Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Official reprint from UpToDate®

www.uptodate.com ©2013 UpToDate®

Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia

Authors Section Editor Deputy Editor

Namita Roy-Chowdhury, PhD Sanjiv Chopra, MD Anne C Travis, MD, MSc, FACG
Jayanta Roy-Chowdhury, MD,
MRCP

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2013. | This topic last updated: Jun 19, 2013.

INTRODUCTION — Jaundice and asymptomatic hyperbilirubinemia are common clinical problems that can be
caused by a variety of disorders, including bilirubin overproduction, impaired bilirubin conjugation, biliary
obstruction, and hepatic inflammation. (See "Classification and causes of jaundice or asymptomatic
hyperbilirubinemia".)

This topic will provide an overview of the diagnostic approach to adults with jaundice or asymptomatic
hyperbilirubinemia. The causes of jaundice and asymptomatic hyperbilirubinemia, detailed discussions of the
specific testing used, and the evaluation of patients with other liver test abnormalities are discussed elsewhere.
(See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia" and "Approach to the patient
with abnormal liver biochemical and function tests".)

CAUSES OF HYPERBILIRUBINEMIA — For clinical purposes, serum bilirubin is fractionated to classify

hyperbilirubinemia into one of two major categories (table 1) (see "Clinical aspects of serum bilirubin
determination"):

Plasma elevation of predominantly unconjugated (indirect) bilirubin. This may be due to the
overproduction of bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation
(algorithm 1).

Plasma elevation of both unconjugated and conjugated (direct) bilirubin. This may be due to
hepatocellular disease, impaired canalicular excretion of bilirubin, or biliary obstruction (algorithm 2). This
is often referred to as conjugated hyperbilirubinemia, even though both fractions of bilirubin are elevated.

Once the hyperbilirubinemia has been classified, the differential diagnosis can be narrowed. (See "Classification
and causes of jaundice or asymptomatic hyperbilirubinemia".)

Unconjugated hyperbilirubinemia may be caused by (table 1):

Hemolysis
Extravasation of blood into tissue
Dyserythropoiesis
Stress situations (eg, sepsis) leading to increased production of bilirubin
Impaired hepatic bilirubin uptake
Impaired bilirubin conjugation

Conjugated hyperbilirubinemia may be caused by (table 1 and table 2):

Biliary obstruction (eg, gallstones, pancreatic or biliary malignancy, AIDS cholangiopathy, parasites)
Viral hepatitis
Alcoholic hepatitis
Nonalcoholic steatohepatitis

1 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Primary biliary cirrhosis

Drugs and toxins
Ischemic hepatopathy
Liver infiltration
Inherited disorders (eg, Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic
cholestasis)
Total parenteral nutrition
Postoperative jaundice
Intrahepatic cholestasis of pregnancy
End-stage liver disease
Organ transplantation (eg, bone marrow, liver)

The frequency with which the different causes occur varies with age and the population being studied. One
report, for example, evaluated the principal diagnoses obtained in 702 adults presenting with jaundice to 24
Dutch hospitals over a two-year period [1]. Pancreatic or biliary carcinoma accounted for 20 percent, gallstones
for 13 percent, and alcoholic cirrhosis for 10 percent.

In some cases, two or more factors contribute to the development of jaundice. This is particularly true in the
following settings: sickle cell anemia, organ transplantation or surgery in general, total parenteral nutrition, and
AIDS. When evaluating these patients, it is necessary to take into account the underlying illness, the type of
therapy administered (eg, drugs, surgery), and the possible associated complications.

DIAGNOSTIC EVALUATION — The diagnostic approach to the jaundiced patient begins with a careful history,
physical examination, and initial laboratory studies. A differential diagnosis is formulated based on those results
and additional testing is performed to narrow the diagnostic possibilities.

Although the evaluation is usually not urgent, jaundice can reflect a medical emergency in a few situations.
These include massive hemolysis (eg, due to Clostridium perfringens sepsis or falciparum malaria), ascending
cholangitis, and fulminant hepatic failure. Expedient diagnosis and appropriate therapy can be life-saving in
these settings.

History and physical examination — Multiple clues to the etiology of a patients’ hyperbilirubinemia can be
obtained from the history, which should seek the following information (see "Approach to the patient with
abnormal liver biochemical and function tests", section on 'History'):

Use of medications, herbal medications, dietary supplements, and recreational drugs

Use of alcohol
Hepatitis risk factors (eg, travel, possible parenteral exposures)
History of abdominal operations, including gallbladder surgery
History of inherited disorders, including liver diseases and hemolytic disorders
HIV status
Exposure to toxic substances
Associated symptoms

Associated symptoms often help narrow the differential diagnosis. As examples:

A history of fever, particularly when associated with chills or right upper quadrant pain and/or a history of
prior biliary surgery, is suggestive of acute cholangitis.

Symptoms such as anorexia, malaise, and myalgias may suggest viral hepatitis.

Right upper quadrant pain suggests extrahepatic biliary obstruction.

Acholic stool (also termed clay colored stool) refers to stool without the yellow-brown color, which is
normally derived mainly from the bilirubin breakdown products, urobilin and stercobilin. Although rare, it
can also be seen in the acute cholestatic phase of viral hepatitis and in prolonged near-complete common
bile duct obstruction from cancer of the pancreatic head or the duodenal ampulla.

The physical examination may reveal a Courvoisier sign (a palpable gallbladder, caused by obstruction distal to

2 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

the takeoff of the cystic duct by malignancy) or signs of chronic liver failure/portal hypertension such as ascites,
splenomegaly, spider angiomata, and gynecomastia. Certain findings suggest specific diseases, such as
hyperpigmentation in hemochromatosis, Kayser-Fleischer rings in Wilson disease, and xanthomas in primary
biliary cirrhosis. (See "Approach to the patient with abnormal liver biochemical and function tests", section on
'Physical examination'.)

Initial laboratory tests — Initial laboratory tests include measurements of serum total and unconjugated
bilirubin, alkaline phosphatase, aminotransferases (aspartate aminotransferase [AST] and alanine
aminotransferase [ALT]), prothrombin time/international normalized ratio (INR), and albumin. The presence or
absence of abnormalities and the type of abnormalities should help to distinguish the various causes of jaundice.
(See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Laboratory tests'.)

However, while liver tests provide a broad guideline for the initial distinction between the different causes of
jaundice, exceptions do occur. As an example, viral hepatitis, which normally presents primarily with an elevation
of serum aminotransferases, may present as a predominantly cholestatic syndrome with marked pruritus.

Normal alkaline phosphatase and aminotransferases — If the alkaline phosphatase and

aminotransferases are normal, the jaundice is likely not due to hepatic injury or biliary tract disease. In such
patients, hemolysis or inherited disorders of bilirubin metabolism may be responsible for the hyperbilirubinemia.
The inherited disorders associated with isolated unconjugated hyperbilirubinemia are Gilbert's and Crigler-Najjar
syndromes; the disorders associated with isolated conjugated hyperbilirubinemia are Rotor and Dubin-Johnson
syndromes. (See "Approach to the diagnosis of hemolytic anemia in the adult" and "Gilbert's syndrome and
unconjugated hyperbilirubinemia due to bilirubin overproduction" and "Crigler-Najjar syndrome".)

Predominant alkaline phosphatase elevation — Elevation of the serum alkaline phosphatase out of
proportion to the serum aminotransferases suggests biliary obstruction or intrahepatic cholestasis. Increased
serum alkaline phosphatase is also found in granulomatous liver diseases, such as tuberculosis or sarcoidosis.
These conditions may or may not be associated with jaundice. (See "Approach to the patient with abnormal liver
biochemical and function tests", section on 'Elevated alkaline phosphatase'.)

An elevation in the serum alkaline phosphatase concentration can also be derived from extrahepatic tissues,
particularly bone. Extrahepatic disorders do not cause jaundice except in rare cases, such as bone tumors
metastasizing to the liver. If necessary, the serum activities of the canalicular enzymes gamma-glutamyl
transpeptidase (GGT) and 5'-nucleotidase can be measured to confirm the hepatic origin of alkaline
phosphatase (algorithm 3). (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5’-nucleotidase,
gamma-glutamyl transpeptidase)".)

Predominant aminotransferase elevation — A predominant elevation of serum aminotransferase activity

suggests that jaundice is caused by intrinsic hepatocellular disease (table 2). The pattern of the elevation may
help identify a specific cause. (See "Approach to the patient with abnormal liver biochemical and function tests",
section on 'Laboratory tests'.)

As an example, alcoholic hepatitis is associated with a disproportionate elevation of the AST compared with the
ALT. The AST elevation is usually less than eight times the upper limit of normal, and the ALT elevation is
typically less than five times the upper limit of normal. The AST to ALT ratio is usually greater than 2.0, a value
rarely seen in other forms of liver disease. (See "Clinical manifestations and diagnosis of alcoholic fatty liver
disease and alcoholic cirrhosis", section on 'Liver test abnormalities'.)

Elevated INR — An elevated INR that corrects with vitamin K administration suggests impaired intestinal
absorption of fat-soluble vitamins and is compatible with obstructive jaundice. On the other hand, an elevated
INR that does not correct with vitamin K suggests moderate to severe hepatocellular disease with impaired
synthetic function (particularly if unexplained hypoalbuminemia is also present).

Subsequent evaluation — Subsequent studies are guided based on findings from the history, physical
examination, and initial laboratory tests.

Unconjugated hyperbilirubinemia — The evaluation of unconjugated hyperbilirubinemia typically involves

evaluation for hemolytic anemia, drugs that impair hepatic uptake of bilirubin, and Gilbert's syndrome (algorithm
1). In a patient with a history consistent with Gilbert's syndrome (eg, the development of jaundice during times of

3 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

stress) additional testing is not required. If this initial evaluation is negative and the unconjugated
hyperbilirubinemia persists, other causes should be sought (eg, Crigler-Najjar syndrome). (See "Approach to the
patient with abnormal liver biochemical and function tests", section on 'Unconjugated (indirect)
hyperbilirubinemia'.)

Conjugated hyperbilirubinemia — In patients with conjugated hyperbilirubinemia, the evaluation will be

based on whether the abnormalities are likely due to biliary obstruction, intrahepatic cholestasis, hepatocellular
injury, or an inherited condition (based on the presence of isolated conjugated hyperbilirubinemia) (algorithm 2).

Suspected biliary obstruction or intrahepatic cholestasis — If there is evidence of biliary obstruction

or intrahepatic cholestasis (eg, elevated conjugated bilirubin and alkaline phosphatase), the first step in the
evaluation is hepatic imaging (eg, ultrasound, magnetic resonance cholangiopancreatography [MRCP],
endoscopic retrograde cholangiopancreatography [ERCP]) to look for evidence of intra- or extrahepatic bile duct
dilation [2]. If imaging is negative, the evaluation typically will also include obtaining an antimitochondrial
antibody to evaluate for primary biliary cirrhosis. (See "Approach to the patient with abnormal liver biochemical
and function tests", section on 'Evaluation of elevated alkaline phosphatase'.)

In most instances, abdominal ultrasound (and less often spiral computed tomography [CT] scan) is the first
imaging test obtained in patients with suspected biliary obstruction with unknown etiology [2]. (See "Approach to
the patient with abnormal liver biochemical and function tests", section on 'Evaluation of elevated alkaline
phosphatase'.)

However, in some cases, other imaging studies may be more appropriate as initial tests:

In the patient with a low probability of obstruction, abdominal CT should be performed and, in the absence
of evidence of obstruction, further evaluation should be directed towards causes of hepatocellular
disease. If, on the other hand, dilated biliary ducts are visualized, direct imaging of the biliary tree (eg, with
ERCP) should be performed.

In the patient with a high expectation of extrahepatic obstruction, endoscopic ultrasound (EUS) or ERCP
can be the initial screening procedure, since a negative US would not preclude the subsequent
performance of ERCP. One study performed percutaneous transhepatic cholangiography (PTC) in 107
patients with clinically suspected bile duct abnormalities but nondilated intrahepatic ducts on CT or
ultrasound [3]. The cholangiogram was diagnostic in 72 patients (67 percent) and 31 (43 percent) showed
poor emptying, stones, or strictures. Because of a high rate of complications, the authors to suggest that
ERCP was preferable to PTC in patients with nondilated ducts.

In the patient with evidence of obstruction but little clue as to the distinction between intrahepatic and
extrahepatic disease, a screening ultrasound may provide information useful in determining the optimal
use of EUS or ERCP versus intrahepatic cholangiography. Decision analysis studies suggest that EUS
may be preferred in this setting when there is an intermediate probability of obstruction [4].

The imaging tests used in the evaluation of biliary obstruction are discussed in detail elsewhere. (See "Approach
to the patient with suspected choledocholithiasis", section on 'Imaging tests' and "Ultrasonography of the
hepatobiliary tract" and "Computed tomography of the hepatobiliary tract" and "Magnetic resonance
cholangiopancreatography" and "Overview of indications for and complications of ERCP and endoscopic biliary
sphincterotomy" and "Endoscopic ultrasound in patients with suspected choledocholithiasis" and "Percutaneous
transhepatic cholangiography".)

Suspected hepatocellular injury — If there is evidence of hepatocellular injury (eg, a predominant

elevation of serum aminotransferases), serologic testing should be performed to evaluate for causes of
hepatocellular dysfunction. (See 'Predominant aminotransferase elevation' above and "Approach to the patient
with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases' and
"Diagnostic approach to the patient with cirrhosis", section on 'Determining the cause of cirrhosis'.)

Testing should include:

Serologic tests for viral hepatitis

4 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Measurement of antimitochondrial antibodies (for primary biliary cirrhosis)

Measurement of antinuclear anti-smooth muscle and liver-kidney microsomal antibodies (for autoimmune
hepatitis)
Serum levels of iron, transferrin, and ferritin (for hemochromatosis)
Thyroid function tests
Antibody screening for celiac disease

Additional testing may also include (based on the clinical scenario):

Serum levels of ceruloplasmin (for Wilson disease)

Measurement of alpha-1 antitrypsin activity (for alpha-1 antitrypsin deficiency)
Testing for adrenal insufficiency

In some cases, liver biopsy may be required to confirm the diagnosis.

Isolated conjugated hyperbilirubinemia — Isolated conjugated hyperbilirubinemia is found in two rare

inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Dubin-Johnson syndrome and Rotor
syndrome should be suspected in patients with mild hyperbilirubinemia (with a conjugated fraction of
approximately 50 percent) in the absence of other abnormalities of standard liver biochemical tests. Normal
levels of serum alkaline phosphatase and GGT help to distinguish these conditions from disorders associated
with biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to
their benign nature. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

Basics topic (see "Patient information: Jaundice in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

For clinical purposes, serum bilirubin is fractionated to classify hyperbilirubinemia into one of two major
categories: unconjugated (indirect) hyperbilirubinemia and conjugated (direct) hyperbilirubinemia (table 1).
This classification, along with findings from the history, physical examination, and initial laboratory testing
is used to narrow the diagnostic possibilities and guide the subsequent evaluation. (See 'Causes of
hyperbilirubinemia' above.)

Multiple clues to the etiology of hyperbilirubinemia can be obtained from the history, which should seek
the following information (see 'History and physical examination' above):

Use of medications or recreational drugs (see "Drugs and the liver: Patterns of drug-induced liver
injury")
Use of dietary supplements or herbal medications (see "Hepatotoxicity due to herbal medications and
dietary supplements")
Use of alcohol (see "Screening for unhealthy use of alcohol and other drugs")
Hepatitis risk factors (eg, travel, parenteral exposure)
History of abdominal operations, including gallbladder surgery
History of inherited disorders including liver diseases and hemolytic disorders

5 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

HIV status
Exposure to toxic substances

Initial laboratory tests include measurements of serum total and unconjugated bilirubin, alkaline
phosphatase, aminotransferases (aspartate aminotransferase and alanine aminotransferase),
prothrombin time/international normalized ratio (INR), and albumin. The presence or absence of
abnormalities and the type of abnormalities help distinguish the various causes of jaundice (algorithm 1
and algorithm 2).

If the alkaline phosphatase and aminotransferases are normal, the jaundice is likely not due to hepatic
injury or biliary tract disease. In such patients, hemolysis or inherited disorders of bilirubin metabolism
may be responsible for the hyperbilirubinemia. (See 'Normal alkaline phosphatase and
aminotransferases' above.)
Elevation of the serum alkaline phosphatase out of proportion to the serum aminotransferases
suggests biliary obstruction or intrahepatic cholestasis. (See 'Predominant alkaline phosphatase
elevation' above.)
A predominant elevation of serum aminotransferase activity suggests that jaundice is caused by
intrinsic hepatocellular disease (table 2). (See 'Predominant aminotransferase elevation' above.)
An elevated INR that corrects with vitamin K administration suggests impaired intestinal absorption of
fat-soluble vitamins and is compatible with obstructive jaundice. On the other hand, an elevated INR
that does not correct with vitamin K suggests moderate to severe hepatocellular disease with
impaired synthetic function (particularly if unexplained hypoalbuminemia is also present). (See
'Elevated INR' above.)

The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia,
drugs that impair hepatic uptake of bilirubin, and Gilbert's syndrome (algorithm 1). (See 'Unconjugated
hyperbilirubinemia' above.)

If there is evidence of biliary obstruction or intrahepatic cholestasis (eg, elevated conjugated bilirubin and
alkaline phosphatase), the first step in the evaluation is hepatic imaging (eg, ultrasound, magnetic
resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography
[ERCP]) to look for evidence of intra- or extrahepatic bile duct dilation. If imaging is negative, the
evaluation typically will also include obtaining an antimitochondrial antibody to evaluate for primary biliary
cirrhosis. (See 'Suspected biliary obstruction or intrahepatic cholestasis' above.)

If there is evidence of hepatocellular injury (eg, a predominant elevation of serum aminotransferases),

serologic testing should be performed to evaluate for causes of hepatocellular dysfunction, such as viral
hepatitis, alcoholic liver disease, and metabolic liver disease (table 2 and table 3). (See 'Suspected
hepatocellular injury' above.)

Isolated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome
and Rotor syndrome. Normal levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase
help distinguish these conditions from disorders associated with biliary obstruction. (See 'Isolated
conjugated hyperbilirubinemia' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Reisman Y, Gips CH, Lavelle SM, Wilson JH. Clinical presentation of (subclinical) jaundice--the Euricterus
project in The Netherlands. United Dutch Hospitals and Euricterus Project Management Group.
Hepatogastroenterology 1996; 43:1190.
2. Saini S. Imaging of the hepatobiliary tract. N Engl J Med 1997; 336:1889.

6 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

3. Teplick SK, Flick P, Brandon JC. Transhepatic cholangiography in patients with suspected biliary disease
and nondilated intrahepatic bile ducts. Gastrointest Radiol 1991; 16:193.
4. Sahai AV, Mauldin PD, Marsi V, et al. Bile duct stones and laparoscopic cholecystectomy: a decision
analysis to assess the roles of intraoperative cholangiography, EUS, and ERCP. Gastrointest Endosc
1999; 49:334.

Topic 3620 Version 7.0

7 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

GRAPHICS

Classification of jaundice according to type of bile pigment and

mechanism

Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Increased bilirubin production* Extrahepatic cholestasis (biliary

obstruction)
Extravascular hemolysis
Choledocholithiasis
Extravasation of blood into tissues
Intrinsic and extrinsic tumors - eg,
Intravascular hemolysis cholangiocarcinoma

Dyserythropoiesis Primary sclerosing cholangitis

Impaired hepatic bilirubin uptake AIDS cholangiopathy

Heart failure Acute and chronic pancreatitis

Portosystemic shunts Strictures after invasive procedures

Some patients with Gilbert's syndrome Certain parasitic infections - eg, Ascaris
lumbricoides, liver flukes
Certain drugs• - rifampin, probenecid,
flavaspadic acid, bunamiodyl Intrahepatic cholestasis

Impaired bilirubin conjugation Viral hepatitis

Crigler-Najjar syndrome types I and II Alcoholic hepatitis

Gilbert's syndrome Nonalcoholic steatohepatitis

Neonates Chronic hepatitis

Hyperthyroidism Primary biliary cirrhosis

Ethinyl estradiol Drugs and toxins - eg, alkylated steroids,

chlorpromazine, herbal medications (eg,
Liver diseases - chronic hepatitis, advanced Jamaican bush tea), arsenic
cirrhosis, Wilson disease
Sepsis and hypoperfusion states

Infiltrative diseases - eg, amyloidosis,

lymphoma, sarcoidosis, tuberculosis

Total parenteral nutrition

Postoperative cholestasis

Following organ transplantation

Hepatic crisis in sickle cell disease

Pregnancy

End-stage liver disease

AIDS: acquired immunodeficiency syndrome.

* Serum bilirubin concentration usually less than 4 mg/dL (68 mmol/L) in the absence of underlying liver
disease.
• The hyperbilirubinemia induced by drugs usually resolves within 48 hours after the drug is discontinued.

8 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Classification of jaundice due to mainly unconjugated

hyperbilirubinemia

9 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Classification of jaundice due to both conjugated and

unconjugated hyperbilirubinemia

10 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Differential diagnosis of hepatocellular jaundice

Neoplasms Infections
Hepatocellular carcinoma Viral

Cholangio carcinoma Hepatitis viruses

Metastases (bronchogenic, GI-tract, Herpes viruses

breast, GU-tract)
"Hemorrhagic" viruses: yellow fever, Ebola, Marburg,
Lymphoma Lassa

Hemangioendothelioma Adenoviruses, enteroviruses, etc

Hepatoblastoma Bacterial

Tuberculosis, leptospirosis, syphilis, pyogenic

Metabolic/hereditary
abscess, brucella, rickettsia, tropheryma whippelii,
Wilson's disease rochalimea

Alpha-1-antitrypsin deficiency Parasitic

Helminths: ascaris, fasciola, clonorchis,

Hemochromatosis
schistosomiasis, echinococcosis
Porphyrias
Protozoa: amebiasis, plasmodia, babesiosis,
Congenital hepatic fibrosis toxoplasmosis, leishmaniasis

Fibropolycystic disease Fungal

Candida, blastomyces, coccidioides, histoplasma,

Systemic cryptococcus
Acute ischemia
Toxic/immunologic
Severe heart failure
Medications (allergic, idiosyncratic)
Tricuspid insufficiency
Alcohol
Constrictive pericarditis
Chlorinated hydrocarbons (carbon tetrachloride,
Budd-Chiari syndrome chloroform)

Venoocclusive disease Amanita phalloides toxin

Telangiectasias Aflatoxin B1

Sarcoidosis Vitamin A

Amyloidosis Pyrrolizidine alkaloids

Arsenic
Miscellaneous
Secondary biliary cirrhosis Phosphorous

Cryptogenic cirrhosis Autoimmune Hepatitis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Overlap syndrome

Autoimmune cholangiopathy

Nonalcoholic steatohepatitis

11 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

12 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Evaluation of elevated serum alkaline phosphatase

AMA: antimitochondrial antibodies; ERCP: endoscopic retrograde

cholangiopancreatography; MRCP: magnetic resonance
cholangiopancreatography; ULN: upper limit of normal.

13 of 14 7/31/56 BE 6:46 PM
Diagnostic approach to the adult with jaundice or asymptomatic hyperb... http://www.uptodate.com/contents/diagnostic-approach-to-the-adult-wi...

Common causes of abnormal liver blood tests

Disease Tests and findings

Alcoholic liver disease History of alcohol abuse

AST/ALT >2 with both being less than 500 IU/mL if alcoholic hepatitis
is present

Chronic hepatitis C ELISA assay for anti-HCV

PCR for HCV RNA if confirmatory test is necessary

Primary biliary Antimitochondrial antibodies as an isolated finding

cirrhosis

Primary sclerosing Strong association with inflammatory bowel disease

cholangitis
Contrastcholangiography to establish the diagnosis

Antinuclear and antismoothmuscle antibodies and ANCA; these are not

diagnostic

Autoimmune hepatitis Hypergammaglobulinemia

Antinuclear and antismooth muscle antibodies and ANCA in type 1;

anti-LKM-1 in type 2

Chronic hepatitis B HBsAg and HBeAg and, in some cases, HBV DNA by hybridization or
bDNA assay

Hereditary Family history of cirrhosis

hemochromatosis
Transferrin saturation and plasma ferritin should be performed but may
be elevated by liver disease itself

Diagnosis established by liver biopsy and calculation of hepatic iron

index or by genetic testing

Wilson disease Family or personal history of cirrhosis at a young age

Serumceruloplasmin reduced in 95 percent of patients

Liver biopsy showsincreased copper content which may also be seen in

cholestatic liver diseases

Alpha-1-antitrypsin Family or personal history of cirrhosis at a young age

deficiency
Serum AAT; phenotyping if low or borderline values

Nonalcoholic fatty liver History of diabetes mellitus or metabolic syndrome

disease
Diagnosis maybe suspected by abnormal liver biochemical tests and
hepatic imagingshowing fatty infiltration and is confirmed by liver
biopsy

14 of 14 7/31/56 BE 6:46 PM