Diagnostic Approach To The Adult With Jaundice or Asymptomatic Hyperbilirubinemia - UpToDate PDF

16/07/2019 Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia - UpToDate
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Diagnostic approach to the adult with jaundice or

asymptomatic hyperbilirubinemia
Authors: Namita Roy-Chowdhury, PhD, FAASLD, Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD
Section Editor: Sanjiv Chopra, MD, MACP
Deputy Editor: Shilpa Grover, MD, MPH, AGAF
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2019. | This topic last updated: Sep 04, 2018.
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".)
REFERENCE RANGES
Liver test reference ranges will vary from laboratory to laboratory. As an example, one hospital's
normal reference ranges for adults are as follows [1]:
● Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)
● Alkaline phosphatase:
• Male: 45 to 115 international unit/L

• Female: 30 to 100 international unit/L
● Alanine aminotransferase:
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● Aspartate aminotransferase:

● Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)
● Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)
● Gamma-glutamyl transpeptidase:

● Prothrombin time: 11.0 to 13.7 seconds
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
● Primary biliary cholangitis
● 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 [2]. 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 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 cholangitis. (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. An exception is uncontrolled Wilson’s Disease, in which
serum alkaline phosphatase activity may be low or normal [3]. The inherited disorders associated
with isolated unconjugated hyperbilirubinemia are Gilbert and Crigler-Najjar syndromes; the
disorders associated with isolated conjugated hyperbilirubinemia are Rotor and Dubin-Johnson
syndromes. (See "Diagnosis of hemolytic anemia in the adult" and "Gilbert syndrome and
unconjugated hyperbilirubinemia due to bilirubin overproduction" and "Crigler-Najjar syndrome"
and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Other
manifestations'.)
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 syndrome (algorithm 1). In a patient with a history consistent with Gilbert syndrome
(eg, the development of jaundice during times of 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 [4]. If imaging is negative,
the evaluation typically will also include obtaining an antimitochondrial antibody to evaluate for
primary biliary cholangitis. (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
[4]. (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 [5]. 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 [6].
The imaging tests used in the evaluation of biliary obstruction are discussed in detail elsewhere.
(See "Choledocholithiasis: Clinical manifestations, diagnosis, and management", section on
'Imaging test characteristics' and "Ultrasonography of the hepatobiliary tract" and "Computed
tomography of the hepatobiliary tract" and "Magnetic resonance cholangiopancreatography" and
"Endoscopic retrograde cholangiopancreatography: Indications, patient preparation, and
complications" 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 "Cirrhosis in adults: Etiologies, clinical manifestations,
and diagnosis", section on 'Determining the cause of cirrhosis'.)
Testing should include:
● Serologic tests for viral hepatitis

● Measurement of antimitochondrial antibodies (for primary biliary cholangitis)
● 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 — Conjugated hyperbilirubinemia without other

routine liver test abnormalities 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".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Abnormal liver
biochemical tests".)
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 education: 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 "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 in primary
care")
• Hepatitis risk factors (eg, travel, parenteral exposure)
• History of abdominal operations, including gallbladder surgery
• History of inherited disorders including liver diseases and hemolytic disorders
• 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 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, endoscopic retrograde
cholangiopancreatography) 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 cholangitis. (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.)
Conjugated hyperbilirubinemia without other routine liver test abnormalities 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.)
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GRAPHICS
Classification of jaundice according to type of bile pigment and mechanism
Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Increased bilirubin production* (continued)
Extravascular hemolysis Extrahepatic cholestasis (biliary obstruction)
Extravasation of blood into tissues Choledocholithiasis
Intravascular hemolysis Intrinsic and extrinsic tumors (eg,

cholangiocarcinoma, pancreatic cancer)
Dyserythropoiesis
Primary sclerosing cholangitis
Wilson disease
AIDS cholangiopathy
Impaired hepatic bilirubin uptake
Acute and chronic pancreatitis
Heart failure
Strictures after invasive procedures
Portosystemic shunts
Certain parasitic infections (eg, Ascaris
Some patients with Gilbert syndrome lumbricoides, liver flukes)
Certain drugs ¶ - rifampin, probenecid, Intrahepatic cholestasis
flavaspadic acid, bunamiodyl
Viral hepatitis
Impaired bilirubin conjugation
Alcoholic hepatitis
Crigler-Najjar syndrome types I and II
Nonalcoholic steatohepatitis
Gilbert syndrome
Chronic hepatitis
Neonates
Primary biliary cholangitis
Hyperthyroidism
Drugs and toxins (eg, alkylated steroids,
Ethinyl estradiol chlorpromazine, herbal medications [eg,
Liver diseases - chronic hepatitis, advanced Jamaican bush tea], arsenic)
cirrhosis Sepsis and hypoperfusion states
Conjugated hyperbilirubinemia Infiltrative diseases (eg, amyloidosis, lymphoma,

sarcoidosis, tuberculosis)
Defect of canalicular organic anion transport
Total parenteral nutrition
Dubin-Johnson syndrome
Postoperative cholestasis
Defect of sinusoidal reuptake of conjugated
bilirubin Following organ transplantation
Rotor syndrome 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.
Graphic 55607 Version 10.0
Classification of jaundice due to mainly unconjugated hyperbilirubinemia
Classification of jaundice due to both conjugated and

unconjugated hyperbilirubinemia
Differential diagnosis of hepatocellular jaundice
Neoplasms Infections
Hepatocellular carcinoma Viral
Cholangio carcinoma Hepatitis viruses
Metastases (bronchogenic, GI Herpes viruses

tract, breast, GU tract)
"Hemorrhagic" viruses: yellow fever, Ebola, Marburg, Lassa
Lymphoma
Adenoviruses, enteroviruses, etc
Hemangioendothelioma
Bacterial
Hepatoblastoma
Tuberculosis, leptospirosis, syphilis, pyogenic abscess, Brucella,
Metabolic/hereditary Rickettsia, Tropheryma whippeli, Rochalimea
Wilson disease Parasitic
Alpha-1 antitrypsin deficiency Helminths: Ascaris, Fasciola, Clonorchis, schistosomiasis, echinococcosis
Hemochromatosis Protozoa: amebiasis, plasmodia, babesiosis, toxoplasmosis,

leishmaniasis
Porphyrias
Fungal
Congenital hepatic fibrosis
Candida, Blastomyces, Coccidioides, Histoplasma, Cryptococcus
Fibropolycystic disease
Toxic/immunologic
Systemic
Medications (allergic, idiosyncratic)
Acute ischemia
Alcohol
Severe heart failure
Chlorinated hydrocarbons (carbon tetrachloride, chloroform)
Tricuspid insufficiency
Amanita phalloides toxin
Constrictive pericarditis
Aflatoxin B1
Budd-Chiari syndrome
Vitamin A
Venoocclusive disease
Pyrrolizidine alkaloids
Telangiectasias
Arsenic
Sarcoidosis
Phosphorous
Amyloidosis
Autoimmune hepatitis
Miscellaneous
Primary biliary cholangitis
Secondary biliary cirrhosis
Primary sclerosing cholangitis
Cryptogenic cirrhosis
Overlap syndrome
Autoimmune cholangiopathy
Nonalcoholic steatohepatitis
GI: gastrointestinal; GU: genitourinary.
Evaluation of elevated serum alkaline phosphatase
AMA: antimitochondrial antibodies; ERCP: endoscopic retrograde

cholangiopancreatography; MRCP: magnetic resonance cholangiopancreatography;
ULN: upper limit of normal.
Common causes of abnormal liver blood tests
Disease Tests and findings
Alcoholic liver History of alcohol abuse

disease
AST/ALT >2 with both being less than 500 international unit/mL if alcoholic hepatitis is present
Chronic hepatitis ELISA assay for anti-HCV

C
PCR for HCV RNA if confirmatory test is necessary
Primary biliary Antimitochondrial antibodies as an isolated finding

cholangitis
IgM elevation
Primary sclerosing Strong association with inflammatory bowel disease

cholangitis
Cholangiography to establish the diagnosis
Antinuclear and antismooth muscle antibodies and ANCA; these are not diagnostic
Autoimmune Hypergammaglobulinemia
hepatitis
Antinuclear and smooth muscle antibodies and ANCA in type 1; anti-LKM-1 in type 2
Chronic hepatitis HBsAg and HBeAg and, in some cases, HBV DNA by hybridization or bDNA assay
B
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 genetic testing or liver biopsy and calculation of hepatic iron index
Wilson disease Family or personal history of cirrhosis at a young age
Serum ceruloplasmin reduced in 95 percent of patients
Liver biopsy shows increased copper content, which may also be seen in cholestatic liver
diseases
Alpha-1 Family or personal history of cirrhosis at a young age

antitrypsin
deficiency Serum AAT; phenotyping if low or borderline values
Nonalcoholic fatty History of diabetes mellitus or metabolic syndrome

liver disease
Diagnosis may be suspected by abnormal liver biochemical tests and hepatic imaging showing
fatty infiltration and is confirmed by liver biopsy
Congestive History of right-sided heart failure, constrictive pericarditis, mitral stenosis, tricuspid
hepatopathy regurgitation, cor pulmonale, cardiomyopathy
Right upper quadrant ultrasonography with Doppler studies of the portal and hepatic veins and
hepatic artery, electrocardiogram, and cardiac ultrasound
AAT: alpha-1 antitrypsin; ANCA: antineutrophil cytoplasmic antibody; anti-LKM-1: anti-liver-kidney microsomal 1
antibodies; ALT: alanine aminotransferase; AST: aspartate aminotransferase; DNA: deoxyribonucleic acid; ELISA:
enzyme-linked immunosorbent assay; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B
virus; HCV: hepatitis C virus; Ig: immunoglobulin; PCR: polymerase chain reaction; RNA: ribonucleic acid.
Contributor Disclosures
Namita Roy-Chowdhury, PhD, FAASLD Nothing to disclose Jayanta Roy-Chowdhury, MD, MRCP,
AGAF, FAASLD Nothing to disclose Sanjiv Chopra, MD, MACP Nothing to disclose Shilpa Grover, MD,
MPH, AGAF Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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16/07/2019 Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia - UpToDate

Official reprint from UpToDate®

Diagnostic approach to the adult with jaundice or

● Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)

• Male: 45 to 115 international unit/L

• Male: 10 to 55 international unit/L

• Male: 10 to 40 international unit/L

● Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)

● Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)

• Male: 8 to 61 international unit/L

● Prothrombin time: 11.0 to 13.7 seconds

Unconjugated hyperbilirubinemia may be caused by (table 1):

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

● Biliary obstruction (eg, gallstones, pancreatic or biliary malignancy, AIDS cholangiopathy,

History and physical examination — Multiple clues to the etiology of a patients'

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

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

● Right upper quadrant pain suggests extrahepatic biliary obstruction.

Normal alkaline phosphatase and aminotransferases — If the alkaline phosphatase and

Predominant alkaline phosphatase elevation — Elevation of the serum alkaline

Predominant aminotransferase elevation — A predominant elevation of serum

As an example, alcoholic hepatitis is associated with a disproportionate elevation of the AST

Unconjugated hyperbilirubinemia — The evaluation of unconjugated hyperbilirubinemia

Conjugated hyperbilirubinemia — In patients with conjugated hyperbilirubinemia, the

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

● In the patient with a high expectation of extrahepatic obstruction, endoscopic ultrasound

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

Testing should include:

● Serologic tests for viral hepatitis

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

● Serum levels of ceruloplasmin (for Wilson disease)

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

Isolated conjugated hyperbilirubinemia — Conjugated hyperbilirubinemia without other

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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

SUMMARY AND RECOMMENDATIONS

• Use of medications or recreational drugs (see "Drug-induced liver injury")

• Elevation of the serum alkaline phosphatase out of proportion to the serum

• A predominant elevation of serum aminotransferase activity suggests that jaundice is

severe hepatocellular disease with impaired synthetic function (particularly if unexplained

● The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic

● If there is evidence of biliary obstruction or intrahepatic cholestasis (eg, elevated conjugated

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

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Topic 3620 Version 17.0

Classification of jaundice according to type of bile pigment and mechanism

Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Extravascular hemolysis Extrahepatic cholestasis (biliary obstruction)

Extravasation of blood into tissues Choledocholithiasis

Intravascular hemolysis Intrinsic and extrinsic tumors (eg,

Conjugated hyperbilirubinemia Infiltrative diseases (eg, amyloidosis, lymphoma,

Rotor syndrome Hepatic crisis in sickle cell disease

End-stage liver disease

AIDS: acquired immunodeficiency syndrome.

Graphic 55607 Version 10.0

Classification of jaundice due to mainly unconjugated hyperbilirubinemia

Graphic 50896 Version 6.0

Classification of jaundice due to both conjugated and

Graphic 62683 Version 6.0

Differential diagnosis of hepatocellular jaundice

Cholangio carcinoma Hepatitis viruses

Metastases (bronchogenic, GI Herpes viruses