Icter

CHAPTER
21
Jaundice
STEVEN D. LIDOFSKY
CHAPTER OUTLINE
Bilirubin Metabolism and Measurement.....................................336
Metabolism............................................................................... 336
Measurement............................................................................ 337
Differential Diagnosis.................................................................338
Isolated Disorders of Bilirubin Metabolism.................................. 338
Liver Disease............................................................................ 340
Bile Duct Obstruction................................................................. 342
Diagnostic Approach to Jaundice..............................................342
Jaundice (also termed icterus) is a condition of yellow discoloration of the skin, conjunctivae, and mucous membranes,
resulting from widespread tissue deposition of the pigmented
metabolite bilirubin. Although jaundice is commonly due to
liver and biliary tract disease, it has many causes, so it is not
surprising that the diagnosis and management of jaundice
have challenged clinicians for centuries.
Clinical and biochemical investigation of the etiology of
jaundice has a rich history. Classification of disorders associated with jaundice appeared as early as the treatises of Hippocrates. By the late 19th century (e.g., see Oslers Principles
and Practice of Medicine), important distinctions had been made
between biliary tract obstruction and nonobstructive causes of
jaundice. It was not until the latter part of the 20th century,
however, that elucidation of the molecular mechanisms of bilirubin metabolism and the development of robust imaging
technologies made it possible to pinpoint the cause of jaundice
in most cases. Despite these advances, an effective management strategy for the jaundiced patient still requires careful
selection of appropriate diagnostic and therapeutic modalities
on the basis of an assessment of the likelihood of possible
underlying causes.
BILIRUBIN METABOLISM
AND MEASUREMENT
Metabolism
Bilirubin is a tetrapyrrole produced by heme degradation. The
metabolism of this hydrophobic and potentially toxic compound has been reviewed in depth elsewhere1,2 and is summarized briefly in Figure 21-1. On average, a healthy adult
produces about 4mg/kg of bilirubin each day (i.e., almost
0.5mmol in a 70-kg person). Under physiologic conditions,
most bilirubin (70% to 80%) is produced from degradation of
hemoglobin from senescent erythrocytes. The remaining 20%
to 30% of bilirubin derives primarily from breakdown of other
heme-containing proteins (e.g., catalase, cytochrome oxidases)
in hepatocytes. Although hemoproteins (e.g., myoglobin) are
also present in extrahepatic tissues, their turnover rate is low,
History and Physical Examination............................................... 343

Initial Laboratory Studies........................................................... 343
Overall Approach....................................................................... 344
Imaging Studies........................................................................ 344
Other Studies............................................................................ 346
Therapeutic Approaches............................................................347
Obstructive Jaundice................................................................. 347
Nonobstructive Jaundice............................................................ 347
so their overall contribution to bilirubin production under

conditions of health is negligible.
Formation of bilirubin from heme involves the actions of
2 enzymes: heme oxygenase, an integral membrane protein of
the smooth endoplasmic reticulum, and biliverdin reductase,
which is located in the cytosol. Heme oxygenase catalyzes the
opening of the heme ring to produce biliverdin. Biliverdin in
turn is converted to bilirubin by biliverdin reductase. The
major sites of bilirubin production depend on the tissue
sources of the hemoprotein precursors. Catabolism of
erythrocyte-derived hemoglobin to bilirubin takes place primarily in macrophages in the spleen, bone marrow, and liver
(Kupffer cells). By contrast, free hemoglobin, haptoglobinbound hemoglobin, and methemalbumin are predominantly
catabolized to bilirubin in hepatocytes.
Bilirubin circulates in plasma tightly but noncovalently
bound to albumin. Excretion of bilirubin requires conversion
by hepatocytes from the native (unconjugated) form to watersoluble conjugates and subsequent export into bile. Bilirubin
metabolism and elimination is a multistep process for which
several inherited disorders have been identified (see later).
Unconjugated bilirubin is taken up across the sinusoidal
(basolateral) membrane of hepatocytes by a carrier-mediated
mechanism, but the responsible transport proteins have not
been precisely defined. Because the uptake of unconjugated
bilirubin is competitively inhibited by certain organic anions
(e.g., bromosulfophthalein [BSP], indocyanine), it has been
speculated that a member of the organic anion transport
protein (OATP) family is involved (see Chapter 64). Support
for a role for OATP1B1 (gene symbol SLCO1B1) in the unconjugated bilirubin uptake process comes from observations in
transfected cells in culture3 and the association of polymorphisms in the OATP1B1 gene with neonatal jaundice (see
Chapter 77)4; however, the importance of OATP1B1 in unconjugated bilirubin uptake by hepatocytes has been disputed.5
The subsequent steps of bilirubin metabolism are better
understood.
After uptake, unconjugated bilirubin is directed by cytosolic binding proteins (e.g., glutathione S-transferase B, fatty
acid binding protein) to the endoplasmic reticulum, where
it is conjugated with bilirubin uridine diphosphate (UDP)
glucuronic acid by the enzyme bilirubin UDPglucuronyl
336
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Chapter 21 Jaundice 337

Hemoglobin
Other hemoproteins
Br
Alb-Br
Plasma
Br
BrG
Urine
MRP3?
OATP?
Canalicular
membrane
B-UGT
BrG
MRP2
Hepatocytes
BrG
Bile
FIGURE 21-1. Schematic overview of bilirubin formation, metabo

lism, and transport. Heme from hemoglobin and other hemo
proteins is converted to biliverdin and then to bilirubin (Br),
predominantly in macrophages in bone marrow and spleen. Br is
released into plasma (in its unconjugated form), where it is tightly
but reversibly bound to albumin (Alb). Br is then taken up at the
sinusoidal membrane of hepatocytes, possibly via a member of
the organic anion transporter (OATP) family. Br is conjugated via
the activity of bilirubin uridine diphosphate-glucuronyl transferase
(B-UGT) to form bilirubin mono- and diglucuronides (BrG). Biliary
secretion of BrG occurs at the canalicular membrane by the
multispecific organic anion transporter MRP2. Under physiologic
conditions, the vast majority of BrG is eliminated in bile. Small
amounts of BrG are transported at the sinusoidal membrane back
into plasma, possibly via the multispecific organic anion trans
porter MRP3, and are recaptured primarily via uptake by OATP
(OATP1B1 and OATP1B3). Remaining plasma BrG enters the
renal circulation, where it undergoes glomerular filtration and
elimination into urine. Therefore, under normal conditions, at least
95% of bilirubin in plasma is present in the unconjugated form.
If abnormally high concentrations of BrG are retained over a
prolonged period, BrG-Alb complexes, which do not dissociate
and cannot undergo glomerular filtration, are formed. MRP, mul
tidrug resistance-associated protein.
transferase (B-UGT). Conjugated bilirubin is then directed primarily toward the canalicular (apical) membrane, where it is
transported into the bile canaliculus by an adenosine triphosphate (ATP)-dependent export pump. The responsible protein,
multidrug resistanceassociated protein-2 (MRP2, gene
symbol ABCC2), can also transport a variety of organic anions,
including BSP, glutathione, and conjugated bile salts.6 In addition to canalicular export, small amounts of bilirubin glucuronides are secreted across the sinusoidal membrane via a
pathway postulated to be mediated by a distinct multispecific
organic ion export pump, MRP3 (gene symbol ABCC3).7 Once
secreted into plasma, conjugated bilirubin can undergo reuptake by the sinusoidal transporters OATP1B1 and OATP1B3
(gene symbol SLCO1B3),8 or it undergoes renal excretion into
urine (see Fig. 21-1). In disorders characterized by cholestasis
(impaired bile flow), MRP3-mediated export of conjugated
bilirubin can be up-regulated.9 With prolonged cholestasis (or
a metabolic disorder of conjugated hyperbilirubinemia [see
later]), excess amounts of conjugated bilirubin in plasma
become covalently bound to albumin, and this covalently
bound bilirubin cannot be excreted into urine.
Under physiologic conditions, virtually all bilirubin in bile

is conjugated and only trace amounts are unconjugated. In
humans, roughly 80% of bilirubin in bile is in the diglucuronide form, and almost all the rest is in the form of monoglucuronides. Resorption of conjugated bilirubin by the gallbladder
and intestine is negligible; the bulk of bilirubin released from
the biliary tract enters the intestine in its conjugated form and
is eliminated in feces. It should be noted, however, that bilirubin can be deconjugated by bacteria in the terminal ileum and
colon and converted to colorless tetrapyrroles called urobilinogens. Up to 20% of urobilinogens are resorbed and ultimately
excreted in bile and urine.
Measurement
In adults, the normal bilirubin concentration is lower than 1
to 1.5mg/dL. Mild hyperbilirubinemia may escape clinical
notice, and in general, jaundice is not evident until the serum
bilirubin concentration exceeds 3mg/dL. In healthy persons,
most bilirubin circulates in its unconjugated form; less than
5% of circulating bilirubin is present in its conjugated form.
In cholestatic conditions, however, the proportion of conjugated bilirubin in plasma may increase as a consequence of
up-regulated MRP3 expression. Therefore, the concentration
and composition of bilirubin in plasma can vary widely
between health and disease. Accurate measurement of serum
bilirubin is of clinical importance in situations that range from
managing neonatal jaundice10 to determining priority for liver
transplantation.11
Many clinical laboratories measure serum bilirubin concentration with a colorimetric technique that employs the
diazo (van den Bergh) reaction, developed in the early part of
the 20th century. In this reaction, bilirubin is cleaved by compounds such as diazotized sulfanilic acid to form an azodipyrrole that can be assayed by spectrophotometry. Conjugated
bilirubin is cleaved rapidly (directly) by diazo reagents. By
contrast, unconjugated bilirubin reacts more slowly because
internal hydrogen bonding reduces the accessibility of the
diazo reagent to the site of chemical cleavage. Therefore, reliable measurement of total bilirubin concentration requires
addition of another (accelerator) compound (e.g., ethanol,
urea) that disrupts this hydrogen bonding and facilitates
cleavage of unconjugated bilirubin by the diazo reagent. Using
this technique, the directly reacting bilirubin, determined in
the absence of accelerator compound, is reported as the direct
bilirubin concentration, whereas the total bilirubin concentration is reported in the presence of the accelerator compound.
The numerical difference between the 2 values is then reported
as the indirect bilirubin concentration.
Although the direct bilirubin concentration is influenced
by changes in conjugated bilirubin levels, the 2 are not equivalent. Similarly, the indirect bilirubin concentration is not
equivalent to the concentration of unconjugated bilirubin. In
particular, reliance on direct and indirect bilirubin measurements can lead to errors in the diagnosis of isolated disorders
of bilirubin metabolism (e.g., suspected Gilberts syndrome
[see later]). Consequently, a number of clinical laboratories
instead employ automated reflectance spectroscopic assays
that more accurately estimate conjugated and unconjugated
bilirubin concentrations. These assays can provide useful
information for the management of neonatal jaundice, in
which the therapy of unconjugated hyperbilirubinemia is distinct from that for other conditions (see later discussion). In
disorders characterized by prolonged cholestasis, however,
such assays may underestimate the conjugated bilirubin
concentration because they do not accurately detect albuminbound conjugated bilirubin (so-called delta bilirubin),
although this is not a general limitation in most cases of
338 Section III Symptoms, Signs, and Biopsychosocial Issues

jaundice. There may be special circumstances in which
confirmation of the diagnosis of an isolated disorder of bilirubin metabolism is important. Under these conditions, the
diagnosis may require more sophisticated chromatographic
techniques that precisely measure concentrations of unconjugated, monoglucuronidated, and diglucuronidated bilirubin,
as well as conjugated bilirubin-albumin complexes.2 In practice, these techniques are not widely used. Even with such
accurate methods, determination of conjugated and unconjugated bilirubin concentrations cannot distinguish hepatic disorders from biliary obstruction. Therefore, in most cases
precise measurements of conjugated and unconjugated bilirubin concentrations in serum are of limited use.
practical standpoint, conditions associated with jaundice can

be classified under the broad categories of isolated disorders
of bilirubin metabolism, liver disease, and bile duct obstruction (Table 21-1).
Isolated Disorders of Bilirubin Metabolism

Unconjugated Hyperbilirubinemia
Three basic mechanisms can lead to isolated unconjugated
hyperbilirubinemia: (1) increased bilirubin production, (2)
decreased hepatocellular uptake of unconjugated bilirubin,
and (3) decreased bilirubin conjugation. In each of these conditions, global liver function and biochemical markers of hepatocellular injury and cholestasis are normal.
DIFFERENTIAL DIAGNOSIS
Increased Bilirubin Production
Jaundice can result from an increase in bilirubin production

or a decrease in hepatobiliary elimination of bilirubin. From a
Processes that can generate excessive bilirubin production

include hemolysis, ineffective erythropoiesis, and resorption
TABLE 21-1 Differential Diagnosis of Jaundice and Hyperbilirubinemia

Disorder
Examples
Isolated Disorders of Bilirubin Metabolism

Unconjugated Hyperbilirubinemia
Increased bilirubin production
Decreased hepatocellular uptake
Decreased conjugation
Hemolysis, ineffective erythropoiesis, blood transfusion, resorption of hematomas

Drugs (e.g., rifampin), Gilberts syndrome (secondary mechanism)
Gilberts syndrome, Crigler-Najjar syndrome, physiologic jaundice of the newborn, drugs (e.g.,
indinavir, atazanavir)
Conjugated or Mixed Hyperbilirubinemia

Dubin-Johnson syndrome
Rotors syndrome
Liver Disease
Hepatocellular Dysfunction
Acute or subacute hepatocellular
injury
Chronic hepatocellular disease
Viral hepatitis, hepatotoxins (e.g., ethanol, acetaminophen, Amanita phalloides); drugs (e.g., isoniazid,
phenytoin); ischemia (e.g., caused by hypotension), vascular outflow obstruction; metabolic disorders
(e.g., Wilson disease); pregnancy-related as in acute fatty liver of pregnancy, pre-eclampsia
Viral hepatitis; hepatotoxins (e.g., ethanol, vinyl chloride, vitamin A); autoimmune hepatitis; celiac
disease; metabolic disorders (e.g., nonalcoholic fatty liver disease, hemochromatosis, Wilson
disease, 1-antitrypsin deficiency)
Hepatic Disorders with Prominent Cholestasis

Infiltrative diseases
Granulomatous diseases such as mycobacterial infections, sarcoidosis, lymphoma, granulomatosis

with polyangiitis; amyloidosis; malignancy
PBC; graft-versus-host disease; drugs (e.g., erythromycin, trimethoprim/sulfamethoxazole); cystic
fibrosis
Benign recurrent intrahepatic cholestasis; drugs (e.g., estrogens, anabolic steroids); TPN; bacterial
infections; paraneoplastic syndromes; intrahepatic cholestasis of pregnancy
Cholangiocyte injury
Miscellaneous conditions
Bile Duct Obstruction
Choledocholithiasis
Bile Duct Diseases
Inflammation, infection
Neoplasms
PSC, AIDS cholangiopathy, injury caused by hepatic arterial chemotherapy, postsurgical strictures
Cholangiocarcinoma
Extrinsic Compression
Neoplasms
Pancreatic carcinoma, metastatic lymphadenopathy, hepatocellular carcinoma, ampullary adenoma/

carcinoma, lymphoma
Pancreatitis
Vascular enlargement
Aneurysm, cavernous transformation of the portal vein (portal cavernoma)
AIDS, acquired immunodeficiency syndrome.

of a hematoma.2 With these disorders, bilirubin concentration
generally does not exceed 4 to 5mg/dL. Jaundice can also
follow massive blood transfusions, because the increased fragility of stored erythrocytes leads to excessive hemoglobin
release, and this can be a major contributor to hyperbilirubinemia in patients with major trauma.12
Decreased Bilirubin Uptake

Selected drugs can interfere with hepatocellular uptake of
bilirubin. For example, the antibiotic rifampin and the immunosuppressive agent cyclosporine A competitively inhibit
the sinusoidal transport protein OATP1B1.13,14 Decreased
bilirubin uptake may also exacerbate hyperbilirubinemia
in patients with Gilberts syndrome (see later), who have
impaired bilirubin conjugation resulting from reduced B-UGT
activity.15
Decreased Bilirubin Conjugation

Three autosomally inherited disorders of unconjugated hyperbilirubinemia are due to impaired bilirubin conjugation (Table
21-2). The most common of these is Gilberts syndrome, which
has a prevalence of approximately 10% in white populations.
Patients with Gilberts syndrome typically present when isolated hyperbilirubinemia is detected as an incidental finding
on routine multiphasic biochemical screening, and clinical
jaundice is uncommon. Serum bilirubin levels may rise 2- to
3-fold with fasting or dehydration but are generally below
4mg/dL. The molecular basis of Gilberts syndrome has been

linked to a reduction in transcription of the B-UGT gene
UGT1A1 as a result of mutations in the promoter region
and, less commonly, in the coding region.1,16 Although
Gilberts syndrome has generally been thought to be an
entirely benign condition, persons with this disorder may be
at increased risk for gallstones and for toxicity of selected
drugs like ironotecan that require glucuronidation for metabolic disposal.16 On the other hand, patients with Gilberts
syndrome may be at decreased risk for cardiovascular disease,
because unconjugated bilirubin has antioxidant properties
that are thought to retard atherosclerosis.17
Mutations in the coding region of UGT1A1 appear to be
responsible for Crigler-Najjar syndrome.18 In type I CriglerNajjar syndrome, B-UGT activity is absent, and marked
unconjugated hyperbilirubinemia is evident shortly after
birth. Because unconjugated bilirubin can cross the bloodbrain barrier, patients with type I Crigler-Najjar syndrome
accumulate bilirubin in the brain (kernicterus), and the resulting neurotoxic effects can lead to death in the neonatal period
(see Table 21-2). Phototherapy (see later) is required to prevent
kernicterus, and liver transplantation can be lifesaving. By
contrast, persons with type II Crigler-Najjar syndrome have
reduced (but not absent) B-UGT activity, and serum bilirubin
levels are lower than in patients with type I Crigler-Najjar
syndrome (see Table 21-2). Patients with type II Crigler-Najjar
syndrome are not ill during the neonatal period and may
not be diagnosed until early childhood. Most patients with
type II Crigler-Najjar syndrome can be treated successfully
TABLE 21-2 Hereditary Disorders of Bilirubin Metabolism and Transport

Syndrome
Parameter
Gilberts
Type I
Crigler-Najjar
Type II
Crigler-Najjar
Dubin-Johnson
Rotors
Incidence
6%-12%
Very rare
Uncommon
Uncommon
Rare
Gene affected
UGT1A1
UGT1A1
UGT1A1
MRP2
OATP1B1 and
OATP1B3
Metabolic
defect
Bilirubin conjugation
No bilirubin
conjugation
Bilirubin
conjugation
Impaired canalicular
export of conjugated
bilirubin
Impaired canalicular
export of conjugated
bilirubin
Plasma bilirubin
(mg/dL)
3 in absence
of fasting or
hemolysis, almost all
unconjugated
Usually >20
(range, 17-50),
all unconjugated
Usually <20
(range, 6-45),
almost all
unconjugated
Usually <7, about half

conjugated
Usually <7, about

half conjugated
Liver histology
Usually normal,
occasional lipofuscin
Normal
Normal
Coarse pigment in
centrilobular hepatocytes
Normal
Other
distinguishing
features
Bilirubin
concentration with
phenobarbital
No response to
phenobarbital
Bilirubin
concentration with
phenobarbital
Bilirubin concentration
with estrogens;
urinary coproporphyrin
I/III ratio
Mild urinary
coproporphyrin I/III
ratio
Prognosis
Normal (theoretical
risk of selected drug
toxicity)
Death in infancy
if untreated
Usually normal
Normal (theoretical risk

of selected drug toxicity)
Normal (theoretical
risk of selected drug
toxicity)
Treatment
None
Phototherapy as
a bridge to liver
transplantation
Phenobarbital for
bilirubin
concentration
Avoid estrogens
None available
MRP2, multidrug resistanceassociated protein-2 gene; OATP, organic anion transporter; UGTIA1, bilirubin uridine diphosphate-glucuronyl transferase gene.

with phenobarbital, an agonist for the constitutive androstane
receptor CAR, which increases UGT1A1 expression,19 and
serum bilirubin levels generally fall to the range of 2 to
5mg/dL.
A related disorder of bilirubin metabolism is physiologic
jaundice of the newborn, which results from delayed developmental expression of B-UGT and generally resolves rapidly in
the neonatal period. A brief course of phototherapy (see later)
may be required to prevent kernicterus.
B-UGT is inhibited competitively by the retroviral protease
inhibitors atazanavir and indinavir, which produce hyperbilirubinemia in more than 25% of patients who receive these
agents; patients with Gilberts syndrome are at higher risk for
this complication.20,21
Conjugated or Mixed Hyperbilirubinemia

Two autosomally inherited disorders, Dubin-Johnson syndrome and Rotors syndrome, are associated with conjugated
or mixed hyperbilirubinemia (i.e., increase in serum concentrations of both conjugated and unconjugated bilirubin). The
mechanisms that underlie these disorders are distinct. In
Dubin-Johnson syndrome, an absence of expression or altered
trafficking of MRP2 impairs secretion of conjugated bilirubin
into the bile canaliculus.6 Compensatory up-regulation of
the sinusoidal export protein MRP3 may prevent hepatocellular overload by potentially toxic organic anions that are
normally secreted by MRP2, and this can contribute to
the degree of hyperbilirubinemia in the disorder.22 The molecular basis of Rotors syndrome is more complex. Studies
in transgenic mice have demonstrated that conjugated bilirubin, which is secreted into plasma by MRP3, is taken up by
the sinusoidal transport proteins OATP1B1 and OATP1B3.8
Combined deficiency of OATP1B1 and OATP1B3 results
in Rotors syndrome and impaired re-uptake of conjugated
bilirubin.8
Dubin-Johnson and Rotors syndromes can be distinguished biochemically and histologically (see Table 21-2). In
Dubin-Johnson syndrome, hepatocytes contain a characteristic
black pigment believed to be formed by aromatic amino acid
metabolites that are putative MRP2 substrates.6 Liver biopsy
is unnecessary in the diagnostic evaluation of patients suspected of having Dubin-Johnson or Rotors syndrome, because
neither disorder is associated with progressive hepatic damage.
It has been speculated that patients with Rotors syndrome
may be at increased risk for toxicity from selected drugs (e.g.,
statin-induced myopathy) that undergo metabolic disposal via
OATP1B-mediated hepatic uptake.8
Liver Disease
Jaundice is a common feature of liver disease, in which hyperbilirubinemia is generally associated with other biochemical
liver test abnormalities. Disorders in which hyperbilirubinemia and jaundice are manifestations of global acute or chronic
hepatocellular dysfunction are distinguished from those for
which cholestasis is the predominant problem.
Acute Hepatocellular Dysfunction

Generalized hepatic dysfunction can be caused by acute or
chronic hepatocellular injury resulting from a variety of conditions that include viral hepatitis, exposure to hepatotoxins,
ischemic hepatitis and other causes of hepatic ischemia, and
certain metabolic derangements. Serum aminotransferase
levels are characteristically elevated (see later). Acute viral
hepatitis is often heralded by anorexia, malaise, and myalgias

before jaundice develops (see Chapters 78 to 83). Five hepatotropic viruses have been isolated: hepatitis A and E viruses,
which are transmitted enterally and are generally self-limited,
and hepatitis B, C, and D, which are transmitted parenterally
and may lead to chronic disease. The diagnosis of each of these
disorders is aided by serologic testing (see later).
One of the most common causes of toxic liver injury is
ingestion of large quantities of the analgesic acetaminophen
(see Chapter 88), which can lead to jaundice and frank liver
failure within several days after exposure. In patients who
survive, jaundice generally resolves and hepatic function
recovers completely in those without preexisting liver disease.
Other drugs that produce idiosyncratic (i.e., dose-independent)
hepatocellular injury and jaundice are discussed elsewhere in
this text (see Chapters 88 and 89). Alcoholic hepatitis should
be a diagnostic consideration in the jaundiced patient with
ethanol dependency (see Chapter 86). Laboratory studies
may help distinguish this entity from most other acute liver
diseases.
Jaundice related to hepatic ischemia may result from
hypotension, hypoxia, hyperthermia, or obstruction to
hepatic outflow secondary to hepatic vein thrombosis (BuddChiari syndrome) or sinusoidal obstruction syndrome (see
Chapter 85).
Wilson disease, an inherited disorder of hepatobiliary
copper secretion, may manifest de novo with clinical features
indistinguishable from those of acute viral hepatitis (see
Chapter 76). The disease should be a diagnostic consideration
in patients younger than age 40, particularly when neurologic
abnormalities are present or if examination of the eyes reveals
copper-laden (Kayser-Fleischer) rings that surround the iris.
Hemolytic anemia is a part of the spectrum of Wilson disease
and contributes to disproportionate hyperbilirubinemia in
these patients. The diagnosis of Wilson disease is confirmed
by biochemical testing and liver copper analysis.
Chronic Hepatocellular Dysfunction

In contrast to acute hepatocellular injury, jaundice does not
typically develop in chronic liver disease unless cirrhosis is
present. Chronic viral hepatitis should be a diagnostic consideration in patients with suspected cirrhosis, especially in
the presence of risk factors for parenteral exposure to causative agents. Diagnosis is aided by serologic testing (see
later). Cirrhosis is part of the spectrum of fatty liver disease,
either in the context of chronic alcohol use (see Chapter 86)
or as a component of the metabolic syndrome (nonalcoholic
fatty liver disease [see Chapter 87]). Certain hereditary metabolic diseases may progress to cirrhosis. Hemochromatosis,
a disorder of hepatocellular injury due to excessive iron
absorption, is the most common of these (see Chapter 75).
Decades of hepatic iron overload are generally required to
produce symptoms, and hemochromatosis often is not diagnosed until middle age. The diagnosis is confirmed by detection of mutations in the HFE gene or by hepatic iron analysis.
Copper-induced hepatic injury in Wilson disease may also
progress to cirrhosis (see Chapter 76). In a jaundiced patient
with chronic lung disease, 1-antitrypsin deficiency should
be suspected (see Chapter 77). In this disorder, misfolded
mutant 1-antitrypsin accumulates in the endoplasmic reticulum of hepatocytes, and liver injury results. The diagnosis
can be confirmed by laboratory testing and liver biopsy.
Autoimmune hepatitis may be associated with systemic
complaints like malaise, fever, and arthralgias (see Chapter
90). The diagnosis is aided by serologic testing and liver
biopsy (see later). Although celiac disease characteristically

causes immune-mediated disease in the small intestine (see
Chapter 107), it may occasionally present as otherwise unexplained chronic liver disease, although rarely if ever with
jaundice.
Hepatic Disorders with Prominent Cholestasis

Intrahepatic cholestatic disorders are characterized by
impaired bile formation in the absence of widespread hepatocellular injury or biliary obstruction. The presentation of these
disorders and associated biochemical abnormalities may
mimic biliary obstruction and can generate diagnostic confusion. Intrahepatic cholestatic disorders can be categorized histologically as those associated with infiltration of the liver,
those associated with injury to cholangiocytes within intrahepatic bile ductules, and those in which major histologic
changes are not evident.
Infiltrative Diseases
Infiltrative diseases of the liver disrupt the network of intrahepatic bile ductules and are often associated with striking
cholestasis. Granulomatous diseases of the liver can be caused
by the following: microbial disorders, drugs and industrial
toxins, lymphoma, and systemic disorders, including sarcoidosis and granulomatosis with polyangiitis (see Chapters 31,
36, and 84). The most common of these disorders that produce
jaundice are tuberculosis and sarcoidosis.23,24 Granulomatous
diseases should be suspected when jaundice accompanies
fever of undetermined origin. Physical examination usually
reveals hepatosplenomegaly, and lymphadenopathy may be
present. Radiographic chest abnormalities often provide a
clue to the diagnosis of sarcoidosis or mycobacterial infection.
Ultimately, diagnosis may require liver biopsy if other tissue
is unavailable. Jaundice is an unusual manifestation of amyloidosis, but when present is invariably accompanied by
marked hepatomegaly.25 The diagnosis of amyloidosis should
also be suspected in the jaundiced patient if there are signs of
involvement of other organs (e.g., macroglossia, malabsorption, heart failure, peripheral neuropathy, proteinuria). In the
absence of other clues, liver biopsy may be necessary. Jaundice
due to extensive neoplastic replacement of hepatic parenchyma is usually heralded by anorexia and weight loss. Noninvasive imaging studies generally lead to the diagnosis
(see later).
Disorders Involving Cholangiocyte Injury

A variety of disorders can lead to cholangiocyte damage. In
many of these, the cholangiocyte is a target of an immunemediated inflammatory response, as is characteristic of PBC
(see Chapter 91). PBC occurs primarily in women. In patients
with jaundice, pruritus is also usually present, and fatigue is
common. Serologic testing (antimitochondrial antibodies) is
generally sufficient, but liver biopsy may be necessary to
confirm the diagnosis or extent of hepatic fibrosis in selected
cases. The cholangiocyte is a target of graft-versus-host
disease (see Chapter 35), and jaundice related to this disorder
develops in some 10% of hematopoietic cell transplant
recipients.26 Certain drugs also produce cholestasis as a
result of cholangiocyte injury (see Chapter 88).27 Examples
include erythromycin, trimethoprim/sulfamethoxazole, and
amoxicillinclavulanic acid (see http://www.livertox.nih.gov).
In general, cholestasis resolves within several months following discontinuation of the causative drug. Cholestasis from
cholangiocyte injury occurs in about 30% of adults with cystic
fibrosis (see Chapters 57 and 77), a genetic disorder of the
cystic fibrosis transmembrane conductance regulator ion

channel protein that is expressed in secretory epithelia.
Cholestasis with Minimal Histologic Abnormalities

Jaundice may accompany conditions characterized by minimal
hepatocellular injury and histologic abnormalities. Several
mechanisms contribute to cholestasis in these conditions,
including mutations in the genes that encode transport proteins involved in bile formation and conditions that interfere
with the function or expression of such proteins.
Benign recurrent cholestasis is an autosomally inherited
disorder associated with mutations in the genes that encode
2 transport proteins that are present on the canalicular
membrane of hepatocytes and regulate bile formation:
the familial intrahepatic cholestasis 1 protein (FIC1, gene
symbol ATP8B1) and the bile salt export pump (BSEP, gene
symbol ABCB11 [see Chapters 64 and 77]).28 FIC1 is a P-type
ATPase believed to function in hepatocytes as a membrane
flippase for aminophospholipids, and FIC1 dysfunction
appears to cause cholestasis by increasing the susceptibility
to canalicular membrane damage by hydrophobic bile
acids.29 BSEP is an ATP-dependent bile salt export pump,30
and impaired BSEP activity leads to cholestasis by reduction
in bile salt secretion.22 Benign recurrent cholestasis represents 1 end of a spectrum of disorders associated with
FIC1 and BSEP mutations; the other end is progressive
familial intrahepatic cholestasis (PFIC) types 1 and 2, diseases that can lead to liver failure in childhood and necessitate liver transplantation.
Patients with benign recurrent cholestasis typically
present before the second decade of life with recurrent episodes of malaise and pruritus in association with jaundice;
fever and abdominal pain are uncommon.31 When performed
during an icteric episode, liver biopsy findings are generally
confined to centrilobular cholestasis; portal-based inflammatory cell infiltrates are uncommon. Cholestatic episodes
may last up to several months and are separated by periods
of clinical remission. Although quality of life may be
adversely affected, the disease does not lead to progressive
liver damage and (unlike PFIC) liver failure does not
occur.
A number of drugs produce histologically bland intrahepatic cholestasis (see Chapter 88). Estrogens reduce bile formation principally by inhibiting bile salt secretion.22 There are
several mechanisms by which this occurs, including downregulation of the sinusoidal bile salt uptake protein Na+taurocholate cotransporting peptide (NTCP, gene symbol
SLC10A1), competitive inhibition of BSEP, and interference
with MRP2 function.32 Jaundice related to the use of oral contraceptives usually develops within 2 months of initiation of
therapy and is generally accompanied by pruritus; these
symptoms resolve promptly with discontinuation of the
drug. Anabolic steroids can produce a syndrome that is clinically indistinguishable from estrogen-induced cholestasis.
The clinical features of cholestasis associated with total parenteral nutrition (possibly related to altered enterohepatic
circulation and diminished neuroendocrine stimulation of
bile flow) may also resemble those related to estrogen and
anabolic steroids, but progressive hepatic fibrosis has also
been described.33
Cholestasis and jaundice also may develop during bacterial infections, likely because of cytokine-dependent downregulation of the transporters NTCP, MRP2, and BSEP.9 As in
other cholestatic disorders, the clinical features may be difficult to distinguish from biliary obstruction, and imaging
studies may be required to resolve this issue.

Jaundice due to intrahepatic cholestasis has been reported
as a paraneoplastic phenomenon (i.e., in the absence of malignant infiltration of the liver) in patients with lymphoma and
urologic malignancies. The latter, referred to as Stauffers syndrome, resolves after successful treatment of the primary
tumor.34 Pathogenesis may relate to tumor-derived secretion
of cytokines35 that interfere with NTCP, MRP2, and BSEP
function.9
Atypical Presentations of Cholestasis

Viral hepatitis rarely may cause profound cholestasis with
marked pruritus.36 Unless the patient has risk factors for viral
hepatitis, no features reliably distinguish this disorder from
other cholestatic syndromes or biliary tract obstruction. A high
level of suspicion and appropriate serologic tests will help
establish the diagnosis. Alcoholic hepatitis manifesting as
fever, jaundice, abdominal pain, and leukocytosis may be difficult to distinguish from bile duct obstruction. Liver biopsy
may be required to confirm the diagnosis.
Jaundice in Pregnancy
Several cholestatic disorders are uniquely encountered in
pregnancy (see Chapter 39). Jaundice uncommonly may
accompany hyperemesis gravidarum, a generally self-limited
disorder of the first trimester, but liver failure is not a feature
of this illness.37 Intrahepatic cholestasis of pregnancy typically
occurs in the third trimester and presents with pruritus and
occasionally with jaundice. Cholestasis generally resolves
within 2 weeks of delivery and often recurs with subsequent
pregnancies. Polymorphisms in the genes encoding the canalicular transporters BSEP, FIC1, MRP2, and MDR3 (gene
symbol ABCB4) and nuclear receptors that modulate their
expression have been associated with this disorder.37 Functional alterations in these transporters may enhance their
sensitivity to the inhibitory effects of estrogens with respect
to bile formation. A far more serious syndrome is acute fatty
liver of pregnancy, which typically occurs in the third trimester and is associated with hepatocellular injury. Jaundice,
when present, is usually accompanied by nausea, abdominal
pain, and evidence of liver failure. Liver biopsy (if performed)
demonstrates microvesicular steatosis. The disorder may be
fatal unless obstetrical delivery is performed promptly. Preeclampsia, a microvascular disorder of the third trimester, is
heralded by hypertension and proteinuria and affects the
liver in about 10% of cases. A particularly severe form, the
HELLP (hemolysis, elevated liver enzyme levels, and a low
platelet count) syndrome, is treated by prompt obstetric
delivery.
Jaundice in the Critically Ill Patient

Establishing the cause of jaundice in the critically ill patient
can present a challenge to intensivists and their consultants.
The differential diagnosis can be quite broad. Predisposing
factors include hepatic ischemia, blood transfusions, hepatotoxic drugs, parenteral nutrition, and occult sepsis,38 and
kidney injury may further contribute to impairment of conjugated bilirubin elimination. The persistence of icterus can be
a source of dismay and frustration to concerned relatives
and other advocates for the patient, who may view jaundice
as the cause rather than a manifestation of the underlying
problems. Notably, even if other clinical parameters improve,
there may be a lag in the resolution of jaundice. Therefore, the
management of jaundice in critical illness requires not only
a careful search for reversible causes but also a great deal
of patience.
Bile Duct Obstruction

Obstructive disorders of the biliary tract include occlusion of
the bile duct lumen, intrinsic disorders of the bile ducts, and
extrinsic compression.
Choledocholithiasis
The most common cause of biliary obstruction is luminal
occlusion by a stone (choledocholithiasis). Three types of
stones have been implicated in this process, with cholesterol
gallstones responsible for the majority of cases. Cholesterol
stones typically originate in the gallbladder and can migrate
into the bile duct (see Chapter 65). In patients with uncon
jugated hyperbilirubinemia, calcium bilirubinate stones
(so-called black pigment gallstones) form in the gallbladder
and may also form in situ at any level of the biliary tract.
Brown pigment gallstones, a distinct type of bilirubinate stone,
can lead to repeated bouts of cholangitis (recurrent pyogenic
cholangitis) in patients from certain regions of Asia (see
Chapter 68) and in patients with prior biliary tract surgery or
endoscopic intervention (see Chapters 66 and 70).
Bile Duct Diseases

Intrinsic narrowing of the bile ducts occurs in inflammatory,
infectious, or neoplastic biliary disease. Congenital disorders
of the bile ducts, including cysts and biliary atresia, are discussed in Chapter 62. PSC, a progressive inflammatory disorder of the bile ducts, is characterized by focal and segmental
biliary strictures (see Chapter 68). Focal narrowing and localized obstruction of the bile ducts is an unusual complication
of acquired immunodeficiency syndrome (so-called AIDS
cholangiopathy [see Chapter 34]). Biliary strictures may also
follow hepatic arterial infusion of certain chemotherapeutic
agents39 or result from surgical injury to the bile duct or
hepatic artery (see Chapters 66 and 70). Neoplasms of the
biliary tract are discussed in Chapter 69.
Extrinsic Compression
Extrinsic compression of the biliary tract may result from neoplastic involvement or inflammation of surrounding viscera.
Rarely, marked enlargement of the surrounding vasculature
(e.g., arterial aneurysms, cavernous transformation of the
portal vein [portal cavernoma]) can compress the bile ducts
(see Chapter 85).
Painless jaundice is a classic feature of carcinoma of the
head of the pancreas (see Chapter 60). Occasionally, hepatocellular carcinoma or periportal lymph nodes enlarged by metastatic tumor or lymphoma obstructs the extrahepatic bile ducts.
Pancreatitis may also produce extrinsic biliary compression as
a result of edema or pseudocyst formation (see Chapters 58
and 59). Rarely, gallstones in the cystic duct or infundibulum
of the gallbladder compress the common hepatic duct (Mirizzis syndrome) and produce jaundice (see Chapter 65).40
DIAGNOSTIC APPROACH TO JAUNDICE

A general algorithm for evaluating the patient with jaundice
is depicted in Figure 21-2. A logical approach involves: (1) a
carefully taken patient history, thorough physical examination, and screening laboratory studies; (2) formulation of a
working differential diagnosis; (3) selection of specialized
tests to narrow the diagnostic possibilities; and (4) development of a strategy for treatment or further testing if unexpected diagnostic possibilities arise.

History, physical
examination,
routine laboratory tests
Alkaline phosphatase
or aminotransferases
elevated?
ERCP
or THC
Evaluate for hemolysis,

hereditary
hyperbilirubinemia
Yes
Therapeutic
intervention
Biliary
obstruction
No
Biliary tract obstruction

a consideration?
Dilated
bile ducts
No
Biochemical studies
for specific causes of
liver disease
Positive
Specific
therapy
Negative
Yes
Consider
liver biopsy
Abdominal
US or CT
Nondilated
bile ducts
No biliary
obstruction
High
Clinical likelihood of
biliary obstruction
Low
Intermediate
Dilated
bile ducts
Consider
MRCP or EUS
Nondilated
bile ducts
FIGURE 21-2. Algorithm for evaluation and management of jaundice and hyperbilirubinemia. THC, transhepatic cholangiography.
History and Physical Examination

The patients history and physical examination provide important clues regarding the cause of jaundice (Table 21-3). A
history of biliary surgery, fever (especially when accompanied
by rigors), and abdominal pain, particularly in the right upper
quadrant, is suggestive of biliary obstruction with cholangitis.
On the other hand, symptoms compatible with a viral prodrome (e.g., anorexia, malaise, myalgias) make acute viral
hepatitis a strong diagnostic possibility, especially if there are
risk factors for potential infectious exposure. A carefully taken
history may suggest that environmental hepatotoxins, ethanol,
or medications underlie the patients icteric liver disease. A
family history of jaundice or liver disease raises the possibility
of hereditary hyperbilirubinemia or genetic liver disease. All
clues must be interpreted with caution; for example, fever and
abdominal pain accompany diseases other than biliary
obstruction, and viral hepatitis may occur coincidentally in
patients with a history of prior biliary surgery. Moreover,
anorexia and malaise are not specific for viral hepatitis, and
gallstones can develop in patients with chronic liver disease.
Nevertheless, when details from the patients history are evaluated in the context of the physical findings and results of
routine laboratory tests, jaundice can be characterized correctly as obstructive or nonobstructive in about 75% of cases,
and this rate has yet to be surpassed by computer-based
modeling.41
Clues offered by the physical examination are also important in the patient with jaundice. Fever or abdominal
tenderness (particularly in the right upper quadrant) suggests

cholangitis, and a palpable abdominal mass suggests a neoplastic cause of obstructive jaundice. The presence of cirrhosis
may be suggested by signs of portal hypertension (e.g., ascites,
splenomegaly, prominent abdominal veins), spider telangiectasias, gynecomastia, and asterixis. Some findings may be
pathognomonic of a specific disorder (e.g., Kayser-Fleischer
rings in Wilson disease).
Initial Laboratory Studies

Essential laboratory tests in the patient with jaundice include
serum total bilirubin, alkaline phosphatase, aminotransferases, complete blood count, and prothrombin time (see
Chapter 73). Serum alkaline phosphatase activity derives from
related isoenzymes expressed on the membranes of multiple
cell types, including the apical membranes of hepatocytes and
cholangiocytes. In these cells, under physiologic conditions,
enzymatic cleavage releases alkaline phosphatase from the
apical membrane into bile; small amounts are released from
the basolateral membrane into plasma as well. Biliary obstruction and intrahepatic cholestasis increase the basolateral
release of alkaline phosphatase, and serum alkaline phosphatase activity increases under these conditions. Consequently,
in a jaundiced patient, a predominant increase in serum alkaline phosphatase (relative to aminotransferase) activity suggests the presence of biliary tract obstruction or intrahepatic
cholestasis. An increase in serum alkaline phosphatase activity

TABLE 21-3 Clues to the Differential Diagnosis of Jaundice: Biliary Obstruction versus Liver Disease
Parameter
Biliary Obstruction
Liver Disease
History
Abdominal pain
Fever, rigors
Prior biliary surgery
Older age
Anorexia, malaise, myalgias (viral prodrome)

Known viral exposure
History of blood product receipt or injection drug use
Exposure to known hepatotoxin
Family history of liver disease
Physical examination
Fever
Abdominal tenderness
Palpable abdominal mass
Abdominal surgical scar
Spider telangiectasias
Stigmata of portal hypertension (e.g., prominent
abdominal veins, splenomegaly, ascites)
Asterixis
Laboratory studies
Predominant elevation of serum alkaline

phosphatase relative to aminotransferases*
Prothrombin time (INR) normal or normalizes with
vitamin K administration
Leukocytosis
Elevated serum amylase or lipase level
Predominant elevation of serum aminotransferase

levels relative to alkaline phosphatase
Prolonged prothrombin time that does not normalize
with vitamin K administration
Thrombocytopenia
Serologies indicative of specific liver disease
*Except early after acute obstruction when the opposite pattern may be seen transiently.
(especially if aminotransferase activity is normal), however,

may reflect release of alkaline phosphatase isoenzymes from
extrahepatic tissues. If there is diagnostic uncertainty, elevated
serum activities of other proteins (e.g., gamma glutamyl transpeptidase, 5-nucleotidase, alkaline phosphatase isoenzymes)
confirm the presence of hepatobiliary disease (see Chapter 73).
The aminotransferasesalanine aminotransferase (ALT), a
cytosolic enzyme found predominantly in hepatocytes, and
aspartate aminotransferase (AST), isozymes of which are
found within hepatocytes and cells from several other tissues
are ordinarily detected in serum in low concentrations. Conditions that produce hepatocellular injury (e.g., viral hepatitis,
toxic liver injury, hepatic ischemia [see earlier]) increase
plasma membrane permeability and release of aminotransferases into plasma. A predominant elevation of serum aminotransferase levels (relative to alkaline phosphatase) suggests
that jaundice is due to hepatocellular injury. There are exceptions to this generalization, however; for example, transient
biliary obstruction from choledocholithiasis may cause a brief
but dramatic elevation (>10 to 20 times normal) of serum aminotransferase activity.42
A complete blood count provides complementary information. Leukocytosis may be a clue to the presence of biliary tract
obstruction or another inflammatory disorder that may be
associated with cholestasis. The presence of anemia raises the
possibility that a hemolytic disorder is responsible for jaundice, especially if isolated hyperbilirubinemia (without other
abnormalities in biochemical liver tests) is detected. Thrombocytopenia is a characteristic finding in cirrhosis and appears
to result from reduced synthesis of the platelet production
regulator thrombopoietin or from increased splenic sequestration associated with portal hypertension.
Prothrombin time reflects the activities of coagulation
factors I, II, V, VII, and X. With impaired hepatic synthesis of
these proteins, prothrombin time is prolonged (often reported
as an increase in the international normalized ratio [INR]),
but this finding is not specific for conditions associated with
hepatocellular injury. Prolongation of prothrombin time can
also be seen with intrahepatic cholestasis or prolonged biliary
obstruction, as a result of impaired absorption of vitamin K, a
fat-soluble cofactor required for synthesis of factors II, VII, IX,
and X. Exogenously administered vitamin K will generally

normalize the prothrombin time in intrahepatic cholestasis or
prolonged biliary obstruction but not in conditions associated
with hepatocellular injury.
Overall Approach
Integration of the patients history, physical examination, and
laboratory study results will provide an estimate of the likelihood that jaundice is due to a disorder of bilirubin production
or metabolism, intrinsic liver disease, or biliary obstruction.
At 1 extreme is the asymptomatic patient with no abnormalities (other than jaundice) on physical examination. Under
these conditions, if the serum alkaline phosphatase and aminotransferase activities, platelet count, and prothrombin time
are normal, liver disease or biliary obstruction is highly
unlikely. In this situation, further testing for specific disorders,
such as an isolated defect in bilirubin metabolism or hemolysis, is warranted (see Fig. 21-2). Alternatively, if the history,
physical examination, and laboratory study results raise the
possibility of biliary obstruction, hepatobiliary imaging is
appropriate. Selection of the appropriate imaging study
depends on the likelihood of bile duct obstruction and the
diagnostic accuracy, cost, complication rate, and availability of
each test (see later), especially if therapeutic intervention at
the time of the study is anticipated.
Imaging Studies
Abdominal US
Abdominal US is usually the initial imaging test in jaundiced
patients with suspected hepatobiliary disease.43-47 US can also
demonstrate cholelithiasis (although bile duct stones may not
be well seen) and intrahepatic lesions more than 1cm in diameter. US has the advantages of being noninvasive, portable,
and less expensive than other imaging studies (Table 21-4).
Disadvantages include dependence on the skill of the operator
for the procedure and potential technical difficulty in obese
patients or patients with excessive bowel gas that overlies
some organs like the pancreas.

TABLE 21-4 Imaging Studies for Evaluation of Jaundice
Sensitivity
(%)
Specificity
(%)
Abdominal US
55-91
82-95
Advantages: noninvasive, portable

Disadvantages: bowel gas may obscure bile duct;
difficult in obese persons, operator dependent
Abdominal CT
63-96
93-100
See disadvantages
Advantages: noninvasive, higher resolution than

US, not operator dependent
Disadvantages: potential for contrast-induced
nephrotoxicity, anaphylaxis
MRCP
82-100
94-98
See disadvantages
ERCP
89-98
89-100
0.2
Advantages: provides direct imaging of bile

ducts; permits direct visualization of
periampullary region and acquisition of tissue
distal to bifurcation of hepatic ducts; permits
simultaneous therapeutic intervention,
especially useful for lesions distal to the
bifurcation of the hepatic ducts
Disadvantages: requires sedation, cannot be
performed if altered anatomy precludes
endoscopic access to the ampulla (e.g.,
Roux-en-Y loop); may cause complications
(e.g., pancreatitis)
Percutaneous THC
98-100
89-100
3.5
0.2
Advantages: provides direct imaging of the bile

ducts, permits simultaneous therapeutic
intervention, especially useful for lesions
proximal to the common hepatic duct
Disadvantages: more difficult with nondilated
intrahepatic bile ducts; may cause
complications
EUS
89-97
67-98
See disadvantages
Advantages: imaging of the bile ducts is superior

to US and CT; permits needle aspiration of
suspected neoplasms
Disadvantages: requires sedation
Test
Morbidity (%)
Mortality
(%)
Advantages and Disadvantages
Advantages: noninvasive, imaging of bile ducts

superior to US and CT
Disadvantages: requires breath holding, may miss
small-caliber bile duct disease
THC, transhepatic cholangiography.
CT
CT of the abdomen with intravenous contrast is an alter
native noninvasive means of evaluating hepatobiliary disease.
Abdominal CT permits accurate measurement of the caliber
of the biliary tract, with sensitivity and specificity rates comparable to those for ultrasonography.43-45,47 Abdominal CT
detects intrahepatic space-occupying lesions as small as 5mm,
is not operator dependent, and provides technically superior
images in obese persons. However, it lacks portability, exposes
the patient to ionizing radiation, and is more expensive than
ultrasonography. The requirement for the use of intravenous
contrast may be problematic in the setting of kidney injury
(see Table 21-4).
MRCP
MRCP is a technical refinement of standard MRI that permits
rapid clear-cut delineation of the biliary tract. MRCP appears
to be superior to conventional ultrasonography or CT for the

detection of biliary tract obstruction48-51 and plays an important role as a diagnostic test in this setting (see Table 21-4).
Moreover, standard MRI can be performed during the same
examination if there is a question of a hepatobiliary mass or if
a contrast allergy precludes CT. It is more expensive than
ultrasonography or CT.
ERCP
ERCP permits direct visualization of the biliary tract. ERCP is
more invasive than ultrasonography, CT, and MRCP (see
Table 21-4) and comparable in cost to MRCP.52 After endoscopic identification of the ampulla of Vater, insertion of
a catheter permits contrast injection into the biliary tract;
sedation and analgesia are necessary. ERCP is highly accurate
in the diagnosis of biliary obstruction.47,53 If a focal cause
of biliary obstruction (e.g., choledocholithiasis, biliary stricture) is identified, maneuvers to relieve obstruction (e.g.,

sphincterotomy, stone extraction, stricture dilation, stent
placement) can be performed during the same session (see
Chapter 70). Similarly, if there is concern about a neoplasm,
biopsy and brushings for cytology can be performed. Acquisition of biopsy specimens and therapeutic interventions via
ERCP are limited largely to lesions distal to the bifurcation of
the right and left hepatic bile ducts. The technical success rate
of diagnostic ERCP is higher than 90%; the technique fails
when the ampulla of Vater cannot be cannulated, as may be
the case in patients with prior abdominal surgery and altered
anatomy (e.g., gastric bypass, choledochojejunostomy). The
major complication of ERCP is pancreatitis, which occurs in at
least 5% of cases,54 and the mortality rate is approximately
0.2%.55 These rates are influenced in part by the patients baseline characteristics and need for therapeutic instrumentation
during the procedure.
Percutaneous Transhepatic Cholangiography

Percutaneous transhepatic cholangiography (THC) is a procedure that complements ERCP. Percutaneous THC requires
passage of a needle through the skin and subcutaneous tissues
into the hepatic parenchyma and advancement into a peripheral bile duct. When bile is aspirated, a catheter is introduced
through the needle, and radiopaque contrast medium is
injected. Sensitivity and specificity of percutaneous THC for
the diagnosis of biliary tract disease are comparable with those
for ERCP.56,57 Like ERCP, interventional procedures like balloon
dilation and stent placement can be performed at the time of
percutaneous THC to relieve focal obstructions of the biliary
tract (see Chapter 70). Percutaneous THC is potentially technically advantageous when the level of biliary obstruction is
proximal to the common hepatic duct or altered anatomy precludes ERCP (see earlier). Percutaneous THC may be technically challenging in the absence of dilatation of the intrahepatic
bile ducts; in this situation, multiple passes may be required,
and visualization of the biliary tract may be unsuccessful in
up to 10% of attempts.58 With percutaneous THC, about 2% of
patients experience complications as a result of bleeding, perforation, and infection; death is rare.59 Percutaneous THC is
more expensive than abdominal ultrasonography and CT
(see Table 21-4).
Endoscopic US
EUS can also detect obstruction of the bile duct and major
intrahepatic bile ducts, with sensitivity and specificity com
parable to those for MRCP.60-62 EUS has the potential advantage of permitting biopsy of suspected malignant lesions,
and under appropriate circumstances, the operator can
proceed directly to ERCP for definitive biliary decompression
(see Table 21-4). The risk of diagnostic EUS is comparable
with that of diagnostic upper endoscopy; when needle
biopsy is used, the mortality rate is roughly 0.1%.63 EUS
may be most useful in circumstances in which the patient
is thought to be at high risk for complications of ERCP or
percutaneous THC.
Nuclear Imaging Studies

Nuclear scintigraphy of the biliary tract, although helpful
in the diagnosis of cholecystitis, is not sufficiently sensitive
to justify its routine use in the diagnostic evaluation of adults
with jaundice.64 Furthermore, hepatic uptake of radiolabeled
derivatives of iminodiacetic acid (e.g., HIDA) is limited
when the serum bilirubin level exceeds 7 to 10mg/ dL.65 One
exception to this generalization is in the evaluation of a potential bile leak, an uncommon cause of jaundice following
biliary surgery, in which scintigraphy has an accuracy rate as

high as 87%.66
Suggested Strategies for Imaging

The order of imaging studies depends largely on the clinical
likelihood of obstructive jaundice (see Fig. 21-2). Several diagnostic strategies have been compared by clinical decision
analysis in the era that predated MRCP and EUS67; no subsequent refinements to this comparison have been published.
Based on the analysis, if the probability of biliary obstruction
is approximately 20%, the positive and negative predictive
values of a strategy that uses ultrasonography as the initial
test are estimated to be 96% and 98%, respectively. If the probability of biliary obstruction is 60%, a strategy that uses ultrasonography as the first test would yield a positive predictive
value of 99%, whereas the negative predictive value would fall
to 89%. The implication is that if the level of suspicion for
biliary tract obstruction is high and ultrasonography does not
show dilated bile ducts, further studies to visualize the biliary
tract should be pursued.
Therefore, in jaundiced patients in whom biliary obstruction is a possibility, abdominal ultrasonography (or CT) is an
appropriate initial approach. If the bile ducts are dilated, the
biliary tract should be imaged directly with ERCP (or percutaneous THC) and appropriate therapy undertaken if biliary
obstruction is found. If the bile ducts are not dilated on
abdominal ultrasonography (or CT), the next step depends on
the clinical likelihood of biliary obstruction. If the likelihood
of biliary obstruction is thought to be low, the patient should
be evaluated for intrinsic liver disease (see later). If the likelihood of biliary obstruction is believed to be intermediate, EUS
or MRCP is a reasonable next step prior to biliary intervention
or evaluation for a hepatic disorder.68 Among patients in
whom biliary obstruction is believed to be likely, ERCP (or
percutaneous THC) should be considered as the next step. If
ERCP or percutaneous THC does not show biliary obstruction, the patient should be evaluated for cholestatic liver
disease. The choice between ERCP and percutaneous THC
will be influenced by various factors (see Table 21-4), including the availability of each procedure at a particular institution, presence or absence of dilated bile ducts on initial
imaging, and suspected level of biliary obstruction. Under
most circumstances, ERCP should be the procedure of choice
because it is comparable to percutaneous THC in accuracy,
technical success rate, and frequency of major complications;
tends to be more widely available; and may offer better postprocedure tolerability (e.g., no need for an external biliary
drainage tube).
Other Studies
Serologic Testing
When imaging studies do not suggest biliary obstruction,
jaundiced patients with biochemical evidence of hepatocellular dysfunction or cholestasis should be evaluated for underlying liver disease. Depending on the disorder suspected,
screening laboratory studies may include viral serologies;
serum levels of iron, transferrin, and ferritin (for hemochromatosis); ceruloplasmin (for Wilson disease); antimitochondrial antibodies (for PBC); antinuclear antibodies, smooth
muscle antibodies, and serum immunoglobulins (for autoimmune hepatitis); and tissue transglutaminase antibodies (for
celiac disease). Confirmation of these diagnoses, as well as
elucidation of diagnoses not revealed by serologic analysis,
may be made by liver biopsy (or small bowel biopsy in the
case of celiac disease).
FIGURE 21-3. Liver histology in biliary tract obstruction. A, Prominent bile duct proliferation (arrows) and a mixed portal-based inflam
matory infiltrate are evident. Periportal hepatocytes show feathery degeneration (arrowheads) indicative of cholate stasis, cytologic
changes caused by prolonged cholestasis (H&E, 200). B, The periportal bilirubin-stained region (arrow) surrounded by necrotic cells
represents a bile infarct (H&E, 40).
Liver Biopsy
Liver biopsy provides precise information regarding lobular
architecture and the extent and pattern of hepatic inflammation and fibrosis and is most helpful for patients with persistent and undiagnosed jaundice. With special histologic stains
(and if appropriate, quantification of iron or copper content),
liver biopsy permits the diagnosis of viral hepatitis, fatty liver
disease, hemochromatosis, Wilson disease, PBC, granulomatous hepatitis, and neoplasms. Occasionally, liver biopsy specimens provide clues to otherwise unsuspected biliary tract
obstruction, the histologic features of which are shown in
Figure 21-3; however, liver histology may be entirely normal
in acute biliary obstruction. Liver biopsy is associated with a
low but definite complication rate, predominantly from bleeding and perforation, and the need for hospitalization in 1% of
cases; the mortality rate is about 0.01%.69
THERAPEUTIC APPROACHES
Obstructive Jaundice
In the patient with bile duct obstruction, therapy is typically
directed at relieving the obstruction. Interventional endoscopic or radiologic approaches include sphincterotomy,
balloon dilation of focal strictures, and placement of drains
or stents (see Chapter 70); the alternative approach is surgery
(see Chapters 66 and 69). The therapeutic strategy chosen
depends in part on the location and likely cause of the
obstructing lesion. Focal intrahepatic strictures may be amenable to an interventional radiologic approach, whereas
lesions distal to the bifurcation of the hepatic ducts may be
more suitably managed endoscopically (e.g., sphincterotomy
for choledocholithiasis); neoplasms generally require surgery
if feasible.
Nonobstructive Jaundice
When jaundice is due to liver disease, optimal treatment is
directed toward the underlying cause (e.g., cessation of
ethanol, discontinuation of the offending drug, administration
of antiviral therapy for hepatitis B, immunosuppressive agents
for autoimmune hepatitis). Therapy for hyperbilirubinemia
per se is generally unnecessary in adults because the neurotoxicity of bilirubin is limited to disorders characterized by
extreme elevations of unconjugated bilirubin in neonates and
infants (e.g., physiologic jaundice of the newborn, type I

Crigler-Najjar syndrome). In these disorders, the risk of neurotoxicity can be reduced with phototherapy, in which exposure to blue or green light produces photoisomerization of
bilirubin to more water-soluble enantiomers that do not
require conjugation for excretion in bile.10,70 One study has
suggested that orlistat, which increases intestinal fat excretion,
traps unconjugated bilirubin intraluminally and can augment
phototherapy- or phenobarbital-induced reduction of unconjugated hyperbilirubinemia in children with type I or type II
Crigler-Najjar syndrome, respectively,71 but this observation
has not yet been confirmed.
Ursodeoxycholic acid (ursodiol), a bile acid that potently
stimulates bile flow, has been studied as a treatment for
several cholestatic disorders.72 Ursodeoxycholic acid improves
biochemical indices and appears to slow disease progression
in PBC (see Chapter 91). Ursodeoxycholic acid has also been
shown to improve biochemical markers and clinical outcomes
in patients with intrahepatic cholestasis of pregnancy,73 and
pilot studies have suggested that it is helpful in improving
biochemical indices of cholestasis related to parenteral nutrition74,75 and in preventing cholestasis following hematopoietic
cell transplantation.76,77 By contrast, although initial pilot
studies suggested that ursodeoxycholic acid reversed cholestasis in PSC, a long-term benefit of this agent in this
disorder has not been demonstrated to date in randomized
controlled trials (see Chapter 68). Additional treatments for
cholestatic disorders are directed toward complications other
than hyperbilirubinemia. One complication is impaired
absorption of fat-soluble vitamins (A, D, E, K), and supplementation of the deficient vitamins is recommended.
Management of pruritus caused by cholestasis is discussed in
Chapter 91.
KEY REFERENCES
Full references for this chapter can be found on
www.expertconsult.com.
1. Bosma PJ. Inherited disorders of bilirubin metabolism.
J Hepatol 2003; 38:107-17.
2. Fevery J. Bilirubin in clinical practice: A review. Liver Int
2008; 28:592-605.
6. Nies AT, Keppler D. The apical conjugate efflux pump
ABCC2 (MRP2). Pflugers Arch 2007; 453:643-59.

7. Borst P, de Wolf C, van de Wetering K. Multidrug
resistance-associated proteins 3, 4, and 5. Pflugers Arch
2007; 453:661-73.
8. van de Steeg E, Stranecky V, Hartmannova H, et al.
Complete OATP1B1 and OATP1B3 deficiency causes
human Rotor syndrome by interrupting conjugated
bilirubin reuptake into the liver. J Clin Invest 2012;
122:519-28.
9. Geier A, Wagner M, Dietrich CG, et al. Principles of hepatic
organic anion transporter regulation during cholestasis,
inflammation and liver regeneration. Biochim Biophys Acta
2007; 1773:283-308.
10. Maisels MJ, McDonagh AF. Phototherapy for neonatal
jaundice. N Engl J Med 2008; 358:920-8.
12. Labori KJ, Raeder MG. Diagnostic approach to the patient
with jaundice following trauma. Scand J Surg 2004; 93:
176-83.
16. Geier A, Wagner M, Dietrich CG, et al. Principles
glucuronidation. Hepatology 2012; 55:1912-21.
22. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile

salt transporters in normal physiology and liver disease.
Gastroenterology 2004; 126:322-42.
27. Padda MS, Sanchez M, Akhtar AJ, et al. Drug-induced
cholestasis. Hepatology 2011; 53:1377-87.
28. van der Woerd WL, van Mil SW, Stapelbroek JM, et al.
Familial cholestasis: Progressive familial intrahepatic
cholestasis, benign recurrent intrahepatic cholestasis and
intrahepatic cholestasis of pregnancy. Best Pract Res Clin
Gastroenterol 2010; 24:541-53.
30. Lam P, Soroka CJ, Boyer JL. The bile salt export pump:
Clinical and experimental aspects of genetic and acquired
cholestatic liver disease. Semin Liver Dis 2010; 30:125-33.
38. Brienza N, Dalfino L, Cinnella G, et al. Jaundice in critical
illness: Promoting factors of a concealed reality. Intensive
Care Med 2006; 32:267-74.
72. Beuers U. Drug insight: mechanisms and sites of action of
ursodeoxycholic acid in cholestasis. Nat Clin Pract
Gastroenterol Hepatol 2006; 3:318-28.
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CHAPTER

Diagnostic Approach to Jaundice..............................................342

History and Physical Examination............................................... 343

so their overall contribution to bilirubin production under

Chapter 21 Jaundice 337

FIGURE 21-1. Schematic overview of bilirubin formation, metabo

Under physiologic conditions, virtually all bilirubin in bile

338 Section III Symptoms, Signs, and Biopsychosocial Issues

practical standpoint, conditions associated with jaundice can

Isolated Disorders of Bilirubin Metabolism

Increased Bilirubin Production

Jaundice can result from an increase in bilirubin production

Processes that can generate excessive bilirubin production

TABLE 21-1 Differential Diagnosis of Jaundice and Hyperbilirubinemia

Isolated Disorders of Bilirubin Metabolism

Hemolysis, ineffective erythropoiesis, blood transfusion, resorption of hematomas

Conjugated or Mixed Hyperbilirubinemia

Hepatic Disorders with Prominent Cholestasis

Granulomatous diseases such as mycobacterial infections, sarcoidosis, lymphoma, granulomatosis

Pancreatic carcinoma, metastatic lymphadenopathy, hepatocellular carcinoma, ampullary adenoma/

Aneurysm, cavernous transformation of the portal vein (portal cavernoma)

AIDS, acquired immunodeficiency syndrome.

Chapter 21 Jaundice 339

Decreased Bilirubin Uptake

Decreased Bilirubin Conjugation

4mg/dL. The molecular basis of Gilberts syndrome has been

TABLE 21-2 Hereditary Disorders of Bilirubin Metabolism and Transport

Usually <7, about half

Usually <7, about

Normal (theoretical risk

340 Section III Symptoms, Signs, and Biopsychosocial Issues

Conjugated or Mixed Hyperbilirubinemia

Acute Hepatocellular Dysfunction

hepatitis is often heralded by anorexia, malaise, and myalgias

Chronic Hepatocellular Dysfunction

Chapter 21 Jaundice 341

Hepatic Disorders with Prominent Cholestasis

Disorders Involving Cholangiocyte Injury

cystic fibrosis transmembrane conductance regulator ion

Cholestasis with Minimal Histologic Abnormalities

342 Section III Symptoms, Signs, and Biopsychosocial Issues

Atypical Presentations of Cholestasis

Jaundice in the Critically Ill Patient

Bile Duct Obstruction

Bile Duct Diseases

DIAGNOSTIC APPROACH TO JAUNDICE

Chapter 21 Jaundice 343

Evaluate for hemolysis,

Biliary tract obstruction

History and Physical Examination

tenderness (particularly in the right upper quadrant) suggests

Initial Laboratory Studies

344 Section III Symptoms, Signs, and Biopsychosocial Issues

Anorexia, malaise, myalgias (viral prodrome)

Predominant elevation of serum alkaline

Predominant elevation of serum aminotransferase

(especially if aminotransferase activity is normal), however,

and X. Exogenously administered vitamin K will generally

Chapter 21 Jaundice 345

Advantages: noninvasive, portable

Advantages: noninvasive, higher resolution than

Advantages: provides direct imaging of bile

Advantages: provides direct imaging of the bile