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Approach to the patient with abnormal liver biochemical and function testsAuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].
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.
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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jan 21, 2015.
INTRODUCTION — Abnormal liver biochemical and function tests are frequently detected in
asymptomatic patients since many screening blood test panels routinely include them [1]. A
population-based survey in the United States conducted between 1999 and 2002 estimated that
an abnormal alanine aminotransferase (ALT) was present in 8.9 percent of respondents.
Although the term "liver function tests" (LFTs) is used commonly, it is imprecise since many of
the tests reflecting the health of the liver are not direct measures of its function. Furthermore,
the commonly used liver biochemical tests may be abnormal even in patients with a healthy
liver. However, for the sake of simplicity, the abbreviation "LFTs" will be used in this discussion
to denote liver biochemical and function tests in general.
This topic review will provide an overview on the evaluation of patients with abnormal liver
biochemical and function tests. Detailed discussions of the individual tests are presented
separately. (See "Liver biochemical tests that detect injury to hepatocytes" and "Enzymatic
measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl
transpeptidase)" and "Classification and causes of jaundice or asymptomatic
hyperbilirubinemia" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation
factors, prothrombin time)".)
COMMON LIVER BIOCHEMICAL AND FUNCTION TESTS — Blood tests commonly obtained
to evaluate the health of the liver include liver enzyme levels, tests of hepatic synthetic function,
and the serum bilirubin level. Elevations of liver enzymes often reflect damage to the liver or
biliary obstruction, whereas an abnormal serum albumin or prothrombin time may be seen in the
setting of impaired hepatic synthetic function. The serum bilirubin in part measures the liver's
ability to detoxify metabolites and transport organic anions into bile.
Liver enzymes — Liver enzymes that are commonly measured in the serum include:
●Serum aminotransferases: alanine aminotransferase (ALT, formerly called SGPT) and
aspartate aminotransferase (AST, formerly called SGOT)
●Alkaline phosphatase
●Gamma-glutamyl transpeptidase (GGT)
●5'-nucleotidase
●Lactate dehydrogenase (LDH)
Aminotransferases — The sensitivity and specificity of the serum aminotransferases
(particularly serum ALT) for differentiating those with liver disease from those without liver
disease depend on the cutoff values chosen to define an abnormal test. A population-based
study from the US National Health and Nutrition Examination Survey examined patients with
known hepatitis C virus infection (n = 259) and compared them with patients at low risk of liver
injury (n = 3747) to determine optimal cutoff values for ALT [2]. The optimal cutoff for men was
an ALT of 29 int. unit/L and for women was an ALT of 22 int. unit/L. (See "Liver biochemical
tests that detect injury to hepatocytes", section on 'Serum aminotransferases'.)
ALT levels correlate with the degree of abdominal adiposity [3], and at least two large studies
suggested that the cutoff values should be adjusted for gender and body mass index [4,5].
However, most patients identified using the lower cutoff values had only mild liver disease or no
identifiable cause of the abnormal laboratory values. Thus, the overall benefit of the proposed
modifications is unclear since it would translate into a large increase in the absolute number of
patients who would require evaluation for an uncertain clinical benefit [6].
There is also wide variability of what is considered to be the upper limit of normal for ALT across
different laboratories [7]. This is likely due to the various reference standards used for different
chemical analyzers or in different laboratories. Thus, comparing values across different
laboratories may not be straightforward.
Alkaline phosphatase — Serum alkaline phosphatase is derived predominantly from the liver
and bones. An elevated alkaline phosphatase can be fractionated to determine if it originates
from the liver or bones, though more often a liver source is confirmed by the simultaneous
elevation of other measures of cholestasis (eg, gamma-glutamyl transpeptidase).
(See 'Confirming an elevated alkaline phosphatase is of hepatic origin' below.)
Other sources may also contribute to serum levels of alkaline phosphatase. Women in the third
trimester of pregnancy, for example, have elevated serum alkaline phosphatase levels due to an
influx into blood of placental alkaline phosphatase. Individuals with blood types O and B can
have elevated serum alkaline phosphatase levels after eating a fatty meal due to an influx of
intestinal alkaline phosphatase. Infants and toddlers occasionally display transient marked
elevations of alkaline phosphatase in the absence of detectable bone or liver disease. Alkaline
phosphatase elevations have been noted in patients with diabetes mellitus [8]. There are also
reports of a benign familial occurrence of elevated serum alkaline phosphatase due to intestinal
alkaline phosphatase. (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-
nucleotidase, gamma-glutamyl transpeptidase)", section on 'Alkaline
phosphatase' and "Transient hyperphosphatasemia of infancy and early childhood".)
Alkaline phosphatase levels also vary with age. Alkaline phosphatase levels are generally
higher in children and adolescents because of physiologic osteoblastic activity. Levels may be
up to three times higher than in healthy adults, with maximum levels in infancy and
adolescence, coinciding with periods of maximum bone growth velocity (figure 1). Also, the
normal serum alkaline phosphatase level gradually increases from age 40 to 65 years,
particularly in women. The normal alkaline phosphatase level for an otherwise healthy 65-year-
old woman is more than 50 percent higher than that for a healthy 30-year-old woman.
Gamma-glutamyl transpeptidase — GGT is found in hepatocytes and biliary epithelial cells,
as well as in the kidney, seminal vesicles, pancreas, spleen, heart, and brain. In normal full-term
neonates, serum GGT activity is six to seven times the upper limit of the adult reference range;
levels decline and reach adult levels by five to seven months of age [9]. (See "Enzymatic
measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl
transpeptidase)", section on 'Gamma-glutamyl transpeptidase'.)
5'-nucleotidase — 5'-nucleotidase is found in the liver, intestine, brain, heart, blood vessels,
and endocrine pancreas, but it is only released into serum by hepatobiliary tissue. Although its
physiologic function is unknown, 5'-nucleotidase specifically catalyzes hydrolysis of nucleotides
such as adenosine 5'-phosphate and inosine 5'-phosphate, in which the phosphate is attached
to the 5 position of the pentose moiety. (See "Enzymatic measures of cholestasis (eg, alkaline
phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)", section on '5'-Nucleotidase'.)
Lactate dehydrogenase — Lactate dehydrogenase (LDH) is commonly obtained when liver
biochemical tests are being checked. LDH is a cytoplasmic enzyme present in tissues
throughout the body (table 1). Five isoenzyme forms of LDH are present in serum and can be
separated by various electrophoretic techniques. The slowest migrating band predominates in
the liver [10,11]. This test is not as sensitive as the serum aminotransferases in liver disease
and has poor diagnostic specificity, even when isoenzyme analysis is used. It is more useful as
a marker of myocardial infarction and hemolysis [10]. (See "Biomarkers suggesting cardiac
injury other than troponins and creatine kinase".)
Function tests — Tests of hepatic synthetic function include:
●Serum albumin
●Prothrombin time/international normalized ratio (INR)
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 [12]:
●Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)
●Alkaline phosphatase
•Male: 45 to 115 int. unit/L
•Female: 30 to 100 int. unit/L
●Alanine aminotransferase (ALT):
•Male: 10 to 55 int. unit/L
•Female: 7 to 30 int. unit/L
●Aspartate aminotransferase (AST):
•Male: 10 to 40 int. unit/L
•Female: 9 to 32 int. 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)
●Gamma-glutamyl transpeptidase (GGT)
•Male: 8 to 61 int. unit/L
•Female: 5 to 36 int. unit/L
●Prothrombin time (PT): 11.0 to 13.7 seconds
However, studies suggest that the optimal cutoff for ALT should be lower than the upper limits
used by many laboratories (ie, it should be approximately 30 int. unit/L for men and 20
int. unit/L for women). (See 'Aminotransferases' above.)
INITIAL EVALUATION — The initial evaluation of a patient with abnormal liver biochemical and
function tests (LFTs) includes obtaining a history to identify potential risk factors for liver disease
and performing a physical examination to look for clues to the etiology and for signs of chronic
liver disease. Subsequent testing is determined based on the information gathered from the
history and physical examination as well as the pattern of LFT abnormalities. (See 'Patterns of
LFT abnormalities' below.)
History — A thorough medical history is central to the evaluation of a patient with abnormal
LFTs. The history should determine if the patient has had exposure to any potential
hepatotoxins (including alcohol and medications), is at risk for viral hepatitis, has other disorders
that are associated with liver disease, or has symptoms that may be related to the liver disease
or a possible predisposing condition.
Alcohol consumption is a common cause of liver disease, though getting an accurate history
can be difficult. Several definitions have been proposed for what constitutes significant alcohol
consumption [13]. We define significant alcohol consumption as an average consumption of
>210 grams of alcohol per week in men or >140 grams of alcohol per week in women over at
least a two-year period, a definition that is consistent with a 2012 joint guideline from the
American Gastroenterological Association, the American Association for the Study of Liver
Diseases, and the American College of Gastroenterology [14]. A standard drink (360 mL [12 oz]
of beer, 150 mL [5 oz] of wine, or 45 mL 1.5 oz] of 80-proof spirits) contains approximately 14
grams of alcohol. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and
alcoholic cirrhosis", section on 'Diagnosis'.)
Questioning about drug use should seek to identify all drugs used, the amounts ingested, and
the durations of use. Drug use is not limited to prescription medications, but also includes over-
the-counter medications, herbal and dietary supplements, and illicit drug use. Features that
suggest drug toxicity include lack of illness prior to ingesting the drug, clinical illness or
biochemical abnormalities developing after beginning the drug, and improvement after the drug
is withdrawn. If an immunologic reaction is suspected, the illness will generally recur upon
reintroduction of the offending substance. However, rechallenge is not advised. (See "Drug-
induced liver injury" and "Hepatotoxicity due to herbal medications and dietary supplements".)
Risk factors for viral hepatitis include potential parenteral exposures (eg, intravenous drug use,
blood transfusion prior to 1992), travel to areas endemic for hepatitis, and exposure to patients
with jaundice. Hepatitis B and C are transmitted parenterally, whereas hepatitis A and E are
transmitted from person to person via a fecal-oral route (often via contaminated food). Hepatitis
E is uncommon in Europe and the United States, but it should be considered in patients who
live in or have travelled to Asia, Africa, the Middle East, or Central America.
(See "Epidemiology, transmission, and prevention of hepatitis B virus
infection" and "Epidemiology and transmission of hepatitis C virus infection" and "Overview of
hepatitis A virus infection in adults" and "Hepatitis E virus infection".)
Patients should be asked about conditions that are associated with hepatobiliary disease, such
as right-sided heart failure (congestive hepatopathy), diabetes mellitus and obesity
(nonalcoholic fatty liver disease), pregnancy (gallstones), inflammatory bowel disease (primary
sclerosing cholangitis, gallstones), early onset emphysema (alpha-1 antitrypsin deficiency),
celiac disease, and thyroid disease. (See "Congestive hepatopathy" and "Epidemiology, clinical
features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Association with
other disorders' and "Epidemiology of and risk factors for gallstones", section on 'Risk factors'.)
Finally, patients should be questioned about occupational or recreational exposure to
hepatotoxins (eg, mushroom picking). Examples of hepatitis due to exposures to hepatotoxins
include industrial chemicals such as vinyl chloride and the mushrooms Amanita
phalloides and Amanita verna, which contain a potent hepatotoxin (amatoxin). (See "Amatoxin-
containing mushroom poisoning including ingestion of Amanita phalloides".)
Physical examination — The physical examination may suggest the presence of chronic liver
disease and it may point to the underlying cause of the liver disease.
●Temporal and proximal muscle wasting suggest longstanding disease
●Stigmata of liver disease include spider nevi, palmar erythema, gynecomastia, and caput
medusae
●Ascites or hepatic encephalopathy may be seen in patients with decompensated cirrhosis
●Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are
commonly seen in advanced alcoholic cirrhosis and occasionally in other types of cirrhosis
●An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister
Mary Joseph's nodule) suggest an abdominal malignancy
●Increased jugular venous pressure, a sign of right-sided heart failure, suggests hepatic
congestion
●A right pleural effusion, in the absence of clinically apparent ascites, may be seen in
advanced cirrhosis
●Neurologic signs and symptoms may be seen in patients with Wilson disease
The abdominal examination should focus on the size and consistency of the liver, the size of the
spleen (a palpable spleen is enlarged), and an assessment for ascites (usually by determining
whether there is a fluid wave, shifting dullness, or bulging of the flanks). Patients with cirrhosis
may have an enlarged left lobe of the liver (which can be felt below the xiphoid) and an enlarged
spleen (which is most easily appreciated with the patient in the right lateral decubitus position).
A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An
enlarged, tender liver could be due to viral or alcoholic hepatitis or, less often, an acutely
congested liver secondary to right-sided heart failure or Budd-Chiari syndrome [15]. Severe right
upper quadrant tenderness with a positive Murphy's sign (respiratory arrest on inspiration while
pressing on the right upper quadrant) suggests cholecystitis or, occasionally, ascending
cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with
peritoneal spread.
Laboratory tests — The pattern of LFT abnormalities may suggest that the underlying cause of
the patient's liver disease is primarily the result of hepatocyte injury (elevated
aminotransferases) or cholestasis (elevated alkaline phosphatase). In addition, the magnitude of
the LFT abnormalities and the ratio of the aspartate aminotransferase (AST) to alanine
aminotransferase (ALT) may make certain diagnoses more or less likely.
Patterns of LFT abnormalities — LFT abnormalities can often be grouped into one of several
patterns: hepatocellular, cholestatic, or isolated hyperbilirubinemia. In addition, the
abnormalities may be acute or chronic based on whether they have been present for more
(chronic) or less (acute) than six months.
●Hepatocellular pattern:
•Disproportionate elevation in the serum aminotransferases compared with the
alkaline phosphatase
•Serum bilirubin may be elevated
•Tests of synthetic function may be abnormal
●Cholestatic pattern:
•Disproportionate elevation in the alkaline phosphatase compared with the serum
aminotransferases
•Serum bilirubin may be elevated
•Tests of synthetic function may be abnormal
●Isolated hyperbilirubinemia: As the name implies, patients with isolated
hyperbilirubinemia have an elevated bilirubin level with normal serum aminotransferases
and alkaline phosphatase
Because the serum bilirubin can be prominently elevated in both hepatocellular and cholestatic
conditions, it is not necessarily helpful in differentiating between the two. Common
hepatocellular diseases associated with an elevated bilirubin and jaundice include viral and toxic
hepatitis (including drugs, herbal therapies and alcohol) and end-stage cirrhosis from any cause
(table 2).
If both the serum aminotransferases and alkaline phosphatase are elevated, the LFT
abnormalities are characterized by the predominant abnormality (eg, if the serum
aminotransferases are 10 times the upper limit of normal and the alkaline phosphatase is twice
the upper limit of normal, the LFT abnormalities would be characterized as primarily
hepatocellular). However, making this distinction is not always possible. The degree of
aminotransferase elevation can occasionally help in differentiating between hepatocellular and
cholestatic processes. While ALT and AST values less than eight times the upper limit of normal
may be seen in either hepatocellular or cholestatic liver disease, values 25 times the upper limit
of normal or higher are seen primarily in hepatocellular diseases.
Abnormal tests of synthetic function may be seen with both hepatocellular injury and
cholestasis. A low albumin suggests a chronic process, such as cirrhosis or cancer, while a
normal albumin suggests a more acute process, such as viral hepatitis or choledocholithiasis. A
prolonged prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and
intestinal malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the
prothrombin time to correct with parenteral administration of vitamin K suggests severe
hepatocellular injury. (See "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation
factors, prothrombin time)".)
AST to ALT ratio — Most causes of hepatocellular injury are associated with an AST that is
lower than the ALT. An AST to ALT ratio of 2:1 or greater is suggestive of alcoholic liver
disease, particularly in the setting of an elevated gamma-glutamyl transpeptidase [16]. In a
study of 271 patients with biopsy-confirmed liver disease, more than 90 percent of the patients
whose AST to ALT ratio was two or greater had alcoholic liver disease [17]. The percentage
increased to greater than 96 percent when the ratio was greater than three. In addition, 70
percent of the patients with known alcoholic liver disease had an AST to ALT ratio greater than
two. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic
cirrhosis", section on 'Liver test abnormalities'.)
However, the AST to ALT ratio is occasionally elevated in an alcoholic liver disease pattern in
patients with nonalcoholic steatohepatitis, and it is frequently elevated in an alcoholic liver
disease pattern in patients with hepatitis C who have developed cirrhosis. In addition, patients
with Wilson disease or cirrhosis due to viral hepatitis may have an AST that is greater than the
ALT, though in patients with cirrhosis the ratio typically is not greater than two. (See "Wilson
disease: Clinical manifestations, diagnosis, and natural history", section on 'Hepatic disease'.)
Magnitude of AST and ALT elevations — The magnitude of AST and ALT elevations vary
depending on the cause of the hepatocellular injury [18-21]. While values may vary in individual
patients, the following are typical AST and ALT patterns:
●Alcoholic fatty liver disease: AST <8 times the upper limit of normal; ALT <5 times the
upper limit of normal
●Nonalcoholic fatty liver disease: AST and ALT <4 times the upper limit of normal
●Acute viral hepatitis or toxin-related hepatitis with jaundice: AST and ALT >25 times the
upper limit of normal
●Ischemic hepatopathy (ischemic hepatitis, shock liver): AST and ALT >50 times the
upper limit of normal (in addition the lactate dehydrogenase is often markedly elevated)
●Chronic hepatitis C virus infection: Wide variability, typically normal to less than twice the
upper limit of normal, rarely more than 10 times the upper limit of normal
●Chronic hepatitis B virus infection: Levels fluctuate; the AST and ALT may be normal,
though most patients have mild to moderate elevations (approximately twice the upper
limit of normal); with exacerbations, levels are more than 10 times the upper limit of normal
Other laboratory abnormalities — Patients with Wilson disease may have a Coombs-negative
hemolytic anemia, a ratio of alkaline phosphatase (int. unit/L) to total bilirubin(mg/dL) of less
than two, or a normal/subnormal alkaline phosphatase. (See "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'Hepatic disease'.)
ELEVATED SERUM AMINOTRANSFERASES — In the setting of hepatocyte damage, alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) are released from hepatocytes,
leading to increased serum levels. The differential diagnosis for elevated serum
aminotransferases is broad and includes viral hepatitis, hepatotoxicity from drugs or toxins,
alcoholic liver disease, ischemic hepatopathy, and malignant infiltration. The evaluation should
take into account the patient's risk factors for liver disease as well as findings from the physical
examination that may point to a particular diagnosis. (See 'History' above and 'Physical
examination' above.)
Acute liver failure — Acute liver failure is characterized by acute hepatocellular injury with
LFTs typically more than 10 times the upper limit of normal, hepatic encephalopathy, and a
prolonged prothrombin time. The evaluation of patients with acute liver failure is discussed in
detail elsewhere. (See "Acute liver failure in adults: Etiology, clinical manifestations, and
diagnosis", section on 'Diagnosis'.)
Marked elevation without liver failure — Patients with marked elevations in their liver function
tests (approximately 15 times the upper limit of normal or higher) often have acute hepatitis,
though in some cases, there may be underlying chronic liver disease (eg, Wilson disease or an
acute exacerbation of hepatitis B virus).
Differential diagnosis — Marked elevations in serum aminotransferase levels may be seen
with:
●Acetaminophen (paracetamol)
●Idiosyncratic drug reactions (table 3)
●Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus;
Epstein-Barr virus; cytomegalovirus) or an acute exacerbation of chronic viral hepatitis
(hepatitis B)
●Alcoholic hepatitis
●Autoimmune hepatitis
●Wilson disease
●Ischemic hepatopathy
●Budd-Chiari syndrome
●Sinusoidal obstruction syndrome (veno-occlusive disease)
●HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally
acute fatty liver of pregnancy
●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma,
melanoma, or myeloma)
●Partial hepatectomy
●Toxin exposure, including mushroom poisoning
●Sepsis
●Heat stroke
●Muscle disorders (acquired muscle disorders [eg, polymyositis], seizures, and heavy
exercise [eg, long distance running])
Evaluation of markedly elevated aminotransferases — For patients with marked elevations
of serum aminotransferases, we obtain the following laboratory tests:
●Acetaminophen level
●Toxicology screen
●Acute viral hepatitis serologies
•IgM anti-hepatitis A
•Hepatitis B surface antigen and IgM anti-hepatitis B core
•Anti-hepatitis C virus antibody, hepatitis C RNA
•In some cases (based on patient history and risk factors): anti-herpes simplex virus
antibodies, anti-varicella zoster antibodies, anti-CMV antibodies, CMV antigen, and,
for Epstein-Barr virus, a complete blood count and monospot
●Serum pregnancy test in women of child-bearing potential who are not already known to
be pregnant
●Autoimmune markers (antinuclear antibodies, anti-smooth muscle
antibodies, anti-liver/kidney microsomal antibodies type 1, immunoglobulin levels)
●Transabdominal ultrasonography with Doppler imaging to look for evidence of vascular
occlusion (eg, Budd-Chiari syndrome)
Additional tests that are indicated in specific circumstances include:
●Ceruloplasmin level in patients suspected of having Wilson disease. (See "Wilson
disease: Clinical manifestations, diagnosis, and natural history", section on 'When to
consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and
natural history", section on 'Diagnosis'.)
●Hepatitis D virus antibodies in patients with acute or chronic hepatitis B. (See "Diagnosis
of hepatitis D virus infection", section on 'Diagnosis of HDV infection'.)
●Hepatitis E virus antibodies in patients who live in or travel to areas endemic for hepatitis
E, such as Asia, Africa, the Middle East, and Central America or in patients who are
pregnant (because of the high rates of acute liver failure in pregnant women with hepatitis
E). Additionally, cases of hepatitis E in the absence of foreign travel have been reported
increasingly in developed countries [22,23], and it is reasonable to test for antibodies to
hepatitis E virus if no other cause for the elevated aminotransferases is found.
(See "Hepatitis E virus infection", section on 'Diagnosis'.)
●Urinalysis to look for proteinuria in women who are pregnant. (See "Preeclampsia:
Clinical features and diagnosis", section on 'Diagnosis'.)
●Serum creatinine kinase or aldolase in patients with risk factors for or symptoms of
muscle disorders.
If the above testing is negative, we typically proceed with a liver biopsy if the acute elevation of
the serum aminotransferases fails to resolve or decline, or if the patient appears to be
developing acute liver failure. If the elevation is less than five times the upper limit of normal and
the patient appears well, we may follow the patient expectantly, checking liver tests every three
to six months.
Mild to moderate elevation — Mild to moderate elevations of the serum aminotransferases
(less than 15 times the upper limit of normal) are often seen with chronic liver disease, though
transient elevations may also be seen in patients with mild hepatic insults (eg, intake of nontoxic
doses of acetaminophen).
Differential diagnosis — Conditions associated with mild to moderate serum aminotransferase
elevations include (table 4):
●Medication use (table 3)
●Chronic viral hepatitis (hepatitis B, C)
●Alcoholic liver disease
●Hemochromatosis
●Nonalcoholic fatty liver disease
●Autoimmune hepatitis
●Wilson disease
●Alpha-1 antitrypsin deficiency
●Congestive hepatopathy
●Adult bile ductopenia
●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma,
melanoma, or myeloma)
●Muscle disorders (eg, subclinical inborn errors of muscle metabolism)
●Thyroid disorders
●Celiac disease
●Adrenal insufficiency
●Anorexia nervosa
●Macro AST (moderate elevations in plasma AST levels due to the presence AST-
immunoglobulin complexes, usually IgG) [24]
Evaluation of mildly or moderately elevated aminotransferases — The initial evaluation of
patients with mildly to moderately elevated serum aminotransferases includes testing for chronic
viral hepatitis, hemochromatosis, and nonalcoholic fatty liver disease (table 5). The majority of
patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing
will have alcoholic liver disease, steatosis, or steatohepatitis [25,26].
We typically start the evaluation of patients LFTs that are 2 to less than 10 times the upper limit
of normal with the following:
●Hepatitis B – Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core
antibody. (See "Diagnosis of hepatitis B virus infection".)
●Hepatitis C – Hepatitis C antibody. (See "Diagnosis and evaluation of chronic hepatitis C
virus infection".)
●Hemochromatosis – Serum iron and total iron binding capacity (TIBC) with calculation of
transferrin saturation (serum iron/TIBC). A transferrin saturation greater than 45 percent
warrants obtaining a serum ferritin. Ferritin should not be obtained as an initial test
because it is an acute phase reactant and therefore less specific than the transferrin
saturation. A serum ferritin concentration of greater than 400 ng/mL (900 pmol/L) in men
and 300 ng/mL (675 pmol/L) in women further supports the diagnosis of
hemochromatosis. (See "Approach to the patient with suspected iron overload", section on
'Making the diagnosis of iron overload'.)
●Nonalcoholic fatty liver disease – The initial evaluation to identify the presence of fatty
infiltration of the liver is radiologic imaging, including ultrasonography, computed
tomography (CT), or magnetic resonance imaging (MRI). Ultrasonography has a lower
sensitivity than CT or MRI but is less expensive. (See "Epidemiology, clinical features, and
diagnosis of nonalcoholic fatty liver disease in adults".)
In a patient with a history of significant alcohol consumption, we generally do not obtain
additional testing if the above tests are negative. For patients with mild LFT elevations (less
than twice the upper limit of normal), we typically recheck the LFTs in six months and only
pursue the above workup if they remain elevated. (See 'History' above.)
If the initial evaluation fails to identify a likely source of the aminotransferase elevation, we test
for the following:
●Autoimmune hepatitis – Serum protein electrophoresis, and if positive, antinuclear
antibodies, anti-smooth muscle antibodies, and anti-liver/kidney microsomal antibodies
(see"Clinical manifestations and diagnosis of autoimmune hepatitis", section on
'Diagnosis')
●Thyroid disorders – Thyroid-stimulating hormone, free T4 concentration, free T3
concentration (see "Diagnosis of and screening for hypothyroidism in nonpregnant
adults" and"Diagnosis of hyperthyroidism")
●Celiac disease: Antibody screening with serum antiendomysial or tissue
transglutaminase antibodies (see "Diagnosis of celiac disease in adults")
If the source of the liver test abnormalities is still unclear, we test for the following:
●Wilson disease – Serum ceruloplasmin, evaluation for Kaiser-Fleisher rings, urinary
copper excretion (see "Wilson disease: Clinical manifestations, diagnosis, and natural
history", section on 'Initial evaluation')
●Alpha-1 antitrypsin deficiency – Serum alpha-1 antitrypsin level, alpha-1 antitrypsin
phenotyping (see "Clinical manifestations, diagnosis, and natural history of alpha-1
antitrypsin deficiency", section on 'Diagnosis')
●Adrenal insufficiency (in patients with symptoms associated with adrenal insufficiency,
such as chronic malaise, anorexia, or weight loss) – 8 AM serum cortisol and plasma
corticotropin (ACTH), and a high-dose ACTH stimulation test (see "Clinical manifestations
of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults")
●Muscle disorders (in patients with symptoms such exercise intolerance, muscle pain, or
muscle weakness) – Creatinine kinase or aldolase (see "Inborn errors of metabolism:
Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations')
A liver biopsy is often considered in patients in whom all of the above testing has been
unrevealing. However, in some settings, the best course may be expectant observation.
We suggest expectant observation in patients in whom the ALT and AST levels are less than
twice the upper limit of normal and no chronic liver condition has been identified by the above
noninvasive testing. We use a conservative estimate for the upper limit of normal for
aminotransferases (approximately 30 int. unit/L for men and 20 int. unit/L for women) since the
higher limits reported by many laboratories likely underestimate the degree of aminotransferase
elevation. In such patients, we will follow their liver biochemical and function tests every six
months. This approach was supported by a preliminary study in which expectant clinical follow-
up was found to be the most cost-effective strategy for managing asymptomatic patients with
negative viral, metabolic, and autoimmune markers and chronically elevated aminotransferases
[27]. A second small study also found that biopsy results rarely affected the management of
such patients [28].
We suggest a liver biopsy in patients in whom the ALT and AST are persistently greater than
twice the upper limit of normal. While it remains unlikely that the biopsy will provide a diagnosis
or lead to changes in management, it is often reassuring to the patient and clinician to know that
there is no serious disorder.
ELEVATED ALKALINE PHOSPHATASE — Cholestasis may develop in the setting of
extrahepatic or intrahepatic biliary obstruction (table 6). In patients with cholestasis, the alkaline
phosphatase is typically elevated to at least four times the upper limit of normal. The magnitude
of the serum alkaline phosphatase level does not distinguish extrahepatic cholestasis from
intrahepatic cholestasis. Lesser degrees of elevation are nonspecific and may be seen in many
other types of liver disease, such as viral hepatitis, infiltrative diseases of the liver, and
congestive hepatopathy. The gamma-glutamyl transpeptidase (GGT) may also be elevated in
the setting of cholestasis. However, elevated levels of serum GGT have been reported in a wide
variety of other conditions. Patients with a predominantly cholestatic pattern typically undergo a
right upper quadrant ultrasound to further characterize the cholestasis as intrahepatic or
extrahepatic.
Confirming an elevated alkaline phosphatase is of hepatic origin — If a patient has an
isolated elevation of the alkaline phosphatase, the first step in the evaluation is to confirm it is of
hepatic origin, since alkaline phosphatase can come from other sources, such as bone and
placenta (algorithm 1). If, however, there are other liver biochemical and function test (LFT)
abnormalities, particularly an elevated bilirubin, confirmation is typically not required.
To confirm an isolated elevation in the alkaline phosphatase is coming from the liver, a GGT
level or serum 5'-nucleotidase level should be obtained. These tests are usually elevated in
parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders.
An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt
an evaluation for bone diseases.
An elevated bone alkaline phosphatase is indicative of high bone turnover, which may be
caused by several disorders including healing fractures, osteomalacia, hyperparathyroidism,
hyperthyroidism, Paget disease of bone, osteogenic sarcoma, and bone metastases. We
generally refer such patients to an endocrinologist for evaluation. Initial testing may include
measurement of serum calcium, parathyroid hormone, 25-hydroxy vitamin D, and imaging with
bone scintigraphy. (See "Bone physiology and biochemical markers of bone turnover", section
on 'Markers of bone turnover' and "Clinical manifestations and diagnosis of Paget disease of
bone", section on 'Clinical manifestations' and "Clinical manifestations, diagnosis, and treatment
of osteomalacia", section on 'Diagnosis and evaluation'.)
Differential diagnosis — If the alkaline phosphatase elevation is isolated (ie, the other LFTs
are normal), is confirmed to be of hepatic origin, and persists over time, chronic cholestatic or
infiltrative liver diseases should be considered (table 6). The most common causes include
partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and
certain drugs, such as androgenic steroids and phenytoin. Infiltrative diseases include
sarcoidosis, other granulomatous diseases, amyloidosis, and less often, unsuspected cancer
that is metastatic to the liver.
Acute or chronic elevation of the alkaline phosphatase in conjunction with other LFT
abnormalities may be due to extrahepatic causes (eg, common bile duct stones, primary
sclerosing cholangitis, malignant biliary obstruction) or intrahepatic causes (eg, PBC, primary
sclerosing cholangitis, infiltrative disease). (See 'Extrahepatic cholestasis' below
and'Intrahepatic cholestasis' below.)
Evaluation of elevated alkaline phosphatase — Testing in patients with an elevated alkaline
phosphatase of hepatic origin typically starts with a right upper quadrant ultrasound to assess
the hepatic parenchyma and bile ducts.
The presence biliary dilatation on ultrasonography suggests extrahepatic cholestasis, whereas
the absence of biliary dilatation suggests intrahepatic cholestasis. However, ultrasonography
may fail to show ductal dilatation in the setting of extrahepatic cholestasis in patients with partial
obstruction of the bile duct or in patients with cirrhosis or primary sclerosing cholangitis, where
scarring prevents the intrahepatic ducts from dilating.
The subsequent evaluation depends on whether the ultrasound suggests extrahepatic
cholestasis or intrahepatic cholestasis. (See 'Extrahepatic cholestasis' below and 'Intrahepatic
cholestasis' below.)
Extrahepatic cholestasis — Although ultrasonography may indicate extrahepatic cholestasis,
it rarely identifies the site or cause of obstruction. The distal bile duct is a particularly difficult
area to visualize by ultrasonography because of overlying bowel gas. Potential causes of
extrahepatic cholestasis include (table 6):
●Choledocholithiasis (the most common cause) (see "Choledocholithiasis: Clinical
manifestations, diagnosis, and management", section on 'Imaging test characteristics')
●Malignant obstruction (pancreas, gallbladder, ampulla, or bile duct cancer) (see "Clinical
manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on
'Diagnostic approach' and "Gallbladder cancer: Epidemiology, risk factors, clinical
features, and diagnosis", section on 'Diagnostic evaluation' and "Ampullary carcinoma:
Epidemiology, clinical manifestations, diagnosis and staging", section on 'Diagnosis and
staging' and "Clinical manifestations and diagnosis of cholangiocarcinoma")
●Primary sclerosing cholangitis with an extrahepatic bile duct stricture (see "Primary
sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on
'Diagnosis')
●Chronic pancreatitis with stricturing of the distal bile duct (rare) (see "Complications of
chronic pancreatitis", section on 'Bile duct or duodenal obstruction')
●AIDS cholangiopathy (see "AIDS cholangiopathy", section on 'Diagnosis')
If ultrasonography suggests obstruction due to a stone or malignancy, or if the onset of the
cholestasis was acute, endoscopic retrograde cholangiopancreatography (ERCP) should be
carried out to confirm the diagnosis and, when possible, facilitate biliary drainage. If the
cholestasis is chronic, or in patients who are at high risk for ERCP, magnetic resonance
cholangiopancreatography (MRCP) or computed tomography (CT) should be obtained. ERCP
can then be performed if there is evidence of an obstructing stone, stricture, or malignancy. If
the results of ERCP or MRCP are negative for biliary tract disease, liver biopsy should be
considered. (See "Endoscopic retrograde cholangiopancreatography: Indications, patient
preparation, and complications", section on 'Indications for ERCP' and "Magnetic resonance
cholangiopancreatography" and "Magnetic resonance cholangiopancreatography", section on
'Clinical use'.)
Intrahepatic cholestasis — There are numerous possible causes of intrahepatic cholestasis
(table 6), including drug toxicity, PBC, primary sclerosing cholangitis, viral hepatitis, cholestasis
of pregnancy, benign postoperative cholestasis, infiltrative diseases, and total parenteral
nutrition. In many cases, a possible cause can be identified based on the patient's history. If
drug-induced cholestasis is suspected, elimination of the offending drug usually leads to
resolution of the cholestasis, though it may take months. If no cause is identified, additional
testing is required.
In patients with intrahepatic cholestasis, antimitochondrial antibodies (AMA) should be checked.
If present, AMA are highly suggestive of PBC, and a liver biopsy may be obtained to confirm the
diagnosis. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cirrhosis",
section on 'Diagnosis'.)
If AMA are absent, additional testing includes:
●MRCP to look for evidence of primary sclerosing cholangitis (see "Primary sclerosing
cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis')
●Testing for hepatitis A, B, C, and E (see 'Elevated serum aminotransferases' above)
●Testing for Epstein-Barr virus and cytomegalovirus (see "Infectious mononucleosis in
adults and adolescents", section on 'Diagnosis' and "Overview of diagnostic tests for
cytomegalovirus infection")
●Pregnancy testing in women of child bearing potential who are not known to be pregnant
(see "Intrahepatic cholestasis of pregnancy", section on 'Diagnosis')
If the above tests are negative and the alkaline phosphatase is persistently more than 50
percent above normal for more than six months, we obtain a liver biopsy. A liver biopsy may
reveal evidence of an infiltrative disease (eg, sarcoidosis or malignancy) or other causes of
cholestasis, such as vanishing bile duct syndrome and adult bile ductopenia. If the alkaline
phosphatase is less than 50 percent above normal, all of the other liver biochemical tests are
normal, and the patient is asymptomatic, we suggest observation alone since further testing is
unlikely to influence management [28].
ISOLATED GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT) ELEVATION — Elevated levels
of serum GGT have been reported in a wide variety of clinical conditions, including pancreatic
disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes
mellitus, and alcoholism. High serum GGT values are also found in patients taking medications
such as phenytoin and barbiturates. GGT is sensitive for detecting hepatobiliary disease, but its
usefulness is limited by its lack of specificity.
An elevated GGT with otherwise normal liver biochemical tests should not lead to an exhaustive
work-up for liver disease. We suggest GGT only be used to evaluate elevations of other serum
enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a
suspicion of alcohol abuse in a patient with an elevated AST and an AST to ALT ratio of greater
than 2:1). (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase,
gamma-glutamyl transpeptidase)".)
ISOLATED HYPERBILIRUBINEMIA — The initial step in evaluating a patient with an isolated
elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the
hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated
(indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from
overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in
conjugated bilirubin is due to decreased excretion into the bile ductules or leakage of the
pigment from hepatocytes into serum. (See "Clinical aspects of serum bilirubin
determination" and "Diagnostic approach to the adult with jaundice or asymptomatic
hyperbilirubinemia".)
Unconjugated (indirect) hyperbilirubinemia — Unconjugated hyperbilirubinemia may be
observed in a number of disorders (table 7). These can be divided into disorders associated
with bilirubin overproduction (such as hemolysis and ineffective erythropoiesis) and disorders
related to impaired hepatic uptake/conjugation of bilirubin (such as Gilbert's disease, Crigler-
Najjar syndrome, and the effects of certain drugs). The evaluation typically involves evaluation
for hemolytic anemia as well as obtaining a history to determine if the patient has Gilbert's
syndrome. In a patient with a history consistent with Gilbert's syndrome (eg, the development of
jaundice during times of stress) additional testing is not required. (See"Gilbert syndrome and
unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Diagnosis'.)
Hemolysis — Hemolysis can usually be detected by obtaining a reticulocyte count and serum
haptoglobin and examining the peripheral blood smear. Hemolytic disorders that cause
excessive heme production may be either inherited or acquired. Inherited disorders include
spherocytosis, sickle cell disease, and deficiency of red cell enzymes, such as pyruvate kinase
and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin rarely
exceeds 5 mg/dL (86 micromol/L). Higher levels may occur when there is coexistent renal or
hepatocellular dysfunction or acute hemolysis. (See "Approach to the diagnosis of hemolytic
anemia in the adult".)
Acquired hemolytic disorders include microangiopathic hemolytic anemia (eg, hemolytic-uremic
syndrome), paroxysmal nocturnal hemoglobinuria, and immune hemolysis. Ineffective
erythropoiesis occurs in cobalamin, folate, and iron deficiencies.
Impaired hepatic uptake or conjugation — Impaired hepatic uptake or conjugation of bilirubin
should be considered in the absence of hemolysis. This is most commonly caused by certain
drugs (including rifampicin and probenecid) that diminish hepatic uptake of bilirubin or by
Gilbert's syndrome (a common genetic disorder associated with unconjugated
hyperbilirubinemia). Much less commonly, indirect hyperbilirubinemia can be caused by two
other genetic disorders: Crigler-Najjar syndrome types I and II.
●Studies in Western populations have estimated that Gilbert's syndrome affects
approximately 3 to 7 percent of the population, with white males predominating over
females by a ratio of 2 to 7:1 [29]. Impaired conjugation of bilirubin is due to reduced
bilirubin uridine diphosphate (UDP) glucuronosyltransferase activity. Affected patients
have mild unconjugated hyperbilirubinemia with serum levels almost always less than
6 mg/dL (103 micromol/L). The serum levels may fluctuate, and jaundice is often identified
only during periods of illness or fasting. In an otherwise healthy adult with mildly elevated
unconjugated hyperbilirubinemia and no evidence of hemolysis, the presumptive diagnosis
of Gilbert's syndrome can be made without further testing. (See "Gilbert syndrome and
unconjugated hyperbilirubinemia due to bilirubin overproduction".)
●Crigler Najjar type I is an exceptionally rare condition found in neonates and is
characterized by severe jaundice (bilirubin >20 mg/dL [342 micromol/L]) and neurologic
impairment due to kernicterus. Crigler-Najjar type II is somewhat more common than type
I. Patients live into adulthood with serum bilirubin levels that range from 6 to
25 mg/dL (103 to 428micromol/L). Bilirubin UDP glucuronosyltransferase activity is
typically present but greatly reduced. Bilirubin UDP glucuronosyltransferase activity can be
induced by the administration of phenobarbital, which can reduce serum bilirubin levels in
these patients. (See "Crigler-Najjar syndrome".)
Conjugated (direct) hyperbilirubinemia — An isolated elevation in conjugated bilirubin 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 direct-reacting 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. In children, other inherited disorders caused by
mutations of bile salt transporters may need to be considered [30]. (See "Inherited disorders
associated with conjugated hyperbilirubinemia".)
Patients with both conditions present with asymptomatic jaundice, typically in the second
decade of life. The defect in Dubin-Johnson syndrome is altered hepatocyte excretion of
bilirubin into the bile ducts, while Rotor syndrome appears to be due to defective hepatic
reuptake of bilirubin by hepatocytes [31].
ISOLATED ABNORMALITIES OF TESTS OF SYNTHETIC FUNCTION — Abnormalities in
tests of liver synthetic function, such as the prothrombin time and serum albumin level, are often
seen in patients with chronic liver disease in conjunction with other liver test abnormalities.
These patients should be evaluated according to the predominant pattern of LFT abnormalities.
(See 'Patterns of LFT abnormalities' above.)
However, isolated abnormalities in the prothrombin time or albumin are typically due to causes
other than liver disease. The evaluation of these abnormalities is discussed elsewhere.
(See "Clinical use of coagulation tests", section on 'Prothrombin time (PT)' and "Overview of
heavy proteinuria and the nephrotic syndrome" and "Protein-losing
gastroenteropathy" and"Malnutrition in children in resource-limited countries: Clinical
assessment", section on 'Protein-energy malnutrition'.)
WHEN TO REFER TO A SPECIALIST — Referral to a gastroenterologist or hepatologist
should be considered for patients with unexplained, persistent LFT elevations (≥2 times the
upper limit of normal for aminotransferases or 1.5 times the upper limit of normal for alkaline
phosphatase) and for patients who are being considered for liver biopsy. We use a conservative
estimate for the upper limit of normal for aminotransferases (approximately 30 int. unit/L for men
and 20 int. unit/L for women) since the higher limits reported by many laboratories likely
underestimate the degree of aminotransferase elevation. (See 'Aminotransferases' above.)
If the LFTs normalize or remain mildly elevated (<2 times the upper limit of normal for
aminotransferases or less than 1.5 times the upper limit of normal for alkaline phosphatase),
expectant management is reasonable in most cases. In such patients, we would follow their liver
biochemical and function tests every six months. It is reasonable to refer such patients to a
gastroenterologist or hepatologist if the LFTs remain elevated without a clear explanation, if they
subsequently increase, or if otherwise warranted by the specific features of the case.
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
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patient might have about a given condition. These articles are best for patients who want a
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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 topics (see "Patient information: Toxic hepatitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Blood tests commonly obtained to evaluate the health of the liver include liver enzyme
levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline
phosphatase, gamma-glutamyl transferase), tests of hepatic synthetic function (albumin,
prothrombin time/international normalized ratio [INR]), and the serum bilirubin level.
(See'Common liver biochemical and function tests' above.)
●The initial evaluation of a patient with abnormal liver biochemical and function tests
(LFTs) includes obtaining a history to identify potential risk factors for liver disease and
performing a physical examination to look for clues to the etiology and for signs of chronic
liver disease. Subsequent testing is determined based on the information gathered from
the history and physical examination as well as the pattern of LFT abnormalities (table
5 and algorithm 1). (See 'Initial evaluation' above.)
●LFT abnormalities can often be grouped into one of several patterns: hepatocellular,
cholestatic, or isolated hyperbilirubinemia. Patients with a hepatocellular process generally
have a disproportionate elevation in the serum aminotransferases compared with the
alkaline phosphatase, while those with a cholestatic process have the opposite findings.
The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic
conditions and therefore is not necessarily helpful in differentiating between the two.
Abnormal tests of synthetic function may be seen with both hepatocellular injury and
cholestasis. (See 'Patterns of LFT abnormalities' above.)
●In the setting of hepatocyte damage, ALT and AST are released from hepatocytes,
leading to increased serum levels. The differential diagnosis for elevated serum
aminotransferases is broad and includes viral hepatitis, hepatotoxicity from drugs or toxins,
alcoholic liver disease, hepatic ischemia, and malignant infiltration. The evaluation should
take into account the patient's risk factors for liver disease as well as findings from the
physical examination that may point to a particular diagnosis. The evaluation often
involves testing for viral hepatitis and autoimmune disease (table 5). Occasionally, a liver
biopsy may be required. (See 'Elevated serum aminotransferases' above.)
●Cholestasis may develop in the setting of extrahepatic or intrahepatic biliary obstruction
(table 6). In patients with cholestasis, the alkaline phosphatase is typically elevated to at
least four times the upper limit of normal. Lesser degrees of elevation are nonspecific and
may be seen in many other types of liver disease, such as viral hepatitis, infiltrative
diseases of the liver, and congestive hepatopathy. Patients with a predominantly
cholestatic pattern typically undergo right upper quadrant ultrasonography to further
characterize the cholestasis as intrahepatic or extrahepatic. (See 'Elevated alkaline
phosphatase' above.)
The presence of biliary dilatation on ultrasonography suggests extrahepatic cholestasis
which may be due to gallstones, strictures, or malignancy. The absence of biliary dilatation
suggests intrahepatic cholestasis. There are numerous possible causes of intrahepatic
cholestasis (table 6), including drug toxicity, primary biliary cirrhosis, primary sclerosing
cholangitis, viral hepatitis, cholestasis of pregnancy, benign postoperative cholestasis,
infiltrative diseases, and total parenteral nutrition. Subsequent testing to identify the
underlying cause may include checking antimitochondrial antibodies, magnetic resonance
cholangiopancreatography, computed tomography, and/or endoscopic retrograde
cholangiopancreatography (algorithm 1). (See 'Evaluation of elevated alkaline
phosphatase' above.)
●The evaluation of isolated hyperbilirubinemia begins with determining whether the
hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated
(indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from
overproduction, impairment of uptake, or impaired conjugation of bilirubin. The evaluation
of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia as
well as obtaining a history to determine if the patient has Gilbert's syndrome. In a patient
with a history consistent with Gilbert's syndrome (eg, the development of jaundice during
times of stress) additional testing is not required. (See 'Isolated hyperbilirubinemia'above
and 'Unconjugated (indirect) hyperbilirubinemia' above.)
An isolated elevation in conjugated bilirubin 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 direct-
reacting 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 'Conjugated (direct) hyperbilirubinemia' above.)Liver biochemical tests that detect injury to hepatocytesAuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].
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.
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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Dec 09, 2014.
INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.
The most common tests used in clinical practice include the serum aminotransferases, bilirubin,
alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver
function tests", although this term is somewhat misleading since most do not accurately reflect
how well the liver is functioning, and abnormal values can be caused by diseases unrelated to
the liver. In addition, these tests may be normal in patients who have advanced liver disease.
Several specialized tests have also been developed (such as indocyanine green clearance),
which, although uncommonly used in clinical practice, can measure specific aspects of hepatic
function.
Despite their limitations, liver biochemical and function tests have many applications in clinical
medicine:
●They provide a noninvasive method to screen for the presence of liver disease. The
serum aminotransferases, for example, are part of panel of tests used to screen all blood
donors in the United States for the presence of transmissible viruses.
●They can be used to measure the efficacy of treatments for liver disease (such as
immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:
Treatment".)
●They can be used to monitor the progression of a disease such as viral or alcoholic
hepatitis.
●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.
As an example, the Child-Turcotte-Pugh score (Child-Pugh class), which incorporates the
prothrombin time and serum bilirubin and albumin concentrations, can predict survival
(table 1).
The pattern of abnormalities on these tests is more accurate than any of the individual tests.
Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the
serum total bilirubin and alkaline phosphatase indicates cholestasis. Recognition of patterns that
are consistent with specific diseases can prompt appropriate additional testing.
The liver biochemical and function tests can be categorized as follows:
●Tests that detect injury to hepatocytes – Most of these tests measure the activity of
hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are
normally intracellular, but are released when hepatocytes are injured.
●Tests of the liver's capacity to transport organic anions and metabolize drugs – These
tests measure the liver's ability to clear endogenous or exogenous substances from the
circulation. The best studied include serum measurements of bilirubin, bile acids, caffeine,
and lidocaine metabolites, a variety of breath tests, and clearance tests such as
bromsulphalein (BSP) and indocyanine green (ICG).
●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess
the biosynthetic capacity of the liver are the serum albumin and the prothrombin time
(which requires the presence of clotting factors produced in the liver). Other tests which
have been use are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and
alpha-1 antitrypsin.
●Tests that detect chronic inflammation in the liver, altered immunoregulation, or viral
hepatitis – These tests include the immunoglobulins, hepatitis serologies, and specific
autoantibodies. Most of these substances are proteins made by B lymphocytes, not by
hepatocytes. However, some are quite specific for certain liver diseases, such as
antimitochondrial antibodies in primary biliary cirrhosis. (See "Clinical manifestations,
diagnosis, and prognosis of primary biliary cirrhosis".)
The liver contains thousands of enzymes, some of which are also present in serum in very low
concentrations. Elevation of an enzyme activity in the serum primarily reflects release from
damaged liver cells. Elevation of serum enzyme tests can be grouped into two categories:
●Enzymes that reflect generalized damage to hepatocytes
●Enzymes that reflect cholestasis
This topic will review the tests that detect injury to hepatocytes. The other categories and
enzymes that reflect cholestasis are discussed separately. (See "Enzymatic measures of
cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)
SERUM AMINOTRANSFERASES — The serum aminotransferases (formerly called
transaminases) are sensitive indicators of liver cell injury [1-3]. The most commonly measured
are alanine aminotransferase (ALT, serum glutamic-pyruvic transaminase [SGPT]) and
aspartate aminotransferase (AST, serum glutamic-oxaloacetic transaminase [SGOT]). These
enzymes catalyze the transfer of the alpha-amino groups of alanine and aspartate, respectively,
to the alpha-keto group of ketoglutarate, which results in the formation of pyruvate and
oxaloacetate.
The serum ALT and AST concentrations are normally less than 30 to 40 int. unit/L (0.5001 to
0.6668 microkatal/liter), although there is some debate as to the optimal cutoff values that
should be used. Several studies have shown that ALT levels are normally higher in men, and
vary directly with body mass index and to a lesser degree with serum lipid levels and age [4,5].
(See "Approach to the patient with abnormal liver biochemical and function tests", section on
'Common liver biochemical and function tests'.) Levels decline in frail older adults, and
consumption of coffee and especially caffeine may lower serum ALT levels by mechanisms that
are incompletely understood [6].
The source of these enzymes in serum has never been clearly established, although they
probably originate in tissues rich in ALT and AST. ALT is present in highest concentration in the
liver [7,8]. AST is found, in decreasing order of concentration, in the liver, cardiac muscle,
skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes and is less
specific than ALT for liver disease.
The location of the aminotransferases within cells is variable. ALT is found exclusively in the
cytosol, while AST occurs in the cytosol and mitochondria [8]. The cytosolic and mitochondrial
forms of AST are immunologically distinct isoenzymes, which can be distinguished by several
laboratory techniques [9]. Approximately 80 percent of AST activity in human liver is derived
from the mitochondrial isoenzyme [8]. In contrast, most of the circulating AST activity in healthy
people is derived from the cytosolic isoenzyme [7].
Neither ALT nor AST has isoenzymes that are tissue specific. As a result, isoenzyme analysis of
serum ALT or AST is of limited clinical utility. Exceptions to this general rule can occur in acute
myocardial infarction and chronic (but not acute) alcoholic liver disease [10,11]. Large increases
in mitochondrial AST occur in serum after extensive tissue necrosis and assay of mitochondrial
AST has been advocated as an accurate test for the detection of myocardial infarction [10].
However, other serum tests, such as troponins, are considered the standard for the diagnosis of
myocardial infarction. (See "Troponins and creatine kinase as biomarkers of cardiac injury".)
Measurement — The activity of the serum aminotransferases reflects the rate at which they
enter and are cleared from the circulation. An elevation in serum ALT and AST is usually related
to damage or destruction of tissues rich in the aminotransferases, or to changes in cell
membrane permeability that permit leakage into the circulation.
Clearance of the serum aminotransferases is similar to that of other proteins and involves
catabolism by the reticuloendothelial system; AST is cleared more rapidly than ALT [12]. The
major site of AST clearance is the hepatic sinusoidal cell [13]. It is unlikely that biliary or urinary
excretion has a significant role since the enzymes are virtually undetectable in the urine and
present in only very small amounts in bile [12,14].
Of the numerous methods developed for measuring ALT and AST activity in serum, the most
specific method involves the indirect measurement of lactate and malate (derived from the
formation of pyruvate and oxaloacetate, respectively, in the aminotransferase reactions) [10].
During this reaction, the reduced form of nicotinamide-adenine dinucleotide (NADH), (the
cofactor in the reaction) is oxidized to NAD. Because NADH, but not NAD, absorbs light at 340
nm, the event can be followed spectrophotometrically by the loss of absorptivity at 340 nm.
The serum aminotransferases may be falsely elevated or decreased under certain
circumstances. Drugs such as erythromycin and para-aminosalicylic acid may produced falsely
elevated aminotransferase values if older colorimetric tests are used [15]. In contrast, falsely low
serum AST (but not ALT) is seen in patients with renal failure [16]. This phenomenon is most
pronounced when the SMA-12/60 autoanalyser is used and presumably reflects interference
with the assay by a retained uremic toxin. Serum AST activity increases significantly after
hemodialysis, indicating removal of the inhibitor, which does not appear to be urea [16].
(See "Serum enzymes in patients with renal failure".) Subnormal values of serum ALT have
been described in patients with Crohn's disease, the reason for which is unclear [17].
Clinical significance — Serum aminotransferases are elevated in most liver diseases and in
disorders that involve the liver (such as various infections, acute and chronic heart failure, and
metastatic carcinoma). Elevations up to eight times the upper limit of normal are nonspecific and
may be found in any of the above disorders. The highest elevations occur in disorders
associated with extensive hepatocellular injury, such as acute viral hepatitis, ischemic hepatitis
(shock liver), and acute drug- or toxin-induced liver injury (eg,acetaminophen toxicity). The
evaluation of the serum aminotransferases in various clinical settings, including use of
the AST/ALT ratio, is discussed in detail separately. (See"Approach to the patient with abnormal
liver biochemical and function tests".)
The extent of liver cell necrosis correlates poorly with the magnitude of serum aminotransferase
elevation; in addition, the absolute elevation in serum aminotransferases is of little prognostic
value since the liver can recover from most forms of acute injury. There is, however, one pattern
that is important to recognize: a rapid decrease in plasma AST and ALT levels, together with a
rise in the plasma bilirubin concentration and prolongation of the prothrombin time, is indicative
of a poor prognosis in patients with acute liver failure. Although a rapid decrease in serum
aminotransferases is usually a sign of recovery from disease, it may also reflect the massive
destruction of viable hepatocytes in patients with acute liver failure, signaling a poor prognosis.
SERUM CONCENTRATIONS OF OTHER HEPATIC ENZYMES — A variety of other hepatic
enzymes have been measured but none is as useful as the aminotransferases for the diagnosis
of hepatic disease.
Lactate dehydrogenase — Lactate dehydrogenase (LDH) is a cytoplasmic enzyme present in
tissues throughout the body (table 2). Five isoenzyme forms of LDH are present in serum and
can be separated by various electrophoretic techniques. The slowest migrating band
predominates in the liver [18,19]. This test is not as sensitive as the serum aminotransferases in
liver disease and has poor diagnostic specificity, even when isoenzyme analysis is used. It is
more useful as a marker of myocardial infarction and hemolysis [18]. (See "Biomarkers
suggesting cardiac injury other than troponins and creatine kinase".)
Glutamate dehydrogenase — Glutamate dehydrogenase, a mitochondrial enzyme, is found
primarily in the liver, heart, muscle and kidneys [20]. In the liver, it is present in highest
concentration in centrilobular hepatocytes [21]. Because of this location, serum glutamate
dehydrogenase has been evaluated as a specific marker for liver disorders such as alcoholic
hepatitis, that primarily affect centrilobular hepatocytes [22]. Although an initial report suggested
that glutamate dehydrogenase may be a sensitive and relatively specific marker for alcoholic
hepatitis, this observation has not been confirmed by others [1,23]. Measurement of serum
glutamate dehydrogenase is seldom performed.
Isocitrate dehydrogenase — Isocitrate dehydrogenase, a cytoplasmic enzyme, is found in the
liver, heart, kidneys, and skeletal muscle [24]. Its activity in serum parallels that of the serum
aminotransferases in acute and chronic hepatitis, but it is less sensitive [25,26]. Although
elevations in serum isocitrate dehydrogenase are relatively specific for liver disorders, increased
concentrations have been reported in disseminated malignancy without detectable hepatic
involvement [27]. Measurement of this enzyme offers no diagnostic advantage over the serum
aminotransferases.
Sorbitol dehydrogenase — Sorbitol dehydrogenase is a cytoplasmic enzyme found
predominantly in the liver with relatively low concentrations in the prostate gland and kidneys
[24]. Its activity in serum parallels that of the aminotransferases in hepatobiliary disorders.
However, it appears to be less sensitive, and values may be normal in cirrhosis and other
chronic liver disorders. Its instability in serum further limits its diagnostic usefulness [24].
SUMMARY AND RECOMMENDATIONS
●A number of blood tests are available that reflect the condition of the liver. The most
common tests used in clinical practice include the serum aminotransferases, bilirubin,
alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as
"liver function tests", although this term is somewhat misleading since most do not
accurately reflect how well the liver is functioning, and abnormal values can be caused by
diseases unrelated to the liver. In addition, these tests may be normal in patients who have
advanced liver disease. (See "Approach to the patient with abnormal liver biochemical and
function tests".)
●The serum aminotransferases (formerly called transaminases) are sensitive indicators of
hepatocyte injury. The most commonly measured are alanine aminotransferase (ALT,
serum glutamic-pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST,
serum glutamic-oxaloacetic transaminase [SGOT]). (See 'Serum
aminotransferases'above.)
●Serum aminotransferases are elevated in most liver diseases and in disorders that
involve the liver (such as various infections, acute and chronic heart failure, and metastatic
carcinoma). Elevations up to eight times the upper limit of normal are nonspecific and may
be found in any of the above disorders. The highest elevations occur in disorders
associated with extensive hepatocellular injury, such as acute viral hepatitis, ischemic
hepatitis (shock liver), and acute drug- or toxin-induced liver injury
(eg, acetaminophentoxicity). (See 'Serum aminotransferases' above.)
●A variety of other hepatic enzymes (such as lactate dehydrogenase) have been
measured, but none is as useful as the aminotransferases for the diagnosis of hepatic
disease. (See 'Serum concentrations of other hepatic enzymes' above.)Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)AuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].
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
All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jan 21, 2015.
INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.
The most common tests used in clinical practice include the serum aminotransferases, bilirubin,
alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver
function tests," although this term is somewhat misleading since most do not accurately reflect
how well the liver is functioning, and abnormal values can be caused by diseases unrelated to
the liver. In addition, these tests may be normal in patients who have advanced liver disease.
Several specialized tests have also been developed (such as indocyanine green [ICG]
clearance), which, although uncommonly used in clinical practice, can measure specific aspects
of hepatic function.
Despite their limitations, liver biochemical and function tests have many applications in clinical
medicine:
●They provide a noninvasive method to screen for the presence of liver disease. The
serum aminotransferases, for example, are part of a panel of tests used to screen all blood
donors in the United States for the presence of transmissible viruses.
●They can be used to measure the efficacy of treatments for liver disease (such as
immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:
Treatment".)
●They can be used to monitor the progression of a disease such as viral or alcoholic
hepatitis.
●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.
As an example, the Child-Turcotte-Pugh score (Child-Pugh class), which incorporates the
prothrombin time and serum bilirubin and albumin concentrations, can predict survival
(table 1). Similarly, the Model for End-stage Liver Disease (MELD) score, based in part
upon the serum bilirubin, is an accurate predictor of three-month mortality and is used
routinely in determining the priority of patients awaiting liver transplantation. (See "Model
for End-stage Liver Disease (MELD)".)
The pattern of abnormalities on these tests is more accurate than any of the individual tests. An
elevation of serum aminotransferases indicates hepatocellular injury, while an elevation of
alkaline phosphatase indicates cholestasis. Recognizing patterns that are consistent with
specific diseases can prompt appropriate additional testing.
The liver biochemical and function tests that are used commonly in clinical practice and that are
used occasionally for specific circumstances can be categorized as follows:
●Tests that detect injury to hepatocytes – Most of these tests measure the concentration
of hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are
normally intracellular but are released when hepatocytes are injured. (See "Liver
biochemical tests that detect injury to hepatocytes".)
●Tests of the liver's capacity to transport organic anions and metabolize drugs – These
tests measure the liver's ability to clear endogenous or exogenous substances from the
circulation. The best studies include serum measurements of bilirubin, bile acids, caffeine,
and lidocaine metabolites, a variety of breath tests, and clearance tests such as
bromsulphalein (BSP) and ICG.
●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess
the biosynthetic capacity of the liver are the serum albumin and the prothrombin time
(which requires the presence of clotting factors produced in the liver). Other tests that have
been used are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and alpha-
1 antitrypsin.
●Tests that detect chronic inflammation in the liver, altered immunoregulation, or viral
hepatitis — These tests include the immunoglobulins, hepatitis serologies, and specific
autoantibodies. Most of these substances are proteins made by B lymphocytes, not by
hepatocytes. However, some are quite specific for certain liver diseases, such as
antimitochondrial antibodies in primary biliary cirrhosis. (See "Clinical manifestations,
diagnosis, and prognosis of primary biliary cirrhosis".)
The liver contains thousands of enzymes, some of which are also present in serum in very low
concentrations. Elevation of an enzyme activity in the serum primarily reflects release from
damaged liver cells. Elevation of serum enzyme tests can be grouped into two categories:
●Enzymes that reflect generalized damage to hepatocytes
●Enzymes that reflect cholestasis
This topic review will discuss the serum tests that reflect cholestasis. The other categories of
liver function tests and enzymes that reflect generalized damage to hepatocytes are discussed
separately. (See "Liver biochemical tests that detect injury to hepatocytes".)
ALKALINE PHOSPHATASE — Alkaline phosphatase refers to a group of enzymes that
catalyze the hydrolysis of a large number of organic phosphate esters at an alkaline pH
optimum. Although alkaline phosphatase is found in many locations throughout the body, its
precise function is not yet known [1]. It appears to have an active role in down-regulating the
secretory activities of the intrahepatic biliary epithelium [2], detoxifying lipopolysaccharide, and
hydrolyzing phosphate esters to generate inorganic phosphate for uptake by various tissues [3].
In bone, the enzyme is involved with calcification. At other sites, it may participate in transport
processes.
At least three separate genes code for the different alkaline phosphatases that exist in multiple
isoenzyme forms [4]. Most of the alkaline phosphatase isoenzymes of clinical interest are
derived from the liver, bone, first trimester placenta, and kidneys, and are coded for by one
gene. They are called tissue unspecific alkaline phosphatase since they have the same
immunologic properties and amino acid sequence. Although these alkaline phosphatase
isoenzymes catalyze the same reactions, they have different physicochemical properties, which
are conferred by carbohydrate and lipid side chains added during posttranslational modification
[1].
A second alkaline phosphatase gene codes for third trimester placental and intestinal alkaline
phosphatase [4]. The third gene codes for a second type of intestinal alkaline phosphatase.
Alkaline phosphatase activity in serum is derived primarily from three sources: liver, bone, and
in some patients the intestinal tract [1,5]. The intestinal contribution (about 10 to 20 percent) is
of importance primarily in people with blood groups O and B who are secretors of the ABH red
blood cell antigen [6]; it is enhanced by consumption of a fatty meal [7,8] and has limited clinical
importance.
Circulating alkaline phosphatase appears to behave like other serum proteins [9]. Its half-life is
seven days, and its clearance from serum is independent of the functional capacity of the liver
or the patency of the bile ducts [9]. Its sites of degradation are unknown.
Mechanism of elevated concentration in hepatobiliary disorders — Increased serum
alkaline phosphatase is derived from tissues whose metabolism is either functionally disturbed
(the obstructed liver) or greatly stimulated (placenta in the third trimester of pregnancy and bone
in growing children). Although the cause of elevated serum alkaline phosphatase levels is
understood in patients with increased bone or placental isoenzymes, the cause in hepatobiliary
disease has been debated [10]. Two theories were proposed in the past: the damaged liver
regurgitates hepatic alkaline phosphatase back into serum; and the damaged liver, particularly if
due to obstructive jaundice, fails to excrete the alkaline phosphatase made in bone, the
intestines, and the liver.
This long-standing debate has been resolved in favor of the regurgitation of liver alkaline
phosphatase into serum. The data supporting this theory are compelling:
●Only hepatic alkaline phosphatase is found in the serum of patients with liver disease,
particularly cholestasis [11].
●The clearance rates of infused placental alkaline phosphatase are the same in patients
with bile duct obstruction and healthy controls [9].
●In experimental bile duct obstruction in rats, the entire increase in serum alkaline
phosphatase activity is due to the leakage of hepatic alkaline phosphatase into serum [12].
The increased serum activity is paralleled by a striking elevation in hepatic alkaline
phosphatase activity and is not accounted for by biliary retention of alkaline phosphatase.
Thus, the elevation in serum alkaline phosphatase in hepatobiliary disease results from
increased de novo synthesis in the liver followed by release into the circulation [13]. Retained
bile acids appear to play a central role in this process; they induce the synthesis of the enzyme
and may cause it to leak into the circulation, perhaps by disruption of hepatic organelles and
solubilization of phosphatase bound to such membranes [14].
The precise manner in which the alkaline phosphatase reaches the circulation is unclear. In
some patients with cholestasis, small vesicles that contain many basolateral (sinusoidal)
membrane enzymes still bound to these membranes, including alkaline phosphatase, have
been found in serum [15].
Measurement — The most widely used procedure for determination of serum alkaline
phosphatase activity involves measuring the release of p-nitrophenol or phosphate from p-
nitrophenylphosphate under specified conditions. The results are expressed in international
units (IU/L), which is the activity of alkaline phosphatase that releases 1 mmol of chromogen or
Pi per minute.
Alkaline phosphatase isoenzymes can be determined using a variety of techniques. Although
the isoenzymes can be separated by electrophoresis, bone and liver isoenzymes differ only
slightly in electrophoretic mobility and often overlap if run on the electrophoretic systems used in
most clinical laboratories. Separation using polyacrylamide gel slabs is the most reliable method
and produces clear-cut separations of the liver, bone, intestinal, and placental isoenzymes.
However, this method is not always available. Electrophoresis on cellulose acetate, with the
addition of heat inactivation, may accomplish the same purpose [16].
A second method is based upon the observation that alkaline phosphatases from individual
tissues differ in their susceptibility to inactivation by heat or 2 mol urea [17]. Placental alkaline
phosphatase and an isoenzyme found in certain cancers, the Regan isoenzyme, are fully heat-
stable after exposure to a temperature of 56°C for 15 minutes [18]. Thus, the finding of an
elevated serum alkaline phosphatase concentration in a patient in whom all the excess activity
is in a heat-stable fraction strongly suggests that the placenta or a tumor is the source of the
elevated enzyme in serum. Unfortunately, in nonselected patients, this method has many
limitations and is not recommended.
Because none of these methods is widely available, the most practical approach is to measure
other enzymes whose elevation reflects liver disease. These include 5'- nucleotidase and
gamma-glutamyl transpeptidase. (See '5'-Nucleotidase' below and 'Gamma-glutamyl
transpeptidase' below.)
Clinical significance — The major value of the serum alkaline phosphatase in the diagnosis of
liver disorders is in the recognition of cholestatic disease (table 2) [19]. However, an elevation in
the alkaline phosphatase concentration is a relatively common finding and does not always
indicate the presence of hepatobiliary disease (algorithm 1). In addition, normal serum values of
alkaline phosphatase vary based upon demographic and clinical circumstances:
●In the 15- to 50-year age group, mean serum alkaline phosphatase activity is somewhat
higher in men than in women [20]. In comparison, in individuals over age 60, the enzyme
activity of women equals or exceeds that of men [21].
●In children, serum alkaline phosphatase activity is considerably elevated in both sexes,
correlates well with the rate of bone growth, and appears to be accounted for by the influx
of enzymes from osteoid tissue [20,22]. Serum alkaline phosphatase in normal adolescent
males may reach mean values three times greater than in normal adults without implying
the presence of hepatobiliary disease (figure 1) [20,23]. Infants and young children
occasionally display marked transient elevation of serum alkaline phosphatase activity in
the absence of detectable liver or bone disease. (See "Transient hyperphosphatasemia of
infancy and early childhood".)
●Patients older than 60 have somewhat higher values (up to 1.5 times normal) than
younger adults [21,24]. The alkaline phosphatase is usually derived from the liver in older
men and from bone in postmenopausal women [21].
●Enzyme activity in serum may double late in normal pregnancy, primarily because of an
influx from the placenta [25].
Identifying the source of the elevated isoenzyme is helpful if an elevated serum alkaline
phosphatase is the only abnormal finding in an apparently healthy person or if the degree of
elevation is higher than expected in the clinical setting. One series evaluated 317 patients in a
university hospital who were evaluated for an increased serum alkaline phosphatase level: the
source of elevation was the liver and bone in 80 and 18 percent, respectively [11]. The
remaining patients had either a mixed or an intestinal source.
If alkaline phosphatase fractionation is not available, differentiation of the source of elevation
can also be accomplished by obtaining additional enzyme tests. The best studied are the serum
5'-nucleotidase and gammaglutamyl transpeptidase (GGT) concentrations (see below); one or
the other can be obtained to evaluate an elevated alkaline phosphatase. An older test, leucine
aminopeptidase, is now rarely used. These enzyme tests are not elevated in bone disorders,
and leucine aminopeptidase and possibly 5'-nucleotidase are not elevated in pregnancy.
Thus, an increased serum concentration of these enzymes in nonpregnant patients indicates
that an elevated serum alkaline phosphatase is due at least in part to hepatobiliary disease.
However, a lack of increased serum 5'-nucleotidase in the presence of an elevated alkaline
phosphatase level does not exclude liver disease because these enzymes do not necessarily
increase in a parallel manner in early or modest hepatic injury [26]. (See "Approach to the
patient with abnormal liver biochemical and function tests".)
Marked elevation — Approximately 75 percent of patients with prolonged cholestasis have
serum alkaline phosphatase values increased to four times the upper limit of normal or more.
Elevations of this magnitude can occur in a variety of diseases associated with extrahepatic or
intrahepatic obstruction (table 2), and the extent of the elevation does not distinguish between
the two:
●Obstructive jaundice due to cancer
●Bile duct stones
●Sclerosing cholangitis (primary or secondary)
●Bile duct stricture
●Drug and toxins associated with cholestasis
●Primary biliary cirrhosis
●Liver allograft rejection
●Infectious hepatobiliary diseases seen in patients with AIDS (eg, cytomegalovirus or
microsporidiosis and tuberculosis with hepatic involvement)
●Infiltrative liver disease (eg, sarcoidosis, tuberculosis, metastatic malignancy,
amyloidosis)
●Alcoholic hepatitis (rarely) [27]
Moderate elevation — Lesser increases in alkaline phosphates activity, up to four times the
upper limit of normal, are nonspecific and occur in all types of liver disease, including viral
hepatitis, chronic hepatitis, cirrhosis, infiltrative diseases of the liver, and congestive heart failure
(table 2) [8,10,28]. Elevations in hepatic alkaline phosphatase of this magnitude can also occur
in disorders that do not directly involve the liver, such as Hodgkin lymphoma, myeloid
metaplasia, intra-abdominal infections, and osteomyelitis [11].
A two- to fourfold elevation in serum alkaline phosphatase levels has been described in several
members of a family who had no evidence of bone or liver disease [29]. The elevation appeared
to be transmitted as an autosomal dominant trait, but the site of the excess alkaline
phosphatase could not be determined.
Isolated or disproportionate elevation — Isolated elevations of hepatic alkaline phosphatase
or disproportionate elevation compared with other tests, such as the serum aminotransferases
and bilirubin, can occur in a number of circumstances including:
●Partial bile duct obstruction due to gallstones or tumor. The mechanism is unknown but
probably represents local areas of bile duct obstruction with induced synthesis of hepatic
alkaline phosphatase and leakage of the alkaline phosphatase into the serum.
●Early in the course of some cholestatic liver diseases such as primary sclerosing
cholangitis and primary biliary cirrhosis.
●Infiltrative diseases such as amyloidosis, sarcoidosis, hepatic abscesses, tuberculosis,
and metastatic carcinoma.
●Ischemic cholangiopathy.
●Extrahepatic diseases such as myeloid metaplasia, peritonitis, diabetes mellitus,
subacute thyroiditis, uncomplicated gastric ulcer, and sepsis. The increase in alkaline
phosphatase in these disorders is thought to be related to hepatic dysfunction despite the
absence of overt liver disease [30].
●Extrahepatic tumors, including osteosarcomas; lung, gastric, head and neck, renal cell,
ovarian, and uterine cancers; and Hodgkin lymphoma, that secrete alkaline phosphatase
(often a form known as the Regan isoenzyme) or cause leakage of hepatic alkaline
phosphatase into serum by an unknown mechanism [11,31].
●Certain drugs such as phenytoin.
●Infants and young children occasionally display marked transient elevation of serum
alkaline phosphatase activity in the absence of detectable liver or bone disease. The
hyperphosphatasemia typically includes elevations in both bone and liver isoenzymes, and
appears to be caused by delayed clearance of the enzyme. The clinical presentation and
evaluation of an infant or child with this finding is discussed separately. (See "Transient
hyperphosphatasemia of infancy and early childhood".)
Subnormal values — Extremely low serum alkaline phosphatase concentrations can be seen
in patients with fulminant Wilson disease complicated by hemolysis [32,33]. (See"Wilson
disease: Diagnostic tests".)
Low values can also occur in patients with hypothyroidism, pernicious anemia, zinc deficiency,
congenital hypophosphatemia, and certain types of progressive familial intrahepatic cholestasis
in children.
Non-hepatic alkaline phosphatase — As noted above, bone is the most likely source of
isolated plasma alkaline phosphatase that is not of liver origin (in nonpregnant patients). An
elevated bone alkaline phosphatase is indicative of high bone turnover, which may be caused
by several disorders including healing fractures, osteomalacia, hyperparathyroidism,
hyperthyroidism, Paget disease of bone, osteogenic sarcoma, and bone metastases. If the
etiology is unclear, referral to an endocrinologist for evaluation is often the next step. Initial
testing may include measurement of serum calcium, parathyroid hormone, 25-hydroxy vitamin
D, and imaging with bone scintigraphy. (See "Bone physiology and biochemical markers of
bone turnover", section on 'Markers of bone turnover' and "Clinical manifestations and diagnosis
of Paget disease of bone", section on 'Clinical manifestations' and "Clinical manifestations,
diagnosis, and treatment of osteomalacia", section on 'Diagnosis and evaluation'.)
Intestinal alkaline phosphatase has multiple biological functions [3,34]. As noted above,
elevated levels in serum are usually of no clinical importance. They are most often found
postprandially after a fatty meal and tend to run in families, suggesting that there may be a
genetic basis [35]. Because elevation is nonspecific, it should not prompt evaluation for a
particular intestinal disorder. Normalization of the level while fasting can help reassure that its
origin is intestinal.
5'-NUCLEOTIDASE — 5'-Nucleotidase is found in the liver, intestine, brain, heart, blood
vessels, and endocrine pancreas [36]. Although its physiologic function is unknown, 5'-
nucleotidase specifically catalyzes hydrolysis of nucleotides such as adenosine 5'-phosphate
and inosine 5'-phosphate, in which the phosphate is attached to the 5 position of the pentose
moiety.
Similar to alkaline phosphatase, 5'-nucleotidase has a subcellular location in hepatocytes [37]. It
is bound to bile canalicular and sinusoidal membranes [38] and must be solubilized, perhaps via
the detergent action of bile acids, to gain access to the circulation. In experimental bile duct
obstruction in rats, bile acid concentrations rapidly reach levels sufficient to disrupt plasma
membranes and solubilize the enzyme [39]. The same phenomenon may occur in hepatobiliary
disorders in which there is any degree of cholestasis [37].
Measurement — Serum 5'-nucleotidase activity is most commonly assayed by measuring the
release of inorganic phosphate using 5'-phosphate as a substrate [40]. A unit of 5'-nucleotidase
activity is designated as equivalent to that amount of enzyme that liberates 1 mg of phosphate
per 100 mL of serum per hour (1 mg/dL per hour). These units are analogous to the old
Bodansky units of alkaline phosphatase activity [41]. The presence of alkaline phosphatase in
serum complicates the assay because it also hydrolyzes the 5'-nucleotide substrates, and
corrections must be made for its activity.
In most series of normal adults, the serum 5'-nucleotidase concentration ranges from 0.3 to 3.2
Bodansky units and is not clearly influenced by gender or race [42,43]. Values are substantially
lower in children than in adults, rise gradually in adolescence, and reach a plateau after age 50
[44].
Clinical significance — Elevations in serum 5'-nucleotidase are seen in the same types of
hepatobiliary diseases associated with an increased serum alkaline phosphatase. Most studies
suggest that serum alkaline phosphatase and 5'-nucleotidase are equally valuable in
demonstrating biliary obstruction or hepatic infiltrative and space-occupying lesions [43,45].
Although values of the two enzymes are generally correlated, the concentrations may not rise
proportionately in individual patients [42,46]. Thus, in selected patients, one enzyme may be
elevated and the other normal.
Conflicting data have been reported for serum 5'-nucleotidase activity during normal pregnancy
[47,48]. In contrast, most studies show that serum 5'-nucleotidase does not rise in bone
disease, [49] and in the few instances in which an increase was observed, it was of low
magnitude [46].
Thus, the major value of the 5'-nucleotidase assay is its specificity for hepatobiliary disease. An
increased serum 5'-nucleotidase concentration in a nonpregnant person suggests that a
concomitantly increased serum alkaline phosphatase is of hepatic origin. However, because of
the occasional dissociation between the two enzymes, a normal serum 5'-nucleotidase does not
rule out the liver as the source of an elevated serum alkaline phosphatase.
GAMMA-GLUTAMYL TRANSPEPTIDASE — Gamma-glutamyl transpeptidase (GGT)
catalyzes the transfer of the gamma-glutamyl group from gamma-glutamyl peptides such as
glutathione to other peptides and to L-amino acids. GGT is present in cell membranes in many
tissues, including the kidneys, pancreas, liver, spleen, heart, brain, and seminal vesicles [50]. It
is thought to play a role in amino acid transport [51].
Measurement — Enzyme activity is most commonly assayed using gamma-L-glutamyl-r-
nitroanilide as a substrate [52]. The liberated product, (chromogen r-nitroaniline) can be
measured spectrophotometrically.
Clinical significance — GGT is present in the serum of healthy individuals. The normal range
is 0 to 30 IU/L (0 to 0.5 mkat/L). Most studies have found values to be comparable in men and
women [53,54], although some reports have noted higher values in men [55]. Newborn infants
have serum GGT activity six to seven times the upper limit of the adult reference range; levels
decline and reach adult levels by five to seven months of age [56]. Serum enzyme activity does
not rise during the course of normal pregnancy [54].
Elevated serum activity is found in diseases of the liver, biliary tract, and pancreas, and reflects
the same spectrum of hepatobiliary disease as alkaline phosphatase, 5'-nucleotidase, and
leucine aminopeptidase. Serum GGT and alkaline phosphatase correlate reasonably well.
There are conflicting data as to whether serum GGT has better sensitivity for hepatobiliary
disease than alkaline phosphatase or leucine aminopeptidase [54,57].
As with serum 5'-nucleotidase, the major clinical value of serum GGT is in conferring organ
specificity to an elevated value for alkaline phosphatase since GGT activity is not increased in
patients with bone disease [54]. However, an elevation in serum GGT is not completely specific
for hepatobiliary disease. High serum GGT values are found in people who take medicines such
as barbiturates or phenytoin [58] or ingest large quantities of alcohol [59] even when values for
other serum enzyme tests and serum bilirubin are normal. In these settings, there is no
correlation between the serum GGT and alkaline phosphatase [50].
An isolated elevation in serum GGT or a GGT elevation out of proportion to that of other
enzymes (such as the alkaline phosphatase and alanine aminotransferase) may be an indicator
of alcohol abuse or alcoholic liver disease [60]. The reasons for this are not well understood.
Although hepatic microsomal GGT may be induced by alcohol [61], neither elevated serum GGT
nor a history or recent alcohol ingestion correlates with hepatic GGT activity in patients with
biopsy-proven alcoholic liver disease [62,63]. In vitro studies suggest an alternative mechanism:
alcohol may cause the leakage of GGT from hepatocytes [61].
Aside from its value in conferring liver specificity to an elevated serum alkaline phosphatase
level and its possible use in identifying patients with alcohol abuse, serum GGT offers no
advantage over aminotransferases and alkaline phosphatase. In one prospective study that
included 1040 nonselected inpatients, 13 percent had an elevated serum GGT activity; only 32
percent had hepatobiliary disease [64]. In the remaining patients, the elevated serum GGT may
have been due to alcohol ingestion or medications, which caused a temporary rise in levels but
without liver disease.
SUMMARY AND RECOMMENDATIONS
●Alkaline phosphatase refers to a group of enzymes that catalyze the hydrolysis of a large
number of organic phosphate esters at an alkaline pH optimum. Although alkaline
phosphatase is found in many locations throughout the body, its precise function is not yet
known.
●The major value of the serum alkaline phosphatase in the diagnosis of liver disorders is
in the recognition of cholestatic disease (table 2). However, an elevation in the alkaline
phosphatase concentration is a relatively common finding and does not always indicate
the presence of hepatobiliary disease. The degree of elevation does not distinguish
between intra- and extra-hepatic cholestasis (algorithm 1). (See "Approach to the patient
with abnormal liver biochemical and function tests".)
●Elevations in serum 5'-nucleotidase are seen in the same types of hepatobiliary diseases
associated with an increased serum alkaline phosphatase. Most studies suggest that
serum alkaline phosphatase and 5'-nucleotidase are equally valuable in demonstrating
biliary obstruction or hepatic infiltrative and space-occupying lesions.
●Elevated serum levels of gamma-glutamyl transpeptidase are found in diseases of the
liver, biliary tract, and pancreas, and reflect the same spectrum of hepatobiliary disease as
alkaline phosphatase, 5'-nucleotidase, and leucine aminopeptidase. Serum GGT and
alkaline phosphatase correlate reasonably well. There are conflicting data as to whether
serum GGT has better sensitivity for hepatobiliary disease than alkaline phosphatase or
leucine aminopeptidase.Classification and causes of jaundice or asymptomatic hyperbilirubinemiaAuthorsNamita Roy-Chowdhury, PhDJayanta Roy-Chowdhury, MD, MRCPSection EditorsSanjiv Chopra, MD, MACPElizabeth B Rand, MDDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Namita Roy-Chowdhury, PhD Nothing to disclose. Jayanta Roy-Chowdhury, MD, MRCP Nothing to disclose. Sanjiv Chopra, MD, MACP Nothing to disclose. Elizabeth B Rand, MD Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].
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
All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Dec 08, 2014.
INTRODUCTION — The normal serum bilirubin concentration in children and adults is less than
1 mg/dL (17 micromol/liter), less than 5 percent of which is present in conjugated form. The
measurement is usually made using diazo reagents and spectrophotometry. Conjugated
bilirubin reacts rapidly ("directly") with the reagents. The measurement of unconjugated bilirubin
requires the addition of an accelerator compound and is often referred to as the indirect
bilirubin. (See "Clinical aspects of serum bilirubin determination".)
Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical
examination cannot detect jaundice until the serum bilirubin is greater than
2 mg/dL (34micromol/liter), twice the normal upper limit. The yellow discoloration is best seen in
the periphery of the ocular conjunctivae and in the oral mucous membranes (under the tongue,
hard palate). Icterus may be the first or only sign of liver disease; thus its evaluation is of critical
importance.
For clinical purposes, the predominant type of bile pigments in the plasma can be used to
classify hyperbilirubinemia into two major categories (table 1 and algorithm 1A-B).
●Plasma elevation of predominantly unconjugated bilirubin due to the overproduction of
bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation
●Plasma elevation of both unconjugated and conjugated bilirubin due to hepatocellular
diseases, impaired canalicular excretion, and biliary obstruction
In some situations, both overproduction and reduced disposition contribute to the accumulation
of bilirubin in plasma.
The frequency with which the different causes of jaundice occur varies markedly depending
upon multiple factors such as age, geography, and socioeconomic class [1]. The causes of
hyperbilirubinemia presenting in the neonatal period are quite different from those presenting
later in life, and are discussed separately. (See "Pathogenesis and etiology of unconjugated
hyperbilirubinemia in the newborn" and "Causes of neonatal cholestasis".)
This topic will review the causes of jaundice. A schematic depiction of the hepatobiliary
excretion pathway with disorders causing jaundice and their main site of interference with
bilirubin metabolism and excretion is presented in the figure (figure 1). The diagnostic approach
to the patient with jaundice is discussed separately. (See "Diagnostic approach to the adult with
jaundice or asymptomatic hyperbilirubinemia".)
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 [2]:
●Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)
●Alkaline phosphatase:
•Male: 45 to 115 int. unit/L
•Female: 30 to 100 int. unit/L
●Alanine aminotransferase (ALT):
•Male: 10 to 55 int. unit/L
•Female: 7 to 30 int. unit/L
●Aspartate aminotransferase (AST):
•Male: 10 to 40 int. unit/L
•Female: 9 to 32 int. 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)
●Gamma-glutamyl transpeptidase (GGT):
•Male: 8 to 61 int. unit/L
•Female: 5 to 36 int. unit/L
●Prothrombin time (PT): 11.0 to 13.7 seconds
DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA — Three basic
pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin uptake, and
impaired bilirubin conjugation, are mainly responsible for unconjugated hyperbilirubinemia. The
physiologic jaundice of the neonate represents a classic example which combines all of these
mechanisms.
Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown
of heme derived from hemoglobin (figure 2). Extravascular or intravascular hemolysis,
extravasation of blood in tissues, or dyserythropoiesis are causes of enhanced heme
catabolism. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin
overproduction".)
Extravascular hemolysis — The reticuloendothelial cells of the spleen, bone marrow, and liver
are responsible for the increased extravascular destruction of erythrocytes which occurs in most
hemolytic disorders. These phagocytic mononuclear cells are rich in heme oxygenase and
biliverdin reductase activities and rapidly degrade heme to bilirubin (figure 2). (See "Bilirubin
metabolism".)
Extravasation — When blood is extravasated into tissues, erythrocytes are phagocytosed by
tissue macrophages that degrade heme to biliverdin and subsequently bilirubin, resulting in the
sequential green and yellow discoloration of the skin overlying a hematoma.
Intravascular hemolysis — With intravascular hemolysis, bilirubin is predominantly formed in
the liver and the kidneys. Hemoglobin released in the circulation is bound to haptoglobin; this
complex is internalized and degraded by hepatocytes. However, circulating haptoglobin may be
depleted with massive hemolysis. In these cases, unbound hemoglobin is converted to
methemoglobin, from which heme is transferred to hemopexin or to albumin forming
methemalbumin. Heme-hemopexin and methemalbumin are internalized by hepatocytes, where
heme is degraded to bilirubin.
A significant fraction of free methemoglobin is filtered by renal glomeruli after dissociation of the
tetrameric globin to two dimers. Only the free (unbound) dimer is small enough to be filtered
across the glomeruli. The heme moiety of filtered methemoglobin is largely degraded by tubular
epithelial cells to bilirubin.
Dyserythropoiesis — Dyserythropoiesis is a term used in a variety of diseases including
megaloblastic and sideroblastic anemias, severe iron deficiency anemia, erythropoietic
porphyria, erythroleukemia, lead poisoning, and a rare disorder of unknown pathogenesis
termed primary shunt hyperbilirubinemia [3,4]. In these disorders, the incorporation of
hemoglobin into erythrocytes is defective, leading to the degradation of a large fraction of
unincorporated hemoglobin heme.
Serum bilirubin concentration — In a stress situation, hemolysis, and therefore unconjugated
bilirubin production, can increase up to 10-fold. The canalicular excretion of bilirubin is the rate-
limiting step in bilirubin elimination since hepatic conjugating capacity normally exceeds
maximum bilirubin production. These relationships account for two findings at a steady state of
maximum bilirubin production in patients with normal hepatic function:
●The serum bilirubin concentration will not exceed 4 mg/dL (68 micromol/liter) in patients
with normal liver function [5]; however, hemolysis can lead to severe hyperbilirubinemia in
patients who have even mild hepatic disease.
●The proportion of conjugated bilirubin in plasma (approximately 3 to 5 percent of the
total) remains normal [6].
There are two reasons why the bilirubin concentration increases during hemolysis in the
presence of normal bilirubin glucuronidation. First, bilirubin is produced mainly outside the liver;
as a result, it must enter the blood stream during transit to the liver. Second, a small amount of
bilirubin taken up by the hepatocyte is transferred to plasma by diffusion or via ATP-consuming
mechanisms. Because conjugated bilirubin is very efficiently cleared, the proportion of
conjugated bilirubin in the plasma (around 5 percent) does not increase until canalicular
excretion capacity is exceeded. At that point, a disproportionate amount of conjugated bilirubin
accumulates.
Bilirubin overproduction with coexisting liver disease — Most liver diseases affect
canalicular excretion, resulting in the accumulation of both conjugated and unconjugated
bilirubin in hepatocytes. In cholestatic states, the canalicular ATP-dependent organic anion
pump, MRP2, is down-regulated. This may lead to upregulation of other forms of MRP, such as
MRP3, in the contiguous membranes of the hepatocyte, resulting in active transport of
unconjugated and conjugated bilirubin into the plasma [7,8]. Thus, plasma bilirubin
accumulating in conditions resulting from a combination of bilirubin overload and liver disease is
always a mixture of unconjugated and conjugated bilirubin. In cases where there is an inherited
deficiency of conjugation (eg, Gilbert syndrome), hemolysis causes almost pure unconjugated
hyperbilirubinemia. The rate-limiting step in these patients is bilirubin glucuronidation, rather
than canalicular excretion. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to
bilirubin overproduction".)
Serum bilirubin level is of particular significance when diagnosing Wilson disease in the setting
of acute liver failure. In contrast to most liver diseases, serum alkaline phosphatase activity is
low or normal in Wilson disease and, because of bilirubin overproduction due to hemolysis, the
serum bilirubin level is high. A serum alkaline phosphatase (int.unit/L)/bilirubin (mg/dl) ratio of
<4 provides 94 percent sensitivity and 96 percent specificity for the diagnosis of Wilson disease
in adult patients presenting with acute liver failure [9]. However, the sensitivity of this ratio may
be reduced in children, probably because of a higher contribution of alkaline phosphatase from
non-hepatic sources [10]. (See "Wilson disease: Clinical manifestations, diagnosis, and natural
history", section on 'Acute hepatitis and acute liver failure'.)
Urobilinogen excretion — As bilirubin excretion in bile increases in states of bilirubin
overproduction, more urobilinogen appears in the stool and urine. However, the amount of
urobilinogen in stool and urine is not proportional to bilirubin excretion since conversion of
bilirubin to urobilinogen is not quantitative [11].
Gallstones — Chronically increased biliary bilirubin excretion can lead to brown or black
pigment stones consisting of precipitated monoconjugated and unconjugated bile pigments.
Black pigment stones generally form in the gallbladder and may contain polymerized bile
pigments. Brown stones form in the bile ducts, often in the presence of infection. They consist of
calcium bilirubinate, mucin glycoproteins, and various other salts.
Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders of
internalization of bilirubin by the hepatocyte result in reduced hepatic bilirubin uptake (figure 3).
Congestive heart failure or portosystemic shunts (spontaneously occurring collaterals in
cirrhosis or surgical shunts) reduce hepatic blood flow and the delivery of bilirubin to
hepatocytes, resulting in predominantly unconjugated hyperbilirubinemia. In some patients with
cirrhosis, the direct contact of plasma with the hepatocytes may be compromised due to
capillarization of the sinusoidal endothelial cells (loss of fenestrae), resulting in a further
reduction in bilirubin uptake [12].
Other causes of abnormal bilirubin uptake include Gilbert syndrome, in which uptake of bilirubin
at the sinusoidal surface of hepatocytes is impaired (see "Gilbert syndrome and unconjugated
hyperbilirubinemia due to bilirubin overproduction"), and the administration of several drugs (eg,
rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a cholecystographic agent).
The drug-induced defect usually resolves within 48 hours after discontinuation of the drug [13].
Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or
absent UDP-glucuronosyltransferase activity is found both in several acquired conditions and
inherited diseases, such as Crigler-Najjar syndrome, type I and II and Gilbert syndrome.
(See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin
overproduction" and "Crigler-Najjar syndrome".) Bilirubin conjugating activity is also very low in
the neonatal liver.
UGT activity toward bilirubin is modulated by various hormones. Hyperthyroidism and ethinyl
estradiol, but not other oral contraceptives, inhibit bilirubin glucuronidation [14]. In comparison,
the combination of progestational and estrogenic steroids results in increased enzyme activity.
Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin
or gentamicin at serum concentrations exceeding therapeutic levels) and by chronic persistent
hepatitis, advanced cirrhosis, and Wilson's disease.
DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA — A variety of
acquired disorders with conjugated hyperbilirubinemia can be categorized according to their
histopathology and pathophysiology: biliary obstruction (extrahepatic cholestasis), intrahepatic
cholestasis, and hepatocellular injury. The differential diagnosis of extrahepatic and intrahepatic
hyperbilirubinemia is summarized in the tables (table 2 and table 3).
Biliary obstruction — In biliary obstruction, both conjugated and unconjugated bilirubin
accumulate in serum. Bilirubin may be transported back to the plasma via an MRP group of
ATP-consuming pumps [8,15]. The serum concentrations of conjugated bilirubin and alkaline
phosphatase can be used as markers for hepatobiliary obstruction. The diagnosis can usually
be established with the help of noninvasive and invasive imaging techniques. (See "Diagnostic
approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)
Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes, where
reversal of glucuronidation may take place. The unconjugated bilirubin formed by this process
may diffuse or be transported back into the plasma.
The differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction is age
dependent. In adults, it includes cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing
cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and chronic
pancreatitis, and strictures after invasive procedures. In children, choledochal cysts and
cholelithiasis are most common. Extrinsic compression from tumors or other anomalies are
seen in all pediatric age groups as well as in adults. In neonates and young infants, important
obstructive processes include biliary atresia and choledochal cysts. (See "Causes of neonatal
cholestasis".)
●In the Mirizzi syndrome, a distended gallbladder caused by an impacted cystic duct stone
may lead to compression of the extrahepatic bile ducts. (See "Mirizzi syndrome".)
●The intrahepatic and extrahepatic portions of the bile ducts can be affected in both PSC
and cholangiocarcinoma. (See "Clinical manifestations and diagnosis of
cholangiocarcinoma".)
●Different parasitic infections can be the cause of biliary obstruction. Adult Ascaris
lumbricoides can migrate from the intestine up the bile ducts, thereby obstructing the
extrahepatic bile ducts. Eggs of certain liver flukes (eg, Clonorchis sinensis, Fasciola
hepatica) can obstruct the smaller bile ducts, resulting in intrahepatic cholestasis.
●AIDS cholangiopathy can be caused by Cryptosporidium sp, cytomegalovirus, or HIV
itself [16]; imaging studies show similar findings to PSC [17] (see "AIDS cholangiopathy").
Only biopsies and bile cultures are able to give a definitive diagnosis.
Establishing the cause of jaundice in patients with AIDS is particularly complex because of its
broad differential diagnosis. It includes viral hepatitis (hepatitis viruses, herpes simplex virus,
Epstein-Barr virus), Mycobacterium tuberculosis and atypical mycobacteria (especially
Mycobacterium avium intracellulare), fungal infections (Cryptococcus neoformans,Histoplasma
capsulatum, Candida albicans, Coccidioides immitis), parasites (Pneumocystis carinii), tumor
infiltration (lymphoma, Kaposi sarcoma), and drug-induced liver disease.
Intrahepatic causes — A number of intrahepatic disorders can lead to jaundice and an
elevated serum alkaline phosphatase (in relation to serum aminotransferases). This
presentation mimics that of biliary obstruction but the bile ducts are patent.
Viral hepatitis — Viral hepatitis can present as a predominantly cholestatic syndrome with
marked pruritus. Unless the patient has risk factors for viral hepatitis, it is difficult to distinguish
this clinically from other causes of cholestasis.
Alcoholic hepatitis — Cholestasis with fever and leukocytosis is often the distinctive sign of
alcoholic hepatitis [18]. The diagnosis should be strongly considered in the jaundiced patient
with ethanol dependency, especially if the ratio of serum AST to ALT exceeds 2.0 with the
values being below 500 int. unit/L. (See "Clinical manifestations and diagnosis of alcoholic fatty
liver disease and alcoholic cirrhosis".)
Nonalcoholic steatohepatitis — Nonalcoholic steatohepatitis has features similar to alcoholic
hepatitis both in terms of histology and signs of cholestasis [19]. A variety of conditions such as
diabetes mellitus, morbid obesity, certain stomach and small bowel operations, and drugs can
cause this disorder. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty
liver disease in adults".)
Primary biliary cirrhosis — Primary biliary cirrhosis typically presents with a cholestatic
picture, though evidence of hepatocellular injury also exists. (See "Clinical manifestations,
diagnosis, and prognosis of primary biliary cirrhosis".)
Drugs and toxins — Drug-induced cholestasis can occur in a dose-related fashion (eg,
alkylated steroids such as methyltestosterone and ethinyl estradiol) or as an idiosyncratic or
allergic reaction in a minority of subjects (eg, chlorpromazine, halothane). Drugs and toxins
causing hepatocellular injury may eventually present as a predominantly cholestatic syndrome
[20]. Therefore, it is imperative in every patient with cholestasis to scrupulously elucidate the
current and past medication history including prescribed and over-the-counter drugs.
Certain plants used in "natural" medicines (eg, Jamaican bush tea) contain pyrrolizidine
alkaloids which may cause veno-occlusive disease of the liver [21,22] (see "Hepatotoxicity due
to herbal medications and dietary supplements"). The outbreak of jaundice that occurred in 84
individuals after accidental methylene dianiline ingestion in England in 1965 has been termed
Epping jaundice [23].
Arsenic, which was used for the treatment of syphilis during the early years of the twentieth
century, also can cause cholestasis. It has recently gained increased attention because of its
contamination of ground water in various parts of the world including West Bengal, India [24],
the southern United States, and Taiwan. In addition to the well-known skin lesions, arsenic-
contaminated drinking water has been associated with hepatic fibrosis and portal hypertension,
usually without the formation of cirrhotic nodules.
Sepsis and low perfusion states — Bacterial sepsis is very often accompanied by cholestasis.
Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the
jaundice in these patients [25-27]. On the other hand, hyperbilirubinemia can promote bacterial
sepsis by increasing intestinal wall permeability and altering mucosal immunity [28]. Signs of
cholestasis can also be found in other low perfusion states of the liver (heart failure,
hypotension) and hypoxemia that is not profound enough to produce hepatic necrosis.
Malignancy — Paraneoplastic syndromes associated with malignancy can induce a reversible
form of cholestasis (Stauffer syndrome) [29]. It has most commonly been described in
association with renal cell carcinoma, though it has also been reported in patients with
malignant lymphoproliferative diseases, gynecologic malignancies, and prostate cancer [30,31].
(See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)
Liver infiltration — Infiltrative processes of the liver (eg, amyloidosis, lymphoma, sarcoidosis,
tuberculosis) can precipitate intrahepatic cholestasis.
Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited diseases
such as Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic
cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and low phospholipid-
associated cholelithiasis (LPAC). BRIC is seen in adolescents and adults, while LPAC presents
mainly in young adults. (See "Inherited disorders associated with conjugated
hyperbilirubinemia".)
Disorders of fatty acid oxidation are characterized by episodes of metabolic decompensation,
with hypoglycemia, liver dysfunction, and/or cardiomyopathy, triggered by fasting or intercurrent
illness. These disorders may present at any age, from birth through adulthood. (See "Metabolic
myopathies caused by disorders of lipid and purine metabolism", section on 'Defects of beta-
oxidation enzymes'.)
Inherited diseases that cause conjugated hyperbilirubinemia that present during the neonatal
period include Alagille syndrome, cystic fibrosis, and disorders of carbohydrate, lipid, or bile acid
metabolism. (See "Causes of neonatal cholestasis".)
Total parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in
patients receiving total parenteral nutrition (TPN). This complication usually requires at least two
to three weeks of therapy for the development of cholestasis [32]. The underlying illness,
preexisting liver disease, hepatotoxic drugs, and the TPN itself all may contribute to the
cholestasis.
TPN promotes bacterial overgrowth in the small intestine, which in turn favors conditions well
known to induce cholestasis such as translocation of intestinal endotoxins into the portal system
[33], bacterial sepsis [34], and the formation of secondary bile acids (eg, lithocholic acid)
(see "Management of the short bowel syndrome in adults"). Other contributing factors to
cholestasis include biliary sludge, which occurs in all patients after six weeks of TPN, and
hepatotoxic factors such as tryptophan degradation products and aluminum contaminants.
Infants are particularly prone to TPN cholestasis, particularly those born prematurely.
Contributing factors and potential treatment approaches are discussed separately.
(See "Causes of neonatal cholestasis", section on 'Intestinal failure-associated liver disease'.)
Postoperative patient — Jaundice occurs regularly in postoperative patients and is usually
multifactorial in origin. Serum unconjugated bilirubin levels may increase because of blood
transfusions, hematoma resorption, and hemolysis after heart surgery. Other contributing
factors include sepsis, TPN, the administration of hepatotoxic drugs during surgery (such as
halothane) [35], postoperative hypoxia, hypotension, or a newly acquired viral hepatitis [36].
Concomitant renal failure will exaggerate the hyperbilirubinemia. (See "Approach to the patient
with postoperative jaundice".)
Surgery also can exacerbate a preexisting hemolytic disease or unmask an underlying genetic
disorder (eg, Gilbert syndrome or glucose-6-phosphate dehydrogenase deficiency).
Following organ transplantation — Intrahepatic cholestasis is common in transplant
recipients (especially bone marrow and liver). These patients are generally very sick, often
require TPN, and receive multiple potentially hepatotoxic drugs including immunosuppressive
agents, which increase the susceptibility to infection.
In addition to the skin and intestinal epithelium, other target sites of graft-versus-host disease in
bone marrow transplants include the small interlobular bile ducts. The resulting inflammation
and destruction lead to cholestasis. Intensive pretransplantation radiation and chemotherapy
predisposes to the development of veno-occlusive disease of the liver, with cholestasis and liver
failure.
Signs of cholestasis after orthotopic liver transplantation may reflect preservation injury of the
donor organ, an operative complication (bile leak, stricture) [37], and chronic allograft rejection
("vanishing bile duct syndrome"). In addition, cholestasis is occasionally the sole indicator of
acute transplant rejection.
Sickle cell disease — Jaundice in patients with sickle cell disease can result from an
interaction of several factors. The average serum bilirubin concentration in these patients is
higher than normal because of the combination of chronic hemolysis and a mild hepatic
dysfunction. Both unconjugated and conjugated bilirubin accumulate in the plasma. Viral
hepatitis, particularly hepatitis C virus, also may contribute in selected patients. (See "Hepatic
manifestations of sickle cell disease".)
Hepatic crisis, which is usually associated with enlargement and tenderness of the liver, is
thought to result from sequestration of sickled erythrocytes. In severe cases, acute attacks of
intrahepatic cholestasis can occur, leading to very high levels of serum bilirubin and bile salts
[38]. This condition must be differentiated from acute biliary obstruction. Bilirubin microliths,
sludge, calcium bilirubinate stones, and black stones consisting of polymers of bilirubin are
almost universal in patients with sickle cell disease [39]. However, biliary obstruction from these
stones is not common.
Finally, cirrhosis can be caused by chronic vascular lesions [40] or iron overload after multiple
blood transfusions (secondary hemochromatosis). (See "Iron overload syndromes other than
hereditary hemochromatosis".)
Intrahepatic cholestasis of pregnancy — Pruritus, usually occurring in the third trimester of
pregnancy but sometimes earlier, typically heralds cholestasis which may evolve into frank
jaundice [41] and may be associated with an increased frequency of stillbirths and prematurity
[42]. All the pathologic changes disappear following delivery. (See "Intrahepatic cholestasis of
pregnancy".)
Intrahepatic cholestasis of pregnancy is thought to be inherited, although the mode of
inheritance is not well defined [43]. A possible relationship to benign recurrent intrahepatic
cholestasis has been postulated (see "Gilbert syndrome and unconjugated hyperbilirubinemia
due to bilirubin overproduction"). It is of crucial importance to distinguish this entity from other
potentially lethal liver disorders in pregnancy such as acute fatty liver and the HELLP syndrome.
(See "Acute fatty liver of pregnancy".)
End-stage liver disease — The hallmarks of end-stage liver disease and cirrhosis, regardless
of its etiology, include jaundice with an elevation of both conjugated and unconjugated bilirubin
as well as portal hypertension and decreased hepatic synthetic function.
Hepatocellular injury — A partial overview of disorders causing hepatocellular jaundice is
presented in the table (table 4). These conditions cannot always be separated clearly from the
cholestatic syndromes because of the variability in presentation of these diseases. There are,
however, characteristic differences between the two mechanisms of hepatic disease.
Hepatocellular injury is typically characterized by the release of intracellular proteins and small
molecules into the plasma. Thus, in contrast to cholestatic syndromes, the elevations in serum
conjugated and unconjugated bilirubin and bile salts are accompanied by elevations in the
serum concentrations of hepatocellular proteins, such as aspartate aminotransferase (AST),
alanine aminotransferase (ALT), and glutathione S-transferase (GST).
With chronic hepatocellular injury, the biochemical profile changes over time as the liver injury
progresses to cirrhosis and liver failure. The elevation of liver enzymes, a marker of active liver
injury, becomes less prominent or even disappears. The primary manifestations at this time
result from impaired hepatic protein synthesis (eg, hypoalbuminemia and a prolonged
prothrombin time) and impaired excretory function, leading to jaundice.
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)" and "Patient
information: Gilbert’s syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●An approach to patients with abnormal liver biochemical tests is presented separately.
(See "Approach to the patient with abnormal liver biochemical and function tests".)
●For clinical purposes, the predominant type of bile pigments in the plasma can be used to
classify hyperbilirubinemia into two major categories, conjugated and unconjugated (table
1 and algorithm 1A-B).
●Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin
uptake, and impaired bilirubin conjugation, are mainly responsible for unconjugated
hyperbilirubinemia.
●A variety of acquired disorders with conjugated hyperbilirubinemia can be categorized
according to their histopathology and pathophysiology: biliary obstruction (extrahepatic
cholestasis), intrahepatic cholestasis, and hepatocellular injury. The differential diagnosis
of extrahepatic and intrahepatic hyperbilirubinemia is summarized in the tables (table
2and table 3).Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)AuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].
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.
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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jun 02, 2014.
INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.
The most common tests used in clinical practice include the serum aminotransferases, bilirubin,
alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver
function tests," although this term is somewhat misleading since most do not accurately reflect
how well the liver is functioning, and abnormal values can be caused by diseases unrelated to
the liver. In addition, these tests may be normal in patients who have advanced liver disease.
Several specialized tests have also been developed (such as indocyanine green clearance),
which, although uncommonly used in clinical practice, can measure specific aspects of hepatic
function.
Despite their limitations, liver biochemical and function tests have many applications in clinical
medicine:
●They provide a noninvasive method to screen for the presence of liver disease. The
serum aminotransferases, for example, were used in the past to screen all blood donors in
the United States for the presence of transmissible viruses before specific viral tests were
available.
●They can be used to measure the efficacy of treatments for liver disease (such as
immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:
Treatment".)
●They can be used to monitor the progression of a disease such as viral or alcoholic
hepatitis.
●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.
As an example, the Child-Pugh score, which incorporates the prothrombin time and serum
bilirubin and albumin concentrations, can predict survival (table 1).
The pattern of abnormalities on these tests is more accurate than any of the individual tests.
Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the
alkaline phosphatase indicates cholestasis. Recognition of patterns that are consistent with
specific diseases can prompt appropriate additional testing.
The liver biochemical and function tests that are used commonly in clinical practice and that are
used occasionally for specific circumstances can be categorized as follows:
●Tests that detect injury to hepatocytes – Most of these tests measure the activity of
hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are
normally intracellular, but are released when hepatocytes are injured. (See "Liver
biochemical tests that detect injury to hepatocytes".)
●Tests of the liver's capacity to transport organic anions and metabolize drugs – These
tests measure the liver's ability to clear endogenous or exogenous substances from the
circulation. The best studied include serum measurements of bilirubin, bile acids, caffeine,
and lidocaine metabolites, a variety of breath tests, and clearance tests such as
bromsulphalein (BSP) and indocyanine green (ICG).
●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess
the biosynthetic capacity of the liver are the serum albumin and the prothrombin time
(which requires the presence of clotting factors produced in the liver). Other tests which
have been use are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and
alpha 1-antitrypsin.
●Tests that detect altered immunoregulation or viral hepatitis – These tests include the
immunoglobulins, hepatitis serologies, and specific autoantibodies. Most of these
substances are proteins made by B lymphocytes, not by hepatocytes. However, some are
quite specific for certain liver diseases, such as antimitochondrial antibodies in primary
biliary cirrhosis. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary
cirrhosis".)
This topic will review the role of the serum albumin and prothrombin time in the evaluation of the
liver's biosynthetic capacity. The other categories of liver function tests are discussed
separately. (See "Approach to the patient with abnormal liver biochemical and function
tests" and "Liver biochemical tests that detect injury to hepatocytes" and "Enzymatic measures
of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl
transpeptidase)" and "Clinical aspects of serum bilirubin determination" and "Tests of the liver's
capacity to transport organic anions and metabolize drugs".)
SERUM PROTEINS — The liver is the major site where serum proteins are synthesized. These
include albumin and the coagulation factors.
Albumin — Albumin is quantitatively the most important plasma protein. Approximately 300 to
500 g of albumin is distributed in the body fluids, and the average adult liver synthesizes
approximately 15 g per day (200 mg/kg per day). The synthesis rate can double in situations in
which there is rapid albumin loss or a fall in the serum albumin concentration.
The serum albumin concentration reflects the rate of synthesis, rate of degradation, and volume
of distribution. Albumin synthesis is regulated by a variety of factors, including nutritional status,
serum oncotic pressure, cytokines, and hormones [1,2]. How these factors operate on a cellular
level is not precisely known but may involve the formation of albumin messenger ribonucleic
acid (mRNA) polysomes within the liver [1-3]. Substances that stimulate albumin synthesis
increase the efficiency of this process. By contrast, inhibitory substances associated with
inflammatory states, such as tumor necrosis factor and interleukin-1, impede albumin synthesis
[4-6].
Little is known about the site of degradation of albumin. The half-life of albumin in serum is
approximately 20 days, with 4 percent of the total albumin pool being degraded daily.
Clinical significance — Hypoalbuminemia does not always reflect the presence of hepatic
synthetic dysfunction since a variety of other conditions may be responsible including systemic
inflammation, the nephrotic syndrome, and malnutrition. Some general observations can be
made in patients with liver disease who do not appear to have these other disorders:
●Serum albumin concentrations tend to be normal in acute viral hepatitis, drug-related
hepatotoxicity, and obstructive jaundice. The possibility of chronic liver disease should be
considered when the serum albumin concentration is below 3 g/dL (30 g/L) in these
patients.
●Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis. The fall in
albumin concentration usually reflects severe liver damage with reduced albumin
synthesis [7]. An exception may occur in patients with ascites who may become
hypoalbuminemic despite good hepatic synthetic function because of the often marked
increase in plasma volume [8].
The serum albumin concentration should not be measured for screening in patients in whom
there is no suspicion of liver disease. This was illustrated in a study that included 449 patients
seen in a general medical practice in whom serum albumin was measured routinely; 13 percent
had an abnormal value, which was found to be clinically significant in only two patients [9].
Serum albumin levels persistently above the laboratory's reference range are usually observed
in normal people who are at the extreme right of the bell-shaped curve. Acute
hyperalbuminemia is seen most commonly in patients with volume depletion, in whom it is often
associated with hemoconcentration as well. A case report described hyperalbuminemia in a
patient consuming a high-protein diet [10]. Hyperalbuminemia is also theoretically possible in
patients with genetic variants that prolong the half-life of albumin in serum.
Coagulation factors — The liver is the major site of synthesis of 11 blood coagulation proteins.
These include
●Factor I (fibrinogen)
●Factor II (prothrombin)
●Factor V
●Factor VII
●Factor IX
●Factor X
●Factor XII
●Factor XIII
Clotting factor deficiency frequently occurs during the course of liver disease. These proteins
can be measured individually or indirectly by more general measures of clotting ability such as
the prothrombin time.
Clinical significance — A prolonged prothrombin time is not specific for liver disease, since it
can result from various congenital or acquired conditions including consumption of clotting
factors (such as disseminated intravascular coagulation or severe gastrointestinal bleeding) and
certain drugs. When these conditions have been excluded, a prolonged prothrombin time
usually reflects one of two disorders:
●A deficiency of vitamin K, which may be induced by inadequate dietary intake, prolonged
obstructive jaundice, intestinal malabsorption, or the administration of antibiotics that alter
the gut flora. In such cases, the prothrombin time typically returns to normal within 24
hours after a single parenteral injection of vitamin K. This response is particularly helpful
diagnostically when evaluating patients who are jaundiced.
●Poor utilization of vitamin K due to advanced parenchymal liver disease. Vitamin K
supplementation is generally ineffective in this setting.
The prothrombin time does not accurately reflect the coagulation status of patients with cirrhosis
[11] or correlate with the risk of bleeding because of concomitant reductions in the hepatic
synthesis of anti-hemostatic factors [12]. (See "Coagulation abnormalities in patients with liver
disease".)
However, the magnitude of elevation of the prothrombin time above control does correlate with
prognosis in some conditions. As an example, an elevation more than five seconds above
control should raise concern about a fulminant course in patients who have acute viral, toxic, or
alcoholic hepatitis [13,14]. A prothrombin time above 100 sec is considered an indication for
liver transplantation [13]. However, some patients, particularly those who
have acetaminophen overdose, recover despite marked elevations in the prothrombin time. A
progressive decline in the prothrombin time in such patients usually heralds recovery.
(See "Acute liver failure in adults: Etiology, clinical manifestations, and
diagnosis" and"Acetaminophen (paracetamol) poisoning in adults: Pathophysiology,
presentation, and diagnosis" and "Acetaminophen (paracetamol) poisoning in adults:
Treatment".)
International normalized ratio — The international normalized ratio (INR) is often used to
express the degree of anticoagulation in patients receiving warfarin. The INR standardizes
prothrombin time measurement based upon characteristics of the thromboplastin reagent used
in the laboratory. This helps to eliminate variability between measurements in which different
thromboplastin reagents are used and thereby assures a stable level of anticoagulation.
In contrast to its use in patients on warfarin, the INR may not be the best expression of
coagulation derangement in patients with liver failure, especially if the same thromboplastin
reagents are not consistently used for measurement [15,16]. This was illustrated in a study in
which various expressions of the prothrombin time (seconds above control, ratio to control,
activity percentage, and INR) were evaluated in 27 patients with chronic or acute liver failure
compared with controls [15]. Only the activity percentage expression eliminated variability in the
prothrombin time results in individual patients when using different thromboplastin reagents.
This observation implies that, in an individual patient with liver failure, interpretation of changes
in the INR may only be accurate when the same thromboplastin is used. Furthermore,
comparison of the degree of synthetic dysfunction using the INR in patients who underwent
testing at centers using different thromboplastin reagents may not be valid [17,18]. This may be
particularly relevant when prioritizing patients for liver transplantation [18]. (See "Model for End-
stage Liver Disease (MELD)".)
A new standardization method for the INR is needed to make the INR more applicable in
patients with liver disease. At least two such modifications have been proposed, both of which
reduced variability when used for calculation of the MELD score [19,20]. (See "Coagulation
abnormalities in patients with liver disease".)
Des-gamma-carboxy prothrombin — The synthesis of factors II, VII, IX, and X requires
vitamin K for the addition of carboxylic acid moieties to the gamma position of glutamic acid
residues in these proteins [21]. (See "Vitamin K and the synthesis and function of gamma
carboxyglutamic acid".) Gamma carboxylation permits these proteins to bind calcium, which is
necessary for them to function normally. An abnormal prothrombin form (des-gamma-carboxy
prothrombin) is released in the absence of vitamin K, in the presence of vitamin K antagonists
such as warfarin, and by certain tumors, such as hepatocellular carcinoma (HCC). Des-gamma-
carboxy prothrombin is produced by the malignant hepatocyte which appears to acquire a
posttranslational defect in the vitamin K-dependent carboxylase system [22]. The serum
concentration of des-gamma-carboxy prothrombin has been evaluated for screening patients at
risk for hepatocellular carcinoma but appears to have lower sensitivity than alpha fetoprotein
(AFP) for tumors <3 cm. (See "Clinical features and diagnosis of primary hepatocellular
carcinoma".)
SUMMARY AND RECOMMENDATIONS
●The most commonly performed tests to assess the biosynthetic capacity of the liver are
the serum albumin and the prothrombin time (which is based upon the presence of clotting
factors produced in the liver). Other tests which have been used are the serum
concentrations of lipoproteins, ceruloplasmin, ferritin, and alpha 1-antitrypsin.
●The liver is the major site where serum proteins are synthesized. These include albumin
and the coagulation factors. The clinical significance of low and high values is described
above. (See 'Serum proteins' above.)
●In contrast to its use in patients on warfarin, the international normalized ratio (INR) may
not be the best expression of coagulation derangement in patients with liver failure.
(See"Coagulation abnormalities in patients with liver disease" and 'International
normalized ratio' above.)