Liver function tests that detect injury to hepatocytes

Author
Marshall M Kaplan, MD
Section Editor
Sanjiv Chopra, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Aug 31 00:00:00 GMT
2010 (More)
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 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"Treatment of autoimmune hepatitis".)

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 ChildPugh 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 serum total bilirubin and alkaline phosphatase indicates
cholestasis. Recognition of patterns that are consistent with specific diseases can prompt appropriate additional testing.
The liver function tests that used in 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.

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, andlidocaine 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 natural history
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 IU/L (0.5001 to 0.6668 kat/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. (See "Approach to the
patient with abnormal liver function tests", section on 'Epidemiology'.) Consumption of coffee and especially caffeine may lower
serum ALT levels by mechanisms that are incompletely understood [4].
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 [5,6]. AST is found, in decreasing order of concentration, in
the liver, cardiac muscle, skeletal muscle, kidneys, brain, the 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 [6]. The cytosolic and mitochondrial forms of AST are immunologically distinct isoenzymes, which can
be distinguished by several laboratory techniques [7]. Approximately 80 percent of AST activity in human liver is derived from
the mitochondrial isoenzyme [6]. In contrast, most of the circulating AST activity in healthy people is derived from the cytosolic
isoenzyme [5].
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 [8,9]. 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 [8]. However, other serum tests, such as
the MB fraction of creatine kinase and 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, involving catabolism by the reticuloendothelial
system; AST is cleared more rapidly than ALT [10]. The major site of AST clearance is the hepatic sinusoidal cell [11]. 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 [10,12].
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 in the aminotransferase
reactions) [8]. 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 [13]. In contrast, falsely low serum AST (but not ALT) is seen in patients with renal failure [14]. 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 [14]. (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 [15].
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, shock liver (ischemic hepatitis), and acute drugor toxin-induced liver injury (eg, acetaminophen intoxication). The evaluation of the serum aminotransferases in various clinical
settings, including use of the AST/ALT ratio, is discussed in detail separately. (See "Patterns of plasma aspartate and alanine
aminotransferase levels with and without liver disease".)
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 fulminant hepatitis. 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 fulminant hepatitis, 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.
Five isoenzyme forms of LDH are present in serum, which can be separated by various electrophoretic techniques. The slowest
migrating band predominates in the liver [16,17]. 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 [16]. (See "Biomarkers of 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 [18]. In the liver, it is present in highest concentration in centrilobular hepatocytes [19]. Because of this
location, serum glutamate dehydrogenase has been evaluated as a specific marker for liver disorders that primarily affect
centrilobular hepatocytes, such as alcoholic hepatitis [20]. 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
[1,21]. 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 [22]. Its activity in serum parallels that of the serum aminotransferases in acute and chronic hepatitis, but it is
less sensitive [23,24]. Although elevations in serum isocitrate dehydrogenase are relatively specific for liver disorders,
increased concentrations have been reported in disseminated malignancy without detectable hepatic involvement [25].
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 [22]. 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 [22].
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 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, shock liver (ischemic hepatitis), and
acute drug- or toxin-induced liver injury (eg, acetaminophen intoxication). (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.)
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REFERENCES

1.

2.

Ellis G, Goldberg DM, Spooner RJ, Ward AM. Serum enzyme tests in diseases of the liver and biliary tree. Am J Clin
Pathol 1978; 70:248.
WROBLEWSKI F. The clinical significance of transaminase activities of serum. Am J Med 1959; 27:911.

3.

ZIMMERMAN HJ, WEST M. SERUM ENZYME LEVELS IN THE DIAGNOSIS OF HEPATIC DISEASE. Am J Gastroenterol
1963; 40:387.

4.

Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase
activity in the United States. Gastroenterology 2005; 128:24.

5.

Boyde, TR, Latner, AL. Starch gel electrophoresis of transaminase in human tissue extracts and serum. Biochem J
1961; 82:52.

6.

Rej R. Aspartate aminotransferase activity and isoenzyme proportions in human liver tissues. Clin Chem 1978;
24:1971.

7.

MORINO Y, KAGAMIYAMA H, WADA H. IMMUNOCHEMICAL DISTINCTION BETWEEN GLUTAMIC-OXALOACETIC

TRANSAMINASES FROM THE SOLUBLE AND MITOCHONDRIAL FRACTIONS OF MAMMALIAN TISSUES. J Biol Chem 1964;
239:943.

8.

Rej, R. Measurement of aminotransferase. I. Aspartate aminotransferase. CRC Crit Rev Clin Lab Sci 1985; 21:99.

9.

Nalpas B, Vassault A, Charpin S, et al. Serum mitochondrial aspartate aminotransferase as a marker of chronic
alcoholism: diagnostic value and interpretation in a liver unit. Hepatology 1986; 6:608.

10.

DUNN M, MARTINS J, REISSMANN KR. The disappearance rate of glutamic oxalacetic transaminase from the
circulation and its distribution in the body's fluid compartments and secretions. J Lab Clin Med 1958; 51:259.

11.

Kamimoto Y, Horiuchi S, Tanase S, Morino Y. Plasma clearance of intravenously injected aspartate aminotransferase
isozymes: evidence for preferential uptake by sinusoidal liver cells. Hepatology 1985; 5:367.

12.

FRANKL HD, MERRITT JH. Enzyme activity in the serum and common duct bile of dogs. Am J Gastroenterol 1959;
31:166.

13.

Sabath LD, Gerstein DA, Finland M. Serum glutamic oxalacetic transaminase. False elevations during administration
of erythromycin. N Engl J Med 1968; 279:1137.

14.

Cohen GA, Goffinet JA, Donabedian RK, Conn HO. Observations on decreased serum glutamic oxalacetic
transaminase (SGOT) activity in azotemic patients. Ann Intern Med 1976; 84:275.

15.

Vadstrup S. Subnormal alanine aminotransferase values in blood of patients with Crohn disease. Scand J
Gastroenterol 2004; 39:554.

16.

Marshall T, Williams J, Williams KM. Electrophoresis of serum isoenzymes and proteins following acute myocardial
infarction. J Chromatogr 1991; 569:323.

17.

Smit MJ, Duursma AM, Bouma JM, Gruber M. Receptor-mediated endocytosis of lactate dehydrogenase M4 by liver
macrophages: a mechanism for elimination of enzymes from plasma. Evidence for competition by creatine kinase MM,
adenylate kinase, malate, and alcohol dehydrogenase. J Biol Chem 1987; 262:13020.

18.

SCHMIDT E, SCHMIDT FW. [Methods and value of determination of glutamic acid dehydrogenase activity in the
serum. A contribution to the importance of examination of enzyme relations in the serum]. Klin Wochenschr 1962; 40:962.

19.

Guder WG, Habicht A, Kleissl J, et al. The diagnostic significance of liver cell inhomogeneity: serum enzymes in
patients with central liver necrosis and the distribution of glutamate dehydrogenase in normal human liver. Z Klin Chem Klin
Biochem 1975; 13:311.

20.

Van Waes L, Lieber CS. Glutamate dehydrogenase: a reliable marker of liver cell necrosis in the alcoholic. Br Med J
1977; 2:1508.

21.

Kaplan, MM, et, al. Biochemical basis for serum enzyme abnormalities in alcoholic liver disease. In: Early
identification of alcohol abuse, Research Monograph No. 17, Chang, NC, Chan, NM (Eds), NIAAA, 1985. p.186.

22.

Rosalki, SB. Enzyme tests in disease of the liver and hepatobiliary tract. In: The principles and practice of diagnostic
enzymology, Wilkinson JH (Ed), Edward Arnold, London 1973. p.303.

23.

BELL JL, SHALDON S, BARON DN. Serum isocitrate dehydrogenase in liver disease and some other conditions. Clin
Sci 1962; 23:57.

24.

STERKEL RL, SPENCER JA, WOLFSON SK Jr, WILLIAMS-ASHMAN HG. Serum isocitric dehydrogenase activity with
particular reference to liver disease. J Lab Clin Med 1958; 52:176.

25.

WEST M, SCHWARTZ MA, COHEN J, ZIMMERMAN HJ. SERUM ENZYMES IN DISEASE. XV. GLYCOLYTIC AND
OXIDATIVE ENZYMES AND TRANSAMINASES IN PATIENTS WITH CARCINOMA OF THE K
Approach to the patient with abnormal liver function tests
Author
Marshall M Kaplan, MD

Section Editor
Sanjiv Chopra, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu Feb 03 00:00:00 GMT
2011 (More)
INTRODUCTION This topic review will provide an overview on the evaluation of patients with abnormal liver biochemical
tests. Detailed discussions on the individual tests and patterns of abnormalities are presented separately. (Search on "Liver
function tests" in the main search menu or search on the individual disease). The American Gastroenterological Association
(AGA) guideline for the evaluation of liver chemistry tests [1], as well as other AGA guidelines, can be accessed through the
AGA web site at file://www.gastro.org/practice/medical-position-statements.
DEFINITIONS Although the term "liver function tests" (LFTs) is commonly used, 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 function tests
may be abnormal even in patients with a healthy liver.
The most common laboratory measures classified as LFTs include the enzyme tests (principally the serum aminotransferases,
alkaline phosphatase, and gamma glutamyl transpeptidase), tests of synthetic function (principally the serum albumin
concentration and prothrombin time), and the serum bilirubin, which measures the liver's ability to detoxify metabolites and
transport organic anions into bile.
The term "liver function tests" will be used to denote these tests throughout this discussion unless particular tests are
specified. There are two aminotransferases: alanine aminotransferase (ALT, formerly called SGPT), and aspartate
aminotransferase (AST, formerly called SGOT).
EPIDEMIOLOGY Abnormal LFTs are frequently detected in asymptomatic patients since many screening test panels now
routinely include them [2]. A population-based survey in the United States conducted between 1999 and 2002 estimated that
an abnormal ALT was present in 8.9 percent of respondents (representing a significant increase compared with results of a
similar survey from a decade earlier) [3]. This may be related to the increase in obesity that has also occurred during this
same time period. The serum ALT correlates with body mass index (BMI) and waist circumference, and the BMI of Americans
has increased significantly [4-6].
Studies evaluating the clinical significance of these abnormalities have produced variable findings, although most have
demonstrated that serious underlying liver disease is uncommon. The differences among individual studies reflect variation in
the prevalence of liver disease in the populations that have been studied and the degree to which an underlying cause of the
abnormalities was sought. Advances in the noninvasive tests to identify the cause of liver disease have permitted a greater
understanding of the spectrum of liver disease encountered in various patient populations.
The following examples illustrate some of the findings:

Abnormal serum aminotransferase levels (ALT >2.25 SD above normal; >55 IU/L) were detected in 99 of 19,877
(0.5 percent) Air Force recruits beginning basic training [7]. Of these, a cause was found in only 12 (including
chronic hepatitis B and C, autoimmune hepatitis, and cholelithiasis). No specific diagnosis was established in the
remaining 87 patients.

The diagnoses observed in two studies that included a total of 249 blood donors with abnormal serum ALT values
included [8,9]: alcoholic liver disease (11 to 48 percent); fatty liver (22 to 56 percent); hepatitis C (17 to 20
percent); miscellaneous causes (4 to 8 percent); and no specific diagnosis (2 to 9 percent).

Another study focused on 81 of 1124 patients who were referred for abnormal serum aminotransferase levels in
whom a diagnosis could not be inferred noninvasively [10]. A liver biopsy revealed steatosis or steatohepatitis in the
majority of patients (84 percent); six patients had fibrosis or cirrhosis, and eight had normal histologic findings.

A fourth study included 354 patients who underwent a liver biopsy to investigate abnormal LFTs (defined as an ALT,
gamma glutamyl transferase, or alkaline phosphatase more than twice the upper limit of normal for at least six
months) [11]. Patients with clinical or serologic features suggesting a specific diagnosis were excluded. The most
frequent finding on liver biopsy was nonalcoholic steatohepatitis or fatty liver (66 percent). The authors considered
information on the biopsy to be important for directing management in 18 percent of patients. In addition, three
families were entered into screening programs for inheritable liver disease.

A population-based study from the United States evaluated the impact of an elevated gamma glutamyl
transpeptidase (GGT) and ALT on overall mortality [12]. An elevated GGT was associated with a modestly increased
mortality from all causes (Hazard Ratio (HR), 1.5; 95% CI, 1.2-1.8), liver disease, cancer, and diabetes, while an
elevated ALT was associated only with an increase in liver-related mortality (HR, 8.2; 95% CI, 2.1-31.9). These
observations should not alter the approach to patients with abnormal liver biochemical tests described in this topic
review.

Several conclusions can be derived from the above observations. First, a diagnosis can be established noninvasively in the vast
majority of patients with abnormal LFTs. Second, appropriate testing can be guided by the pretest probability of specific forms
of liver disease. Third, 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. Finally, on a population-level, abnormal liver biochemical
tests may be a marker for worse health outcomes.
It is important to emphasize that false positive results are more likely in patients who have a low pretest probability of having
liver disease. This is a particular concern when abnormal LFTs are detected as part of a panel of laboratory tests drawn for
other reasons. Normal test reference values are usually arbitrarily defined as those occurring within two standard deviations
from the mean. As a result, 5 percent of healthy individuals who have a single screening test will have an abnormal result (2.5
percent will have an abnormally high result). As more tests are ordered, the likelihood of a false positive test increases; a
screening panel containing 20 independent tests in a patient with no disease will yield at least one abnormal result 64 percent
of the time (table 1).
In addition, individual patients can have baseline fluctuation in aminotransferases. In a large, cross-sectional population-based
study, more than 30 percent of adults with abnormal LFTS were reclassified as being normal upon retesting [13]. The study did
not examine whether these patients had underlying liver disease but supports confirming abnormal test results.
The sensitivity and specificity of the serum aminotransferases (particularly serum ALT) for discriminating those with and
without liver disease depends upon the cutoff values chosen to define an abnormal test. ALT levels correlate with the degree of
trunk fat [14], 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 with 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 numbers of patients who would require evaluation for an uncertain clinical benefit [15].
Another consideration is that there is wide variability on what is considered to be the upper limit of normal for ALT across
different laboratories [16]. This is likely due to the references used for different chemical analyzers. Thus, comparing values
across different labs may not be straightforward. In addition, cutoff levels for recognition of liver disease differ based on the
reference used at the specific laboratory.
HISTORY A complete medical history is the single most important part of the evaluation of the patient with elevated LFTs.
Important considerations include:

The use of or exposure to any chemical or medication (including prescription and over-the-counter medications as
well as herbal therapies) which may be temporally related to the onset of LFT abnormalities

The duration of LFT abnormalities

The presence of any accompanying symptoms such as jaundice, arthralgias, myalgias, rash, anorexia, weight loss,
abdominal pain, fever, pruritus, and changes in the urine and stool

While none of the latter symptoms are specific for any one condition, they may suggest a particular diagnosis and help guide
further testing. A history of arthralgias and myalgias predating jaundice, for example, suggests viral or drug-related hepatitis,
while jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests
choledocholithiasis and ascending cholangitis.
The patient should also be carefully questioned about possible parenteral exposures including transfusions, intravenous and
intranasal drug use, tattoos, and sexual activity. Other important questions include recent travel history, exposure to people
with jaundice, exposure to possibly contaminated foods, occupational exposure to hepatotoxins, and alcohol consumption.
PHYSICAL EXAMINATION The physical examination should focus upon findings suggesting the presence of liver disease.
Specific findings may provide clues toward diagnosis of an underlying cause.

Temporal and proximal muscle wasting suggest longstanding diseases

Stigmata of chronic liver disease include spider nevi, palmar erythema, gynecomastia, caput medusae

Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced
Laennec's 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

Jugular venous distension, 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

The abdominal examination should focus on the size and consistency of the liver, the size of the spleen (a palpable spleen is
enlarged), and should include an assessment for ascites (usually by determining whether there is a fluid wave or shifting
dullness). 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 viral or alcoholic hepatitis
or, less often, an acutely congested liver secondary to right-sided heart failure [17]. Severe right upper quadrant tenderness
with respiratory arrest on inspiration (Murphy's sign) suggests cholecystitis or, occasionally, ascending cholangitis. Ascites in
the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.
LABORATORY TESTING A critical step in guiding the evaluation is determining the overall pattern of the abnormal LFTs,
which can be broadly divided into two categories:

Patterns predominantly reflecting hepatocellular injury

Patterns predominantly reflecting cholestasis

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. (See "Liver function tests that detect injury to hepatocytes".)
The serum albumin and a prothrombin time should be obtained to assess liver function. 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. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and
malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with
parenteral administration of vitamin K indicates severe hepatocellular injury. (See "Tests of the liver's biosynthetic capacity (eg,
albumin, coagulation factors, prothrombin time)".)
The presence of bilirubin in the urine reflects direct hyperbilirubinemia and therefore underlying hepatobiliary disease. In
contrast to conjugated bilirubin, unconjugated bilirubin is tightly bound to albumin; as a result, it is not filtered by the
glomerulus and present in the urine unless there is underlying renal disease.
Conjugated bilirubin may be found in the urine when the total serum bilirubin concentration is normal because the renal
reabsorptive capacity for conjugated bilirubin is low and the methods used can detect urinary bilirubin concentrations as low as
0.05 mg/dL (0.9 mmol/L). Thus, bilirubinuria may be an early sign of liver disease. (See "Clinical aspects of serum bilirubin
determination".)
COMMON PATTERNS OF LFT ABNORMALITIES Consensus on the cost-effective approach to the evaluation of patients
with abnormal LFTs has not been established. Thus, the decision to pursue specific testing should be guided by the pretest
probability of the underlying liver disease, the pattern of abnormalities, and suggestive features obtained from the history and
physical examination. The following sections will provide recommendations for the initial evaluation of patients with common
patterns of LFT abnormalities. The recommendations are based upon the epidemiology and clinical features of the various
disorders, the accuracy of diagnostic testing, and clinical experience.
MILD CHRONIC ELEVATION IN SERUM AMINOTRANSFERASES The laboratory evaluation of patients with chronic
(defined as six months or greater), mild elevation (defined approximately as less than four times the upper limit of normal) of
one or both of the aminotransferases is best achieved in a stepwise fashion to eliminate unnecessary testing. On the other
hand, it is sometimes convenient for patients (particularly in the referral setting) if several blood tests are obtained
simultaneously since they can be processed on the same sample, thereby eliminating a return visit for additional testing.
Furthermore, the order of the testing may change if the history and physical examination raise the pretest probability of a
particular diagnosis. Thus, the steps outlined below are meant to be general guidelines (table 2).
The approach to patients with marked elevations in serum aminotransferases is discussed separately. (See "Patterns of plasma
aspartate and alanine aminotransferase levels with and without liver disease".)
Step one The first step should be to identify medications and supplements that can cause elevation of the serum
aminotransferases, to assess for alcohol use, and to test for viral hepatitis B and C, hemochromatosis, and fatty liver.
Medications Almost any medication can cause an elevation of liver enzymes. Common causes include nonsteroidal antiinflammatory drugs, antibiotics, statins, antiepileptic drugs, and antituberculous drugs. In addition, herbal preparations and
illicit drug use may also be the cause. (See "Drugs and the liver: Patterns of drug-induced liver injury" and "Hepatotoxicity due
to herbal medications and dietary supplements".)
Questioning should also include nonprescription medications; acetaminophen, for example, can cause aminotransferase
elevation among healthy adults even when taken in recommended doses. In a study of healthy volunteers taking
acetaminophen (4 g daily for 14 days), about 20 percent experienced an ALT elevation more than five times the upper limit of
normal (compared with 3 percent taking placebo) [18]. An increase from 1 to 2 times the upper limit of normal was observed
in 50 to 70 percent of patients. Elevation was not observed before three days of administration.
A careful history and review of laboratory data are critical for identifying a medication as the cause of elevated serum
aminotransferases. However, the diagnosis of drug-induced liver injury can be difficult. The relationship to drug ingestion and
toxicity is not always clear; patients may be taking multiple medications, making identification of the offending agent difficult,

and the development of abnormal LFTs can occasionally be delayed, obscuring its relationship to hepatotoxicity. In addition,
patients may have concomitant diseases (such as alcoholism), which can produce similar clinical and laboratory abnormalities.
Features suggesting 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.
If the identified medication is essential to the patient's well-being and no suitable substitute is available, the clinician needs to
make a risk-benefit analysis to determine if a drug should be continued despite the aminotransferase elevation. A liver biopsy
is occasionally necessary to determine the nature and severity of liver injury.
Alcohol abuse The diagnosis of alcohol abuse can be difficult because many patients conceal this information. Several short
questionnaires are of assistance in detecting occult alcohol abuse. (See "Screening for alcohol misuse".) In addition, the
diagnosis is supported by an AST to ALT ratio of 2:1 or greater. In a study of hundreds of patients who had liver biopsy
confirmed liver disorders, more than 90 percent of the patients whose AST to ALT ratio was two or greater had alcoholic liver
disease [19]. The percentage increased to greater than 96 percent when the ratio was greater than three. However,
subsequent studies have revealed that the AST/ALT ratio may also be occasionally elevated in an alcoholic pattern in patients
with nonalcoholic steatohepatitis, and is frequently elevated in an alcoholic pattern in patients with hepatitis C who have
developed cirrhosis. (See "Patterns of plasma aspartate and alanine aminotransferase levels with and without liver disease".)
Several other patterns of laboratory abnormalities may also be supportive of the diagnosis of alcohol abuse:

A twofold elevation of the gamma glutamyltransferase (GGT) in patients whose AST to ALT ratio is greater than 2:1
strongly suggests alcohol abuse. However, an elevated GGT by itself is insufficiently specific to establish the
diagnosis [20]. (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5-nucleotidase, gammaglutamyl transpeptidase)".)

It is rare for the AST to be greater than eightfold elevated and even less common for the ALT to be greater than
fivefold elevated. The ALT may even be normal even in patients with severe alcoholic liver disease.

Hepatitis B The pretest probability for hepatitis B is increased in patients with a history of parenteral exposures and in
patients from parts of the world where a high disease prevalence exists (eg, in Southeast Asia, China, and sub-Saharan Africa).
(See "Epidemiology, transmission, and prevention of hepatitis B virus infection" and "Epidemiology and transmission of
hepatitis C virus infection".)
The proper initial testing for patients suspected of having chronic hepatitis B includes:

Hepatitis B surface antigen (HBsAg)

Hepatitis B surface antibody (HBsAb)

Hepatitis B core antibody (HBcAb)

Patients who are surface antigen and core antibody positive are chronically infected and additional testing (hepatitis B "e"
antigen and "e" antibody and a hepatitis B DNA [HBV DNA]) is indicated. A positive HBsAb and HBcAb indicates immunity to
hepatitis B and another cause of aminotransferase elevation should be sought. The presence of a positive HBV DNA in the
presence or absence of the "e" antigen indicates viral replication. A positive HBV DNA and a negative "e" antigen indicates that
the patient has a precore mutant of hepatitis B. Both of these situations warrant further evaluation with a liver biopsy and
possible treatment. A positive hepatitis B surface antigen with a negative HBV DNA and a negative "e" antigen suggests that
the patient is a carrier of hepatitis B and in a non-replicative state. The presence of a carrier state does not explain elevated
aminotransferases, and another cause needs to be sought. (See "Serologic diagnosis of hepatitis B virus infection".)
Hepatitis C Chronic hepatitis C is very common in the United States and other parts of the world. The risk is highest in
individuals with a history of parenteral exposure (blood transfusions, intravenous drug use, occupational), cocaine use, tattoos,
body piercing, and high risk sexual behavior. (See"Epidemiology and transmission of hepatitis C virus infection".)
The actual sequence of diagnostic testing in an individual patient depends upon the clinical setting. Initial evaluation typically
begins with an antibody test. Subsequent testing depends upon the clinical setting. (See "Screening for and diagnostic
approach to hepatitis C virus infection", section on 'Summary and recommendations'.)
Hereditary hemochromatosis Hereditary hemochromatosis (HHC) is a common genetic disorder. Population screening has
shown that the frequency of heterozygotes is about 10 percent in Caucasian populations in the United States and western
Europe, with a frequency of about 5 per 1000 (0.5 percent) for the homozygous state. (See "Clinical manifestations of
hereditary hemochromatosis".)
Screening should begin with a fasting serum iron and total iron binding capacity (TIBC), which permits the calculation of the
iron or transferrin saturation (serum iron/TIBC). An iron saturation of 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 iron saturation. A serum ferritin concentration of greater than 400 ng/mL in men and 300 ng/mL in women further
supports the diagnosis of HHC. (See "Pathophysiology and diagnosis of iron overload syndromes".)

A liver biopsy should be performed if screening tests suggest iron overload to quantify hepatic iron and to assess the severity
of liver injury, and genetic testing should be done. A hepatic iron index (hepatic iron concentration in micromoles per gram dry
weight divided by the patient's age) greater than 1.9 is consistent with homozygous HHC. (See "Hepatic iron concentration and
hepatic iron index in the diagnosis of iron overload and hereditary hemochromatosis".) A liver biopsy is not necessary for
patients less than 40 years of age with genotypically defined hemochromatosis (C282Y homozygous) with normal liver function
tests.
Genetic testing has not replaced liver biopsy in the diagnosis of HHC. Not every patient who is homozygous for the HFE
mutation has iron overload and not every patient with HHC has the identified HFE mutation. Thus, the biopsy may still be
required to identify iron overload in some patients and is critical to determine the amount of fibrosis. Patients with HHC and
cirrhosis continue to have a high risk of developing hepatocellular carcinoma even with depletion of body iron stores. These
patients need to be identified and screened appropriately. (See "Clinical features and diagnosis of primary hepatocellular
carcinoma".)
Hepatic steatosis and steatohepatitis Hepatic steatosis and an associated condition, non-alcoholic steatohepatitis
(NASH), may present solely with mild elevations of the serum aminotransferases, which are usually less than fourfold elevated.
NASH is a condition more common in women and associated with obesity and type 2 diabetes mellitus. (See "Epidemiology,
clinical features, and diagnosis of nonalcoholic steatohepatitis".) In contrast to alcohol related liver disease, the ratio of AST to
ALT is usually less than one.
The initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging including ultrasound,
computed tomographic imaging, or magnetic resonance imaging. Ultrasonography has a lower sensitivity than CT or MRI
scanning, but is less expensive. Thus, in a patient in whom there is a high pretest probability of steatosis and tests for hepatitis
B, C, and HHC are unremarkable, the least expensive test to look for steatosis is ultrasonography. However, radiologic imaging
cannot identify inflammation. Thus, the differentiation between steatosis and NASH requires a liver biopsy. Nevertheless,
because of the absence of effective medical therapy for NASH, we do not advocate a liver biopsy unless one of the following is
present:

Peripheral stigmata of chronic liver disease

Splenomegaly

Cytopenia

Abnormal iron studies

Diabetes and/or significant obesity in an individual over the age of 45

Step two The next set of tests should look for non-hepatic causes of elevated aminotransferases, which include principally
muscle disorders and thyroid disease. Much less common causes are occult celiac disease and adrenal insufficiency.
Muscle disorders Elevated serum aminotransferases may be caused by disorders that affect organs other than the liver,
most commonly striated muscle. Serum AST and ALT may both be elevated with muscle injury. Their ratio depends in part
upon when they are assessed relative to the muscle injury [21]. Immediately after muscle injury, the AST/ALT ratio is generally
greater than three, but approaches one within a few days because of a faster decline in the serum AST. Peak AST and ALT
levels are variable. In one series, peak AST levels range from as low as 235 IU to as high as 10,000 IU while peak ALT ratios
range from as low as 115 IU/L to as high as 850 IU/L [21].
Conditions that can cause this include subclinical inborn errors of muscle metabolism, acquired muscle disorders (such as
polymyositis), seizures, and heavy exercise (such as long distance running). If striated muscle is the source of increased
aminotransferases, serum levels of creatine kinase, LDH, and aldolase will be elevated at least to the same degree. The
creatine kinase or aldolase levels should be determined if other more common hepatic conditions have been ruled out (table
2).
Thyroid disorders Thyroid disorders can produce elevated aminotransferases by unclear mechanisms [22,23]. An assay for
thyroid stimulating hormone (TSH) is a reasonable screening test for hypothyroidism while a full set of thyroid function tests
should be checked if hyperthyroidism is suspected. (See "Diagnosis of and screening for hypothyroidism" and "Diagnosis of
hyperthyroidism".)
Celiac disease Several reports have described elevated serum aminotransferases in patients with undiagnosed celiac
disease [24]. The cause is uncertain. In one report, the serum AST ranged from 29 to 80, and the serum ALT ranged from 60
to 130 with the ALT usually slightly greater than AST [25]. Serum aminotransferases returned to normal in all but one patient
one year following a gluten free diet. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults",
section on 'Liver disease'.)
The diagnosis of celiac disease is suggested by appropriate antibody screening with serum antiendomysial IgA or anti tissue
transglutaminase IgA antibodies (algorithm 1). (See "Diagnosis of celiac disease".)
Adrenal insufficiency Aminotransferase elevation (1.5 to 3 times the upper limit of normal) has been described in patients
with adrenal insufficiency (due to Addison's disease or secondary causes), including those without obvious clinical features of

the disorder [26-28]. Aminotransferases normalize within one week following appropriate treatment. (See "Diagnosis of
adrenal insufficiency in adults".)
Anorexia nervosa Anorexia nervosa has been associated with aminotransferase elevation by mechanisms that are not well
understood. In a series of 214 women, 12 percent had aminotransferase elevation [29]. In another series, elevated serum
aminotransferases were associated with lower body temperature and pulse rate and a lower BMI [30]. Profound serum
aminotransferase elevation associated with liver dysfunction has been described in case reports [31-34]. (See "Anorexia
nervosa in adults and adolescents: Medical complications and their management".)
Step three The next set of tests is aimed at identifying rarer liver conditions.
Autoimmune hepatitis Autoimmune hepatitis (AIH) is a condition found primarily in young to middle-aged women. The
diagnosis is based upon the presence of elevated serum aminotransferases, the absence of other causes of chronic hepatitis,
and features (serological and pathological) suggestive of AIH. (See "Clinical manifestations and diagnosis of autoimmune
hepatitis".)
A useful screening test for AIH is the serum protein electrophoresis (SPEP). More than 80 percent of patients with autoimmune
hepatitis will have hypergammaglobulinemia. A greater than twofold polyclonal elevation of the immunoglobulins supports the
diagnosis. Additional tests commonly ordered include antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), and
liver-kidney microsomal antibodies (LKMA). ANA and SMA have reported sensitivities of 28 and 40 percent, respectively. LKMA
positive autoimmune hepatitis is rare in the United States, Australia, and Japan. (See"Measurement and clinical significance of
antinuclear antibodies".)
A reasonable approach to diagnosing autoimmune hepatitis is to start with an SPEP. An ANA and SMA should be obtained in
patients who have a polyclonal increase in gamma globulin. Elevated gamma globulins and high titer autoantibodies should
prompt a liver biopsy to confirm the diagnosis of AIH. Patients (especially young women) with negative viral serologies and
persistently elevated aminotransferases greater than 100 u/L should undergo liver biopsy even in the absence of elevated
gamma globulins and autoantibodies. If the biopsy is consistent with chronic active hepatitis, patients should receive a trial of
corticosteroids since approximately 20 percent of patients with steroid responsive hepatitis will not have a positive ANA or SMA
at the time of presentation [35].
Wilson disease Wilson disease, a genetic disorder of biliary copper excretion, may cause elevated aminotransferases in
asymptomatic patients. While the prevalence of Wilson disease is very low, it is a treatable liver disease and needs to be
identified. (See "Diagnosis of Wilson disease".)
Patients usually present between ages 5 to 25, but the diagnosis should be considered in patients up to the age of 40.
However, the range of ages in cases reports spans from age 3 to 80. The initial screening test for Wilson disease is a serum
ceruloplasmin, which will be reduced in approximately 85 percent of patients. Patients should also be examined by an
ophthalmologist for Kayser-Fleischer rings. If the ceruloplasmin is normal and Kayser-Fleischer rings are absent, but there is
still a suspicion of Wilson disease, the next test is a 24-hour urine collection for quantitative copper excretion. A value of
greater than 100 mcg/day is suggestive of the diagnosis. (See "Patient information: Collection of a 24-hour urine specimen".)
The diagnosis is usually confirmed by a liver biopsy for quantitative copper. Patients with Wilson disease have liver copper
levels of greater than 250 mcg/gm of dry weight. While the gene responsible for Wilson disease has been identified, the
number of disease specific mutations is so great that molecular diagnosis is not yet feasible except in family members of a
proband with a known mutation.
Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin deficiency is an uncommon cause of chronic liver disease in adults.
Decreased levels of alpha-1 antitrypsin can be detected either by direct measurement of serum concentrations or by the
absence of the alpha-1 peak on a serum protein electrophoresis. However, serum concentrations of alpha-1 antitrypsin can be
increased in response to inflammation resulting in a falsely negative test. As a result, obtaining an alpha-1 antitrypsin
phenotype is probably the most cost-effective test. In adults, alpha-1 antitrypsin deficiency should be suspected in patients
who have a history of emphysema either at a young age or out of proportion to their smoking history. (See "Extrapulmonary
manifestations of alpha-1 antitrypsin deficiency".)
Adult bile ductopenia Adult bile ductopenia is a rare inherited condition that presents with elevated aminotransferases. In
mild forms, patients are asymptomatic, while in more serious forms, patients have pruritus and elevations of plasma alkaline
phosphatase. The diagnosis is based upon liver biopsy findings. In the healthy liver, there are approximately 1.5 to 2 bile ducts
cut in cross section per portal triad. In adult bile ductopenia, there are typically fewer than 1.2. (See "Hepatic ductopenia and
vanishing bile duct syndrome".)
Some patients respond to ursodeoxycholic acid (12 to 15 mg/kg body weight per day). Such patients have normalization of the
plasma aminotransferases and generally do not progress to cirrhosis. By contrast, in the severe form, the disease progresses
despite treatment, and patients may eventually require liver transplantation.
Step four A liver biopsy is often considered in patients in whom all of the above testing has been unyielding. However, in
some settings, the best course may be observation.
Whom to observe We recommend observation only in patients in whom the ALT and AST are less than twofold elevated
and no chronic liver condition has been identified by the above noninvasive testing. 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
[36]. Another study included 36 patients with a chronic elevation of the serum ALT, AST, or alkaline phosphatase (50 percent or
greater above normal) [37]. Patients with a strong suspicion for a particular liver disease were excluded. The remainder
underwent a liver biopsy, which changed the diagnosis in only 5 patients and influenced treatment in 12 patients, 10 of whom

were offered investigational therapy. The authors concluded that the biopsy results only infrequently clarified the presumptive
diagnosis and that no proven therapy exists for many such patients.
Whom to biopsy We recommend a liver biopsy in patients in whom the ALT and AST are persistently greater than twofold
elevated. 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.
ISOLATED HYPERBILIRUBINEMIA Isolated hyperbilirubinemia occurs principally in two settings (see "Bilirubin
metabolism"):

Overproduction of bilirubin

Impaired uptake, conjugation, or excretion of bilirubin

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 or unconjugated. An increase in unconjugated bilirubin in serum
results from either overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in conjugated
bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment. (See "Clinical aspects of
serum bilirubin determination" and "Diagnostic approach to the patient with jaundice or asymptomatic hyperbilirubinemia".)
Unconjugated hyperbilirubinemia Indirect hyperbilirubinemia may be observed in a number of disorders (table 3). 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).
Hemolysis Hemolysis can usually be detected by obtaining a reticulocyte count, haptoglobin, and examining the peripheral
smear. Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders
include spherocytosis, sickle cell anemia, 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. Higher levels may occur when there is
coexistent renal or hepatocellular dysfunction or in acute hemolysis such as a sickle cell crisis. (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) which diminish
hepatic uptake of bilirubin, or Gilbert's syndrome (a common genetic disorder associated with unconjugated
hyperbilirubinemia). Much less commonly, indirect hyperbilirubinemia can be caused by two other genetic disorders: CriglerNajjar syndrome, types I and II.

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. Impaired conjugation of bilirubin is due to reduced bilirubin UDP glucuronosyl
transferase activity. Affected patients have mild unconjugated hyperbilirubinemia with serum levels almost always
less than 6 mg/dL. 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's
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) 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. Bilirubin
UDP glucuronosyl transferase activity is typically present but greatly reduced. Bilirubin UDP glucuronosyl transferase
activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these
patients. (See "Crigler-Najjar syndrome".)

Conjugated hyperbilirubinemia Elevated conjugated hyperbilirubinemia is found in two rare inherited conditions: DubinJohnson syndrome and Rotor syndrome. (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 DubinJohnson syndrome is altered excretion of bilirubin into the bile ducts, while Rotor syndrome appears to be due to defective
hepatic storage of bilirubin.
Dubin-Johnson 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 function tests. Normal levels of
serum alkaline phosphatase and gamma-glutamyltranspeptidase 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.
ISOLATED ELEVATION OF THE ALKALINE PHOSPHATASE AND/OR GAMMA GLUTAMYL TRANSPEPTIDASE Serum
alkaline phosphatase is derived predominantly from the liver and bones, although other sources may contribute to serum levels

in some settings. Women in the third trimester of pregnancy, for example, have elevated serum alkaline phosphatase due to an
influx into blood of placental alkaline phosphatase. Individuals with blood types O and B can have elevated serum alkaline
phosphatase 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. 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)" 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 physiological 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 gradually increases from age 40 to 65, particularly in women. The normal alkaline phosphatase for an
otherwise healthy 65-year-old woman is more than 50 percent higher than a healthy 30-year-old woman.
Determining the source of the alkaline phosphatase The first step in the evaluation of an elevated alkaline
phosphatase is to identify its source. Although electrophoretic separation on either polyacrylamide gel or Sepharose is the most
sensitive and specific way to do this, these tests are not widely available. If gel electrophoresis is not available, either a 5'nucleotidase or GGT 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 5'-nucleotidase or
GGT should prompt an evaluation for bone diseases. (algorithm 2). (See "Enzymatic measures of cholestasis (eg, alkaline
phosphatase, 5-nucleotidase, gamma-glutamyl transpeptidase)", section on 'Clinical significance'.)
Initial testing for alkaline phosphatase of hepatic origin Chronic cholestatic or infiltrative liver diseases should be
considered in patients in whom the alkaline phosphatase is determined to be of liver origin and persists over time. The most
common causes include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile
ductopenia, and certain drugs such as androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other
granulomatous diseases, and less often unsuspected cancer metastatic to the liver.
Initial testing should include a right upper quadrant ultrasound (which can assess the hepatic parenchyma and bile ducts) and
an antimitochondrial antibody (AMA), which is highly suggestive of PBC (algorithm 2). The presence of biliary dilatation
suggests obstruction of the biliary tree. In patients with biliary dilatation or choledocholithiasis cholangiography (either MRCP
or ERCP depending upon the clinical setting and degree of suspicion for a stone) should be done to identify the cause of
obstruction and to allow for an intervention such as stone removal or stent placement. Patients with a positive AMA should
have a liver biopsy to verify the diagnosis of PBC.
Patients in whom initial testing is unrevealing We suggest a liver biopsy and either an ERCP or magnetic resonance
cholangiopancreatogram (MRCP) if the AMA and ultrasound are both negative and the alkaline phosphatase is persistently more
than 50 percent above normal for more than six months. If the alkaline phosphatase is less than 50 percent above normal, all
of the other liver tests are normal, and the patient is asymptomatic, we suggest observation alone since further testing is
unlikely to influence management [37].
Gamma glutamyl transpeptidase Gamma glutamyl transpeptidase (GGT) is found in hepatocytes and biliary epithelial
cells. 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 5 to 7 months of age [38]. GGT is sensitive for detecting hepatobiliary disease, but its
usefulness is limited by its lack of specificity. 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,
and alcoholism. High serum GGT values are also found in patients taking medications such as phenytoin and barbiturates.
(See"Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5-nucleotidase, gamma-glutamyl transpeptidase)".)
Some authorities have advocated using the GGT to identify patients with occult alcohol use. The reported sensitivity of an
elevated GGT for detecting alcohol ingestion has ranged from 52 to 94 percent [20,39]. Its lack of specificity makes its use for
this purpose questionable. A population-based study found that men with increased GGT levels who also had a hyperechogenic
liver by ultrasound (suggesting the presence of steatosis) has increased all-cause mortality rates but more data are needed
[40].
We suggest GGT 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:ALT ratio of
greater than 2:1). An elevated GGT with otherwise normal liver tests should not lead to an exhaustive work-up for liver
disease.
EVALUATION OF PATIENTS WITH SIMULTANEOUS ELEVATION OF SEVERAL LFTS The previous sections have
discussed the evaluation of isolated elevations of LFTs. The following sections will focus upon common presentations of patients
who have elevation of several of the tests simultaneously. As discussed above, it is helpful to attempt to divide this group of
patients into those with a predominantly hepatocellular process and those with a predominantly cholestatic process, although
the distinction is not always possible. Patients with a predominantly cholestatic pattern may be further divided into those with
intra- or extrahepatic cholestasis (table 4).
The degree of aminotransferase elevation can occasionally help in differentiating between hepatocellular and cholestatic
processes. While ALT and AST values less than eight times normal may be seen in either hepatocellular or cholestatic liver
disease, values 25 times normal or higher are seen primarily in hepatocellular diseases. On the other hand, patients with
jaundice from cirrhosis may have normal or only slight elevations of the aminotransferases. (See "Patterns of plasma aspartate
and alanine aminotransferase levels with and without liver disease".)

Predominantly hepatocellular pattern with jaundice Common hepatocellular diseases that can cause jaundice include
viral and toxic hepatitis (including drugs, herbal therapies and alcohol) and end-stage cirrhosis from any cause (table 5).
Wilson disease should be considered in young adults.
Autoimmune hepatitis predominantly occurs in young to middle-aged women (although it may affect men and women of any
age) and should particularly be considered in patients who have other autoimmune diseases.
Alcoholic hepatitis Alcoholic hepatitis can be differentiated from viral and toxin related hepatitis by the pattern of the
serum aminotransferases. Patients with alcoholic hepatitis typically have an AST:ALT ratio of at least 2:1. The AST rarely
exceeds 300 U/L. In contrast, patients with acute viral hepatitis and toxin related injury severe enough to produce jaundice
typically have aminotransferases greater than 500 U/L with the ALT greater than or equal to the AST.
Viral hepatitis Patients with acute viral hepatitis can develop jaundice. Appropriate testing for suspected acute viral
hepatitis includes a:

Hepatitis A IgM antibody

Hepatitis B surface antigen

Hepatitis B core IgM antibody

Hepatitis C viral RNA

Patients with acute hepatitis C are usually asymptomatic. As a result, acute hepatitis C is an uncommon cause of acute viral
hepatitis that is clinically evident. Nevertheless, testing for acute HCV is reasonable and should be performed by requesting an
assay for serum hepatitis C viral RNA since hepatitis C antibody may take weeks to months to become detectable.
(See "Screening for and diagnostic approach to hepatitis C virus infection".)
Toxic hepatitis Drug induced hepatocellular injury can be classified either as predictable or unpredictable. Predictable drug
reactions are dose-dependent and affect all patients who ingest a toxic dose of the drug in question. The classic example
is acetaminophen hepatotoxicity. Unpredictable, or idiosyncratic, drug reactions are not dose dependent and occur in a minority
of patients. Virtually any drug can cause an idiosyncratic reaction. As discussed above, features suggesting 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.
Environmental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl
chloride, herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea), and the mushrooms Amanita phalloides or
verna containing highly hepatotoxic amatoxins.
Shock liver (ischemic hepatitis) Patients who have a prolonged period of systemic hypotension (such as following a
cardiac arrest or patients with severe heart failure) may develop ischemic injury to several organs including the liver. Striking
increases in serum aminotransferases (exceeding 1000 IU/L or 50 times the upper limit of normal) and lactic dehydrogenase
may be seen [41-43]. Patients may also develop jaundice, hypoglycemia, and hepatic synthetic dysfunction. The majority of
patients have concomitant deterioration of renal function. The prognosis depends mostly upon the underlying condition.
Hepatic function usually returns to normal within several days of the acute episode. (See "Ischemic hepatitis, hepatic
infarction, and ischemic cholangiopathy".)
Wilson disease Patients with Wilson disease can occasionally present with acute and even fulminant hepatitis. The
diagnosis should be considered in patients younger than 40, particularly those who have concomitant hemolytic anemia.
(See "Pathogenesis and clinical manifestations of Wilson disease" and "Diagnosis of Wilson disease".)
Autoimmune hepatitis Patients with autoimmune hepatitis can present with acute and even fulminant hepatitis. The
diagnosis is established by the clinical setting, exclusion of other causes, serologic testing, and in some cases a liver biopsy.
(See "Clinical manifestations and diagnosis of autoimmune hepatitis".)
Predominantly cholestatic pattern The first step in evaluating patients whose LFT pattern predominantly reflects
cholestasis is to determine whether the cholestasis is due to intra- or extrahepatic causes (table 4). However, the distinction is
not always straightforward since the history, physical examination, and laboratory tests are often not helpful.
A reasonable first step is to obtain a right upper quadrant ultrasound, which has a number of advantages compared to other
imaging modalities. It is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and
extrahepatic biliary tree with a high degree of sensitivity and specificity. (See "Ultrasonography of the hepatobiliary tract".)
The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic
cholestasis. False negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis
or primary sclerosing cholangitis where scarring prevents the intrahepatic ducts from dilating.
Extrahepatic cholestasis Although ultrasonography may indicate extrahepatic cholestasis, it rarely identifies the site or
cause of obstruction. The distal common bile duct is a particularly difficult area to visualize by ultrasound because of overlying
bowel gas. Appropriate next tests include computerized tomography (CT) and endoscopic retrograde cholangiopancreatography
(ERCP). CT scanning is better than ultrasonography for assessing the head of the pancreas and for identifying
choledocholithiasis in the distal common bile duct, particularly when the ducts are not dilated.

Choledocholithiasis is the most common cause of extrahepatic cholestasis. The clinical presentation can range from
mild right upper quadrant discomfort with only minimal elevations of the enzyme tests to ascending cholangitis with
jaundice, sepsis, and circulatory collapse. Choledocholithiasis is usually associated with elevation of the serum
alkaline phosphatase out of proportion to the aminotransferases, although elevation of aminotransferases to greater
than 1000 IU/L have been described [44].
ERCP is the gold standard for identifying choledocholithiasis. It is performed by introducing a side-viewing endoscope
orally into the duodenum. The ampulla of Vater is visualized and a catheter is advanced through the ampulla.
Injection of dye allows for the visualization of the common bile duct and the pancreatic duct. The success rate for
cannulation of the common bile duct ranges from 80 to 95 percent depending on the operator's experience. In
addition to its diagnostic capabilities, ERCP allows for therapeutic interventions including the removal of common bile
duct stones and the placement of stents.
In patients in whom ERCP is unsuccessful, transhepatic cholangiography can provide the same information. Magnetic
resonance cholangiopancreatography (MRCP) is a rapidly developing, non-invasive technique for imaging the bile and
pancreatic ducts, which may replace ERCP as the initial diagnostic test in cases where the need for intervention is felt
to be small. (See "Magnetic resonance cholangiopancreatography".) Choledocholithiasis can also be detected with
endoscopic ultrasound. (See "Endoscopic ultrasound in patients with suspected choledocholithiasis".)

Malignant causes include pancreatic, gallbladder, ampullary, and cholangiocarcinoma. The latter is most commonly
associated with PSC and is exceptionally difficult to diagnose because its appearance is often identical to PSC.
Pancreatic, gallbladder, and cholangiocarcinoma are rarely resectable and have poor prognoses. Ampullary carcinoma
has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to
metastases from other cancers may cause obstruction of the extrahepatic biliary tree.

Patients with primary sclerosing cholangitis may have clinically important strictures limited to the extrahepatic biliary
tree. Patients who have a dominant stricture can be managed effectively with serial endoscopic dilatations.

Chronic pancreatitis uncommonly causes strictures of the distal common bile duct where it passes through the head
of the pancreas. (See"Complications of chronic pancreatitis".)

AIDS cholangiopathy (usually due to infection of the bile duct epithelium with CMV or Cryptosporidium) has a
cholangiographic appearance similar to PSC. Patients usually present with greatly elevated serum alkaline
phosphatase levels (around 800 IU/L) with a normal or near normal bilirubin level. Thus, these patients do not
typically present with jaundice. (See "AIDS cholangiopathy".)

Intrahepatic cholestasis The list of possible causes of intrahepatic cholestasis is long and varied (table 4). A number of
conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. As examples,
hepatitis B and C can cause a cholestatic hepatitis (fibrosing cholestatic hepatitis), which has histological features which mimic
large duct obstruction. This disease variant has been reported in patients who have undergone solid organ transplantation.
(See "Hepatitis C virus infection and renal transplantation".) Hepatitis A, alcoholic hepatitis, EBV, and CMV can also present as
cholestatic liver disease.

Drug induced cholestasis usually is reversible after elimination of the offending drug, although it may take many
months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and
contraceptive steroids. Cholestatic hepatitis has also been reported
withchlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, erythromycin estolate, trimethoprimsulfamethoxazole, and penicillin based antibiotics such as ampicillin and dicloxacillin. Rarely drug induced cholestasis
may be chronic and associated with progressive fibrosis. This pattern has been described with chlorpromazine
and prochlorperazine. (See "Drugs and the liver: Patterns of drug-induced liver injury".)

Primary biliary cirrhosis is a disease predominantly of middle-aged women in which there is a progressive destruction
of interlobular bile ducts. The diagnosis is made by the presence the antimitochondrial antibody which is found in 95
percent of patients. (See "Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis".)

Primary sclerosing cholangitis (PSC) is characterized by the destruction and fibrosis of larger bile ducts. The disease
may involve only the intrahepatic ducts and present as intrahepatic cholestasis. However, in 65 percent of patients
with PSC, both intra- and extrahepatic ducts are involved. The diagnosis of PSC is made by ERCP in which the
pathognomonic findings are multiple strictures of bile ducts with dilatations proximal to the strictures. The majority
of patients with PSC have inflammatory bowel disease. (See "Clinical manifestations and diagnosis of primary
sclerosing cholangitis".)

The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which there are a decreased
number of bile ducts seen in liver biopsy specimens. This picture is seen in patients who develop chronic rejection
after liver transplantation, in rare cases of sarcoidosis, in patients taking certain drugs including chlorpromazine, and

idiopathically. There are also familial forms of intrahepatic cholestasis. Benign recurrent cholestasis is an autosomal
recessive disease marked by recurrent, self-limited episodes of jaundice and pruritus. Cholestasis of pregnancy
occurs in the second and third trimesters and resolves after delivery. (See "Inherited disorders associated with
conjugated hyperbilirubinemia".)

Other causes of intrahepatic cholestasis include total parenteral nutrition, non-hepatobiliary sepsis, benign postoperative cholestasis, and a paraneoplastic syndrome (Stauffer's syndrome) associated with a number of different
malignancies, including Hodgkin lymphoma, medullary thyroid cancer, hypernephroma, renal sarcoma, T-cell
lymphoma, prostate cancer, and several gastrointestinal malignancies.

SUMMARY AND RECOMMENDATIONS

The most common laboratory measures classified as liver function tests include the enzyme tests (principally the
serum aminotransferases, alkaline phosphatase, and gamma glutamyl transpeptidase), tests of synthetic function
(principally the serum albumin concentration and prothrombin time), and the serum bilirubin, which reflects hepatic
transport capability. (See 'Definitions' above.)

A complete medical history is the single most important part of the evaluation of the patient with elevated LFTs.
(See 'History' above.)

The physical examination should focus upon findings suggesting the presence of liver disease. (See 'Physical
examination' above.)

A critical step in guiding the evaluation is determining the overall pattern of the abnormal LFTs, which can be broadly
divided into two categories: (1) patterns predominantly reflecting hepatocellular injury, (2) patterns predominantly
reflecting cholestasis. (See 'Laboratory testing' above.)

The decision to pursue specific testing should be guided by the pretest probability of the underlying liver disease, the
pattern of abnormalities, and suggestive features obtained from the history and physical examination. (See 'Common
patterns of LFT abnormalities' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES

1.

American Gastroenterological Association. American Gastroenterological Association medical position statement:

evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364.

2.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;
342:1266.

3.

Ioannou GN, Boyko EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferase activity in the
United States in 1999-2002. Am J Gastroenterol 2006; 101:76.

4.

Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels.
Ann Intern Med 2002; 137:1.

5.

Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with serum alanine transaminase activity in healthy
subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis
C. MULTIVIRC Group. Hepatology 1998; 27:1213.

6.

Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and
associated factors: NHANES 1999-2004. Gastroenterology 2007; 133:1814.

7.

Kundrotas LW, Clement DJ. Serum alanine aminotransferase (ALT) elevation in asymptomatic US Air Force basic
trainee blood donors. Dig Dis Sci 1993; 38:2145.

8.

Katkov WN, Friedman LS, Cody H, et al. Elevated serum alanine aminotransferase levels in blood donors: the
contribution of hepatitis C virus. Ann Intern Med 1991; 115:882.

9.

Hultcrantz R, Glaumann H, Lindberg G, Nilsson LH. Liver investigation in 149 asymptomatic patients with moderately
elevated activities of serum aminotransferases. Scand J Gastroenterol 1986; 21:109.

10.

Daniel S, Ben-Menachem T, Vasudevan G, et al. Prospective evaluation of unexplained chronic liver transaminase
abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999; 94:3010.

11.

Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence
of diagnostic serology. J Hepatol 2001; 35:195.

12.

Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the
United States population. Gastroenterology 2009; 136:477.

13.

Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test
results. Ann Intern Med 2008; 148:348.

14.

Ruhl CE, Everhart JE. Trunk fat is associated with increased serum levels of alanine aminotransferase in the United
States. Gastroenterology 2010; 138:1346.

15.

Kaplan MM. Alanine aminotransferase levels: what's normal? Ann Intern Med 2002; 137:49.

16.

Dutta A, Saha C, Johnson CS, Chalasani N. Variability in the upper limit of normal for serum alanine
aminotransferase levels: a statewide study. Hepatology 2009; 50:1957.

17.

Myers RP, Cerini R, Sayegh R, et al. Cardiac hepatopathy: clinical, hemodynamic, and histologic characteristics and
correlations. Hepatology 2003; 37:393.

18.

Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of
acetaminophen daily: a randomized controlled trial. JAMA 2006; 296:87.

19.

Cohen JA, Kaplan MM. The SGOT/SGPT ratio--an indicator of alcoholic liver disease. Dig Dis Sci 1979; 24:835.

20.

Moussavian SN, Becker RC, Piepmeyer JL, et al. Serum gamma-glutamyl transpeptidase and chronic alcoholism.
Influence of alcohol ingestion and liver disease. Dig Dis Sci 1985; 30:211.

21.

Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases.
Hepatology 2005; 41:380.

22.

Huang MJ, Liaw YF. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 1995; 10:344.

23.

Saha B, Maity C. Alteration of serum enzymes in primary hypothyroidism. Clin Chem Lab Med 2002; 40:609.

24.

Abdo A, Meddings J, Swain M. Liver abnormalities in celiac disease. Clin Gastroenterol Hepatol 2004; 2:107.

25.

Bardella MT, Vecchi M, Conte D, et al. Chronic unexplained hypertransaminasemia may be caused by occult celiac
disease. Hepatology 1999; 29:654.

26.

Olsson RG, Lindgren A, Zettergren L. Liver involvement in Addison's disease. Am J Gastroenterol 1990; 85:435.

27.

Boulton R, Hamilton MI, Dhillon AP, et al. Subclinical Addison's disease: a cause of persistent abnormalities in
transaminase values. Gastroenterology 1995; 109:1324.

28.

Roblin X, Boudemaghe T, Le Gall S, et al. Use of the Synacthene test in the assessment of aminotransferase
elevation. J Hepatol 2002; 36:139.

29.

Miller KK, Grinspoon SK, Ciampa J, et al. Medical findings in outpatients with anorexia nervosa. Arch Intern Med
2005; 165:561.

30.

Ozawa Y, Shimizu T, Shishiba Y. Elevation of serum aminotransferase as a sign of multiorgan-disorders in severely

emaciated anorexia nervosa. Intern Med 1998; 37:32.

31.

Di Pascoli L, Lion A, Milazzo D, Caregaro L. Acute liver damage in anorexia nervosa. Int J Eat Disord 2004; 36:114.

32.

Rivera-Nieves J, Kozaiwa K, Parrish CR, et al. Marked transaminase elevation in anorexia nervosa. Dig Dis Sci 2000;
45:1959.

33.

Furuta S, Ozawa Y, Maejima K, et al. Anorexia nervosa with severe liver dysfunction and subsequent critical
complications. Intern Med 1999; 38:575.

34.

De Caprio C, Alfano A, Senatore I, et al. Severe acute liver damage in anorexia nervosa: two case reports. Nutrition
2006; 22:572.

35.

Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993; 18:998.

36.

Das A, Post AB. Should liver biopsy be done in asymptomatic patients with chronically elevated transaminases: A
cost-utility analysis (abstract). Gastroenterology 1998; 114:A9.

37.

Sorbi D, McGill DB, Thistle JL, et al. An assessment of the role of liver biopsies in asymptomatic patients with chronic
liver test abnormalities. Am J Gastroenterol 2000; 95:3206.

38.

Cabrera-Abreu JC, Green A. Gamma-glutamyltransferase: value of its measurement in paediatrics. Ann Clin Biochem
2002; 39:22.

39.

Orrego H, Blake JE, Israel Y. Relationship between gamma-glutamyl transpeptidase and mean urinary alcohol levels
in alcoholics while drinking and after alcohol withdrawal. Alcohol Clin Exp Res 1985; 9:10.

40.

Haring R, Wallaschofski H, Nauck M, et al. Ultrasonographic hepatic steatosis increases prediction of mortality risk
from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50:1403.

41.

Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J Gastroenterol 1992; 87:831.

42.

Fuchs S, Bogomolski-Yahalom V, Paltiel O, Ackerman Z. Ischemic hepatitis: clinical and laboratory observations of 34
patients. J Clin Gastroenterol 1998; 26:183.

43.

Henrion J, Schapira M, Luwaert R, et al. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases.
Medicine (Baltimore) 2003; 82:392.

44.

Nathwani RA, Kumar SR, Reynolds TB, Kaplowitz N. Marked elevation in serum transaminases: an atypical
presentation of choledocholithiasis. Am J Gastroenterol 2005; 100:295.
Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)
Author
Marshall M Kaplan, MD
Section Editor
Sanjiv Chopra, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Wed Sep 22 00:00:00 GMT
2010 (More)
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 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"Treatment of autoimmune hepatitis".)

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 ChildPugh 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 function tests that used in 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 function 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, andlidocaine 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 natural history
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.
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, the degradation, and the volume of distribution. Albumin
synthesis is regulated by a variety of influences including nutritional status, serum oncotic pressure, cytokines, and hormones
[1,2]. How these influences 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. In 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. Its half-life 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 liver diseases such as 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 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 routinely measured; 13 percent had an abnormal value, which was found to be clinically significant in only two patients
[9].
Serum albumin levels persistently above the lab's reference range are usually observed in normal people who are at the
extreme right of the bell-shaped curve. Acute hyperalbuminemia is most commonly seen 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 its half
life.
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

Factors XII and 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,
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]. On the other hand, the
magnitude of elevation of the prothrombin time above control correlates 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 [12,13]. A prothrombin time above 100 sec is considered an indication for liver transplantation [12].
(See "Acute liver failure: Definition and etiology".) However, some patients recover despite marked elevations in the
prothrombin time, particularly those who have acetaminophen overdose. A progressive decline in the prothrombin time in such
patients usually heralds recovery. (See "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 receivingwarfarin. 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 assure 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 [14,15]. 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 and acute liver failure compared to controls [14]. 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 [16,17]. This may be particularly relevant when prioritizing patients for liver transplantation [17]. (See "Model for Endstage 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
[18,19]. (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 [20]. (See "Vitamin K and the
synthesis 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 [21]. 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 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 requires 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 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.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES

1.

Rothschild MA, Oratz M, Schreiber SS. Serum albumin. Hepatology 1988; 8:385.

2.

Pietrangelo A, Panduro A, Chowdhury JR, Shafritz DA. Albumin gene expression is down-regulated by albumin or
macromolecule infusion in the rat. J Clin Invest 1992; 89:1755.

3.

Sun X, Martin V, Weiss RH, Kaysen GA. Selective transcriptional augmentation of hepatic gene expression in the rat
with Heymann nephritis. Am J Physiol 1993; 264:F441.

4.

Moshage HJ, Janssen JA, Franssen JH, et al. Study of the molecular mechanism of decreased liver synthesis of
albumin in inflammation. J Clin Invest 1987; 79:1635.

5.

Perlmutter DH, Dinarello CA, Punsal PI, Colten HR. Cachectin/tumor necrosis factor regulates hepatic acute-phase
gene expression. J Clin Invest 1986; 78:1349.

6.

Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 1984; 311:1413.

7.

Rothschild MA, Oratz M, Zimmon D, et al. Albumin synthesis in cirrhotic subjects with ascites studied with carbonate14C. J Clin Invest 1969; 48:344.

8.

Lieberman FL, Reynolds TB. Plasma volume in cirrhosis of the liver: its relation of portal hypertension, ascites, and
renal failure. J Clin Invest 1967; 46:1297.

9.

Veldhuyzen van Zanten SJ, Depla AC, Dekker PC, et al. The clinical importance of routine measurement of liver
enzymes, total protein and albumin in a general medicine outpatient clinic: a prospective study. Neth J Med 1992; 40:53.

10.

Mutlu EA, Keshavarzian A, Mutlu GM. Hyperalbuminemia and elevated transaminases associated with high-protein
diet. Scand J Gastroenterol 2006; 41:759.

11.

Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal
conventional coagulation tests. Hepatology 2005; 41:553.

12.

O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure.
Gastroenterology 1989; 97:439.

13.

Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology
1995; 21:240.

14.

Robert A, Chazouillres O. Prothrombin time in liver failure: time, ratio, activity percentage, or international
normalized ratio? Hepatology 1996; 24:1392.

15.

Denson KW, Reed SV, Haddon ME, et al. Comparative studies of rabbit and human recombinant tissue factor
reagents. Thromb Res 1999; 94:255.

16.

Deitcher SR. Interpretation of the international normalised ratio in patients with liver disease. Lancet 2002; 359:47.

17.

Trotter JF, Brimhall B, Arjal R, Phillips C. Specific laboratory methodologies achieve higher model for endstage liver
disease (MELD) scores for patients listed for liver transplantation. Liver Transpl 2004; 10:995.

18.

Tripodi A, Chantarangkul V, Primignani M, et al. The international normalized ratio calibrated for cirrhosis (INR(liver))
normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology 2007; 46:520.

19.

Bellest L, Eschwge V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin
time standardization in hepatology. Hepatology 2007; 46:528.

20.

Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamic
acid as a component of prothrombin. J Biol Chem 1974; 249:6347.

21.

Weitz IC, Liebman HA. Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review.
Hepatology 1993; 18:990.