A s s e s s m e n t o f Ja u n d i c e i n

the Hospitalized Patient

a b,
Priya Kathpalia, MD , Joseph Ahn, MD, MS *

KEYWORDS
! Jaundice ! Cholestasis ! Hyperbilirubinemia ! Benign postoperative jaundice
! Cholestasis of sepsis

KEY POINTS
! Jaundice signifies a disorder in bilirubin metabolism.
! A thorough assessment of the clinical history and physical exam findings together with
laboratory analysis and imaging studies are required to determine the cause of jaundice.
! The clinician must be able to recognize which conditions associated with jaundice warrant
urgent endoscopy or evaluation for liver transplantation.

OVERVIEW

Jaundice originates from the Latin word “galbinus,” which describes a yellow-green
color. Icterus comes from the Greek word “ikteros,” which meant both yellow bird
and jaundice; historically, yellow birds were used as a “cure” for jaundice.1 However,
it has since come to be understood that jaundice is not a disease but rather a feature of
disordered bilirubin metabolism that often signifies liver dysfunction. In general, the
yellow discoloration occurs as a result of bilirubin deposition in the sclerae, mucosa,
and skin when levels rise higher than 3 mg/dL.2 Management is aimed at identifying
and addressing the cause of the dysregulation in bilirubin metabolism.
Jaundice in the hospitalized patient is not an uncommon consultation for the general
gastroenterologist. The National Hospital Ambulatory Medical Care Survey analyzed
more than 1 billion emergency department visits from 1995 to 2004 and found that
400,000 patients had a diagnosis of jaundice. Nearly 50% of these were older than
age 15; certainly the frequency and cause of jaundice depends on the patient popu-
lation being studied.3

Disclosures: None.
a
Division of Gastroenterology and Hepatology, University of California, San Francisco, 513
Parnassus Avenue, Med Sci Room S-356, San Francisco, CA 94143, USA; b Division of Gastroen-
terology and Hepatology, Oregon Health & Science University, 3181 Southwest Sam Jackson
Park Road, Portland, OR 97239–3098, USA
* Corresponding author.
E-mail address: [email protected]

Clin Liver Dis 19 (2015) 155–170

http://dx.doi.org/10.1016/j.cld.2014.09.009 liver.theclinics.com
1089-3261/15/$ – see front matter ! 2015 Elsevier Inc. All rights reserved.
156 Kathpalia & Ahn

This article provides a systematic approach to evaluating jaundice in adult patients

with a focus on conditions that require urgent endoscopic intervention or evaluation
for liver transplantation.

PATHOGENESIS

More than 75% of bilirubin is made from senescent red blood cell (RBC) breakdown in
the reticuloendothelial system, with the remaining coming from ineffective RBC pro-
duction or heme proteins, such as myoglobin and cytochrome enzymes.2,4 Hepato-
cytes take up and conjugate this bilirubin within the sinusoids before excretion in
the biliary tree.
Unconjugated bilirubin is fat-soluble, allowing it to cross the blood-brain barrier. In
the newborn, it is this unconjugated hyperbilirubinemia that can lead to kernicterus.
Unconjugated bilirubin becomes conjugated via the glucuronosyltransferase enzyme;
in this form, the bilirubin becomes soluble in bile. Conjugated bilirubin can then be
transported to the gallbladder where it is stored, transported to the duodenum to be
excreted in stool, or converted into urobilinogen and excreted via the kidney
(Fig. 1). The components of bile are integral for fat metabolism, absorption of fat-
soluble vitamins, and excretion of bilirubin and its waste products.
It is postulated that bile flow can be altered by specific cytokines (tumor necrosis
factor-a, interleukin-1 and -6) by upregulating expression of intercellular adhesion
molecules, which in turn alters bile flow.5 Bile flow can also be affected by endotoxins
and exotoxins that are associated with infections or inflammatory states. Thus it is not
surprising that common causes of hyperbilirubinemia encompass various viral and
bacterial infectious etiologies.
Highlights:
! Bilirubin is produced by senescent RBC breakdown, ineffective RBC production,
and heme proteins
! The enzyme glucuronosyltransferase conjugates bilirubin, which is then con-
verted to urobilinogen in the liver before being stored or excreted in the bile ducts
! Bile flow can be altered by cytokines in inflammatory states

DIFFERENTIAL DIAGNOSIS

Rather than providing an exhaustive differential, this article focuses on the most com-
mon conditions and those diagnoses that should not be missed.

Fig. 1. Overview of bilirubin metabolism.

 Assessment of Jaundice in the Hospitalized Patient 157

Isolated Disorders of Bilirubin Metabolism

Jaundice may be a result of a primarily nonhepatic cause that results in dysregulation
of bilirubin metabolism (Fig. 2). Conditions that result in an increased heme load, such
as hemolytic anemias, resorption of hematomas, excessive blood transfusions, and
ineffective erythropoiesis (ie, from thalassemias), increase unconjugated bilirubin pro-
duction. A genetic condition, Gilbert syndrome, affects 3% to 7% of the population
and leads to isolated unconjugated hyperbilirubinemia.6,7 In this entirely benign con-
dition, the glucuronosyltransferase enzyme is impaired, especially in situations of
stress, such as after surgery, pain, or fasting with a resultant elevation of total bilirubin
as high as 5.3 mg/dL reported in some studies.8
Major Points:
! Conditions that increase heme protein load can result in unconjugated
hyperbilirubinemia
! Gilbert syndrome, a benign genetic condition, can also lead to impaired bilirubin
conjugation

Extrahepatic Disease Processes

Certain extrahepatic diseases can also lead to jaundice and must be considered in the
differential, especially if patients present with isolated bilirubin elevation. The most
common cause of extrahepatic biliary obstruction is choledocholithiasis, which can
lead to hyperbilirubinemia with associated elevations in aspartate aminotransferase,
alanine aminotransferase, and alkaline phosphatase. Superimposed infections in pa-
tients with choledocholithiasis can result in acute cholangitis (discussed later).
Choledocholithiasis is often associated with concurrent abdominal pain but can also
be asymptomatic. Biliary obstruction can also be caused by strictures related to chol-
angiocarcinoma; pancreatic cancer; metastatic disease to adjacent lymph nodes;
postoperative strictures (after cholecystectomy or liver transplantation); or external
compression of the common bile duct by a cystic duct stone or stone in the neck of
the gallbladder, known as Mirizzi syndrome. Primary sclerosing cholangitis often oc-
curs in the setting of inflammatory bowel disease (primarily ulcerative colitis) and
can lead to tight strictures that impair bile flow. Large pancreatic cysts or pseudo-
cysts, especially at the head of the pancreas, can also lead to similar compression.
In addition, abscesses or larger fluid collections can also cause external compression

Fig. 2. Disease states leading to isolated unconjugated hyperbilirubinemia.

158 Kathpalia & Ahn

of the biliary tree. Bilomas may develop after cholecystectomy or other intra-
abdominal procedures and can result in external compression of the biliary tree.9
Major Points:
! Choledocholithiasis and biliary strictures can lead to extrahepatic cholestasis

Intrahepatic Disease Processes

Intrahepatic disease processes that cause jaundice involve a mixed hepatocellular
and cholestatic process, generally involving pathology that affects the parenchyma
and bile ducts. Thus the differential for hepatocellular jaundice is broad, ranging
from (1) acute liver injury or acute liver failure, (2) chronic liver diseases with predom-
inant hepatocellular injury, and (3) infiltrative diseases with more prominent cholestasis
than hepatocellular injury.

Acute liver injury or acute liver failure

Jaundice is often the presenting sign in patients with no previous liver disease who
develop acute liver injury or failure. Acute liver injury and acute liver failure involve
elevated serum aminotransferases with a new coagulopathy (international normalized
ratio "1.5). In the latter, hepatic encephalopathy is also present distinguishing be-
tween the two entities and signifying a worse prognosis. Known causes include toxin
or drug-induced liver injury (DILI), autoimmune hepatitis, ischemic hepatitis, and viral
hepatitis. Viral hepatitis must be excluded with diagnostic testing for hepatitis A, B,
and C. Hepatitis D must be considered in patients with underlying chronic hepatitis
B, or in those with risk factors for parenteral transmission of viral hepatitis. Hepatitis
E should be considered in the immunosuppressed patient and in those with exposure
risk factors. Although rare, Wilson disease can also present as acute liver failure; this
diagnosis should be considered and not missed, especially in young patients.10
DILI is one of the more common causes of acute liver injury that can present as jaun-
dice within days or weeks of starting a new medication. Zimmerman11,12 reported that
a three-fold elevation of transaminases and a two-fold increase in total bilirubin
without overt symptoms of cholestasis, in the absence of other causes of acute liver
injury, portended worse outcomes with a mortality of 10% to 50%. Given the potential
for significant severity and high mortality of DILI, clinicians should have a high suspi-
cion for DILI in patients presenting with jaundice after starting on antibiotics or other
new medications.5,11–14 Various medications have been known to cause DILI
(Box 1). Antibiotics including penicillin derivatives, erythromycin, antituberculosis
drugs (ethambutol, isoniazid), nitrofurantoin, and antifungals have all been cited as
causes.11,12,14–16 Aside from antibiotics, however, various antihypertensive agents,
including the commonly prescribed b-blockers and angiotensin-converting enzyme in-
hibitors, have been reported as being associated with DILI. In addition, antiepileptics
and mood-stabilizing agents including valproic acid and phenytoin have also been
known to cause DILI.
In addition, a thorough history should be obtained to exclude the use of any herbal
or nonprescribed supplements or over-the-counter medications. Various weight loss
and body building supplements, in addition to herbal remedies targeted as joint pain
remedies, have been implicated in DILI.17

Chronic liver diseases

Patients with underlying chronic liver disease can present with hyperbilirubinemia as
their initial presentation. Thus, underlying viral hepatitis, alcoholic liver disease, hemo-
chromatosis, a1-antitrypsin deficiency, nonalcoholic steatohepatitis, primary biliary
cirrhosis, and autoimmune hepatitis should be considered because they can lead to
 Assessment of Jaundice in the Hospitalized Patient 159

Box 1
Various medications known to cause drug-induced liver injury

Analgesics: Nonsteroidal anti-inflammatory drugs, gold salts

Antibiotics: Amoxicillin-clavulanic acid, flucloxacillin, erythromycin, ethambutol, fluconazole,
isoniazid, nitrofurantoin, rifampin, sulfamethoxazole, terbinafine
Anticonvulsants: Phenytoin, valproic acid
Antihypertensives: Angiotensin-converting enzyme inhibitors, b-blockers, methyldopa
Hormonal agents: Androgens, estrogens, oral contraceptives, tamoxifen
Immunosuppresants: Azathioprine, cyclosporine
Psychotropic medications: Benzodiazepines, tricyclic antidepressants
Herbal remedies: Hydroxycut, green tea, anabolic steroids, kava, glucosamine

fibrosis and cirrhosis. Patients with new-onset jaundice with underlying chronic liver
disease should be evaluated as to the cause of their decompensation, such as infec-
tion, development of hepatocellular carcinoma, or cholangiocarcinoma, in addition to
the common causes of acute liver injury described previously. In addition, DILI por-
tends a worse prognosis in patients with underlying chronic liver disease.
Infiltrative diseases
Although these conditions can also become chronic, they present with more of a
cholestatic process than hepatocellular injury; the first clinical symptom is often jaun-
dice. Malignancies (primarily lymphomas), amyloidosis, tuberculosis, various vasculit-
ides, sarcoidosis, granulomatous hepatitis, and stricturing biliary diseases are among
those diseases known to infiltrate the liver that must be considered in patients pre-
senting with jaundice.
Major Points:
! Acute liver failure entails acute liver injury with signs of coagulopathy
! DILI is one of the more common causes of acute liver injury. Several medications
have been implicated (see Box 1)
! Chronic and infiltrative liver diseases can lead to jaundice depending on the
extent and severity of underlying condition

Entities Not to Be Missed

Acute cholangitis
Patients can develop acute ascending cholangitis when there is an obstruction of the
bile duct with a superimposed bacterial infection. Although underlying choledocholi-
thiasis is the most common cause of cholangitis, primary sclerosing cholangitis with
severe stricturing disease and malignancies causing alteration of bile have also
been known to be causes of cholangitis.
In addition to sudden-onset jaundice, up to 75% of patients with acute cholangitis
present with concurrent right upper quadrant pain and fever, collectively known as
Charcot triad.18 Given the pathology, these patients often have hyperbilirubinemia
and elevated alkaline phosphatase, although early in the course of the disease it is
not uncommon to have a disproportionate elevated serum aminotransferases that
can mimic viral hepatitis.18,19 Diagnosis is generally made based on the clinical pre-
sentation, although imaging studies can help confirm the diagnosis; ultrasound often
160 Kathpalia & Ahn

reveals the presence of gallstones, whereas computed tomography (CT) of the

abdomen better delineates the biliary tree and can identify ductal dilatation.
Once diagnosis is suspected, aggressive intravenous hydration and broad-
spectrum antibiotics should be initiated. Endoscopic retrograde cholangiopancrea-
tography (ERCP) allows for diagnostic and therapeutic intervention (biliary stent
placement, stone removal, sphincterotomy, and so forth) and should be performed
urgently, or emergently if the patient is in septic shock.20

Benign postoperative jaundice

Before 1990, posttransfusion hepatitis was a significant concern in patients presenting
with jaundice in the immediate postoperative period. However, with improvements in
screening methods before transfusion, this is no longer a significant issue. There are a
variety of scenarios that can cause postoperative jaundice (Box 2). One must consider
Gilbert syndrome that may have gone unrecognized before surgery but becomes
apparent because of the stress of surgery. Another entity is directly related to the
amount of blood transfusions required during prolonged operations; these patients
can experience isolated, mainly indirect hyperbilirubinemia within 2 to 4 days after sur-
gery because of the excessive heme load from the blood transfusions.
In addition, depending on the anesthetics or induction drugs used, and their modes
of excretion, in combination with the degree of ischemia and hypoperfusion experi-
enced intraoperatively, isolated hyperbilirubinemia and transient jaundice are not
uncommon.21
Patients undergoing any degree of liver resection can experience jaundice as a
result of hepatic insufficiency. In these patients, jaundice can persist for weeks to
months until the liver regenerates.22
Despite notable jaundice and bilirubin reaching as high as 40 mg/dL, synthetic liver
functioning is generally preserved in these patients; therefore, the clinician can distin-
guish this condition from acute liver injury or acute liver failure.23

Cholestasis of sepsis
Cholestasis of sepsis was first described in 1836 after a patient with sepsis related to
lobar pneumonia presented with jaundice.24 Since then, it has become a well-
recognized condition thought to occur secondary to abnormalities in the breakdown
of bilirubin itself caused by hepatocyte dysfunction or from an excess of bilirubin pro-
duction (Box 3). In the patient with sepsis, excess bilirubin production may be second-
ary to cholestasis, ischemia from prolonged hypotension or hypoxia, or direct
hepatocellular injury. Depending on the antibiotics used for management of sepsis,
superimposed DILI is not uncommon and can potentiate hepatic injury. Sulfa drugs,
penicillin derivatives, and cephalosporins in particular have been implicated in this
setting.16

Box 2
Questions for the clinician to consider in patients with postoperative jaundice

Does the patient have underlying Gilbert syndrome?

Did the patient receive significant blood transfusions intraoperatively?
Were hepatically metabolized anesthetics used at time of induction?
Did the patient experience hypotension intraoperatively?
Did the patient undergo some degree of liver resection?
 Assessment of Jaundice in the Hospitalized Patient 161

Box 3
Mechanisms leading to cholestasis of sepsis

1. Ischemia/hypoperfusion
2. Hepatocellular injury
3. Drug-induced liver injury
4. Hemolysis, toxin production

Hemolysis, either intravascular or extravascular, can also lead to increased bilirubin

production. Prior studies, dating back to the 1980s, have suggested that toxin produc-
tion itself during septic states can lead to profound hemolysis and even shock. For
example, 52 patients with toxic shock syndrome caused by Staphylococcus
aureus–related infections related to tampon use were studied in one case series; at
least 50% of these patients had hyperbilirubinemia and transamintis thought to be
related to the bacterial exotoxin production.25,26 Aside from S aureus, exotoxin from
Clostridium perfringens has been found to cause massive hemolytic anemia that
can lead to hyperbilirubinemia and jaundice, and endotoxin produced by Salmonella
typhi causes direct necrosis of the hepatocytes. Sepsis itself, a profound inflammatory
state, can lead to massive cytokine production that can contribute to cholestasis and
even direct hepatocyte injury as seen in severe cases of Salmonella infection.16
Although cholestasis and elevated serum aminotransferases in these patients can
be severe, studies have shown that these findings are not necessarily related to the
severity of the infection and generally improve rapidly with resolution of the underlying
sepsis.27

Intrahepatic cholestasis of pregnancy

As of 2010, the prevalence of intrahepatic cholestasis of pregnancy (ICP) was reported
to be 0.001% to 0.32% in the United States, and 2% to 4% in Scandinavia and Chile.
The Hispanic population within the United States has been noted to have an especially
high predilection possibly because of genetic predisposition, hormonal variations, and
nutritional differences.28,29 Although a relatively rare diagnosis, ICP is the most com-
mon reason for consultation for liver abnormalities in the pregnant patient.30 The clini-
cian must be able to distinguish jaundice caused by ICP from acute fatty liver of
pregnancy (often associated with multiorgan impairment, disseminated intravascular
coagulation, or preeclampsia) and other causes of hepatitis.
ICP is generally a result of a genetic mutation in the transporter responsible for the
excretion of bile salts; the defect is more prominent with increased levels of estrogen,
as in pregnancy or with oral contraceptive use.31 Interestingly, multiparity is consid-
ered a risk factor for cholestasis of pregnancy because of the higher estrogen levels.
Symptoms often occur late in the second or early in the third trimester of pregnancy
when estrogen levels are at their highest. Aside from being jaundiced, these pregnant
patients often complain of extreme pruritus in the limbs, hands, and feet. Laboratory
testing reveals an increase in serum total bile salts, serum bilirubin (rarely higher than
5–6 mg/dL), and alkaline phosphatase levels, produced by the bile canaliculi and the
placenta.32,33 Although predominantly a cholestatic process, this diagnosis may also
be associated with mild elevated serum aminotransferases, with aspartate amino-
transferase and alanine aminotransferase levels rarely exceeding 200 IU/L.34 If clinical
suspicion is high, and other etiologies have been excluded, there is no need to perform
liver biopsy in these patients.
162 Kathpalia & Ahn

Prognosis is excellent for the mother without associated mortality, although the pru-
ritus can be especially burdensome closer to term.35 Ursodeoxycholic acid is a preg-
nancy category B drug, and is widely used to ameliorate the symptoms of pruritus.
Cholestyramine and antihistamines, such as hydroxyzine, must be used with caution
because they are pregnancy category C drugs and may lead to vitamin K malabsorp-
tion and neonatal withdrawal syndrome, respectively. However, fetal demise has been
reported at 11% in some studies and is thought to be caused by cardiac conduction
abnormalities and arrythmias that may occur as unexcreted bile salts cross the
placenta.28,36,37 Thus, fetal monitoring is often performed more frequently in the last
trimester in this patient population and labor is often induced at the first sign of fetal
distress or by 37 weeks.32,38
Post–bone marrow transplant syndromes
Despite strides made in the treatment of hematologic malignancies, the liver can
become affected by the side effects of induction therapies, such as high-dose chemo-
therapy and radiation used before allogeneic hematopoietic stem cell transplantation
(HSCT). Veno-occlusive disease (VOD) is thought to occur about 20 to 30 days after
HSCT and has an incidence of 10% to 60% depending on the type and dosage of con-
ditioning regimen.39
Although the exact inciting event that leads to VOD is unclear, some degree of dam-
age occurs in the hepatic venules that eventually leads to obliteration and necrosis of
the centrilobular zones of the liver. Because the sinusoidal endothelial cells are more
often affected than hepatic venules, it was proposed that the name be changed from
VOD to sinusoidal obstruction syndrome (SOS); hence, these two terms are often used
interchangeably.40
Patients who have had prior HSCT, who received abdominal irradiation or condition-
ing regimens with busulfan/melphalan, or who have known underlying liver diseases
are more likely to develop VOD/SOS complications post-HSCT. These patients gener-
ally present with jaundice, abdominal pain from capsular stretching caused by hepa-
tomegaly, and fluid retention or ascites as outflow obstruction ensues.41 Bilirubin
levels are generally greater than 2 mg/dL. Diagnosis is generally made clinically and
generally liver biopsy is unnecessary. Treatment is supportive and aimed at symptom
control: diuretics and salt restriction and removal of any potential hepatotoxic agents
are key.
VOD/SOS can be difficult to distinguish from acute graft-versus-host disease
(GVHD) that generally occurs 3 weeks post-HSCT as engraftment ensues. In addi-
tion to cholestasis, GVHD patients generally have hepatocellular injury as evi-
denced by elevated serum aminotransferases. Unlike VOD/SOS, GVHD rarely
causes liver injury alone and causes more systemic symptoms; these patients
often have intestinal or skin manifestations that can help to distinguish this con-
dition.42 Transjugular liver biopsy may be useful to distinguish VOD/SOS from
GVHD if the diagnosis is unclear because the treatment of the latter involves
more aggressive immunosuppressive regimens that would be ineffective for the
former diagnosis.43
Major Points:
! Acute cholangitis: Underlying choledocholithiasis, stricturing disease, or malig-
nancies altering bile flow can lead to cholangitis and often require emergent
ERCP
! Benign postoperative jaundice: Gilbert syndrome, liver hypoperfusion intraoper-
atively, massive blood transfusions perioperatively, and various anesthetics can
lead to isolated hyperbilirubinemia
 Assessment of Jaundice in the Hospitalized Patient 163

! Cholestasis of sepsis: Cytokines released during infectious states, particularly

during sepsis, can lead to ischemia, direct hepatocellular injury, or hemolysis
that leads to cholestasis
! ICP: Genetic mutations can result in ICP in the pregnant patient during the late
second or early third trimester and can be fatal to the fetus
! Post–bone marrow transplant syndromes: SOS must be distinguished from
acute GVHD

DIAGNOSTIC APPROACH

A careful history with a thorough review of systems and physical examination help aid in
the diagnosis of jaundice in the hospitalized patient. Chopra and Griffin44 reported, “The
diagnosis of jaundiced caused by extrahepatic biliary obstruction can be made with
90% accuracy from results of only the medical history, physical examination, and routine
laboratory tests.” Pasanen and coworkers45 studied 220 patients with jaundice and
created a diagnostic scoring system (using duration of jaundice, serum protein levels,
age, and presence of fevers) to help compare the sensitivity and specificity of clinical
evaluation and imaging modalities; clinical evaluation alone had a sensitivity of 86%
without adding any other studies to help aid in the diagnosis. Although clinical history
and examination plays a large role in diagnosing the cause of the jaundice, laboratory
markers and imaging studies can provide further insight on the underlying pathology.
History
The clinical presentation of jaundice can vary from being an incidental finding with mild
scleral icterus to overt discoloration throughout the body. When evaluating a patient
with jaundice, the timing of symptoms and the rate of development of jaundice can
be essential in making the diagnosis. The presence of abdominal pain or symptoms
may point toward choledocholithiasis.
In addition, the clinician should ask in detail about alcohol and drug use, the route of
drug administration, use of any over-the-counter medications or herbal remedies, sex-
ual and travel histories, tattoos and in what type of setting they were placed, history of
prior blood transfusions, prior surgeries, presence of similar symptoms previously,
and any significant family history. It is important to assess for underlying chronic liver dis-
ease and/or occult cirrhosis and the possibility of undiagnosed congenital liver diseases.
A thorough review of symptoms with special consideration to constitutional symp-
toms, color of urine and stool, weight loss, pruritus, abdominal pain, and associated
arthralgias and malaise can help provide clues to distinguishing between the possible
etiologies of the jaundice (Box 4).
Major Points:
! It is essential to understand the rate of development of jaundice and timing of
symptoms to help establish the underlying diagnosis
! A detailed social and medication history can help provide clues as to the
diagnosis

Box 4
Key findings in the history that may point toward a certain diagnosis

Infectious etiology: Fevers, chills, fatigue, nausea and vomiting, acute-onset jaundice
Noninfectious etiology: Pruritus, weight loss, abdominal pain
Autoimmune etiology: Arthralgias, malaise, fatigue, slow-onset jaundice
164 Kathpalia & Ahn

Physical Examination
Certain findings on the physical examination alone can help determine the severity and
cause of the underlying liver disease. For example, the clinician may perform a more
extensive work-up for chronic liver disease if spider angiomata, palmar erythema,
Dupuytren contractures, ascites, caput medusa, or clubbing are observed on exami-
nation. If Wilson disease is suspected, an ophthalmologic consultation should be ob-
tained to look for Kayser-Fleischer rings or sunflower cataracts. Hyperpigmentation of
the skin and metacarpal changes together with signs of cardiomyopathy (jugular
venous distention or extra S3 or S4 heart sounds) point the clinician to consider the
diagnosis of hereditary hemochromatosis.
Major Points:
! A thorough physical examination can help identify signs of end-stage liver
disease
! Wilson disease and hemochromatosis have particular physical examination find-
ings that are highly specific for those diseases

Laboratory Findings
Laboratory testing may help the clinician determine whether the jaundice is caused by
obstruction alone or if there is a concurrent mixed obstructive process. It is ideal to
obtain prior laboratory testing, if available, to help serve as a baseline and comparison.
In addition, historical laboratory findings can also allow for an assessment of the rate
of development of jaundice and can help the clinician correlate the new clinical symp-
toms with recent events (ie, surgical procedures, new medications, toxin exposures,
trauma, and so forth).
The initial laboratory work-up should include a complete blood count with peripheral
smear (to look for signs of hemolysis) along with a complete metabolic panel (Box 5). If
there is a mild elevation in the liver function tests and bilirubin, but the patient is
asymptomatic, the blood work should simply be repeated. Alkaline phosphatase is
present in the bile canaliculi and can serve as a direct marker for biliary obstruction.
However, it can also be produced by bone, placenta, and the kidney. Thus, if the alka-
line phosphatase alone is elevated, g-glutamyltranspeptidase, found in the biliary
epithelium, can help distinguish biliary from nonbiliary causes of alkaline phosphatase

Box 5
Overview of basic laboratory studies and their significance in the work-up of jaundice

Complete blood count: To check hemoglobin; peripheral smear to look for signs of hemolysis
(schistocytes) especially if liver function tests normal
Alanine aminotransferase: Primarily cytosolic enzyme, more specific for liver injury
Aspartate aminotransferase: Cytosolic and mitochondrial enzyme; less sensitive and specific
compared with alanine aminotransferase
Bilirubin: Total and fractionated can help determine intrahepatic versus extrahepatic cause
Alkaline phosphatase: Primarily found in bile canaliculi of the liver, but also produced by bone,
placenta, and kidney
g-Glutamyltranspeptidase: Found in biliary epithelium, poor specificity
5-Nucleotidase: Confirmatory test along with alkaline phosphatase and g-
glutamyltranspeptidase to suggest hepatobiliary process
International normalized ratio: Marker of synthetic liver functioning
 Assessment of Jaundice in the Hospitalized Patient 165

despite its limited specificity. Another serum marker, 5-nucleotidase, often a send-out
test in most institutions, can help confirm a hepatobiliary process as the cause of the
alkaline phosphatase elevation.4 Bilirubin should be fractionated to help distinguish
intrahepatic versus extrahepatic causes. Coagulation studies can aid in the assess-
ment of the degree of hepatic dysfunction.
After the basic work-up is completed, further laboratory studies can be ordered based
on the clinician’s suspicion for the underlying cause of jaundice (Box 6). For example,
autoimmune markers may be helpful in a young woman with constitutional symptoms
or arthralgias. Primary biliary cirrhosis may be considered in an elderly woman with pru-
ritus and jaundice, whereas primary sclerosing cholangitis should be prominent on the
differential in a young patient with inflammatory bowel disease and new onset of jaun-
dice. Serologic markers for viral hepatitis should be ordered based on the patient’s
risk factors and travel history. Wilson disease and hereditary hemochromatosis might
be considered in younger patients especially with family history of liver disease.
Major Points:
! A basic laboratory work-up including complete blood count, complete metabolic
panel, and coagulation studies should be performed on all patients with new-
onset jaundice
! Once this basic work-up is completed, further autoimmune markers, viral serol-
ogies, or other disease-specific laboratory findings can be ordered at the clini-
cian’s discretion
Imaging Studies
There are a variety of imaging studies of varying diagnostic value in the work-up for
jaundice (Table 1). Ultrasound is considered first-line therapy in the assessment of
jaundice because of its cost-effectiveness and lack of radiation exposure. Studies
suggest increased sensitivity in nonobese patients with higher bilirubin concentrations
and prolonged duration of jaundice.47 Ultrasound can provide direct visualization of

Box 6
Laboratory markers that may aid in understanding the cause of the jaundice

Autoimmune markers
Autoimmune hepatitis: ANA, ASMA, anti-LKM1
Primary biliary cirrhosis: AMA
Primary sclerosing cholangitis: p-ANCA
Viral hepatitis serologies
Other viral serologies: CMV, VZV, EBV, HSV, HIV
Wilson disease: Urinary copper, serum ceruloplasmin
Hemochromatosis: Iron saturation, ferritin, HFE gene testing
a1-Antitrypsin deficiency: Measurement of enzyme activity or serum protein electrophoresis46
Malignancy: Tumor markers AFP, CEA, CA19-9

Abbreviations: AFP, alpha-fetoprotein; AMA, anti mitochondrial antibody; ANA, antinuclear

antibody; anti-LKM1, liver kidney microsomal type 1 antibody; ASMA, anti smooth muscle anti-
body; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CMV, cytomegalo-
virus; EBV, Epstein-Barr virus; HFE, hemochromatosis; HIV, human Immunodeficiency virus;
HSV, herpes simplex virus; p-ANCA, perinuclear antineutrophil cytoplasmic antibodies; VZV,
varicella zoster virus.
166 Kathpalia & Ahn

Table 1
Diagnostic modalities (from least to most invasive) to consider ordering in the patient with
jaundice

Type of Study Advantages/Disadvantages

Ultrasound Can assess for biliary dilatation, gallstones, venous flow
Is cheap, has low radiation
MRI/CT scan Can identify obstructive masses, features of cirrhosis
Has more radiation than ultrasound
Percutaneous transhepatic Useful for higher biliary obstructions, ductal malignancies
cholangiography Allows for stent placement
ERCP Identifies extrahepatic biliary disease causing jaundice
Allows for removal of stones, biliary stent placement
Liver biopsy Helps to distinguish hepatocellular injury from obstructive
process
Can measure hepatic venous pressure gradient (HVPG) via
transjugular approach

the biliary dilatation, presence of gallstones, and if performed with Doppler can assess
the patency of the portal and hepatic veins and the hepatic artery. However, ultra-
sound has limitations in obese patients and is an operator-dependent test.
Based on institutional availability and the findings on ultrasound, MRI or CT scans
are generally obtained next and can more precisely identify obstructive masses,
parenchymal liver disease, and features of cirrhosis.2 However, cholesterol stones
can be missed on CT because they are isodense with bile, which is why ultrasound
is considered the gold standard for cholelithiasis.48
Next, imaging studies that allow for direct therapeutic intervention can be per-
formed. Assy and colleagues5 found that “percutaneous transhepatic cholangiog-
raphy (PTC) and ERCP have in common 99% sensitivity and specificity for the
diagnosis of biliary obstruction, and both are capable of demonstrating the site and
the nature of the obstruction in more than 90% of patients.”49 Both PTC and ERCP
not only aid in diagnosis by direct visualization of the obstruction, but these tests
also allow for direct therapeutic intervention whether it be stone removal, sphincterot-
omy, stent placement, or drainage maneuvers if necessary. PTC is preferred for higher
biliary obstructions (eg, at the bifurcation of the hepatic ducts), whereas endoscopic
ultrasound and ERCP remain the gold standard for extrahepatic biliary disease
causing jaundice. Magnetic resonance cholangiopancreatography is a useful test in
the patient with low pretest probability of finding an obstructive lesion that would
require therapeutic intervention or in the patient with multiple comorbidities where
diagnosis should be fully confirmed before proceeding with the more invasive
ERCP. In the event of an obstructive lesion, magnetic resonance cholangiopancrea-
tography may help guide planning between ERCP and PTC.50
Major Points:
! Ultrasound is the most cost-effective and safe imaging study to perform in the
work-up for jaundice
! PTC and ERCP allow for direct visualization of the biliary tree with the ability to
provide therapeutic interventions concurrently if necessary

Other Diagnostic Modalities

Hepatobiliary Iminodiacetic Acid (HIDA) Scan scans may be helpful if ultrasound is
equivocal but there is still a high clinical suspicion of biliary obstruction. However,
 Assessment of Jaundice in the Hospitalized Patient 167

this is a nuclear medicine test and thus can be more time consuming than other imag-
ing modalities.51
Liver biopsy is considered the gold standard diagnostic modality but given possible
morbidity, is not considered a first-line diagnostic test. The experienced clinician rea-
ches for the liver biopsy at the appropriate time, generally when the patient continues
to have abnormal liver function tests with jaundice without definitive signs of obstruc-
tion on imaging or endoscopic studies. The transjugular approach, often done in the
interventional radiology suite, is associated with reduced bleeding complications
and is preferred, especially if the patient has a degree of coagulopathy. Transjugular
liver biopsies also allow for measurement of the hepatic venous pressure gradient
that can assess for underlying portal hypertension in the patient with jaundice. Biopsy
can guide not only therapy but also provide prognostic information based on the
degree of liver injury.4
Major Points:
! HIDA scans are useful if there is a high suspicion of biliary obstruction
! Liver biopsy, although the gold standard diagnostic modality for evaluating jaun-
dice, is infrequently obtained, especially if a diagnosis can be made clinically

PROGNOSIS

In most cases of jaundice, the underlying cause is often multifactorial (ie, an elderly pa-
tient started on antibiotics for septic shock from an acute abdomen, in the intensive
care unit with hypotension requiring pressors, and now with persistent jaundice). How-
ever, if triggers are identified and addressed, most patients without underlying chronic
liver disease recover with time. Prompt diagnosis and treatment of the triggers that led
to the jaundice in the first place is key to reducing morbidity and mortality.
Major Points:
! Generally, prognosis is favorable if the underlying cause of jaundice is deter-
mined and the patient has no prior chronic liver disease

WHAT NOT TO MISS

Given the high mortality with acute liver failure if left untreated, the jaundiced patient
presenting with altered mental status and coagulopathy without pre-existing liver dis-
ease requires special attention. In addition, those diseases, such as obstructive chol-
angitis, that have potential therapeutic interventions (ie, ERCP) should not be missed.
Those diseases with genetic predisposition, such as Wilson disease, hereditary
hemochromatosis, and a1-antitrypsin deficiency, must not be missed because early
diagnosis allows for possible medical therapy and genetic screening and earlier inter-
vention for family members.
Major Points:
! It is especially important for the clinician to diagnose acute liver failure given the
high associated morbidity

WHEN TO REFER TO A TRANSPLANT CENTER

Patients with acute liver failure should be referred emergently to determine candidacy
for liver transplant.
Aside from the more acute presentation, those jaundiced patients with known com-
plications of end-stage liver disease (including hepatic encephalopathy, ascites,
spontaneous bacterial peritionitis, and variceal bleeding) who are otherwise transplant
168 Kathpalia & Ahn

candidates should be referred for assessment of suitability as candidates for

transplant.
If clinical history and examination findings, laboratory testing, and imaging modal-
ities still do not provide guidance on the underlying diagnosis, these patients should
be referred to a gastroenterologist or hepatologist for further work-up. Similarly,
patients with a known trigger who have persistent liver enzyme abnormalities with clin-
ical symptoms should be referred for closer monitoring; if their clinical status worsens
and they require emergent transplantation, it is helpful for these patients to have
already established care at a liver transplant center.
Major Points:
! Patients with acute liver failure should be referred to a liver transplant center to
determine suitability for transplantation
! Patients with cirrhosis should be closely followed by a gastroenterologist or hep-
atologist to monitor and treat associated complications of end-stage liver dis-
ease and assess the potential need and candidacy for transplant

FUTURE DIRECTION

Currently, few studies have assessed the outcomes of patients with jaundice because
of the heterogeneity of causes and multiple confounding of variables that can lead to
jaundice. Further data on the outcomes of jaundice are needed and may be obtained
with multicenter registries and insurance and closed system data set analysis. Such
studies are eagerly awaited.
Major Points:
! Multicenter registries may provide outcome-based data on jaundice to guide
future diagnostic and therapeutic interventions

ACKNOWLEDGMENTS

The authors thank Dr Anjana Pillai of Emory University and Dr Brintha Enestvedt and
Dr Sharlene D’Souza of OHSU for their helpful comments and review of the article.

REFERENCES

1. Habib HA, Saunders M. The yellow bird of jaundice: recognizing biliary obstruc-
tion. Nursing 2011;41(10):28–35.
2. Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004;69(2):
299–304.
3. Wheatley M, Heilpern K. Jaundice: an emergency department approach to diag-
nosis and management. Emerg Med Pract 2008;10(3):1–24.
4. Winger J, Michelfelder A. Diagnostic approach to the patient with jaundice. Prim
Care 2011;38:469–82.
5. Assy N, Jacob G, Spira G, et al. Diagnostic approach to patient with cholestatic
jaundice. World J Gastroenterol 1999;5(3):252–62.
6. Mousavi S, Malek M, Babaei M. Role of overnight rifampin test in diagnosing Gil-
bert’s syndrome. Indian J Gastroenterol 2005;24:108–10.
7. Horsfall LJ, Nazareth I, Pereira SP, et al. Gilbert’s syndrome and the risk of a
death: a population-based cohort study. J Gastroenterol Hepatol 2013;28(10):
1643–7.
 Assessment of Jaundice in the Hospitalized Patient 169

8. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced
expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome.
N Engl J Med 1995;333(18):1171–5.
9. Dasgupta TK, Sharma V. Intrahepatic bilomas: a possible complication of chole-
cystectomy? Br J Clin Pract 1992;46(4):272–3.
10. Polson J, Lee WM. AASLD position paper: the management of acute liver failure.
Hepatology 2005;41(5):1179–97.
11. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis 2000;4:73–96.
12. Zimmerman HJ. Drug-induced liver disease. In: Schiff ER, Sorrell MF,
Maddrey WC, editors. Schiff’s diseases of the liver. 8th edition. Philadelphia: Lip-
pincott-Raven Publishers; 1999. p. 973–1064.
13. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced
liver disease. Hepatology 2005;42(2):481–9.
14. Senior JR. Regulatory perspectives. In: Kaplowitz N, DeLeve LD, editors. Drug-
induced liver disease. New York: Marcel Dekker; 2003. p. 739–54.
15. Fairley C, McNeil J, Desmond P, et al. Risk factors for development of flucloxacil-
lin associated jaundice. BMJ 1993;306:233–5.
16. Chand N, Sanyal AJ. Sepsis induced cholestasis. Hepatology 2007;45(1):
230–41.
17. Rossi S, Navarro V. Herbs and liver injury: a clinical perspective. Clin Gastroen-
terol Hepatol 2014;12:1069–76.
18. Kinney T. Management of ascending cholangitis. Gastrointest Endosc Clin N Am
2007;17:289–306.
19. van Erpecum K. Complications of bile-duct stones: acute cholangitis and pancre-
atitis. Best Pract Res Clin Gastroenterol 2006;20(6):1139–52.
20. Attasaranya S, Fogel E, Lehman G. Choledocholithiasis, ascending cholangitis,
and gallstone pancreatitis. Med Clin North Am 2008;92(4):925–60.
21. Faust TW, Reddy KR. Postoperative jaundice. Clin Liver Dis 2004;8(1):151–66.
22. Fevery J. Bilirubin in clinical practice: a review. Liver Int 2008;28(5):592–605.
23. Molina E, Raddy R. Postoperative jaundice. Clin Liver Dis 1999;3(3):477–88.
24. Garvin IP. Remarks on pneumonia biliosa. South Med Surg J 1837;1:536–44.
25. Shands K, Schmid G, Dan B, et al. Toxic-shock syndrome in menstruating
women. Association with tampon use and Staphylococcus aureus, and clinical
features in 52 cases. N Engl J Med 1980;303:1436–42.
26. Banks J, Foulis AK, Ledingham I, et al. Liver function in septic shock. J Clin Pathol
1982;35:1249–52.
27. Pirovino M, Meister F, Rubli E, et al. Preserved cytosolic and synthetic liver function
in jaundice of severe extrahepatic infection. Gastroenterology 1989;96:1589–95.
28. Pathak B, Sheibani L, Lee R. Cholestasis of pregnancy. Obstet Gynecol Clin
North Am 2010;37(2):269–82.
29. Lee RH, Goodwin TM, Greenspoon J, et al. The prevalence of intrahepatic chole-
stasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol
2006;26:527–32.
30. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol
2014;124:120–33.
31. Keitel V, Vogt C, Häussinger D, et al. Combined mutations of canalicular trans-
porter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenter-
ology 2006;131(2):624–9.
32. Davies MH, da Silva RC, Jones SR, et al. Fetal mortality associated with chole-
stasis of pregnancy and the potential benefit of therapy with ursodeoxycholic
acid. Gut 1995;37:580–4.
170 Kathpalia & Ahn

33. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: re-
lationships between bile acid levels and fetal complications rates. Hepatology
2004;40(2):467–74.
34. Hay JE. Liver disease in pregnancy. Hepatology 2008;47(3):1067–76.
35. Matin A, Sass DA. Liver disease in pregnancy. Gastroenterol Clin North Am 2011;
40(2):335–53.
36. Mays JK. The active management of intrahepatic cholestasis of pregnancy. Curr
Opin Obstet Gynecol 2010;22(2):100–3.
37. Williamson C, Gorelik J, Eaton BM, et al. The bile acid taurocholate impairs rat
cardiomyocyte function: a proposed mechanism for intra-uterine fetal death in
obstetric cholestasis. Clin Sci (Lond) 2001;100:363–9.
38. Geenes V, Chappell LC, Seed PT, et al. Association of severe intrahepatic chole-
stasis of pregnancy with adverse pregnancy outcomes: a prospective
population-based case-control study. Hepatology 2014;59:1482–91.
39. Qi K, Li H, An L, et al. The correlation between platelet activation and liver injury
by conditioning and bone marrow transplantation. Transplant Proc 2014;46:
1523–30.
40. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinu-
soidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002;
22(1):27–42.
41. Baron F, Deprez M, Beguin Y. The veno-occlusive disease of the liver. Haemato-
logica 1997;82(6):718–25.
42. Sinicrope F. Gastrointestinal complications: Hepatic Complications of Bone
Marrow Transplantation. In: Kufe DW, Pollock RE, Weichselbaum RR, et al, edi-
tors. Holland-Frei Cancer Medicine, 6th edition. Chapter 155. Hamilton (ON):
BC Deckerl; 2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK13099/.
43. McDonald GB, Shulman HM, Wolford JL, et al. Liver disease after human marrow
transplantation. Semin Liver Dis 1987;7:210–29.
44. Chopra S, Griffin PH. Laboratory tests and diagnostic procedures in evaluation of
liver disease. Am J Med 1985;79(221):230.
45. Pasanen PA, Pikkarainen P, Alhava E, et al. Evaluation of a computer-based diag-
nostic score system in the diagnosis of jaundice and cholestasis. Scand J Gas-
troenterol 1993;28(8):732–6.
46. Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J
2003;79:307–12.
47. Gold RP, Casarella WJ, Stern G, et al. Transhepatic cholangiography: the radio-
logical method of choice in suspected obstructive jaundice. Radiology 1979;
133(1):39–44.
48. Malhotra A, Rabouhans J. Computer tomography in emergency radiology. In:
Chan O, editor. ABC of Emergency Radiology. Malden (MA): Blackwell Publish-
ing/BMJ Books; 2007. p. 35–151.
49. Khan MA, Khan AA, Shafqat F. Comparison of ultrasonography and cholangiog-
raphy (ERCP/PTC) in the differential diagnosis of obstructive jaundice. J Pak Med
Assoc 1996;46:188–90.
50. Gentile N, Greenlund A. 66-year-old woman with painless jaundice. Mayo Clin
Proc 2012;87(10):1021–4.
51. Kim EE, Moon TY, Delpassand ES. Nuclear hepatobiliary imaging. Radiol Clin
North Am 1993;31(4):923–33.