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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 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
Hypercholemia
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.
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.
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.
Failure to Thrive
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