Liver function tests that detect injury to hepatocytesAuthorMarshall M Kaplan, MDSection EditorSanjiv Chopra, MDDeputy EditorAnne C Travis, MD, MSc, FACGDisclosuresLast 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)INTRODUCTIONA 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 asindocyanine greenclearance), 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 Child-Pugh score, which incorporates the prothrombin time and serum bilirubin and albumin concentrations, can predict survival (table 1).The pattern of abnormalities on these tests is more accurate than any of the individual tests. Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the 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, andlidocainemetabolites, a variety of breath tests, and clearance tests such as bromsulphalein (BSP) andindocyanine 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 cholestasisThis 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 AMINOTRANSFERASESThe 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 creatinekinase and troponins, are considered the standard for the diagnosis of myocardial infarction. (See"Troponins and creatine kinase as biomarkers of cardiac injury".)MeasurementThe 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 aserythromycinandpara-aminosalicylic acidmay 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 significanceSerum 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,acetaminophenintoxication). 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 ENZYMESA variety of other hepatic enzymes have been measured but none is as useful as the aminotransferases for the diagnosis of hepatic disease.Lactate dehydrogenaseLactate 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 dehydrogenaseGlutamate 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 dehydrogenaseIsocitrate 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 dehydrogenaseSorbitoldehydrogenase 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,acetaminophenintoxication). (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.)Use of UpToDate is subject to theSubscription and License Agreement.REFERENCES1. Ellis G, Goldberg DM, Spooner RJ, Ward AM. Serum enzyme tests in diseases of the liver and biliary tree. Am J Clin Pathol 1978; 70:248.2. 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 KApproach to the patient with abnormal liver function testsAuthorMarshall M Kaplan, MDSection EditorSanjiv Chopra, MDDeputy EditorAnne C Travis, MD, MSc, FACGDisclosuresLast 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)INTRODUCTIONThis 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 atfile://www.gastro.org/practice/medical-position-statements.DEFINITIONSAlthough 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).EPIDEMIOLOGYAbnormal 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.HISTORYA 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 stoolWhile 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 EXAMINATIONThe 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 cirrhosisThe 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 TESTINGA 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 cholestasisPatients 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 Kdeficiency 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 ABNORMALITIESConsensus 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 AMINOTRANSFERASESThe 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 oneThe 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.MedicationsAlmost any medication can cause an elevation of liver enzymes. Common causes include nonsteroidal anti-inflammatory 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 abuseThe 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, gamma-glutamyl 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 BThe 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 CChronic 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 hemochromatosisHereditary 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 isnotnecessary for patients less than 40 years of age with genotypically defined hemochromatosis (C282Y homozygous) with normal liver function tests.Genetic testing hasnotreplaced 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 steatohepatitisHepatic 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 45Step twoThe 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 disordersElevated 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 creatinekinase, 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 disordersThyroid 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 diseaseSeveral 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 insufficiencyAminotransferase 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 nervosaAnorexia 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 threeThe next set of tests is aimed at identifying rarer liver conditions.Autoimmune hepatitisAutoimmune 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 diseaseWilson disease, a genetic disorder of biliarycopperexcretion, 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 quantitativecopperexcretion. 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 quantitativecopper. 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 deficiencyAlpha-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 ductopeniaAdult 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 toursodeoxycholic 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 fourA 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 observeWe 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 biopsyWe 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 HYPERBILIRUBINEMIAIsolated hyperbilirubinemia occurs principally in two settings (see"Bilirubin metabolism"): Overproduction of bilirubin Impaired uptake, conjugation, or excretion of bilirubinThe 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 hyperbilirubinemiaIndirect 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).HemolysisHemolysis 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 conjugationImpaired hepatic uptake or conjugation of bilirubin should be considered in the absence of hemolysis. This is most commonly caused by certain drugs (including rifampicin andprobenecid) 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: Crigler-Najjar 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 ofphenobarbital, which can reduce serum bilirubin levels in these patients. (See"Crigler-Najjar syndrome".)Conjugated hyperbilirubinemiaElevated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson 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 Dubin-Johnson 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 TRANSPEPTIDASESerum 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 phosphataseThe 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 originChronic 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 andphenytoin. 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 unrevealingWe 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 transpeptidaseGamma 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 asphenytoinand 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 LFTSThe 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 jaundiceCommon 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 hepatitisAlcoholic 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 hepatitisPatients 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 RNAPatients 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 hepatitisDrug 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 isacetaminophenhepatotoxicity. 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 diseasePatients 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 hepatitisPatients 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 patternThe 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 cholestasisAlthough 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 cholestasisThe 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,erythromycinestolate,trimethoprim-sulfamethoxazole, and penicillin based antibiotics such asampicillinanddicloxacillin. Rarely drug induced cholestasis may be chronic and associated with progressive fibrosis. This pattern has been described with chlorpromazine andprochlorperazine. (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 includingchlorpromazine, 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 includetotal parenteral nutrition, non-hepatobiliary sepsis, benign post-operative 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 theSubscription and License Agreement.REFERENCES1. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364.2. Pratt DS, Kaplan MM. 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Am J Gastroenterol 2005; 100:295.Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)AuthorMarshall M Kaplan, MDSection EditorSanjiv Chopra, MDDeputy EditorAnne C Travis, MD, MSc, FACGDisclosuresLast 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)INTRODUCTIONA 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 asindocyanine greenclearance), 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 Child-Pugh score, which incorporates the prothrombin time and serum bilirubin and albumin concentrations, can predict survival (table 1).The pattern of abnormalities on these tests is more accurate than any of the individual tests. Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the alkaline phosphatase indicates cholestasis. Recognition of patterns that are consistent with specific diseases can prompt appropriate additional testing.The liver 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 meas