Background

Cholestasis is defined as a decrease in bile flow due to impaired secretion by

hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts.
Therefore, the clinical definition of cholestasis is any condition in which
substances normally excreted into bile are retained. The serum concentrations of
conjugated bilirubin and bile salts are the most commonly measured.

Not all substances normally excreted into bile are retained to the same extent in
various cholestatic disorders. In some conditions, serum bile salts may be
markedly elevated while bilirubin is only modestly elevated and vice versa.
However, demonstrable retention of several substances is needed to establish a
diagnosis of cholestasis. Only in rare disorders of bilirubin metabolism (eg,
Dubin-Johnson syndrome, Rotor syndrome) does an isolated increase in the serum
concentration of conjugated bilirubin appear, so increased serum conjugated
bilirubin indicates cholestasis. The histopathologic definition of cholestasis is the
appearance of bile within the elements of the liver, usually associated with
secondary cell injury.

Pathophysiology

The mechanisms of cholestasis can be broadly classified into hepatocellular,

where an impairment of bile formation occurs, and obstructive, where impedance
to bile flow occurs after it is formed. The typical histopathologic features of
hepatocellular cholestasis include the presence of bile within hepatocytes and
canalicular spaces, in association with generalized cholate injury. Typical of
obstructive cholestasis is bile plugging of the interlobular bile ducts, portal
expansion, and bile duct proliferation in association with centrilobular cholate
injury. [1]
Bile is a highly complex water-based medium containing inorganic ions and many
classes of organic amphiphiles, the formation of which involves multiple
mechanisms and levels of regulation. The transport of solute into the canaliculus
by specific transporters creates chemical and osmotic gradients and promotes
water flow by a paracellular pathway. Several of these specific transporters have
been identified, and their function has been characterized. The identification of
defective transporters in some familial cholestatic disorders has led to improved
understanding of the molecular mechanisms of human cholestasis. [2, 3, 4]

Redundancies in the mechanisms of solute transport that result in bile formation

are noted. From what is currently known about the process, seemingly few, if any,
of the known transporters are absolutely essential in the process. Therefore, the
absence or impairment of a single transporter is not expected to result in failure of
bile formation. Instead, a process of amplification is required to produce clinical
cholestasis. A primary mechanism of amplification is the retention of hydrophobic
bile salts, strong detergents that cause membrane injury and impairment of
membrane function. Retained bile salts down-regulate new bile acid synthesis,
which results in a reduction of the bile salt pool and in reduced enterohepatic
recirculation.

Retention of cholesterol results in increased cholesterol content of membranes that

reduces their fluidity and impairs the function of integral membrane proteins.
These amplification mechanisms result in further retention of damaging
substances, accelerated membrane injury and dysfunction, and ultimately,
generalized failure of the excretory mechanism for bile. This converging pathway
makes the differentiation of cholestatic diseases on clinical grounds very difficult.

Obstructive cholestasis is usually the result of physical obstruction of the biliary

system at the level of the extrahepatic bile ducts. However, obstruction or paucity
of small bile ducts can result in functional obstruction of the entire biliary system.
This may be the mechanism involved in the cholestasis observed in Alagille
syndrome, which is associated with heart, skeleton, eye, kidney, and facial
manifestations. The prognosis mainly depends on the severity of the liver and
heart diseases.

Retention of bile salts results in injury to biological membranes throughout the

body. The liver is most affected. The retention of hydrophobic bile salts results in
their incorporation into membranes, which alters membrane fluidity and function.
Bile salt injury of hepatocyte membranes is an important amplifier of cholestasis.
The retention of secondary cholestatic bile acids, such as lithocholic acid, results
in further membrane injury.

Owing to an immaturity of hepatobiliary function, the number of distinct disorders

presenting with cholestatic jaundice may be greater during the neonatal period
than at any other period. The differential diagnosis of cholestasis in neonates and
infants is therefore much broader than in older children and adults. This is because
the immature liver is relatively sensitive to injury, and the response of the
immature liver is more limited. Cholestasis develops in response to a wide variety
of insults. Although the reasons for this are not entirely clear, it is considered the
result of immaturity of several critical mechanisms of bile formation. So-called
physiologic cholestasis of infancy results from immaturity of these mechanisms.
Early enteral feedings as tolerated is the best way to prevent and manage
cholestasis in preterm infants. [5]

The effects of cholestasis are profound and widespread. Although the principal
effects involve the function of the liver and intestine, secondary effects can
involve every organ system. The primary effects are bile retention, regurgitation
of bile into serum, and reduction in bile delivery to the intestine. These result in
secondary effects that lead to worsening liver disease and systemic illness.
Retention of Conjugated Bilirubin and Its Regurgitation Into Serum

Excretion of conjugated bilirubin is the rate-limiting step of bilirubin clearance.

During cholestasis, conjugation of bilirubin continues but excretion is reduced.
The mechanism by which conjugated bilirubin regurgitates into serum is unclear,
but it may differ according to the disease etiology. In hepatocellular cholestasis,
where bile formation is reduced, conjugated bilirubin is likely to efflux directly
from the hepatocyte via diffusion or vesicular exocytosis. On the other hand, in
obstructive cholestasis, conjugated bilirubin possibly enters the canalicular space
and effluxes back through a weakened tight junction.

The presence of elevated serum concentration of conjugated bilirubin is a

principal sign of cholestasis. It results in jaundice, which can be detected by
scleral icterus at a concentration as low as 2 mg/dL, and by dark urine. The
concentration of conjugated bilirubin is affected by the rate of production of
bilirubin, the degree of cholestasis, and alternate pathways of elimination,
principally renal excretion. The magnitude of elevation is not diagnostically
important because it does not reflect the type or degree of cholestasis. For
example, whereas other investigations clearly indicate that patients with neonatal
giant cell hepatitis typically have more bile flow than patients with biliary atresia,
the serum conjugated bilirubin concentration is usually higher in neonatal giant
cell hepatitis. This probably reflects an increase in bilirubin production.

Alternate elimination pathways, principally by way of the kidneys, limit the

absolute elevation of conjugated bilirubin. Conjugated bilirubin concentration
rarely exceeds 30 mg/dL, although such elevated levels can occur. Because
conjugated bilirubin is relatively weakly bound to albumin, it can dissociate
relatively easily and be filtered into the urine. The parents of children with
cholestasis frequently report dark urine or a stained diaper, and examination of the
urine is a useful starting point in the evaluation of an infant with jaundice.
Increased Serum Concentration of Nonconjugated Bilirubin

Increased serum concentration of nonconjugated bilirubin is present in most

patients with cholestasis. The rate of bilirubin conjugation is probably reduced by
end-product inhibition or as the result of hepatocyte injury. The rate of bilirubin
production may also be increased as the result of hemolysis that can accompany
cholestasis.

Newer methods of measuring bilirubin in serum have resulted in the discovery of

a fraction of serum bilirubin that is covalently bound to albumin, known as delta
bilirubin or biliprotein. This fraction may account for a large proportion of total
bilirubin in patients with cholestatic jaundice but is absent in patients with
nonconjugated hyperbilirubinemia.

Hypercholemia

Hypercholemia, or increased serum bile salt concentration, is a universal

consequence of cholestasis. The transport of bile salts from plasma to bile is the
principal driving force for bile formation. Failure to transport bile salts may be a
principal mechanism of cholestasis or may be a consequence of the effects of
cholestasis on hepatocyte function. In either case, the liver cell retains bile salts,
resulting in down-regulation of new bile acid synthesis and in an overall reduction
in the total pool size. Bile salts are regurgitated from the hepatocyte, which results
in an increase in the concentration of bile salts in the peripheral circulation.
Furthermore, the uptake of bile salts entering the liver in portal vein blood is
inefficient, which results in spillage of bile salts into the peripheral circulation.

Overall, patients with cholestasis have an increase in serum concentration of bile

salts, an increase in hepatocyte concentration of bile salts, a decrease of bile salts
in the enterohepatic circulation, and a decrease in the total bile salt pool size.
Pruritus

One very common clinical consequence of cholestasis is pruritus. Several links to

its pathogenesis have been proposed, including the role of bile acids, endogenous
opioid and serotonins, and lysophosphatidic acid. The mechanism of pruritus in
liver disease is not entirely understood, and major debate concerns its relationship
to the retention of bile salts. The serum or tissue concentrations of bile salts do not
correlate well with the degree of pruritus, although all patients with pruritus
related to liver disease have significant elevations of serum bile salts. Therapeutic
approaches that reduce pruritus generally also reduce serum bile salt
concentrations.

Newer theories suggest that patients have differing sensitivities to elevated bile
salt concentrations, which act on peripheral pain afferent nerves to produce the
sensation of itching. This stimulation involves opiate-mediated pathways, and
opiate antagonists can block cholestasis-associated itching. Itching does not
appear to be associated with histamine release, and antihistamine therapy is
generally ineffective. Ultraviolet B phototherapy has been successfully used to
treat pruritus.

Decock et al have reported that ultraviolet B phototherapy appears to be a

promising and well-tolerated treatment for cholestasis-associated pruritus. [6]

For patients with cholestasis, pruritus may be a minimal problem, or it may

seriously impair the quality of life. Scratching is the most measurable effect of
pruritus. The degree of pruritus can be quantitated by clinical findings related to
scratching, which has been useful in monitoring patient response to therapy.

Hyperlipidemia
Hyperlipidemia is characteristic of some but not all cholestatic diseases. Serum
cholesterol is elevated in cholestasis because its metabolic degradation and
excretion are impaired. Bile is the normal excretory pathway for cholesterol, and
with reduced bile formation, cholesterol is retained. Cholesterol retention can
cause an increase in membrane cholesterol content and a reduction in membrane
fluidity and membrane function, thereby amplifying the cholestasis. Furthermore,
bile salts are the metabolic products of cholesterol, and in cholestasis, synthesis of
bile salts is reduced. Much of plasma cholesterol is in the form of lipoprotein-X,
an abnormal lipoprotein observed only in the serum of patients with cholestasis.

The contribution of dietary cholesterol to the elevated serum cholesterol in

patients with cholestasis is probably minimal, and limiting the diet in order to
reduce serum cholesterol is not justified because that maneuver may have
secondary effects on nutrition. Furthermore, the use of oral bile salt–binding
agents, such as cholestyramine, has little effect on serum cholesterol in this
setting. Agents that block the synthesis of cholesterol have been used sparingly in
cholestasis and cannot be recommended at this time. The proper approach to
treating hypercholesterolemia in cholestatic liver disease is to treat the liver
disease itself.

Xanthomas

Xanthomas may result from the deposition of cholesterol into the dermis. The
development of xanthomas is more characteristic of obstructive cholestasis than of
hepatocellular cholestasis. Xanthomas may develop rapidly over a few months in
acute extrahepatic biliary obstruction. Acutely developing xanthomas are usually
the eruptive type, which are white pustular lesions pinpoint to 2 mm in diameter,
that appear first on the trunk and in the diaper area. See the image below.

Eruptive xanthomas. Courtesy of Duke University Me

Eruptive xanthomas. Courtesy of Duke University Medical Center.

Failure to Thrive

One of the major clinical effects of cholestasis, particularly chronic cholestasis, is

failure to thrive. The mechanisms of failure to thrive include malabsorption,
anorexia, poor nutrient use, hormonal disturbances, and secondary tissue injury.
Malabsorption in cholestatic liver disease results from reduced delivery of bile
salts to the intestine, which results in inefficient digestion and absorption of fats.
Digestion is affected because bile salts are important for the function of bile salt–
dependent lipase activity and the stabilization of the lipase-colipase complex. In
addition, bile salts are important in stabilization of lipid emulsions, which is
important for increasing the surface area on which lipase works.

Absorption is inefficient because of reduced formation of intestinal micelles,

which are important for removing the end products of lipolysis and effecting their
absorption. The result of these events is the malabsorption of fat and fat-soluble
vitamins.

Malabsorption of fat results in the loss of a source of calories that is important in

infant nutrition. Furthermore, the delivery of fat into the colon can result in
colonic secretion and diarrhea. Adults with fat malabsorption often experience
anorexia. This may also occur in infants, but more often, infants take increased
amounts of formula to compensate for loss of calories. Finally, the loss of fat into
the stool also results in calcium wasting through the formation of calcium soaps of
fatty acids. This may play an important role in bone disease in children and adults
with chronic cholestasis.

The treatment of fat malabsorption principally involves dietary substitution. In

older patients, a diet that is rich in carbohydrates and proteins can be substituted
for a diet containing long-chain triglycerides. In infants, substitution may not be
possible, and the substitution of a formula containing medium-chain triglycerides
may improve fat absorption and nutrition.

The malabsorption of fat-soluble vitamins can result in vitamin deficiency states.

Vitamins E, D, K, and A are all malabsorbed in cholestasis, and in that order. [7]
Vitamin E deficiency can result in peripheral neuropathy and possibly hemolysis.
Vitamin D deficiency results in osteomalacia and rickets. Vitamin K deficiency
causes coagulopathy and possibly reduced brain development. Vitamin A
deficiency does not result in clinical disease in cholestasis. In chronic cholestasis,
careful attention must be paid to prevent fat-soluble vitamin deficiencies. This is
accomplished by administering fat-soluble vitamins and monitoring the response
to therapy.

Epidemiology

Mortality/Morbidity

Cholestasis is not a primary cause of death. However, it is the cause of

considerable morbidity as indicated above in Pathophysiology.

Sex

No clear difference in the incidence of cholestasis between males and females is

observed. Incidence is equal in most genetic diseases leading to cholestasis.
However, several conditions have a female dominance, including biliary atresia,
[8] drug-induced cholestasis, and of course, cholestasis of pregnancy.

Age

Cholestasis is observed in people of every age group. However, newborns and

infants are more susceptible and more likely to develop cholestasis as a
consequence of immaturity of the liver.
Young gestational age, low birth body weight, more sepsis episodes, and long
duration of parenteral nutrition are risk factors associated with parenteral
nutrition-associated cholestasis. [9]