnormal finding, it must discontinued. Cyclical parenteral nutrition may help
be shown to be of hepatic origin before it is assumed the situation when patients are fed intermittently (see
to indicate liver disease. Chapter 14).
258 Liver disorders and gallstones

CASE 1 CASE 2
A 52-year-old woman was referred to the hepatology A 22-year-old woman who was an intravenous drug
clinic because of jaundice, pruritus, hepatomegaly, addict was referred to the hepatology clinic because
xanthelasma and the following abnormal liver test of the following abnormal liver test results:
results: Plasma
Plasma Bilirubin 93 µmol/L (< 20)
Bilirubin 93 µmol/L (< 20) Alanine aminotransferase 761 U/L (< 42)
Alanine aminotransferase 111 U/L (< 42) Alkaline phosphatase 306 U/L (< 250)
Alkaline phosphatase (ALP) 826 U/L (< 250) Albumin 44 g/L (35–45)
Albumin 34 g/L (35–45) g-Glutamyl transferase 324 U/L (< 55)
g-Glutamyl transferase (GGT) 764 U/L (< 55) Urinary bilirubin positive.
She had a positive test result for anti-mitochondrial Further investigations, including hepatitis screen,
antibodies. showed her to be hepatitis B positive.
DISCUSSION DISCUSSION
Subsequent studies, including liver biopsy, showed Note the grossly elevated plasma aminotransferase
the patient to have primary biliary cirrhosis. Note activities, indicative of extensive hepatocyte damage.
the predominant cholestatic biochemical picture Intravenous drug addicts are at increased risk
with raised plasma ALP and GGT activities. This of hepatitis B infection. The urinary bilirubin is
condition is associated with hyperlipidaemia, hence positive, as the hyperbilirubinaemia is predominantly
the xanthelasma, and is more common in middle- conjugated, that is, water soluble.
aged women with other autoimmune disorders.
There may also be raised plasma IgM concentration
more sporadically than hepatitis A. It has a longer
and osteoporosis and osteomalacia.
incubation period, of between 40 and 180 days.
Some patients may be anicteric; some may develop
Acute hepatitis fulminant hepatitis or chronic active hepatitis and
The biochemical findings in acute hepatitis are later cirrhosis and hepatocarcinoma. They may
predominantly those of cell membrane damage with an become asymptomatic carriers of the disease.
increase in plasma ALT activity greater than that of AST. ● Hepatitis C (non-A, non-B hepatitis), which may be
There may be a superimposed cholestatic picture and, the result of sexual transmission or the transfusion
in very severe cases, impaired prothrombin synthesis. of blood products, has an incubation period of
between 15 and 50 days. It may progress to cirrhosis.
Viral hepatitis
In all types there may be a 3- to 4-day history of
Viral hepatitis may be associated with many viral anorexia, nausea and tenderness or discomfort over the
infections, such as infectious mononucleosis (Epstein– liver before the onset of jaundice. Some patients remain
Barr virus), rubella and cytomegalovirus. However, the anicteric. Plasma aminotransferase activities are very
term is most commonly used to describe three principal high from the onset of symptoms; they peak about
types of viral infection in which the clinical features of 4 days later, when jaundice becomes detectable, but
the acute illness are very similar, although they have a may remain elevated for several months. Once jaundice
different incubation period: appears, some of the initial symptoms improve.
● Hepatitis A (‘infectious hepatitis’), transmitted by In the early stages there is often a cholestatic
the faecal–oral route as a food-borne infection, is element, with pale stools due to reduced intestinal
relatively common in schools and other institutions bilirubin, and dark urine due to a rise in plasma
and has an incubation period of between 15 and 45 conjugated bilirubin concentration; unconjugated
days. Relapses may occur, but it rarely progresses to bilirubin concentrations also increase due to impaired
chronic hepatitis. hepatocellular conjugation.
● Hepatitis B (‘serum hepatitis’) is transmitted by Plasma bilirubin concentrations rarely exceed
blood products and other body fluids; it occurs 350 µmol/L, and the plasma ALP activity is only
 Diseases of the liver 259

moderately raised, or even normal. If hepatocellular after exposure to the virus in about 50 per cent of
damage is severe and extensive, the prothrombin time patients.
may be increased and, in patients with cholestasis, It should be noted that there are other possible
malabsorption of vitamin K may be a contributory viruses that can cause liver dysfunction such as hepatitis
factor. D and E. Hepatitis D is a ribonucleic acid (RNA)
subviral satellite and needs hepatitis B to propagate,
Serological findings
while hepatitis E is a RNA virus spread more commonly
Testing for viral antigens, or for antibodies synthesized by the oral–faecal route.
in response to the virus, can be used to diagnose viral
hepatitis. Alcoholic hepatitis
Hepatitis A viral (HAV) antibodies of the IgM class Alcoholic hepatitis occurs in heavy drinkers, often
are detectable in the plasma of patients at the onset of after a period of increased alcohol intake. Although
symptoms. The presence of an IgG anti-HAV antibody the clinical features may mimic acute viral hepatitis,
is suggestive of previous infection. Most cases of the plasma aminotransferase activities and bilirubin
hepatitis A recover completely. concentration are not usually as markedly elevated,
Hepatitis B viral (HBV) infection, during the although GGT may be.
prodromal illness, can be diagnosed by the presence in There is no perfect laboratory marker of alcohol
the plasma of a viral surface antigen (HBsAg) and a core abuse. A raised mean corpuscular red cell volume
antigen (HBe), an internal component of the virus. These (MCV), hypertriglyceridaemia, hyperuricaemia and
antigens are short lived. During the next few weeks, elevated plasma GGT are clues, but are not specific.
an antibody response occurs, with the appearance of Increased plasma desialylated or carbohydrate-
plasma antibodies to the viral core (anti-HBc), to HBe deficient transferrin of greater than 2 per cent or
and finally to the surface antibody (anti-HBs), which raised plasma sialic acid levels have been proposed as
may be used to document previous infection (Fig. 17.3). markers of alcohol abuse, as sialic acid metabolism may
The presence of the HBe antigen correlates with be perturbed in the presence of high concentrations
infectivity, and its disappearance is a good prognostic of alcohol. Note that the consumption of more than
sign; HBsAg may persist, especially in patients with an 80 g a day of alcohol may raise GGT concentrations,
impaired immune response, and indicates chronicity not necessarily by hepatic damage, but by enzyme
associated with raised plasma aminotransferase activities. induction.
Hepatitis C viral (HCV; non-A, non-B hepatitis)
infection is often diagnosed by exclusion. Anti-HCV Drugs and other toxins
anti-bodies may be detected in plasma about 12 weeks
Various drugs and other toxins are hepatotoxic,
sometimes directly and sometimes due to a
hypersensitivity reaction; in the latter case, the damage
is not dose related. The clinical picture may resemble
Plasma ALT
that of acute viral hepatitis or cholestasis. A drug
U/L

history is an essential part of the assessment of a patient

presenting with liver disease. Table 17.2 lists some of
SYMPTOMS these agents.
Anti-HBc
Chronic hepatitis
HBsAg
Titre

The finding of persistent, (usually only slightly) raised

Anti-HBs
plasma aminotransferase activities, sometimes with
0 1 2 3 4 5 6 7 8 9 10
chronic or recurrent symptoms suggesting liver disease,
Time after infection (months) may be due to several disorders. It may be the only
abnormal biochemical finding.
Figure 17.3 Serological and biochemical changes
following infection with hepatitis B virus. anti-HBc,
Chronic persistent hepatitis
antibody to the viral core; anti-HBs, antibody to viral
surface; ALT, alanine aminotransferase; HBsAg, viral This is a term used to describe the finding of raised
surface antigen. plasma aminotransferase activities without clinical
260 Liver disorders and gallstones

Table 17.2 Some drug effects on the liver

Hepatic necrosis Acute hepatitis-like Chronic hepatitis Cholestasis

reaction
Carbamazepine +
Chlorambucil + +
Chlorpromazine +
Cytotoxic drugs + a

Erythromycin +
Ferrous sulphate +a
Halothane + + +
Indometacin +
Isoniazid + +
Methotrexate +
Methyldopa + + + +
Nitrofurantoin + + +
Paracetamol + a
+
Phenothiazines +
Phenylbutazone + +
Phenytoin +
Salicylate (aspirin) + a

17-a-alkylated steroids (oral contraceptives) +

Statins, e.g. simvastatin + +
Valproate + +
a
Indicates that the damage is dose dependent and predictable.

signs or symptoms and without a significant change muscle and antinuclear antibodies. As the disease
in activity over many years. The activities rarely exceed progresses, more cells are destroyed and the plasma AST
three times the upper reference limits. Jaundice is activity may rise to or exceed that of ALT; slight jaundice
unusual. may develop. If there is significant hepatocellular
destruction, the plasma albumin concentration falls.
Chronic active hepatitis
This is caused by active hepatocellular destruction with Cirrhosis
episodes of relapses and remissions. It may progress to Cirrhosis is the end result of many inflammatory
cirrhosis. It occurs at any age, but is most common in and metabolic diseases involving the liver, including
women. It may: prolonged toxic damage, usually due to alcohol. In
‘cryptogenic cirrhosis’, the cause is unknown. The
● be associated with, or a consequence of, viral
fibrous scar tissue distorts the hepatic architecture,
infections such as HBV or HCV, or may be drug
and regenerating nodules of hepatocytes disrupt the
induced,
blood supply, sometimes increasing the pressure in the
● be part of an autoimmune process that sometimes
portal vein, causing portal hypertension. Blood may be
involves more than one organ,
shunted from the portal into the hepatic vein, bypassing
● have no obvious cause.
the liver.
The earliest findings that differentiate it from In the early stages there may be no abnormal
chronic persistent hepatitis are an increasing plasma biochemical findings. During phases of active cellular
IgG concentration, perhaps detected by a rising plasma destruction, the plasma AST, and sometimes ALT,
g-globulin concentration, and the presence of smooth activities rise. In advanced cases, the biochemical
 Diseases of the liver 261

Table 17.3 Child–Pugh scores for severity of cirrhosis

CASE 3
Grade Plasma Plasma Ascites/ INR
A 50-year-old known alcoholic man attended the bilirubin albumin encephalopathy
general medical clinic because of ascites and the (µmol/L) (g/L)
following abnormal liver test results: A Normal > 35 None < 1.7
Plasma B 34–50 28–35 Mild 1.7–2.3
Bilirubin 52 µmol/L (< 20) C >50 < 28 Severe > 2.3
Alanine aminotransferase 76 U/L (< 42) INR, international normalized ratio.
Alkaline phosphatase 271 U/L (< 250)
Albumin 18 g/L (35–45)
g-Glutamyl transferase 324 U/L (< 55) follow an overdose of a liver toxin such as paracetamol
(acetaminophen). The biochemical findings may
DISCUSSION
include any or all of those of acute hepatitis. Jaundice is
The abnormal liver test results and
progressive. In the final stage, the number of hepatocytes,
hypoalbuminaemia together with ascites supported
and so the total amount of aminotransferases released,
the diagnosis of cirrhosis, secondary to his alcohol
may be so reduced that plasma activities fall despite
problem. Hypoalbuminaemia may be due to many
continuing damage to the remaining cells. This finding
disorders, such as gross proteinuria, but in the
should not be interpreted as a sign of recovery. Other
presence of hepatic disease suggests a reduction in
features may include the following:
hepatic synthetic capacity typical of cirrhosis.
● Hypovolaemia and hypotension, which are due to
loss of circulating fluid in ascites and in the oedema
findings are mostly associated with a reduced fluid formed because of hypoalbuminaemia, and
functioning cell mass. The vascular shunting allows which may be aggravated by vomiting. The resultant
antigenic substances, which have been absorbed from low renal blood flow may have two consequences:
the intestine, to bypass the normal hepatic sinusoidal – increased antidiuretic hormone (ADH) and
filtering process, and to stimulate increased synthesis secondary hyperaldosteronism, causing elec-
of IgG and IgA, producing the typical serum protein trolyte disturbances, especially hypokalaemia,
electrophoretic pattern of b–g fusion (see Chapter 19). and sometimes dilutional hyponatraemia (see
Portal hypertension and impaired lymphatic Chapter 2),
drainage lead to the accumulation of fluid in the – renal circulatory insufficiency, causing oliguria,
peritoneal cavity (ascites). This may be aggravated by a high plasma creatinine concentration and
hypoalbuminaemia, which may also cause peripheral uraemia despite reduced urea synthesis.
oedema. In advanced cirrhosis, the findings of ● Impaired hepatic deamination of amino acids, causing
hepatocellular failure develop. accumulation of amino acids in plasma with overflow
There are a number of causes of ascites including amino aciduria and sometimes hyperammonaemia.
cirrhosis, malignancy or infection, nephrotic syndrome, If the reduced formation of urea from amino acids is
hypothyroidism, pancreatitis and cardiac failure. not balanced by renal retention due to the decrease
Primary hepatocellular carcinoma may develop in a in glomerular filtration rate (GFR), the plasma urea
cirrhotic liver. concentration may be low.
The Child–Pugh classification system is a way of ● Impairment of hepatic gluconeogenesis may cause
grading the severity of cirrhosis in the face of portal hypoglycaemia.
hypertension (Table 17.3). Survival for patients with
Treatment of end-stage liver disease
grade C cirrhosis is usually less than 1 year.
Liver transplantation may be the only possible treatment
Hepatocellular failure and hepatic for end-stage liver disease. Complications include graft
encephalopathy failure, hepatic artery thrombosis, infection and acute
Liver damage severe enough to cause obvious clinical and chronic rejection. Both acute rejection (which
signs of impaired hepatocellular function may be occurs in up to 80 per cent of recipients) and chronic
caused by severe hepatitis or advanced cirrhosis, or may rejection (occurring in about 10 per cent of cases) are
262 Liver disorders and gallstones

associated with a rise in plasma bilirubin concentration

and ALP activity; chronic rejection may be irreversible. CASE 4
The indications for hepatic transplantation may include A 70-year-old man with known colonic carcinoma,
prolonged prothrombin time and plasma bilirubin operated on 2 years previously, was found by his
more than 300 µmol/L. general practitioner to have the following liver test
Hepatic infiltration and malignant disease results:
Invasion of the liver by secondary carcinoma, or Plasma
infiltration by lymphoma or granulomas such Bilirubin 33 µmol/L (< 20)
as sarcoidosis, may be associated with abnormal Alanine aminotransferase 62 U/L (< 42)
biochemical tests. Sometimes the only abnormal Alkaline phosphatase (ALP) 408 U/L (< 250)
finding is raised plasma AST activity; the ALT activity Albumin 35 g/L (35–45)
may also be raised to a lesser extent or there may be g-Glutamyl transferase (GGT) 527 U/L (< 55)
GGT elevation. The picture may reflect cholestasis, An abdominal ultrasound scan showed multiple
with or without jaundice. space-occupying lesions within the liver.
Metabolic function is rarely demonstrably impaired.
DISCUSSION
If a primary hepatocellular carcinoma develops,
either in a cirrhotic liver or de novo, the plasma The patient was eventually found to have widespread
aminotransferase and ALP activities usually rise rapidly, hepatic secondaries from his colonic tumour and
and plasma a-fetoprotein concentrations are often very died a few months later. The combination of raised
high; this latter finding is not diagnostic of primary plasma ALP and GGT activities is suggestive of
hepatic malignancy (see Chapter 24). hepatic space-occupying lesions, particularly in the
absence of major cholestasis.
Metabolic liver disease
A group of rare metabolic disorders, most of which
are inherited, is associated with liver disease, especially
cirrhosis.
CASE 5
A healthy 43-year-old man, on no medication, had
Haemochromatosis the following results from tests performed during a
Idiopathic haemochromatosis is a genetically private healthcare screening programme:
determined disorder in which slightly increased Plasma
intestinal absorption of iron over many years produces Bilirubin 43 µmol/L (< 20)
large iron deposits of parenchymal distribution, Unconjugated bilirubin 36 µmol/L (< 5)
including the liver (see Chapter 21). Alanine aminotransferase 21 U/L (< 42)
Alkaline phosphatase 126 U/L (< 250)
a1-Antitrypsin deficiency
Albumin 40 g/L (35–45)
a1-Antitrypsin deficiency (see Chapter 19) is γ-Glutamyl transferase 24 U/L (< 55)
associated with neonatal hepatitis in individuals with Urinary bilirubin negative.
the PiZZ phenotype, which progresses to cirrhosis Normal full blood count, reticulocytes, plasma
in childhood. The condition can also present in haptoglobin concentration and blood film.
adulthood, and often there is basal emphysema
DISCUSSION
particularly in smokers (Fig. 17.4).
The raised concentration of plasma bilirubin is
Galactosaemia predominantly unconjugated. There is no evidence
of haemolysis and the other liver function tests are
This autosomal recessive disorder, due most
normal. A likely diagnosis is of Gilbert’s syndrome.
commonly to a deficiency of galactose-1-phosphate
This is a common condition and its diagnosis is based
uridyltransferase, may cause cirrhosis of the liver if
on the exclusion of liver disease and haemolysis in the
untreated. Liver transplantation may be indicated if
presence of a modest concentration of unconjugated
hepatocellular carcinoma, a complication of cirrhosis,
hyperbilirubinaemia.
develops (see Chapter 27).
 Jaundice 263

Wilson’s disease Non-alcoholic steatotic hepatitis or fatty liver

This is a rare, recessively inherited disorder caused by Non-alcoholic fatty liver disease (NAFLD) refers to
reduced biliary excretion of copper and by impaired a spectrum of liver disease ranging from fatty liver
hepatic incorporation of copper into caeruloplasmin. (steatosis) to non-alcoholic steatotic hepatitis (NASH)
The symptoms are due to the excessive accumulation through to cirrhosis (irreversible, fibrosis and scarring).
of copper in the liver, brain and kidneys and present This is associated with insulin resistance (see Chapter
with evidence of acute liver failure, chronic hepatitis 12). It is one of the most common causes of abnormal
or cirrhosis in children or in young adults (see also liver function tests. Plasma aminotransferases are
Chapter 14). usually raised and may relate to body mass index. It is
important to exclude other liver disorders, and hepatic
Reye’s syndrome ultrasound may show increased echogenicity of the liver.
This rare disorder presents as acute hepatitis, associated The biochemical features of NAFLD may improve with
with marked encephalopathy, severe metabolic acidosis dietary measures and treatment of hyperlipidaemia
and hypoglycaemia in children typically between (see Chapter 13).
the ages of 3 and about 12 years. There is acute fatty
infiltration of the liver. The plasma aminotransferase Hepatorenal syndrome
activities are high, but plasma bilirubin levels are only This syndrome occurs when cirrhosis and often portal
slightly raised. hypertension presents in conjunction with renal
The aetiology is uncertain, but the condition may be dysfunction. It is thought to be due to impaired renal
precipitated by viral infections, such as influenza A or perfusion due to vasoconstriction of renal arteries.
B, drugs such as salicylates and sodium valproate, and Usually the creatinine clearance is less than 40 mL/min
certain toxins; it has been recommended that children and plasma creatinine is greater than about 130 µmol/L,
should not be given aspirin. One possible mechanism with a urine volume of less than 500 mL/day and
is that there is uncoupling of mitochondrial oxidative urinary sodium less than 10 mmol/L.
phosphorylation. A number of inherited metabolic
disorders, particularly those involving fatty acid
Drugs and liver fibrosis
oxidation, may present with a Reye-like syndrome in
children under the age of about 3 years. Some drugs such as methotrexate can cause hepatic
fibrosis. Conventional liver function tests are insensitive
to liver fibrosis. Increased serum procollagen-3
N-terminal peptide (P3NP) is a marker of fibrosis and
may reduce the need for liver biopsy.

JAUNDICE
Haemolytic jaundice
There are many causes of haemolysis, including sickle-
cell anaemia, thalassaemia and spherocytosis, and it
can also be drug or autoimmune induced. In adults,
unconjugated hyperbilirubinaemia is usually mild
because of the large reserve of hepatic secretory capacity.
The plasma bilirubin concentration is usually less than
70 µmol/L. Erythrocytes contain high amounts of AST
and lactate dehydrogenase (LDH1 and LDH2) (see
Chapter 18). Blood reticulocytes may be raised, with
Figure 17.4 Patient with severe a1-antitrypsin
abnormal blood film and a low plasma haptoglobin
deficiency, showing hepatosplenomegaly, who
developed cirrhosis and oesophageal varices. concentration. A haemolytic component may be seen
Reproduced with kind permission from Nyhan WL and in alcoholic hepatitis known as Zieve’s syndrome.
Barshop BA. Atlas of Inherited Metabolic Diseases, Urinary bilirubin concentration is usually not raised in
3rd edition. London: Hodder Arnold, 2012. haemolysis (acholuric jaundice).
264 Liver disorders and gallstones

Jaundice in the newborn infant Diagnosis of Gilbert’s syndrome is by exclusion

Red cell destruction, together with immature hepatic of haemolysis and other hepatic disorders. It should
processing of bilirubin, may cause a high plasma level be remembered that sometimes thyrotoxicosis
of unconjugated bilirubin in the newborn infant; so- can cause raised unconjugated bilirubin due to
called physiological jaundice is common. Normal full- reduced UGT activity and so can reabsorption of a
term babies may show jaundice between days 2 and 8 large haematoma due to haemoglobin breakdown.
of life. Prolonged fasting (48 h with calorie intake restricted
Physiological jaundice rarely exceeds 100 µmol/L. to 300 kcal/day) may result in a rise, predominantly
Jaundice on the first day of life is invariably pathological, in the unconjugated bilirubin fraction, of around
as are levels of bilirubin exceeding 100 mmol/L or if 100 per cent if Gilbert’s syndrome is present.
the hyperbilirubinaemia is conjugated. As a result Increases are also seen after the administration of
of haemolytic disease, the plasma concentration of 50 mg intravenous nicotinic acid. However, these
unconjugated bilirubin may be as high as 500 µmol/L dynamic tests are not without side effects and are
and may exceed the plasma protein-binding capacity; rarely used.
free unconjugated bilirubin may be deposited in the Crigler–Najjar syndrome
brain, causing kernicterus. Neonatal jaundice and its This is due to a rare deficiency of hepatic UGT, and is
treatment are discussed more fully in Chapter 26. a more serious condition. It usually presents at birth.
The plasma unconjugated bilirubin may increase to
The inherited hyperbilirubinaemias concentrations that exceed the binding capacity of
There is a group of inherited disorders in which either albumin and so cause kernicterus. The defect may
unconjugated or conjugated hyperbilirubinaemia is the be complete (type I), and inherited as an autosomal
only detectable abnormality. recessive condition, or partial (type II), and inherited
as an autosomal dominant condition.
Unconjugated hyperbilirubinaemia In type II drugs that induce enzyme synthesis,
Gilbert’s syndrome such as phenobarbital, may reduce plasma bilirubin
concentration.
This is a relatively common (3–7 per cent of the
population) familial condition, which may be present Conjugated hyperbilirubinaemia
at any age but usually develops after the second decade. Dubin–Johnson syndrome
Plasma unconjugated bilirubin concentrations are This is probably harmless and is due to defective
usually between 20 µmol/L and 40 µmol/L and rarely excretion of conjugated bilirubin, but not of bile acids.
exceed 80 µmol/L. They fluctuate, and may rise during It is characterized by slightly raised plasma conjugated
intercurrent illness, dehydration, menstruation and bilirubin levels that tend to fluctuate. Because the
fasting. The condition is probably harmless but must bilirubin is conjugated, it may be detectable in the
be differentiated from haemolysis and liver disease. urine. Plasma ALP activities are normal. There may
It often becomes evident when plasma bilirubin be hepatomegaly, and the liver is dark brown in
concentrations fail to return to normal after an attack appearance due to the presence of a pigment with the
of hepatitis, or during any mild illness, which, because staining properties of lipofuscin. The diagnosis may be
of the jaundice, may be misdiagnosed as hepatitis. confirmed by the characteristic staining of a specimen
Conjugated bilirubin is less than 20 per cent of the obtained by liver biopsy.
total bilirubin.
Rotor’s syndrome
Mutations in the hepatic uridine diphosphate
glucuronyl transferase (UGT) gene are present, but Rotor’s syndrome is similar in most respects to Dubin–
not all patients with the polymorphism develop the Johnson syndrome, but the liver cells are not pigmented
phenotype. Hepatic UGT activity is decreased to (Box 17.1).
approximately 30 per cent of normal in individuals
with Gilbert’s syndrome. Decreased activity has been BILE AND GALLSTONES
attributed to an expansion of thymine–adenine repeats Bile acids and bile salts
in the promoter region of the UGT1A1 gene, the Four bile acids are produced in humans. Two of these,
principal gene encoding this enzyme. cholic acid and chenodeoxycholic acid, are synthesized
 Bile and gallstones 265

Box 17.1 Some of the causes of jaundice

Conjugated hyperbilirubinaemia
Drugs, e.g. see Table 17.2
Infections, e.g. hepatitis, cytomegalovirus, Epstein– Primary bile acids Cholate Chenodeoxycholate
Barr virus, sepsis
Damage to bile ducts, e.g. primary biliary cirrhosis, Taurine/glycine
sclerosing cholangitis conjugates
Alcohol, haemochromatosis, Wilson’s disease
Gallstones, cholangiocarcinoma, bile duct strictures,
pancreatic tumours Deconjugation by
intestinal bacteria
Metabolic disorders, e.g. a1-antitrypsin, Reye’s syndrome,
fatty liver, intrahepatic cholestasis of pregnancy
Diffusion infiltration, e.g. sarcoid, lymphoma, amyloid Secondary bile acids Deoxycholate Lithocholate
Inborn errors, e.g. Dubin–Johnson syndrome, Rotor’s
Figure 17.5 Synthesis of bile acids in the liver and
syndrome
their conversion to secondary bile salts in the intestine.
Unconjugated hyperbilirubinaemia
Physiological jaundice of the newborn
Gilbert’s syndrome
Crigler–Najjar syndrome isosmotic amount of water. Consequently, gall bladder
Haemolysis bile is 10 times more concentrated than hepatic bile;
Rarely thyrotoxicosis sodium is the major cation and bile salts the major
anions. The concentrations of other non-absorbable
molecules, such as conjugated bilirubin, cholesterol
in the liver from cholesterol and are called primary and phospholipids, also increase.
bile acids. They are secreted in bile as sodium salts, Gallstones
conjugated with the amino acid glycine or taurine
(primary bile salts). These are converted by bacteria Although most gallstones contain all biliary
within the intestinal lumen to the secondary bile salts, constituents, they consist predominantly of one.
deoxycholate and lithocholate, respectively (Fig. 17.5). Only about 10 per cent contain enough calcium to be
Secondary bile salts are partly absorbed from the radio-opaque and in this way they differ from renal
terminal ileum and colon and are re-excreted by the liver calculi. They can be shown on gall bladder ultrasound
(enterohepatic circulation of bile salts). Therefore, bile (Fig. 17.6).
contains a mixture of primary and secondary bile salts.
Deficiency of bile salts in the intestinal lumen leads
to impaired micelle formation and malabsorption of
fat (see Chapter 13). Such deficiency may be caused by
cholestatic liver disease (failure of bile salts to reach the
intestinal lumen) or by ileal resection or disease (failure
of reabsorption causing a reduced bile salt pool). Bile
salts are also important biochemical modulators and
activate various nuclear receptors.
Formation of bile
Between 1 L and 2 L of bile is produced daily by the
liver. This hepatic bile contains bilirubin, bile salts,
phospholipids and cholesterol, as well as electrolytes Figure 17.6 Ultrasound of the gall bladder
in concentrations similar to those in plasma. Small demonstrating a cluster of gallstones (arrowed).
amounts of protein are also present. Reproduced with kind permission from Kinirons M and
In the gall bladder there is active reabsorption of Ellis H. French’s Index of Differential Diagnosis, 15th
sodium, chloride and bicarbonate, together with an edition. London: Hodder Arnold, 2011.
266 Liver disorders and gallstones

Pigment stones colic, obstructive jaundice (Table 17.4), which is

Pigment stones are found in such chronic haemolytic usually intermittent, or acute pancreatitis if the
states as hereditary spherocytosis. Increased breakdown pancreatic duct is also occluded.
of haemoglobin increases bilirubin formation and ● Rarely, gallstones may be associated with gallstone
therefore biliary secretion. The stones consist mostly of ileus or carcinoma of the gall bladder.
bile pigments, with variable amounts of calcium. They
are small, hard and dark green or black, and are usually Treatment of gallstones
multiple. Rarely, they contain enough calcium to be The most common treatment for symptomatic gallstones
radio-opaque. is cholecystectomy, either open or laparoscopic. The
following are some alternative approaches:
Cholesterol gallstones
● Dissolving the gallstone: the bile acid ursodeoxycholic
Cholesterol is most likely to precipitate if bile is acid reduces the relative saturation of bile with
supersaturated with it; further precipitation on a cholesterol and so facilitates dissolving cholesterol
nucleus of crystals causes progressive enlargement. stones, particularly small, uncalcified ones.
Not all patients with a high biliary cholesterol ● Shock-wave lithotripsy: the stone is shattered into tiny
concentration suffer from bile stones. Changes in fragments and can then pass through the cystic duct.
the relative concentrations of different bile salts may
favour precipitation. The stones may be single or INVESTIGATION OF SUSPECTED LIVER
multiple. They are described as mulberry-like and DISEASE
are either white or yellowish; the cut surface appears The commonly available biochemical laboratory
crystalline. tests for the diagnosis of liver disease involve the
There is no clear association between measurement of plasma levels of:
hypercholesterolaemia and the formation of cholesterol
gallstones, although both may be more common in ● bilirubin – excretory function,
obese individuals. However, there may be an increased ● aminotransferases (ALT and/or AST) – hepatocellular
incidence in patients taking some lipid-lowering drugs, damage,
such as the fibric acid derivatives. ● alkaline phosphatase – cholestasis,
● albumin and/or prothrombin time – synthetic
Mixed stones function,
Most gallstones contain a mixture of bile constituents, ● g-glutamyl transferase – enzyme induction,
usually with a cholesterol nucleus as a starting point. cholestasis or hepatocellular damage.
They are multiple-faceted, dark-brown stones with a The initial selection of investigations depends on the
hard shell and a softer centre and may contain enough age of the patient, the history and clinical features.
calcium to be radio-opaque.
Jaundice as a presenting feature (Fig. 17.7)
Consequences of gallstones
Whereas a patient with chronic liver disease may present
Gallstones may remain silent for an indefinite length with jaundice, the differential diagnosis of jaundice with
of time and be discovered only at laparotomy for an bilirubinuria (due to conjugated bilirubin) in a previously
unrelated condition. They may, however, lead to various
clinical consequences. Table 17.4 Some causes of obstructive jaundice or
cholestasis
● Biliary colic.
● Acute cholecystitis: obstruction of the cystic duct Dilated ducts/mechanical Undilated ducts/non-mechanical
by a gallstone causes chemical irritation of the gall obstruction (extrahepatic) obstruction (intrahepatic)
bladder mucosa by trapped bile and secondary Gallstones Primary biliary cirrhosis
bacterial infection. Pancreatic carcinoma Primary sclerosing cholangitis
● Chronic cholecystitis may also be associated with
Pancreatic duct stricture Cholestatic drug reaction
gallstones.
Cholangiocarcinoma
● Obstruction of the common bile duct occurs if a stone
lodges in it. The patient may present with biliary Parasite infections
 Investigation of suspected liver disease 267

Hyperbilirubinaemia

Predominantly unconjugated Predominantly conjugated

bilirubin bilirubin

Exclude drug causes (see Table 17.2) Exclude drug causes (see Table 17.2)

Yes No Yes No

Evidence of haemolysis? Evidence of

hepatocellular disease?

Yes No
Yes No
Consider
Gilbert’s syndrome Evidence of
or rare causes in intrahepatic cholestasis?
Box 17.1

Yes No
(see Table 17.4)
Evidence of
extrahepatic cholestasis?

Yes No
(see Table 17.4)
Consider rare causes
(see Box 17.1)
Figure 17.7 Algorithm for the investigation of jaundice in an adult.

well patient is usually between acute hepatocellular – signs of liver decompensation such as liver flap,
damage and cholestasis. A suggested scheme is as follows ‘liver palms’, spider naevi, ascites etc.
(for neonatal jaundice, see Chapter 26): ● Measure plasma bilirubin and unconjugated/
conjugated bilirubin fractions:
● When taking the history pay special attention to: – Predominantly unconjugated hyperbilirubi-
– recent exposure to hepatitis or infectious naemia with plasma conjugated bilirubin
mononucleosis, including a sexual and levels less than about 10 per cent of the total,
occupational history, and with little or no bilirubinuria, may suggest
– recent administration of blood or blood haemolysis as a cause. Haemolysis is supported
products, by a raised reticulocyte count and diagnostic
– medication and alcohol intake (see Table 17.2), blood film, reduced plasma haptoglobin
– intravenous drug abuse or tattoos, and raised plasma lactate dehydrogenase
– associated symptoms such as abdominal pain, concentrations.
pruritus, weight loss or anorexia and nausea, – If haemolysis is excluded, consider Gilbert’s
– recent changes in the colour of the urine or syndrome provided other liver tests are normal
stools, and other hepatic disorders have been excluded.
– recent foreign travel. ● A fresh urine sample should be examined. This test
● On clinical examination, look for: may show the presence of bilirubin if conjugated
– severity of jaundice, hyperbilirubinaemia is present. Dark-yellow or
– hepatomegaly and splenomegaly, brown urine suggests biliary obstruction. An absence
268 Liver disorders and gallstones

of urinary urobilinogen is seen in biliary obstruction. – alcohol intake and medication history, for
Reagent strips are available for testing for bilirubin example paracetamol,
and urobilinogen in urine. – the presence, or history, of other autoimmune
● Pale stools suggest biliary obstruction as a cause of disorders,
jaundice. – jaundice, pruritus or features of malabsorption,
● Whatever the results of the urine and stool inspection – family history of liver disease.
and testing, request plasma aminotransferase, ALP ● Request tests for plasma bilirubin, aminotransferases
and GGT assays: (ALT and AST), albumin, GGT and ALP:
– In hepatitis, there is a predominant increase in – A raised plasma ALT activity higher than that
the concentrations of plasma aminotransferases; of the AST may be due to reversible alcoholic
usually the plasma ALT activity is higher than hepatitis, to chronic persistent hepatitis, or to
the AST activity. If hepatitis or infectious early chronic active hepatitis.
mononucleosis is suggested by the history, – A raised plasma AST activity higher than
request serological tests. that of ALT may be due to cirrhosis or severe
– In cholestasis, there is predominant elevation chronic active hepatitis.
of the plasma ALP and GGT activities. Bile duct – A high plasma ALP activity with raised GGT
dilatation should be sought using ultrasound concentration suggests cholestasis.
or other radiological tests: – Aminotransferase levels of more than 10 times
• if the bile ducts are dilated, there is normal suggest primary hepatocyte damage, as
obstruction that may require surgery, in viral hepatitis or caused by drugs/toxins.
• if the plasma ALP activity is high but ● An alcohol-related aetiology is supported by a
dilated ducts are not demonstrated, there is macrocytosis and plasma GGT concentration, but
probably intrahepatic cholestasis. neither test is fully diagnostic. See above.
● Other tests, such as ferritin and iron saturation ● Check hepatitis serology, for example A, B and C.
(haemochromatosis), and autoantibody (such as ● Detectable plasma mitochondrial or smooth-muscle
smooth muscle, p-anti-neutrophil cytoplasmic antibodies are suggestive of primary biliary cirrhosis
antigen, mitochondrial, nuclear antibodies) and or chronic active hepatitis, respectively.
immunoglobulin levels, may also be indicated. ● A raised plasma ferritin concentration with high
● If acute alcoholic hepatitis is suspected, contributory iron saturation (see Chapter 21) may reveal
evidence may be the finding of a disproportionately haemochromatosis.
high plasma GGT activity compared with those of the ● Plasma protein electrophoresis and immunoglobulin
aminotransferases. There may also be macrocytosis, assay may help in the diagnosis of:
hypertriglyceridaemia and hyperuricaemia. – cirrhosis – high plasma IgG and IgA
● In obstructive jaundice (biliary obstruction), the plasma concentrations causing b–g fusion on the
ALP is usually more than four to five times and GGT electrophoretic strip,
more than 10 times normal. Liver/biliary ultrasound is – alcoholic cirrhosis – may present with raised
useful to distinguish between obstructive jaundice with IgA concentration,
dilated biliary ducts or undilated ducts. Endoscopic – chronic active hepatitis – a high plasma IgG
retrograde cholangiopancreatography (ERCP) or concentration and normal IgA,
percutaneous cholangiography may be indicated. – primary biliary cirrhosis – a high plasma IgM
● If the diagnosis is in doubt, a liver biopsy may be concentration.
indicated, although there may be a risk of bleeding A low plasma albumin concentration (hypo-
and therefore the prothrombin time should be albuminaemia) in the face of abnormal liver function
measured beforehand. tests can be seen in cirrhosis implying chronicity.
● A prolonged prothrombin time implies poor hepatic
Suspected liver disease showing abnormal synthetic capacity, for example clotting factors, and
plasma hepatic enzymes is prognostic in paracetamol overdose. It is also
● Relevant points in the clinical evaluation are: important if a liver biopsy is considered.
– a previous history of hepatitis, intravenous ● Significant infiltration of the liver by tumour
drug use, occupational and sexual history, cells, or by granulomas such as sarcoidosis
 Investigation of suspected liver disease 269

(possibly with raised plasma angiotensin- and type 2 diabetes mellitus or impaired glucose
converting enzyme activity), may occur. In this regulation.
situation raised plasma AST activity may be the ● If primary hepatocellular carcinoma is suspected,
most sensitive test, despite a normal plasma ALT the plasma a-fetoprotein level may also be high.
activity. Hepatic space-occupying lesions may ● Low plasma copper and caeruloplasmin
additionally present with raised GGT and ALP concentrations may suggest Wilson’s disease (see
concentrations, and a liver ultrasound is useful to Chapter 15), and plasma a1-antitrypsin deficiency
detect these. can result in cirrhosis (see Chapter 19).
● A fatty liver may be revealed by liver ultrasound ● Radionuclide scans or other imaging procedures
as this may show increased echogenicity. This may (CT or MRI) may be useful. A liver biopsy may be
be associated with hypertriglyceridaemia, obesity indicated to clarify a histological diagnosis.

SUMMARY
● The liver has an enormous synthetic capacity and is ● Raised plasma aminotransferase activities suggest
involved in numerous metabolic pathways, including hepatocyte damage and raised hepatic ALP
vitamin storage, amino acid deamination, bile salt and concentration is associated with cholestasis.
cholesterol synthesis, and the production of various ● Plasma GGT is a sensitive marker of hepatic
proteins such as clotting factors and hormones. damage but its activity can also be raised as a result
● Compounds ‘released’ from the liver into the plasma of drug enzyme induction, hypertriglyceridaemia
can be used as markers of liver damage, including and increased alcohol intake.
bilirubin, ALT, AST, GGT and ALP. ● A prolonged prothrombin time and low plasma
● Hyperbilirubinaemia can be due to raised albumin concentration may both reflect reduced
unconjugated or conjugated bilirubin concentration. hepatic synthetic capacity.
The former may be due to haemolysis and the latter
to hepatic or extrahepatic causes.