Special Considerations in Interpreting Liver Function Tests DAVID E. JOHNSTON, M.D.

University of New Mexico School of MedicineAlbuquerque, New Mexico

A number of pitfalls can be encountered in the interpretation of common blood liver function tests. These tests can be normal in patients with chronic hepatitis or cirrhosis. The normal range for aminotransferase levels is slightly higher in males, nonwhites and obese persons. Severe alcoholic hepatitis is sometimes confused with cholecystitis or cholangitis. Conversely, patients who present soon after passing common bile duct stones can be misdiagnosed with acute hepatitis because aminotransferase levels often rise immediately, but alkaline phosphatase and gamma-glutamyltransferase levels do not become elevated for several days. Asymptomatic patients with isolated, mild elevation of either the unconjugated bilirubin or the gamma-glutamyltransferase value usually do not have liver disease and generally do not require extensive evaluation. Overall hepatic function can be assessed by applying the values for albumin, bilirubin and prothrombin time in the modified Child-Turcotte grading system.

The commonly used liver function tests (LFTs) primarily assess liver injury rather than hepatic function. Indeed, these blood tests may reflect problems arising outside the liver, such as hemolysis (elevated bilirubin level) or bone disease (elevated alkaline phosphatase [AP] level).

Abnormal LFTs often, but not always, indicate that something is wrong with the liver, and they can provide clues to the nature of the problem. However, normal LFTs do not always mean that the liver is normal. Patients with cirrhosis and bleeding esophageal varices can have normal LFTs. Of the routine LFTs, only serum albumin, bilirubin and prothrombin time (PT) provide useful information on how well the liver is functioning.

The general subject of LFTs1,2 and the differential diagnosis of abnormal LFTs in asymptomatic patients3-5 have been well reviewed. This article discusses some common pitfalls in the interpretation of LFTs. Hints for interpreting these tests are presented in Table 1.

TABLE 1 Helpful Hints for Interpreting Liver Function Tests

Situation Comments

Mildly elevated ALT level (less than 1.5 times

ALT value could be normal for gender, ethnicity or body mass index.Consider muscle injury or myopathy.

normal) Alcoholic hepatitis Laboratory values can appear cholestatic, and symptoms

can mimic cholecystitis.Minimal elevations of AST and ALT often occur.

AST level greater than 500 U per L

The AST elevation is unlikely to result from alcohol intake alone.In a heavy drinker, consider acetaminophen toxicity.

Common bile duct stone Condition can simulate acute hepatitis.AST and ALT become elevated immediately, but elevation of AP and GGT is delayed.

Isolated elevation of GGT level

This situation may be induced by alcohol and aromatic medications, usually with no actual liver disease.

Isolated elevation of AP level (asymptomatic patient with normal GGT level)

Consider bone growth or injury, or primary biliary cirrhosis. AP level rises in late pregnancy.

Isolated elevation of unconjugated bilirubin level

Consider Gilbert syndrome or hemolysis.

Low albumin level Low albumin is most often caused by acute or chronic inflammation, urinary loss, severe malnutrition or liver disease; it is sometimes caused by gastrointestinal loss (e.g., colitis or some uncommon small bowel disease).Normal values are lower in pregnancy.

Blood ammonia level Blood ammonia values are not necessarily elevated in patients with hepatic encephalopathy.Determination of blood ammonia levels is most useful in patients with altered mental status of new onset or unknown origin.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; AP=alkaline phosphatase; GGT=gamma-glutamyltransferase.

Markers of Hepatocellular Injury

The most commonly used markers of hepatocyte injury are aspartate aminotransferase (AST, formerly serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT, formerly serum glutamate-pyruvate transaminase [SGPT]). While ALT is cytosolic, AST has both cytosolic and mitochondrial forms.

Hepatocyte necrosis in acute hepatitis, toxic injury or ischemic injury results in the leakage of enzymes into the circulation. However, in chronic liver diseases such as hepatitis C and cirrhosis, the serum ALT level correlates only moderately well with liver inflammation. In hepatitis C, liver cell death occurs by apoptosis (programmed cell death) as well as by necrosis. Hepatocytes dying by apoptosis presumably synthesize less AST and ALT as they wither away. This probably explains why at least one third of patients infected with hepatitis C virus have persistently normal serum ALT levels despite the

presence of inflammation on liver biopsy.6,7 Patients with cirrhosis often have normal or only slightly elevated serum AST and ALT levels. Thus, AST and ALT lack some sensitivity in detecting chronic liver injury. Of course, AST and ALT levels tend to be higher in cirrhotic patients with continuing inflammation or necrosis than in those without continuing liver injury.

Typical ALT or AST Distribution

FIGURE 1. Typical population distribution of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. The population distributions for these aminotransferases do not follow a bell-shaped curve but are skewed, with a long "tail" at higher values. By convention, values above the 97.5th percentile are considered elevated (shaded area). Although average values for ALT and AST are similar in different populations, the distributions are more skewed in males and in nonwhite ethnic groups (i.e., blacks and Hispanics).

Figure 1 adapted with permission from Quinn PG, Johnston DE. Detection of chronic liver disease: costs and benefits. Gastroenterologist 1997;5:58-77.

As markers of hepatocellular injury, AST and ALT also lack some specificity because they are found in skeletal muscle. Levels of these aminotransferases can rise to several times normal after severe muscular exertion or other muscle injury, as in polymyositis,8 or in the presence of hypothyroidism, which can cause mild muscle injury and the release of aminotransferases. In fact, AST and ALT were once used in the diagnosis of myocardial infarction.

Slight AST or ALT elevations (within 1.5 times the upper limits of normal) do not necessarily indicate liver disease. Part of this ambiguity has to do with the fact that unlike the values in many other biochemical tests, serum AST and ALT levels do not follow a normal bell-shaped distribution in the population.9 Instead, AST and ALT values have a skewed distribution characterized by a long "tail" at the high end of the scale (Figure 1).5 For example, the mean values for ALT are very similar from one population to another, but the degree to which the distribution is skewed varies by gender and ethnicity. The ALT distributions in males and nonwhites (i.e., blacks and Hispanics) tend to have a larger tail at the high end, so that more values fall above the upper limits of normal set for the average population.10,11

AST and ALT values are higher in obese patients, probably because these persons commonly have fatty livers.12 ALT levels have been noted to decline with weight loss.13

Depending on the physician's point of view, the upper limits of normal for AST and ALT levels could be set higher for more obese persons.

Rare individuals have chronically elevated AST levels because of a defect in clearance of the enzyme from the circulation.14 For both AST and ALT, the average values and upper limits of normal in patients undergoing renal dialysis are about one half of those found in the general population.15 Mild elevations of ALT or AST in asymptomatic patients can be evaluated efficiently by considering alcohol abuse, hepatitis B, hepatitis C and several other possible diagnoses (Table 2).5

Various liver diseases are associated with typical ranges of AST and ALT levels (Figure 2). ALT levels often rise to several thousand units per liter in patients with acute viral hepatitis. The highest ALT levels--often more than 10,000 U per L--are usually found in patients with acute toxic injury subsequent to, for example, acetaminophen overdose or acute ischemic insult to the liver. AST and ALT levels usually fall rapidly after an acute insult.

TABLE 2 Causes of Elevated ALT or AST Values in Asymptomatic Patients*

A Autoimmune hepatitisB Hepatitis BC Hepatitis CD Drugs or toxinsE EthanolF Fatty liverG Growths (i.e., tumors)H Hemodynamic disorder (congestive

heart failure)I Iron (hemochromatosis), copper

(Wilson's disease) or alpha1-antitrypsin deficiency

M Muscle injury

ALT=alanine aminotransferase; AST=aspartate aminotransferase.

*--The differential diagnosis of elevated aminotransferase values is presented as a mnemonic, with the disorders not necessarily listed in the order of incidence or importance. Alcohol, hepatitis B and hepatitis C account for more than three fourths of all cases of cirrhosis.

Adapted with permission from Quinn PG, Johnston DE. Detection of chronic liver disease: costs and benefits. Gastroenterologist 1997;5:58-77.

Lactate dehydrogenase (LDH) is less specific than AST and ALT as a marker of hepatocyte injury. However, it is worth noting that LDH is disproportionately elevated after an ischemic liver injury.16

It is especially important to remember that in patients with acute alcoholic hepatitis, the serum AST level is almost never greater than 500 U per L and the serum ALT value is almost never greater than 300 U per L. The reasons for these limits on AST and ALT elevations are not well understood. In typical viral or toxic liver injury, the serum ALT level rises more than the AST value, reflecting the relative amounts of these enzymes in hepatocytes. However, in alcoholic hepatitis, the ratio of AST to ALT is greater than 1 in 90 percent of patients and is usually greater than 2.17 The higher the AST-to-ALT ratio, the greater the likelihood that alcohol is contributing to the abnormal LFTs. In the absence of alcohol intake, an increased AST-to-ALT ratio is often found in patients with cirrhosis.

The elevated AST-to-ALT ratio in alcoholic liver disease results in part from the depletion of vitamin B6 (pyridoxine) in chronic alcoholics.18 ALT and AST both use pyridoxine as a coenzyme, but the synthesis of ALT is more strongly inhibited by pyridoxine deficiency than is the synthesis of AST. Alcohol also causes mitochondrial injury, which releases the mitochondrial isoenzyme of AST.

Patients with alcoholic hepatitis can present with jaundice, abdominal pain, fever and a minimally elevated AST value, thereby leading to a misdiagnosis of cholecystitis. This is a potentially fatal mistake given the high surgical mortality rate in patients with alcoholic hepatitis.19

Typical AST or ALT Values in Disease

FIGURE 2. Typical serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values for various diseases. Note that the horizontal axis is a log scale. As shown, the aminotransferases are often normal in patients with cirrhosis. In patients with uncomplicated alcoholic hepatitis, the AST value is rarely greater than 500 U per L and is usually

no more than 200 to 300 U per L. The highest peak aminotransferase values are found in patients with acute ischemic or toxic liver injury.

Markers of Cholestasis

Cholestasis (lack of bile flow) results from the blockage of bile ducts or from a disease that impairs bile formation in the liver itself. AP and gamma-glutamyltransferase (GGT) levels typically rise to several times the normal level after several days of bile duct obstruction or intrahepatic cholestasis. The highest liver AP elevations--often greater than 1,000 U per L, or more than six times the normal value--are found in diffuse infiltrative diseases of the liver such as infiltrating tumors and fungal infections.

Diagnostic confusion can occur when a patient presents within a few hours after acute bile duct obstruction from a gallstone. In this situation, AST and ALT levels often reach 500 U per L or more in the first hours and then decline, whereas AP and GGT levels can take several days to rise.

Both AP and GGT levels are elevated in about 90 percent of patients with cholestasis.20 The elevation of GGT alone, with no other LFT abnormalities, often results from enzyme induction by alcohol or aromatic medications in the absence of liver disease. The GGT level is often elevated in persons who take three or more alcoholic drinks (45 g of ethanol or more) per day.21 Thus, GGT is a useful marker for immoderate alcohol intake. Phenobarbital, phenytoin (Dilantin) and other aromatic drugs typically cause GGT elevations of about twice normal. A mildly elevated GGT level is a typical finding in patients taking anticonvulsants and by itself does not necessarily indicate liver disease.22,23

Serum AP originates mostly from liver and bone, which produce slightly different forms of the enzyme. The serum AP level rises during the third trimester of pregnancy because of a form of the enzyme produced in the placenta. When serum AP originates from bone, clues to bone disease are often present, such as recent fracture, bone pain or Paget's disease of the bone (often found in the elderly). Like the GGT value, the AP level can become mildly elevated in patients who are taking phenytoin.22,23

If the origin of an elevated serum AP level is in doubt, the isoenzymes of AP can be separated by electrophoresis. However, this process is expensive and usually unnecessary because an elevated liver AP value is usually accompanied by an elevated GGT level, an elevated 5´-nucleotidase level and other LFT abnormalities.

In one study,24 isolated AP elevations were evaluated in an unselected group of patients at a Veterans Affairs hospital. Most mild AP elevations (less than 1.5 times normal)

Patients with cirrhosis often have normal or only slightly elevated serum aspartate aminotransferase or alanine aminotransferase values.

resolved within six months, and almost all greater elevations had an evident cause that was found on routine clinical evaluation.

Persistently elevated liver AP values in asymptomatic patients, especially women, can be caused by primary biliary cirrhosis, which is a chronic inflammatory disorder of the small bile ducts. Serum antimitochondrial antibody is positive in almost all of these patients.

Indicators of How Well the Liver Functions

BilirubinBilirubin results from the enzymatic breakdown of heme. Unconjugated bilirubin is conjugated with glucuronic acid in hepatocytes to increase its water solubility and is then rapidly transported into bile. The serum conjugated bilirubin level does not become elevated until the liver has lost at least one half of its excretory capacity. Thus, a patient could have obstruction of either the left or right hepatic duct without a rise in the bilirubin level.

Because the secretion of conjugated bilirubin into bile is very rapid in comparison with the conjugation step, healthy persons have almost no detectable conjugated bilirubin in their blood. Liver disease mainly impairs the secretion of conjugated bilirubin into bile. As a result, conjugated bilirubin is rapidly filtered into the urine, where it can be detected by a dipstick test. The finding of bilirubin in urine is a particularly sensitive indicator of the presence of an increased serum conjugated bilirubin level.

In many healthy persons, the serum unconjugated bilirubin is mildly elevated to a concentration of 2 to 3 mg per dL (34 to 51 µmol per L) or slightly higher, especially after a 24-hour fast. If this is the only LFT abnormality and the conjugated bilirubin level and complete blood count are normal, the diagnosis is usually assumed to be Gilbert syndrome, and no further evaluation is required. Gilbert syndrome was recently shown to be related to a variety of partial defects in uridine diphosphate-glucuronosyl

transferase, the enzyme that conjugates bilirubin.25

Mild hemolysis, such as that caused by hereditary spherocytosis and other disorders, can also result in elevated unconjugated bilirubin values, but hemolysis is not usually present if the hematocrit and blood smear are normal. The presence of hemolysis can be confirmed by testing other markers, such as haptoglobin, or by measuring the reticulocyte count.

Severe defects in bilirubin transport and conjugation can lead to markedly elevated unconjugated bilirubin levels, which can cause serious neurologic damage (kernicterus) in infants. However, no serious form of liver disease in adults causes elevation of

The gamma-glutamyltransferase level is often elevated in persons who have three or more alcoholic drinks per day; thus, it is a useful marker for immoderate alcohol intake.

unconjugated bilirubin levels in the blood without also causing elevation of conjugated bilirubin values.

When a patient has prolonged, severe biliary obstruction followed by the restoration of bile flow, the serum bilirubin level often declines rapidly for several days and then slowly returns to normal over a period of weeks. The slow phase of bilirubin clearance results from the presence of delta-bilirubin, a form of bilirubin chemically attached to serum albumin.26 Because albumin has a half-life of three weeks, delta-bilirubin clears much more slowly than bilirubin-glucuronide. Clinical laboratories can measure delta-bilirubin concentrations, but such measurements are usually unnecessary if the physician is aware of the delta-bilirubin phenomenon.

Albumin Although the serum albumin level can serve as an index of liver synthetic capacity, several factors make albumin concentrations difficult to interpret.27 The liver can synthesize albumin at twice the healthy basal rate and thus partially compensate for decreased synthetic capacity or increased albumin losses. Albumin has a plasma half-life of three weeks; therefore, serum albumin concentrations change slowly in response to alterations in synthesis. Furthermore, because two thirds of the amount of body albumin is located in the extravascular, extracellular space, changes in distribution can alter the serum concentration.

In practice, patients with low serum albumin concentrations and no other LFT abnormalities are likely to have a nonhepatic cause for low albumin, such as proteinuria or an acute or chronic inflammatory state. Albumin synthesis is immediately and severely depressed in inflammatory states such as burns, trauma and sepsis, and it is commonly depressed in patients with active rheumatic disorders or severe end-stage malnutrition. In addition, normal albumin values are lower in pregnancy.

Prothrombin Time The liver synthesizes blood clotting factors II, V, VII, IX and X. The prothrombin time (PT) does not become abnormal until more than 80 percent of liver synthetic capacity is lost. This makes PT a relatively insensitive marker of liver dysfunction. However, abnormal PT prolongation may be a sign of serious liver dysfunction. Because factor VII has a short half-life of only about six hours, it is sensitive to rapid changes in liver synthetic function. Thus, PT is very useful for following liver function in patients with acute liver failure.

An elevated PT can result from a vitamin K deficiency. This deficiency usually occurs in patients with chronic cholestasis or fat malabsorption from disease of the pancreas or small bowel. A trial of vitamin K injections (e.g., 5 mg per day administered subcutaneously for three days) is the most practical way to exclude vitamin K deficiency in such patients. The PT should improve within a few days.

Patients with low serum albumin levels and no other liver function test abnormalities are likely to have a nonhepatic cause for low albumin, such as proteinuria.

Blood Ammonia Measurement of the blood ammonia concentration is not always useful in patients with known or suspected hepatic encephalopathy. Ammonia contributes to hepatic encephalopathy; however, ammonia concentrations are much higher in the brain than in the blood and therefore do not correlate well.28 Furthermore, ammonia is not the only waste product responsible for encephalopathy. Thus, blood ammonia concentrations show only a mediocre correlation with the level of mental status in patients with liver disease. It is not unusual for the blood ammonia concentration to be normal in a patient who is in a coma from hepatic encephalopathy.

Blood ammonia levels are best measured in arterial blood because venous concentrations can be elevated as a result of muscle metabolism of amino acids. Blood ammonia concentrations are most useful in evaluating patients with stupor or coma of unknown origin. It is not necessary to evaluate blood ammonia levels routinely in patients with known chronic liver disease who are responding to therapy as expected.

TABLE 3 Grading Liver Function Using the Child-Turcotte Class as Modified by Pugh*

Points

Feature 0 1 2

Albumin More than 3.5 g per dL (35 g per L)

2.8 to 3.5 g per dL (28 to 35 g per L)

Less than 2.8 g per dL (28 g per L)

Bilirubin Less than 2 mg per dL (34 µmol per L)

2 to 3 mg per dL (34 to 51 µmol per L)

More than 3 mg per dL

Prolongation of prothrombin time

Less than 4 seconds

4 to 6 seconds More than 6 seconds

Ascites None Controlled RefractoryEncephalopathy None Controlled Refractory

*--The Child-Turcotte class, as modified by Pugh, often known simply as the "Child class," is calculated by adding the points as determined by the patient's laboratory results: class A=0 to 1; class B=2 to 4; class C=5 and higher. The classes indicate severity of liver dysfunction: class A is associated with a good prognosis, and class C is associated with limited life expectancy. Ascites and encephalopathy are graded as "none," "controlled with routine medical therapy" or "refractory to medical therapy."

Adapted with permission from Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.

Grading Liver Function by Child-Turcotte Class

In communicating among themselves, many physicians use the Child-Turcotte class as modified by Pugh, often termed the "Child class," to convey information about overall liver function and prognosis (Table 3).29 This grading system can be used to predict overall life expectancy and surgical mortality in patients with cirrhosis and other liver diseases.30

For elective general abdominal surgery, perioperative mortality is in the neighborhood of several percent for patients who fall into the Child class A, 10 to 20 percent for those in class B and approximately 50 percent for those in class C.31 These percentages must be balanced by prognostic considerations when transplantation becomes an option. The presence of cirrhosis by itself is not an indication for liver transplantation, and transplantation is rarely performed in patients who fall into Child class A. For example, the 10-year survival rate is as high as 80 percent in patients with hepatitis C and cirrhosis who have Child class A liver function and no variceal bleeding.32 However, once patients with any type of liver disease fall into the Child-Turcotte class B or class C category, survival is significantly reduced and transplantation should be considered.

Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient

Am Fam Physician. 2005 Mar 15;71(6):1105-1110.

Mild elevations in liver chemistry tests such as alanine transaminase and aspartate transaminase can reveal serious underlying conditions or have transient and benign etiologies. Potential causes of liver transaminase elevations include viral hepatitis, alcohol use, medication use, steatosis or steatohepatitis, and cirrhosis. The history should be thorough, with special attention given to the use of medications, vitamins, herbs, drugs, and alcohol; family history; and any history of blood-product transfusions. Other common health conditions, such as diabetes, heart disease, and thyroid disease, can cause or augment liver transaminase elevations. The recent American Gastroenterological Association guideline regarding the evaluation and management of abnormal liver chemistry tests proposes a practical, algorithmic approach when the history and physical examination do not reveal the cause. In addition to liver chemistries, an initial serologic evaluation includes a prothrombin time; albumin; complete blood count with platelets; hepatitis A, B, and C serologies; and iron studies. Depending on the etiology, management strategies may include cessation of alcohol use, attention to medications, control of diabetes, and modification of lifestyle factors such as obesity. If elevations persist after an appropriate period of observation, further testing may include ultra-sonography and other serum studies. In some cases, biopsy may be indicated.

Hepatic transaminase tests such as alanine transaminase (ALT) and aspartate transaminase (AST) often are part of standard laboratory panels in asymptomatic outpatients, similar to screening tests for blood donors and for life insurance applicants.

The evaluation of an abnormal ALT or AST level in an asymptomatic patient therefore is a common challenge encountered by primary care physicians.

According to the American Gastroenterological Association (AGA), 1 to 4 percent of the asymptomatic population may have elevated serum liver chemistries.1 This is consistent with the usual definition of an elevated transaminase level of the top 2.5 percent of the population range. Although one study2 of 19,877 asymptomatic young Air Force trainees found that only 0.5 percent had elevated ALT levels, physicians who have more patients with obesity, diabetes, and hyperlipidemia will have to address this issue more often.

Given the frequency of this problem, physicians should develop an informed approach to the investigation of transaminase elevations. An audit of primary care practices found that these abnormalities are not always investigated appropriately and that opportunities to intervene in treatable cases sometimes are missed.3 No controlled clinical trials have compared approaches to the management of abnormal transaminase levels. However, the AGA recently published a technical review1 and a position statement4 on the evaluation of liver chemistry tests. This article reviews the interpretation of ALT and AST levels and summarizes the AGA recommendations on addressing reported elevations.

Strength of Recommendations

Key clinical recommendation LabelReferences

An algorithmic approach to evaluating mildly abnormal liver functions is recommended.

C 1

In the asymptomatic patient with negative serum testing and mild transaminase elevations, a period of lifestyle modification can be tried.

C 1

If abnormalities persist at the six-month follow-up visit, an ultrasonography of the liver is the recommended imaging modality.

C 1

ALT and AST are not useful screening tests in an otherwise healthy population.

C 1,10

The AST/ALT ratio is only somewhat helpful in diagnosis. C 5,7

ALT = alanine transaminase; AST = aspartate transaminase.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. See page 1046 for more information.

Markers of Hepatic Injury and Necrosis

ALT and AST are two of the most reliable markers of hepatocellular injury or necrosis. Their levels can be elevated in a variety of hepatic disorders. Of the two, ALT is thought to be more specific for hepatic injury because it is present mainly in the cytosol of the liver and in low concentrations elsewhere. AST has cytosolic and mitochondrial forms and is present in tissues of the liver, heart, skeletal muscle, kidneys, brain, pancreas, and lungs, and in white and red blood cells. AST is less commonly referred to as serum glutamic oxaloacetic transaminase and ALT as serum glutamic pyruvic transaminase.

Although levels of ALT and AST can be extremely elevated (exceeding 2,000 U per L in cases of hepatocyte injury and necrosis related to drugs, toxins, ischemia, and hepatitis), elevations less than five times the upper limit of normal (i.e., about 250 U per L and below) are much more common in primary care medicine. The range of possible etiologies at this level of transaminase elevation is broader (Table 1 5 ,6) and the tests less specific. It also is important to recall that patients with normal ALT and AST levels can have significant liver disease in the setting of chronic hepatocyte injury (e.g., cirrhosis, hepatitis C).

TABLE 1Etiology of ALT or AST Elevations When Less Than Five Times Normal

Common hepatic causes

Alcohol

Cirrhosis

Hepatitis B (chronic)

Hepatitis C (chronic)

Steatosis/steatohepatitis

Medications/toxins

Acute viral hepatitis

Less common hepatic causes

Autoimmune hepatitis

Hemochromatosis

Alpha1-antitrypsin deficiency

Wilson’s disease

Nonhepatic causes

Celiac disease

Hemolysis

Myopathy

Hyperthyroidism

Strenuous exercise

Macro-AST

ALT = alanine transaminase; AST = aspartate transaminase.

Adapted with permission from Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000; 342:1267, with additional information from reference 5.

The ratio of AST to ALT has some clinical utility, but has important limitations. In many forms of acute and chronic liver injury or steatosis (fatty infiltration of the liver), the ratio is less than or equal to 1. This is particularly true in patients with hepatitis C. However, an AST/ALT ratio greater than 2 characteristically is present in alcoholic hepatitis. A recent study7 of 140 patients with nonalcoholic steatohepatitis (NASH; confirmed by liver biopsy) or alcoholic liver disease found a mean AST/ALT ratio of 0.9 in patients with NASH and 2.6 in patients with alcoholic liver disease. Within the population studied, 87 percent of patients with an AST/ALT ratio of 1.3 or less had NASH (87 percent sensitivity, 84 percent specificity). The severity of NASH as measured by the degree of fibrosis increased, as did the AST/ALT ratio. A mean ratio of 1.4 was found in patients with cirrhosis related to NASH. Wilson’s disease, a rare problem, can cause the AST/ALT ratio to exceed 4.5 While these ratios are suggestive of certain conditions, there is too much overlap between groups to rely on them exclusively when making a diagnosis.

Lactate dehydrogenase (LDH) is a less specific marker of hepatocellular necrosis and usually does not add diagnostic information to that obtained with ALT and AST testing. An exception to this is the transient but massive rise of LDH in cases of ischemic hepatitis and its sustained elevation that, along with elevated alkaline phosphatase levels, suggests malignant infiltration of the liver.5

Elevations of ALT and AST are not exclusive to liver pathology. Hyperthyroidism has been found in several studies to increase serum levels of liver enzymes including ALT and AST.8 Genetic influences on the level of ALT also are possible. A study9 of Danish

twins showed that genetic factors accounted for 33 to 66 percent of the variation in ALT, gamma glutamyl transpeptidase, LDH, and bilirubin in patients 73 to 94 years of age. The AGA technical review states that serum ALT has diurnal variation, may vary day to day, and may be affected by exercise. It also notes that serum AST may be 15 percent higher in black men than white men.1

Another cause of elevated liver transaminase levels is muscle injury. Strenuous exercise or myopathy can cause elevations (especially of AST) without causing any other symptoms. A creatine kinase or other muscle marker can be obtained to confirm or exclude such a process.

Annual screening of healthy, asymptomatic patients for liver disease using ALT and AST levels is not useful. A Japanese study10 assessed the accuracy of ALT and AST for detecting hepatitis C, excess alcohol use, and fatty liver disease in male bank employees and found the positive predictive value of the test to be low. Only 3.9 percent of the men with an abnormal ALT level had hepatitis C; 8 percent were excessive users of alcohol; and 35.7 percent had fatty liver.

Management

A thorough medical history and physical examination are the cornerstone of the evaluation of patients with mildly elevated liver transaminase levels.1  The history should attempt to identify risk factors for disease, with special attention directed toward family history, medications, vitamins, herbal supplements, drug use, alcohol use, abnormal liver testing, blood-product transfusions, and symptoms of liver disease. Table 2 6 lists selected medications and herbal supplements that may cause elevated transaminase levels. Physicians should ask patients directly about their use of illicit drugs, herbal supplements, and other alternative “supplements” because these sometimes are omitted from the patient’s initial response to questions.

TABLE 2Common Agents That Can Cause Liver Transaminase Elevations

Medications Herbal supplements/vitamins

Acetaminophen Chaparral leaf

Amiodarone (Cordarone) Ephedra

Amoxicillin-clavulanic acid Gentian

Carbamazepine (Tegretol) Germander

Fluconazole (Diflucan) Jin bu huan

Glyburide (Micronase) Kava

Medications Herbal supplements/vitamins

Heparin Scutellaria (skullcap)

Isoniazid (INH) Senna

Ketoconazole (Nizoral) Shark cartilage

Labetalol (Normodyne) Vitamin A

Nitrofurantoin (Furadantin)

Nonsteroidal anti-inflammatory drugs

Phenytoin (Dilantin)

Protease inhibitors

Sulfonamides

Trazodone (Desyrel)

Information from reference 6.

The presence of other significant health conditions that can cause or augment liver transaminase elevations also should be noted; examples are diabetes, heart disease (including congestive heart failure), thyroid disease, muscle disease, and cancer. Physical findings and sequelae of liver dysfunction are given in Table 3.

TABLE 3Clues in the Evaluation of Mildly Elevated Liver Transaminase Levels

Clinical clue Suggested diagnosis

Longstanding alcohol abuse Cirrhosis

Intravenous drug use, history of blood product transfusions, nonsterile needle exposure, AST/ALT ratio < 1.0

Hepatitis B or C

Obesity, diabetes, hyperlipidemia, AST/ALT ratio < 1.0 Steatosis/steatohepatitis

AST/ALT ratio > 2.0 Alcoholic liver disease, Wilson’s disease

Clinical clue Suggested diagnosis

Increased iron levels Hemochromatosis

Polypharmacy, illicit drug use, or certain herbal supplement use

Substance/medication-induced

Frequent, strenuous exercise Exercise-induced

Intestinal bloating; oily, bulky stools Celiac sprue

Hypergammaglobulinemia Autoimmune hepatitis

Reduced ceruloplasmin levels, Kayser-Fleischer ring Wilson’s disease

Depressed thyroid-stimulating hormone levels Hyperthyroidism

ALT = alanine transaminase; AST = aspartate transaminase. [corrected]

Once the history and physical examination are completed, additional testing can help discern the etiology of the transaminase elevation (Figure 1).4

Management of Mild ALT and AST Abnormalities

Figure 1.

Algorithm to manage mild ALT and AST abnormalities. (ALT = alanine transaminase; AST = aspartate transaminase.)

Adapted with permission from American Gastroenterological Association. Medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002; 123:1365.

INITIAL LABORATORY EVALUATION

Additional laboratory tests should be obtained when the history and physical examination show no obvious etiology for ALT and AST elevations. Ferritin, total iron-binding capacity, and serum iron can be used to look for hemochromatosis, while hepatitis A, B, and C serologies are used to rule out acute or chronic hepatitis.

Despite the emergence of widespread vaccination, hepatitis B remains a common cause of chronic liver disease in adults. Testing for hepatitis C is essential because its incidence has increased in the past decade, and new treatment strategies have been developed that can address this frequently missed problem.11

A prothrombin time (PT) and serum albumin should be ordered to identify patients with abnormalities of protein synthesis and liver function. Evaluation should be accelerated for patients with impaired hepatic synthetic function. A complete blood count with platelets also should be ordered. In addition to ruling out infection, neutropenia or thrombocytopenia can, along with an elevated PT, suggest advanced liver disease. An elevated mean red cell volume suggests heavy alcohol intake. Alkaline phosphatase and bilirubin are markers for hepatic cholestasis and should be ordered as part of the initial laboratory evaluation. While sometimes useful, they often are normal in the presence of hepatic injury.

LIFESTYLE MODIFICATION

If the patient is asymptomatic and the initial serum testing is negative, a period of lifestyle modification can be attempted. Effective lifestyle modification includes complete abstinence from alcohol, control of diabetes and hyperlipidemia, weight loss in overweight patients, and stopping or changing potentially hepatotoxic medications and supplements. Such lifestyle changes directly impact several of the causes of mild transaminase elevation (Table 1).5,6 These seemingly small modifications may be all that is needed to correct the abnormalities.

FOLLOW-UP AND IMAGING STUDIES

A repeat set of liver chemistries should be obtained after six months. If the patient’s presentation changes or the physician has concern for an evolving process, shorter intervals can be used. If abnormalities persist at the six-month follow-up visit, ultra-sonography of the liver is recommended. Computed tomography of the abdomen also is used in this setting, although clinical trials have not demonstrated an advantage of this more expensive modality.

Steatohepatitis (or nonalcoholic fatty liver disease) often is discovered by imaging. This condition may be the most frequent cause of mild liver chemistry elevations and is especially common in patients who are obese, and those who have diabetes or hyperlipidemia. One study12 of patients referred to a hospital-based gastroenterology practice found that in 83 percent of patients with elevated transaminase levels whose serum evaluation was otherwise negative, liver biopsy revealed steatosis or steatohepatitis. In 10 percent of the patients, however, liver biopsy was normal—a reminder that, at times, mildly elevated transaminase levels do not represent any underlying pathology. Excellent reviews of the management of nonalcoholic fatty liver disease have been published.13,14

If the diagnosis is not apparent from the ultrasound examination, further testing is suggested for alpha1-antitrypsin deficiency (alpha1-antitrypsin levels), Wilson’s disease (serum ceruloplasmin), celiac disease (antigliadin and anti-endomysial antibody), and autoimmune hepatitis (antinuclear antibody, anti–smooth-muscle antibody), as well as for nonhepatic causes of transaminase elevation. According to the AGA, the decision to perform a liver biopsy needs to be made on an individual basis, taking into consideration the patient’s age, lifestyle, liver chemistry abnormalities, desire for prognostic information, and associated comorbid conditions.1 Only with chronic mild transaminase elevations would an asymptomatic patient be considered a possible candidate for biopsy.