Cholestasis

Definisi: penghentian atau supresi aliran empedu, dengan penyebab intrahepatik atau
ekstrahepatik
Etiologi
Within the Liver: Causes include acute hepatitis, alcoholic liver disease, primary biliary cirrhosis with inflammation and scarring of the bile ducts,
cirrhosis due to viral hepatitis B or C ), drugs, hormonal effects on bile flow during pregnancy (a condition called cholestasis of pregnancy (see ),
and cancer that has spread to the liver
Outside the Liver: Causes include a stone in a bile duct, narrowing (stricture) of a bile duct, cancer of a bile duct, cancer of the pancreas, and
inflammation of the pancreas (pancreatitis)
Causes
!bstructive cholestasis
o Biliary atresia
o Congenital bile duct anomalies (choledochal cysts)
o Cholelithiasis
o "rimary sclerosing cholangitis
o #nfectious cholangitis (cholangitis)
o Cholangitis associated with $angerhans cell histiocytosis
o Cholestasis with ductal paucity
o %lagille syndrome
o &onsyndromic ductal paucity
o Ductopenic allograft re'ection
(epatocellular cholestasis
o (epatitis (hepatitis %, hepatitis B, hepatitis C)
o %lpha)*antitrypsin deficiency
o #nborn errors of bile acid synthesis
o Drug*induced cholestasis
o +otal parenteral nutrition (+"&),associated cholestasis
o "rogressive familial intrahepatic cholestasis
"atofisiologi
) (epatoselular - ter'adi kesalahan saat pembentukan empedu
%danya empedu dalam sel hepatosit dan sel kanalikuli, ada hubungannya dengan asam
kolat
. !bstruktif - ter'adi kesulitan aliran empedu saat empedu sudah terbentuk
Symptoms
/aundice, dark urine, light*colored stools, and generali0ed itchiness are characteristic symptoms of cholestasis /aundice results from e1cess
bilirubin deposited in the skin, and dark urine results from e1cess bilirubin e1creted by the kidneys 2etention of bile products in the skin may
cause itching, with subse3uent scratching and skin damage 4tools may become light*colored because the passage of bilirubin into the intestine
is blocked 4tools may contain too much fat (a condition called steatorrhea) because bile cannot enter the intestine to help digest fat in foods
5atty stools may be foul*smelling +he lack of bile in the intestine also means that calcium and vitamin D 4!6E +2%DE &%6E4
4EE E27!C%$C#5E2!$
are poorly absorbed #f cholestasis persists, a deficiency of these nutrients can cause loss of bone tissue 8itamin 9, which is needed for blood
clotting, is also poorly absorbed from the intestine, causing a tendency to bleed easily
"rolonged 'aundice due to cholestasis produces a muddy skin color and fatty yellow deposits in the skin :hether the person has other
symptoms, such as abdominal pain, loss of appetite, vomiting, or fever, depends on the cause of cholestasis
Diagnosis
% doctor tries to determine whether the cause is within or outside the liver on the basis of symptoms and the results of a physical e1amination
2ecent use of drugs that can cause cholestasis suggests a cause within the liver 4mall, spiderlike blood vessels visible in the skin, an enlarged
spleen, and fluid in the abdominal cavity (ascites), which are signs of chronic liver disease, also suggest a cause within the liver
5indings that suggest a cause outside the liver include certain kinds of abdominal pain (such as intermittent pain in the upper right side of the
abdomen and sometimes also in the right shoulder ) and an enlarged gallbladder (felt during the physical e1amination or detected by imaging
studies)
4ome findings do not indicate whether the cause is within or outside the liver +hey include heavy alcohol intake, loss of appetite, nausea, and
vomiting
+ypically, the blood levels of two en0ymes, alkaline phosphatase and gamma*glutamyl transpeptidase, are very high in people with cholestasis %
blood test that measures the level of bilirubin indicates the severity of the cholestasis but not its cause %n imaging study, usually
ultrasonography, is almost always done if blood test results are abnormal Computed tomography (C+) or sometimes magnetic resonance
imaging (62#) may be done in addition to or instead of ultrasonography #f the cause appears to be within the liver, a liver biopsy (see Diagnostic
+ests for $iver, 7allbladder, and Biliary Disorders: Biopsy of the $iver) may be done and usually establishes the diagnosis #f the cause appears to
be blockage of the bile ducts, more precise images of these ducts are usually needed +ypically, either endoscopic retrograde
cholangiopancreatography (E2C") or magnetic resonance cholangiopancreatography (62C") is done 62C" uses magnetic resonance imaging
(see 4ymptoms and Diagnosis of Digestive Disorders: Computed +omography and 6agnetic 2esonance #maging) #n E2C", a contrast agent is
in'ected and 1*rays are taken
Treatment
% blockage of the bile ducts can usually be treated with surgery or endoscopy (using a fle1ible viewing tube with surgical instruments attached) %
blockage within the liver may be treated in various ways depending on the cause #f a drug is the suspected cause, the doctor stops its use #f
acute hepatitis is the cause, cholestasis and 'aundice usually disappear when hepatitis has run its course % person with cholestasis is advised to
avoid or stop using any substance that is to1ic to the liver, such as alcohol and certain drugs
Cholestyramine 4!6E +2%DE &%6E4
;<E4+2%&
, taken by mouth, can be used to treat itchiness +his drug binds with certain bile products in the intestine, so they cannot be reabsorbed to irritate
the skin <nless the liver is severely damaged, taking vitamin 9 can improve blood clotting 4upplements of calcium and vitamin D 4!6E
+2%DE &%6E4
4EE E27!C%$C#5E2!$
are often taken if the cholestasis persists, but they are not very effective in preventing loss of bone tissue
Pathophysiology
+he 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 +he typical
histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and
canalicular spaces, in association with generali0ed cholate in'ury +ypical of obstructive cholestasis is bile
plugging of the interlobular bile ducts, portal e1pansion, and bile duct proliferation in association with
centrilobular cholate in'ury
Bile is a highly comple1 water*based medium containing inorganic ions and many classes of organic
amphiphiles, the formation of which involves multiple mechanisms and levels of regulation +he transport of
solute into the canaliculus by specific transporters creates chemical and osmotic gradients and promotes
water flow by a paracellular pathway 4everal of these specific transporters have been identified, and their
function has been characteri0ed +he identification of defective transporters in some familial cholestatic
disorders has led to improved understanding of the molecular mechanisms of human cholestasis +his
sub'ect was recently reviewed in depth
2edundancies in the mechanisms of solute transport that result in bile formation are noted 5rom what is
currently known about the process, seemingly few, if any, of the known transporters are absolutely
essential in the process +herefore, the absence or impairment of a single transporter is not e1pected to
result in failure of bile formation #nstead, a process of amplification is re3uired to produce clinical
cholestasis % primary mechanism of amplification is the retention of hydrophobic bile salts, strong
detergents that cause membrane in'ury and impairment of membrane function 2etained bile salts down*
regulate new bile acid synthesis, which results in a reduction of the bile salt pool and in reduced
enterohepatic recirculation
2etention of cholesterol results in increased cholesterol content of membranes that reduces their fluidity
and impairs the function of integral membrane proteins +hese amplification mechanisms result in further
retention of damaging substances, accelerated membrane in'ury and dysfunction, and ultimately,
generali0ed failure of the e1cretory mechanism for bile +his converging pathway makes the differentiation
of cholestatic diseases on clinical grounds very difficult
!bstructive cholestasis is usually the result of physical obstruction of the biliary system at the level of the
e1trahepatic bile ducts, often by a stone or tumor (owever, obstruction or paucity of small bile ducts can
result in functional obstruction of the entire biliary system +his may be the mechanism involved in the
cholestasis observed in %lagille syndrome, which is associated with heart, skeleton, eye, kidney, and facial
manifestations
2etention of bile salts results in in'ury to biological membranes throughout the body +he liver is most
affected +he retention of hydrophobic bile salts results in their incorporation into membranes, which alters
membrane fluidity and function Bile salt in'ury of hepatocyte membranes is an important amplifier of
cholestasis +he retention of secondary cholestatic bile acids, such as lithocholic acid, results in further
membrane in'ury Bile salts may be a mediator of hepatic fibrosis as well #n'ury to 2BCs can result in spur*
cell hemolytic anemia
6any patients with chronic cholestasis have an asthmalike syndrome, which may be 3uite severe and
unresponsive to conventional asthma therapy :hee0ing disappears with effective therapy of cholestasis,
which suggests that it is a secondary event +he authors= opinion is that retention of bile salts results in
irritation of respiratory membranes and the asthmalike picture "atients with chronic cholestasis also have
fre3uent nosebleeds, probably from the same mechanism +hese patients may have life*threatening
nosebleeds without abnormal coagulation parameters and with no clinically apparent anatomic problem in
the nasal airway
+he differential diagnosis of cholestasis in neonates and infants is much broader than in older children and
adults +his is because the immature liver is relatively sensitive to in'ury, and the response of the immature
liver is more limited Cholestasis develops in response to a wide variety of insults %lthough the reasons for
this are not entirely clear, it is considered the result of immaturity of several critical mechanisms of bile
formation 4o*called physiologic cholestasis of infancy results from immaturity of these mechanisms +his is
better termed physiologic hypercholemia and is characteri0ed by the elevation of serum bile salt
concentrations in healthy infants to a level e3ual to many adults with pathologic cholestasis
+his developmental condition probably helps to establish the infant=s sensitivity to various insults that would
not produce cholestasis in adults, such as gram*negative sepsis, heart failure, metabolic disease, and
e1posure to minimally to1ic substances
Because of this, looking beyond the liver for the cause of cholestasis in newborns or young infants is wise
#f no other cause is found and liver disease is suspected, a more focused diagnostic investigation can be
undertaken
+he effects of cholestasis are profound and widespread %lthough the principal effects involve the function
of the liver and intestine, secondary effects can involve every organ system +he primary effects are bile
retention, regurgitation of bile into serum, and reduction in bile delivery to the intestine +hese result in
secondary effects that lead to worsening liver disease and systemic illness +he retention of bile
constituents results in > clinically important events
Retention of conjugated bilirubin and its regurgitation into serum
E1cretion of con'ugated bilirubin is the rate*limiting step of bilirubin clearance During cholestasis,
con'ugation of bilirubin continues but e1cretion is reduced +he mechanism by which con'ugated bilirubin
regurgitates into serum is unclear, but it may differ according to the disease etiology #n hepatocellular
cholestasis, where bile formation is reduced, con'ugated bilirubin is likely to efflu1 directly from the
hepatocyte via diffusion or vesicular e1ocytosis !n the other hand, in obstructive cholestasis, con'ugated
bilirubin possibly enters the canalicular space and efflu1es back through a weakened tight 'unction
+he presence of elevated serum concentration of con'ugated bilirubin is a principal sign of cholestasis #t
results in 'aundice, which can be detected by scleral icterus at a concentration as low as . mg?d$, and by
dark urine +he concentration of con'ugated bilirubin is affected by the rate of production of bilirubin, the
degree of cholestasis, and alternate pathways of elimination, principally renal e1cretion +he magnitude of
elevation is not diagnostically important because it does not reflect the type or degree of cholestasis 5or
e1ample, whereas other investigations clearly indicate that patients with neonatal giant cell hepatitis
typically have more bile flow than patients with biliary atresia, the serum con'ugated bilirubin concentration
is usually higher in neonatal giant cell hepatitis
)
+his probably reflects an increase in bilirubin production
%lternate elimination pathways, principally by way of the kidneys, limit the absolute elevation of con'ugated
bilirubin Con'ugated bilirubin concentration rarely e1ceeds @A mg?d$, although such elevated levels can
occur Because con'ugated bilirubin is relatively weakly bound to albumin, it can dissociate relatively easily
and be filtered into the urine +he parents of children with cholestasis fre3uently report dark urine or a
stained diaper, and e1amination of the urine is a useful starting point in the evaluation of an infant with
'aundice
Increased serum concentration of nonconjugated bilirubin
#ncreased serum concentration of noncon'ugated bilirubin is present in most patients with cholestasis +he
rate of bilirubin con'ugation is probably reduced by end*product inhibition or as the result of hepatocyte
in'ury +he rate of bilirubin production may also be increased as the result of hemolysis that can
accompany cholestasis
&ewer 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 +his fraction may
account for a large proportion of total bilirubin in patients with cholestatic 'aundice but is absent in patients
with noncon'ugated hyperbilirubinemia +his comple1 is formed in plasma by a nonen0ymatic process that
involves acyl migration of bilirubin from its glucuronide ester with the formation of an amide linkage
between ) propionic acid side chain and a lysine residue of plasma albumin +he presence of large
3uantities of delta bilirubin indicates long*standing cholestasis %ny amount of delta bilirubin in cord blood
or the blood of a newborn is an important sign indicating cholestasis that antedates birth
Hypercholemia
(ypercholemia, or increased serum bile salt concentration, is a universal conse3uence of cholestasis +he
transport of bile salts from plasma to bile is the principal driving force for bile formation 5ailure to transport
bile salts may be a principal mechanism of cholestasis or may be a conse3uence of the effects of
cholestasis on hepatocyte function #n 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 si0e Bile salts are
regurgitated from the hepatocyte, which results in an increase in the concentration of bile salts in the
peripheral circulation 5urthermore, 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
2educed flu1 of bile salts into bile results in reduced delivery into the intestine and reduced enterohepatic
recirculation Because the movement of bile salts in the enterohepatic circulation represents the ma'or
driving force for bile formation, the degree of cholestasis is amplified by these events
!verall, 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 si0e
Pruritus
!ne very common clinical conse3uence of cholestasis is pruritus +he mechanism of pruritus in liver
disease is not entirely understood, and ma'or debate concerns its relationship to the retention of bile salts
+he 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 +herapeutic
approaches that reduce pruritus generally also reduce serum bile salt concentrations &ewer 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 +his stimulation involves opiate*mediated
pathways, and opiate antagonists can block cholestasis*associated itching #tching does not appear to be
associated with histamine release, and antihistamine therapy is generally ineffective
5or patients with cholestasis, pruritus may be a minimal problem, or it may seriously impair the 3uality of
life 4cratching is the most measurable effect of pruritus +he degree of pruritus can be 3uantitated by
clinical findings related to scratching, which has been useful in monitoring patient response to therapy
4cratching leads to abrasions and skin mutilation in some patients 4econdary skin infections can occur
Constantly Bscratching the unscratchable itchB has serious conse3uences +hese children e1perience loss
of sleep, attention deficits, poor school performance, and a form of hyperkinesis that may have importance
regarding energy balance +he psychological ramifications have not been reported, but older children
e1press helplessness and can become suicidal <nremitting and untreatable pruritus can be an indication
for liver transplantation
+he effects of pruritus are age*dependent +he authors are often asked why young infants with cholestasis
do not itch Confidently, the response is that they do itch but are developmentally incapable of scratching
4cratching involves the use of arms, forearms, and fingers in a coordinated motion that occurs at a typical
fre3uency +he ability to scratch is not yet developed in young infants
+he cutaneous signs of scratching begin to appear, usually around the ears or the nasal bridge, in infants
aged >*C months 5rom there, they e1pand over the head, then the trunk, and finally to the limbs by the
time the baby reaches age ).*)D months +he mutilating scratching observed in older patients does not
appear until well after the first birthday +he fact that young infants do not scratch does not mean that they
do not itch Cholestatic babies are often irritable and do not sociali0e well Eoung infants with those signs
almost invariably proceed to scratching as they age, and irritability probably represents their response to
pruritus
Hyperlipidemia
(yperlipidemia is characteristic of some but not all cholestatic diseases 4erum cholesterol is elevated in
cholestasis because its metabolic degradation and e1cretion are impaired Bile is the normal e1cretory
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 5urthermore, bile salts are the metabolic products of
cholesterol, and in cholestasis, synthesis of bile salts is reduced 6uch of plasma cholesterol is in the form
of lipoprotein*F, an abnormal lipoprotein observed only in the serum of patients with cholestasis #ts
centrifugation density is similar to a low*density lipoprotein, but the structure is very different #t has a high
phospholipid and albumin content and a platelike rouleau structure when viewed under the electron
microscope
+he marked elevation of serum cholesterol observed in children with cholestasis, which often e1ceeds
),AAA mg?d$ and sometimes can be as high as D,AAA mg?d$, probably does not have as great an effect on
the cardiovascular system as a similar elevation of low*density lipoprotein in familial hypercholesterolemia
+his may be because of the packaging of cholesterol into lipoprotein*F, which lacks the surface protein
constituents necessary to interact with vascular endothelium %lthough it should be considered in a
therapeutic strategy, the potential for cardiovascular disease is probably low 5ew studies of children with
chronic cholestasis have demonstrated accelerated cardiovascular disease
+he 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 'ustified because that
maneuver may have secondary effects on nutrition 5urthermore, the use of oral bile salt,binding agents,
such as cholestyramine, has little effect on serum cholesterol in this setting %gents that block the synthesis
of cholesterol have been used sparingly in cholestasis and cannot be recommended at this time +he
proper approach to treating hypercholesterolemia in cholestatic liver disease is to treat the liver disease
itself
Xanthomas
Fanthomas may result from the deposition of cholesterol into the dermis +he development of 1anthomas is
more characteristic of obstructive cholestasis than of hepatocellular cholestasis Fanthomas may develop
rapidly over a few months in acute e1trahepatic biliary obstruction %cutely developing 1anthomas are
usually the eruptive type, which are white pustular lesions pinpoint to . mm in diameter, that appear first on
the trunk and in the diaper area 4ee the image below
Eruptive xanthomas. Courtesy of Duke University Medical Center.
"lanar 1anthomas that occur first around the eyes but also in the creases of the palms and soles and on
the neck develop more slowly and are principally observed in chronic cholestasis syndromes 5inally,
tuberous 1anthomas are associated with very long duration of cholestasis and develop over the e1tensor
surfaces, such as the elbows, %chilles tendons, and knees +hese are unusual in pediatric patients
Failure to thrive
!ne of the ma'or clinical effects of cholestasis, particularly chronic cholestasis, is failure to thrive +he
mechanisms of failure to thrive include malabsorption, anore1ia, poor nutrient use, hormonal disturbances,
and secondary tissue in'ury 6alabsorption 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 stabili0ation
of the lipase*colipase comple1 #n addition, bile salts are important in stabili0ation of lipid emulsions, which
is important for increasing the surface area on which lipase works
%bsorption is inefficient because of reduced formation of intestinal micelles, which are important for
removing the end products of lipolysis and effecting their absorption +he result of these events is the
malabsorption of fat and fat*soluble vitamins
6alabsorption of fat results in the loss of a source of calories that is important in infant nutrition
5urthermore, the delivery of fat into the colon can result in colonic secretion and diarrhea %dults with fat
malabsorption often e1perience anore1ia +his may also occur in infants, but more often, infants take in
increased amounts of formula to compensate for loss of calories 5inally, the loss of fat into the stool also
results in calcium wasting through the formation of calcium soaps of fatty acids +his may play an important
role in bone disease in children and adults with chronic cholestasis
+he treatment of fat malabsorption principally involves dietary substitution #n older patients, a diet that is
rich in carbohydrates and proteins can be substituted for a diet containing long*chain triglycerides #n
infants, substitution may not be possible, and the substitution of a formula containing medium*chain
triglycerides may improve fat absorption and nutrition +his, however, has not clearly been proven, and
therapeutic formulas containing medium*chain triglycerides may not be worth their e1pense Bile salt
therapy to replace missing bile salts is not practical <rsodeo1ycholic acid, which is used to treat some
cholestatic conditions, does not form mi1ed micelles and has no effect on fat absorption
+he malabsorption of fat*soluble vitamins can result in vitamin deficiency states 8itamins E, D, 9, and %
are all malabsorbed in cholestasis, and in that order
.
8itamin E deficiency can result in peripheral
neuropathy and possibly hemolysis 8itamin D deficiency results in osteomalacia and rickets 8itamin 9
deficiency causes coagulopathy and possibly reduced brain development 8itamin % deficiency does not
result in clinical disease in cholestasis #n chronic cholestasis, careful attention must be paid to prevent fat*
soluble vitamin deficiencies +his is accomplished by administering fat*soluble vitamins and monitoring the
response to therapy
Mortality/Morbidity
Cholestasis is not a primary cause of death (owever, it is the cause of considerable morbidity as indicated
above in "athophysiology
ex
&o clear difference in the incidence of cholestasis between males and females is observed #ncidence is
e3ual in most genetic diseases leading to cholestasis (owever, several conditions have a female
dominance, including biliary atresia, drug*induced cholestasis, and of course, cholestasis of pregnancy
!ge
Cholestasis is observed in people of every age group (owever, newborns and infants are more
susceptible and more likely to develop cholestasis as a conse3uence of immaturity of the liver
Eoung gestational age, low birth body weight, more sepsis episodes, and long duration of parenteral
nutrition are risk factors associated with "arenteral nutrition associated cholestasis
"istory
"atients with cholestasis may present clinically in many different ways depending on the disease process
#n most cases, scleral icterus is noted before any other signG it may be apparent at con'ugated
bilirubin levels as low as . mg?d$
%t higher levels of con'ugated bilirubin, dark urine may be noted secondary to the filtering of
bilirubin into the urine
Cutaneous 'aundice may not be noted until bilirubin levels reach H mg?d$ or higher
#n patients with cholestasis, another common presentation is severe pruritus secondary to elevated
bile acids
o %t high concentrations (H times the reference range), retained bile acids can cause
maddening pruritus in which patients are unable to sleep or concentrate and may resort to
cutaneous mutilation for relief
o #nfants who are unable to scratch may become very irritable in response to the pruritus #n
chronic cholestasis, cholesterol deposits called 1anthomas may form in the skin +his may
be a visible signal of severe cholestasis Because of the poor bile flow in patients with
cholestasis, they may also have inefficient digestion and absorption of dietary fats +hese
patients often demonstrate failure to thrive and have problems with fat*soluble vitamin
deficiency and steatorrhea
Physical
%s noted above, the physical signs of cholestasis are usually scleral icterus or cutaneous 'aundice, or both
+hese patients may have physical evidence of scratching or e1coriation if they also have severe bile acid
retention
Fanthomas look like small white papules or pla3ues and are usually found on the trunk and diaper
area and in areas of friction (eg, diaper line, creases of hands, elbows, neck)
%nother important physical finding in patients with cholestasis may be evidence of failure to thrive
with altered anthropometrics, such as reduced height and reduced weight for height due to fat
malabsorption
Differential Diagnoses
#ther Problems to $e Considered
/aundice not due to cholestasis
&oncon'ugated hyperbilirubinemia
Dubin*/ohnson syndrome
2otor syndrome
Carotinemia
Dark urine not due to bilirubinuria
(ematuria
Drug ingestion
Dehydration
"ruritus not due to cholestasis
%topic disease
Drug ingestion
Behavior disorder
Fanthomatosis not due to cholestasis
5amilial hypercholesterolemia
Cerebrotendinous 1anthomatosis
6alabsorption not due to cholestasis
"ancreatic insufficiency
#ntestinal mucosal diseases
4mall bowel bacterial overgrowth
Bile acid malabsorption
#leal resection
%orkup
&aboratory tudies
4erum bilirubin levels are elevated in virtually all patients with cholestasis
4erum direct or con'ugated bilirubin levels are elevated in virtually all cholestatic diseases and not
in other diseases causing hyperbilirubinemia
+otal serum bile salt concentration levels are elevated in virtually all cholestatic diseases
;ualitative serum and urine bile acids by mass spectroscopy are used to identify genetically
determined errors in bile acid synthesis
+he total serum cholesterol level is elevated in virtually all obstructive cholestatic diseases,
whereas the high*density lipoprotein ((D$) level is within the reference range or low +otal
cholesterol is within the reference range in certain hepatocellular cholestatic diseases, whereas
the (D$ level is within the reference range or low
4erum lipoprotein*F levels are elevated in virtually all obstructive cholestatic diseases
4erum alkaline phosphatase levels are elevated in virtually all obstructive cholestatic diseases and
most hepatocellular cholestatic diseases
4erum H=*nucleotidase levels are elevated in virtually all obstructive cholestatic diseases and most
hepatocellular cholestatic diseases
4erum gamma*glutamyl transferase (77+) levels are elevated in virtually all obstructive
cholestatic diseases and many hepatocellular cholestatic diseases % small number of
hepatocellular cholestatic diseases occur in which the 77+ level is within the reference range or
low (eg, progressive familial intrahepatic cholestasis, inborn errors of bile acid synthesis)
5ecal fat levels are elevated in virtually all cholestatic diseases
'maging tudies
<ltrasonography of liver and bile ducts is used to identify anatomic causes of obstructive
cholestasis (eg, choledochal cyst, gallstones)
%bdominal C+ scanning is used to identify anatomic causes of obstructive cholestasis (eg,
choledochal cyst, gallstones)
Biliary nuclear medicine study (ie, hepatoiminodiacetic acid I(#D%J scanning) is used to identify
anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones) and to differentiate
between obstructive and hepatocellular cholestasis (ie, biliary atresia versus neonatal hepatitis)
Endoscopic retrograde cholangiography is used to identify anatomic causes of obstructive
cholestasis (eg, choledochal cyst, gallstones)
"ercutaneous transhepatic cholangiography is used to identify anatomic causes of obstructive
cholestasis (eg, choledochal cyst, gallstones)
Procedures
$iver biopsy is the single most useful test to determine the cause of cholestasis but re3uires a high
degree of e1pertise in interpretation
E1ploratory surgery is a very useful tool for diagnosing neonatal cholestasis !lder literature
suggested that e1ploratory surgery placed patients with neonatal hepatitis at risk, but this is not the
case with modern anesthesia and surgical techni3ues
o #f surgical disease is in 3uestion, initiate e1ploratory surgery to provide a definitive
demonstration of bile duct anatomy
o #n institutions with less e1perience and e1pertise, perform e1ploratory surgery more
fre3uently, rather than less so
!perative cholangiography is simple, straightforward, time*efficient, and definitive
"istologic (indings
6any histologic findings are disease specificG therefore, refer to articles about disease states (see
Causes) +he typical histopathologic features of hepatocellular cholestasis include the presence of
bile within hepatocytes and canalicular spaces, in association with generali0ed cholate in'ury
+ypical of obstructive cholestasis is bile plugging of the interlobular bile ducts, portal e1pansion,
and bile duct proliferation in association with centrilobular cholate in'ury
Differentiating between idiopathic neonatal hepatitis and biliary atresia is a diagnostic challenge
:ith e1pert evaluation, nothing contributes as much to that differential diagnosis as the findings on
percutaneous liver biopsy
+he landmark )KCD paper of Brough and Bernstein demonstrated the diagnostic usefulness of the
percutaneous liver biopsy
>
#n this study of )HL patients, the authors compared the original
pathologic diagnosis to the ultimate diagnosis that included surgical findings and long*term follow*
up +he original diagnosis was an error in )A patients (>@M), which makes biopsy an e1cellent
diagnostic procedure +he type of error observed in these )A patients was more important #n K of
)A misdiagnoses, the pathologic diagnosis was obstructive disease when the patient actually had
neonatal hepatitis or alpha)*antitrypsin deficiency +his error led to e1ploratory surgery to confirm
the diagnosis, which was of little harm to the patient #n only ) patient with biliary atresia was the
pathologic diagnosis that of hepatitis, which led to delay in the diagnosis of this surgical obstructive
disease +hus, in only ) of )HL patients (A>M) did a diagnostic error lead to meaningful clinical
conse3uences
$iver biopsy, therefore, has a very high sensitivity and specificity for the diagnosis of biliary atresia,
with somewhat less specificity for the diagnosis of neonatal hepatitis
)reatment
Medical Care
6uch medical care in patients with cholestasis is disease specificG therefore, refer to articles about disease
states (see Causes) 4ome medical care is specifically directed at cholestasis and its conse3uences
Cholestasis often does not respond to medical therapy of any sort 4ome reports indicate success
in children with chronic cholestatic diseases with the use of ursodeo1ycholic acid (.A*@A mg?kg?d),
which acts to increase bile formation and antagoni0es the effect of hydrophobic bile acids on
biological membranes "henobarbital (H mg?kg?d) may also be useful in some children with chronic
cholestasis !piate antagonists can block cholestasis*associated itching
+he 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
'ustified because that maneuver may have secondary effects on nutrition 5urthermore, oral bile
salt,binding agents, such as cholestyramine, have little effect on serum cholesterol in this setting
%gents that block the synthesis of cholesterol have been used sparingly in cholestasis and cannot
be recommended at this time +he proper approach to treating hypercholesterolemia in cholestatic
liver disease is to treat the liver disease itself
+reatment of fat malabsorption principally involves dietary substitution #n older patients, a diet that
is rich in carbohydrates and proteins can be substituted for a diet containing long*chain
triglycerides #n infants, that may not be possible, and substitution of a formula containing medium*
chain triglycerides may improve fat absorption and nutrition +his, however, has not clearly been
proven, and therapeutic formulas containing medium*chain triglycerides may not be worth their
e1pense Bile salt therapy to replace missing bile salts is not practical <rsodeo1ycholic acid,
which is used to treat some cholestatic conditions, does not form mi1ed micelles and has no effect
on fat absorption
#n chronic cholestasis, careful attention must be paid to prevent fat*soluble vitamin deficiencies
+his is accomplished by administering fat*soluble vitamins and monitoring the response to therapy
%dminister vitamin E as tocopherol polyethylene glycol succinate (+"74) to achieve sufficient
absorption in the setting of reduced intestinal bile salt concentrations
urgical Care
4urgical care is disease specificG therefore, refer to articles about disease states (see Causes)
Consultations
2eferral to a specialist in gastroenterology or hepatology is indicated for any patient with
cholestatic liver disease, particularly if it is severe or prolonged
Diet
4ee 6edical Care
Medication
Choleretic agents
<rsodeo1ycholic acid acts to increase bile formation and antagoni0es the effect of hydrophobic bile acids
on biological membranes
Ursodeoxycholic acid *!ctigall+ Urso,
4hown to promote bile flow in cholestatic conditions associated with a patent e1trahepatic biliary system
Decreases the cholesterol content of bile and therefore reduces bile stone and sludge formation
Dosing
Interactions
ontraindications
Precautions
!dult
)A*)H mg?kg?d "! divided bid
Pediatric
.A*@A mg?kg?d "! divided bid
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
$arbiturates
+hese agents are used to induce hepatic en0yme metabolism in order to decrease serum bilirubin levels in
some patients with cholestasis in order to improve function
Phenobarbital *&uminal,
6ainly used as an anticonvulsant, which interferes with transmission of impulses from thalamus to corte1 of
brain, resulting in imbalance in central inhibitory and facilitatory mechanisms <sed in cholestasis to induce
the CE"DHA system in treatment of neonatal hyperbilirubinemia and lowering of bilirubin in chronic
cholestasis
Dosing
Interactions
ontraindications
Precautions
!dult
<p to @A mg?d "! has been describedG ad'ust dose to maintain serum bilirubin levels within target range
Pediatric
H mg?kg?d "!
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
-itamins
5at*soluble vitamins %, D, E, and 9 must be administered as individual supplements to assure proper
absorption
Phytonadione *!.uaMEP"/)#0,
8itamin 9 5at*soluble vitamin absorbed by the gut and stored in the liver &ecessary for the function of
clotting factors in the coagulation cascade <sed to replace essential vitamins not obtained in sufficient
3uantities in the diet or to further supplement levels
Dosing
Interactions
ontraindications
Precautions
!dult
)A mg "!?#8?#6?4C should replenish the liver stores
Pediatric
) mg #6
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
-itamin E *&i.ui E,
8itamin E "revention and treatment of hemolytic anemia secondary to vitamin deficiency or need for
dietary supplementation "rotects polyunsaturated fatty acids in membranes from attack by free radicals
and protects 2BC against hemolysis
Dosing
Interactions
ontraindications
Precautions
!dult
2D% dose: L*)A mg?d "! ().*)H #<?d)
+herapeutic dose: HA*.AAA #<?d "!
Deficiency: @A* to HA*mg tab?cap "! 3d
("! dose is usually D*H times the 2D%)
Pediatric
2D% dose: @*)A mg?d "!
+herapeutic dose: )*)AA mg?kg?d "!
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
-itamin ! *!.uasol !,
&eeded for bone development, growth, visual adaptation to darkness, testicular and ovarian function, and
as a cofactor in many biochemical processes
Dosing
Interactions
ontraindications
Precautions
!dult
Dietary supplement: DAAA*HAAA #<?d "!
2D%: .>CA #<?d (females) and @@@A #<?d (males)
Pediatric
Dietary supplement:
N> months: )HAA #<?d "!
> months to @ years: )HAA*.AAA #<?d "!
D*> years: .HAA #<?d "!
C*)A years: @@AA*@HAA #<?d "!
O)A years: %dminister as in adults
Deficiency:
N) year: )A,AAA #<?kg?d #6 for H d, then C,HAA*)H,AAA #<?d for )A d
)*L years: H,AAA*)A,AAA #<?kg?d #6 for H d, then )C,AAA*@H,AAA #<?d for )A d
OL years: )AA,AAA #<?d #6 for @ d, then HA,AAA #<?d for )D d
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Ergocalciferol *Drisdol+ Calciferol,
8itamin D 4timulates absorption of calcium and phosphate from small intestine and promotes release of
calcium from bone into blood "! solution comes as LAAA <?m$ (.AA mcg?m$, DA <?mcg)
Dosing
Interactions
ontraindications
Precautions
!dult
)A,AAA*LA,AAA <?d "! plus )*. g?d "! elemental phosphorus
Pediatric
#nfants and healthy children: )A mcg?d "! (DAA <)
8itamin D,dependent rickets: CH*).H mcg?d "! (@AAA*HAAA <)G not to e1ceed )HAA mcg?d
&utritional rickets and osteomalacia: .H*).H mcg?d "! ()AAA*HAAA <) in normal absorptionG .HA*>HA mcg?d
"! ()A,AAA*.H,AAA <?d) in malabsorption
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
#pioid antagonists
+hese agents are used to alleviate pruritus caused by cholestasis +hey block opioid*mediated pathways of
afferent nerves, which may be producing the itching sensation
0altrexone *1e-ia,
Cyclopropyl derivative of o1ymorphone that acts as a competitive antagonist at opioid receptors Do not
administer this medication until the patient is opioid*free for C*)A d %vailable as HA*mg tab
Dosing
Interactions
ontraindications
Precautions
!dult
#nitial dose: .H mg "!G if no withdrawal signs within ) h, administer another .H mg
6aintenance dose: HA*)HA mg @ times?wk
Pediatric
)A mg?d "! increasing over @*D wkG not to e1ceed .H*@A mg?d
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
$ile salt resins
Bile acid,binding resins form a nonabsorbable comple1 with bile acids in the intestine, which inhibits
enterohepatic reuptake of intestinal bile salts and thereby increases the fecal losses of bile salt,bound low*
density lipoprotein cholesterol
Cholestyramine *2uestran+ Prevalite,
6ay use as ad'unct in primary hypercholesterolemia 5orms a nonabsorbable comple1 with bile acids in the
intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts Dose based on resin content
Dosing
Interactions
ontraindications
Precautions
!dult
D g "! 3d?bidG not to e1ceed .D g?d or > doses?dG mi1 with water or 'uice and drink immediately
Pediatric
.DA mg?kg?d "! divided tidG mi1 with water or 'uice and drink immediately
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
Dosing
Interactions
ontraindications
Precautions
!ntibiotics
%ntitubercular agents induce liver en0ymes and ameliorate pruritus secondary to cholestasis
1ifampin *1imactane+ 1ifadin,
#nhibits 2&% synthesis in bacteria by binding to beta subunit of D&%*dependent 2&% polymerase, which, in
turn, blocks 2&% transcription
Dosing
Interactions
ontraindications
Precautions
!dult
>AA mg "!?#8 3d
Pediatric
)A*.A mg?kg?d "!?#8G not to e1ceed >AA mg?d
(ollo34up
(urther 'npatient Care
5ollow*up care in patients with cholestasis is disease specificG therefore, refer to articles about
disease states (see Causes)
Patient Education
5or e1cellent patient education resources, see e6edicine=s $iver, 7allbladder, and "ancreas
Center, Cholesterol Center, and Ear, &ose, and +hroat Center %lso, visit e6edicine=s patient
education articles 7allstones and &osebleeds
Miscellaneous
Medicolegal Pitfalls
Cholestasis is not a disease but a symptom of a diseaseG therefore, it is a signal or marker that
disease e1ists
Cholestasis is never normal and should at all times be investigated for the underlying etiology
5ailure to investigate the cause of a patient=s cholestasis may lead to the neglect of a progressive
and significant disease process that will cause the patient harm
#gnoring cholestasis or watching it progress without an understanding of the cause may be
considered malpractice if avoidable harm to the patient occurs as a result
pecial Concerns
6alnutrition is common in infants and children with chronic liver disease #ts etiology is
multifactorial but is generally due to decreased dietary intake, impaired digestion and absorption,
and increased energy e1penditure
Children and especially infants need to be periodically assessed for malnutrition and for vitamin
deficiencies because it contributes to a poorer outcome when liver transplantation is considered