MARSHALL M. KAPLAN, MD, Professor of Medicine, Tufts University School of Medicine; and Chief Emeritus, Division of Gastroenterology, Tufts-New England
Medical Center, Boston, Mass.
EMMET B. KEEFFE, MD, Professor of Medicine, Stanford University School of Medicine; and Chief of Hepatology and Codirector, Liver Transplant
Program, Stanford University Medical Center, Stanford, Calif.
A common challenge in primary care is to determine the significance of mildly elevated serum enzyme levels and to distinguish
patients with serious chronic liver disease from those who have false-positive results secondary to disease of another organ
system or to an often insignificant hepatic condition such as fatty liver. Honing skills in this area can help physicians
refine their diagnoses of hepatocellular or cholestatic liver disease and provide optimal care.
AMINOTRANSFERASE LEVELS
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are the most widely used indicators of hepatic injury
and represent markers of hepatocellular necrosis. Both are normally present in serum at low levels, usually less than 30 to
40 U/L.1 All persistent elevations of aminotransferase levels warrant evaluation, since an explanation can almost always be uncovered.
Elevated aminotransferase values need, first, to be confirmed by repeat testing. Repetition is especially important because
in some subgroups (eg, blood donors) approximately one third of patients with a mild ALT elevation have normal values on repeat
testing. Second, a complete medical and family history needs to be taken in tandem with the physical examination. The history
should include medication use, alcohol use, OTC or illicit drug use, blood transfusions, previous episodes of jaundice or
hepatitis, history of abdominal pain, family history of liver disease or cirrhosis, sexual history, and systemic illnesses
such as malignancy, diabetes, or obesity with rapid weight loss. A family history of liver disease or cirrhosis may be present
in the patient who has alcoholic liver disease, hemochromatosis, Wilson's disease, or alpha1-antitrypsin deficiency.
If the ALT and AST levels are less than twice the upper limits of normal and no chronic liver condition is identified, observation
alone is recommended. In one study supporting this approach, close clinical follow-up was the most cost-effective strategy
for asymptomatic patients with negative test results for viral, metabolic, and autoimmune markers of liver disease and chronically
elevated aminotransferase levels.2 Another study evaluated 36 patients with a chronic elevation (at least 50% above normal) of ALT, AST, or alkaline phosphatase
(ALP) levels.3 Patients with strong evidence of a particular liver disease were excluded. Although all patients underwent liver biopsy,
the results led to a treatment change in only 2 of them.
Current recommendations stipulate that if the ALT and AST levels are persistently higher than twice the normal value, a liver
biopsy should be performed. Although the results of the biopsy are unlikely to lead to a diagnosis other than fatty liver
or to changes in management, they often provide reassurance to the patient and physician that no serious disorder is present.
Degree of elevation as diagnostic clue
TABLE 1: Characteristics of elevated concentrations of liver enzymes
|
In an asymptomatic patient with an isolated AST or ALT elevation, the first diagnostic clue is the degree of elevation. Although
there is no uniformly agreed-upon definition of what constitutes mild, moderate, or marked elevation of individual liver enzymes,
a working definition has been proposed (see Table 1).4Mild elevations are typically found in nonalcoholic fatty liver disease, including simple fatty liver and nonalcoholic steatohepatitis
(NASH) and chronic viral hepatitis. Moderate elevations may be seen in chronic viral hepatitis, alcoholic hepatitis, and a
number of miscellaneous chronic liver diseases, with or without cirrhosis. Marked elevation of aminotransferase levels is
typical of severe acute viral hepatitis, toxic or drug-induced hepatic necrosis, and shock or ischemia to the liver. The finding
of extremely high levels (greater than 2000-3000 U/L) should always raise concern for acetaminophen overdose, use of excessive
therapeutic doses of acetaminophen by an alcoholic patient, or shock and/or ischemia to the liver.
Do values need to be adjusted?
Studies have questioned whether previously established values for defining a normal ALT range are accurate and have suggested
that the upper limit of normal should be revised downward.5 Although this would greatly increase the number of asymptomatic patients diagnosed with hepatic steatosis and clinically
mild hepatitis C infection, it would also increase the number of healthy patients with abnormal ALT values by many millions
each year. In addition, previously acceptable blood donors with hepatic steatosis would become ineligible for giving blood
under the revised ALT standards.
In proposing a narrower revision of the normal ALT range, one study suggests that values for sex and body mass index (BMI)
be adjusted.6 Although some authorities recognize the merits of adjusting the values for sex, they argue that values for BMI should not
be adjusted, since many obese patients need to be made aware of their significant liver disease. Note that some clinical laboratories
have already begun adjusting aminotransferase reference ranges by sex.
POSSIBLE CAUSES OF ELEVATED AMINOTRANSFERASE LEVELS
TABLE 2: Tests for identifying possible causes of elevated aminotransferase levels
|
Common causes of elevated aminotransferase levels include hepatic steatosis (fatty infiltration of the liver), NASH, alcohol-related
liver injury, chronic hepatitis B and C infection, hemochromatosis, and autoimmune hepatitis. Blood tests can be ordered to
identify possible causes; some experts find it more efficient to order all the blood tests in the first group listed in the
table, unless the history strongly suggests a definitive diagnosis, such as alcohol abuse (see Table 2). Other authorities
prefer a prioritized approach, suggesting that physicians
- Repeat the interview on alcohol use or talk to a family member if they suspect the reliability of the history
- Evaluate the patient for risk factors for nonalcoholic fatty liver disease
- Perform the antibody test for hepatitis C infection
- Test for hepatitis B infection
- Check for hemochromatosis
- Assess for less common diseases such alpha1-antitrypsin deficiency, Wilson's disease, and occult celiac sprue, particularly if there are any clues to these disorders.
Alcoholic liver disease
Alcoholic liver disease, one of the most common causes of chronic liver disease in the US population, should be suspected
in any patient who consumes more than 70 to 80 g/d of alcohol (about 5 drinks). Women are at risk at lower consumption rates
(about 2 drinks a day). The diagnosis of alcoholic liver disease is supported by the finding of an AST to ALT ratio of at
least 2:1. The degree of aminotransferase elevation may also be helpful in identifying alcohol abuse. It is rare for the AST
level to be more than 8 times the normal value in patients with alcohol abuse, and it is even less common for the ALT level
to be more than 5 times the normal value in such patients. In fact, the ALT level may be normal, even in patients with severe
alcoholic liver disease.
Measurement of gamma-glutamyltransferase (GGT) levels may also be helpful.* A GGT level that is twice the normal value in
patients with an AST to ALT ratio of at least 2:1 strongly suggests alcohol abuse. However, the lack of specificity of the
GGT level precludes its use as a single test.
*GGT is sometimes called gamma-glutamyltranspeptidase (GGT P).
Medication, herbs, and other substances
A meticulous history and a review of laboratory data are critical for identifying a medication as the cause of elevated aminotransferase
levels. Liver injury caused by drugs and other chemicals accounts for no more than 1% to 2% of chronic hepatitis cases.7 Drugs commonly involved in chronic liver injury include antibiotics, antiepileptics, inhibitors of hydroxymethylglutaryl-CoA
reductase, NSAIDs, and antituberculosis drugs.
The easiest way to determine whether a medication is responsible for an elevated aminotransferase level is to stop treatment
and see whether the test results return to normal reference ranges. If the identified medication is essential to the patient's
well-being and no suitable substitute is available, you need to make a risk-benefit analysis to determine whether the drug
should be continued despite the abnormal test result.
Viral hepatitis
The risk of chronic hepatitis C virus (HCV) infection is highest in patients with a history of parenteral exposure to the
virus (because of blood transfusions, IV drug use, or work-related duties), cocaine use, tattoos, body piercing, and high-risk
sexual behavior. The prevalence of HCV infection in the US population is estimated at 4.1 million (1.6% of the population)
with most individuals being unaware of their infection.8 In most patients with viral hepatitis, the ALT level is usually 1.5 to 2 times higher than the AST level, but as cirrhosis
develops in hepatitis B virus (HBV) or HCV infection, the AST to ALT ratio normalizes or the AST level may be slightly higher.
The initial test for diagnosis of HCV infection is an enzyme immunoassay (EIA) for antibodies to HCV, which has a sensitivity
of 92% to 97%, depending on the assay.9 A positive test result in a patient with risk factors for infection is sufficient to make the diagnosis, but the diagnosis
is usually confirmed by measurement of serum levels of HCV RNA by means of a reverse transcriptase polymerase chain reaction
test. A positive finding should prompt consideration of liver biopsy to assess the severity of damage. Patients with HCV infection
and evidence of hepatic fibrosis are usually treated.
Initial tests for HBV infection include serologic tests for hepatitis B surface antigen, hepatitis B surface antibody, and
hepatitis B core antibody. A positive test result for hepatitis B surface antibody and core antibody indicates the presence
of immunity to HBV, and another cause for the elevated aminotransferase levels should be sought. A positive test result for
hepatitis B surface antigen and core antibody indicates the presence of infection. Tests to determine whether there is active
viral replication, including serologic tests for the presence of hepatitis B e antigen, hepatitis B e antibody, and hepatitis
B virus DNA, should be undertaken. In patients with an HBV DNA titer greater than 105 copies/mL and elevated ALT levels, whether the findings for hepatitis B e antigen are positive or negative, liver biopsy
and antiviral treatment need to be considered.
Autoimmune hepatitis
Autoimmune hepatitis occurs primarily in young to middle-aged women with the ratio of female to male patients being 4:1.10 Serum protein electrophoresis is a useful screening test. More than 80% of patients with autoimmune hepatitis have hypergammaglobulinemia;
a finding of more than twice the normal level of polyclonal immunoglobulins is most suggestive of the diagnosis. Although
additional serologic tests for antinuclear antibodies, antibodies against smooth muscle, and liver-kidney microsomal antibodies
are commonly ordered, these antibodies may not be present in some patients with autoimmune hepatitis. A liver biopsy is essential
to confirm the diagnosis.
Nonalcoholic fatty liver disease
The prevalence of nonalcoholic fatty liver disease in the general US population has been estimated to be as high as 20%; for
NASH, the estimated prevalence is around 3%.11 In contrast to patients with alcohol-related liver disease, patients with NASH (in the absence of cirrhosis) usually have
an AST to ALT ratio that is less than 1:1.12
Traditional thinking has held that NASH most commonly affects obese, diabetic, middle-aged women, but recent experience has
shown that men are also affected and that obesity and diabetes may be absent. In addition, fatty liver disease occasionally
results from medications, including prednisone, methotrexate (Rheumatrex, Trexall), synthetic estrogens, amiodarone (Cordarone,
Pacerone), tamoxifen, nifedipine, and diltiazem. It can also result from heavy exposure to organic solvents, long-term IV
feeding, and several rare genetic diseases.
In some patients with NASH, the condition may progress to cirrhosis, so just how aggressively to evaluate fatty liver disease
is a controversial issue. Ultrasound or CT scan can often identify fatty infiltration of the liver, but no specific medical
therapy currently exists. Drugs used to treat type 2 diabetes, such as pioglitazone (Actos), rosiglitazone (Avandia), and
metformin (Glucophage), are being investigated and, in some patients, improve ALT levels and liver histology after 2 years.
There are no long-term data concerning their efficacy. Vitamin E and ursodiol (Actigall) have been tried and are not effective.
Basic treatment consists of weight loss, control of diabetes, and management of hyperlipidemia.
Other less common causes of elevated aminotransferase levels
If other causes of aminotransferase elevation have been ruled out, the patient should be tested for the following diseases.
These conditions are seen infrequently, and a liver biopsy is usually needed for confirmation and assessment of hepatic damage.
Hemochromatosis
This disease, which occurs in 1 in 300 individuals in the general population, is suggested by a high percentage of iron
saturation and often confirmed by detection of 2 copies of the HFE gene.13 Serum ferritin levels are less reliable because they often increase in tandem with ALT and AST levels in many different
liver diseases. Most symptomatic patients are aged 40 to 50 and have lethargy, arthralgia, and decreased libido, but most
affected persons are asymptomatic. Because of potentially severe consequences if treatment is not initiated early, always
consider the diagnosis of hemochromatosis when minor elevations of liver enzymes are detected.
Wilson's disease
A genetic disorder of biliary copper excretion, Wilson's disease may cause elevated aminotransferase levels in patients
with no other symptoms of the disease. Clinical onset is usually between ages 5 and 25, but the diagnosis should be considered
in patients up to age 75. Occurring in approximately 1 in 30,000 people, this rare disorder can be specifically diagnosed
by the findings of Kayser-Fleischer rings, a low serum ceruloplasmin level, elevated urinary copper excretion, and high hepatic
copper concentration.
Alpha
1
-antitrypsin deficiency
A genetic condition that is more prevalent among whites, alpha1-antitrypsin deficiency is a not-uncommon metabolic disease that affects the liver. A reduced alpha1-antitrypsin level, typically to 20% of normal values, or a decreased alpha1-globulin concentration on serum electrophoresis, or both, suggests the condition. Confirmation of the diagnosis is made by
assaying for the protease inhibitor phenotype because alpha1-antitrypsin levels can be elevated in response to inflammation, thus providing a false-negative result.
Occult celiac sprue
Recently recognized as a cause of elevated values on liver tests, celiac sprue is diagnosed by measuring antiendomysial,
antigliadin, and tissue transglutaminase antibodies. These findings should be evaluated—particularly if weight loss, abdominal
distention, flatulence, and steatorrhea are present (though these symptoms are often absent) and other causes of liver function
elevations have been ruled out. In a recent study, occult celiac sprue was the cause of chronically elevated aminotransferase
levels in 13 of 140 asymptomatic patients who were referred to a liver clinic.14
CAUSES OF ELEVATED ALP LEVELS
Elevated ALP levels have been observed most commonly in patients with obstructive hepatobiliary diseases, infiltrative diseases
of the liver including primary and metastatic tumors, drug-induced liver disease, and primary biliary cirrhosis. Mild elevation
of ALP levels is also common in the third trimester of pregnancy and in physiologic bone growth, and it is not uncommon in
otherwise healthy patients older than 50. Measurements of serum 5'-nucleotidase or GGT levels, which tend to rise in tandem
with ALP levels when the source is hepatic, usually identify the source of an elevated ALP result.
CAUSES OF ELEVATED GGT LEVELS
Elevated GGT levels can reflect both hepatocellular and cholestatic causes of liver disease. Elevations in both GGT and ALP
levels strongly suggest that the ALP elevation is of hepatobiliary origin. GGT is a microsomal enzyme, and an elevated level
without an increase in the ALP level is most often caused by excessive consumption of alcohol, alcohol abuse with alcoholic
liver disease, or drugs that induce microsomal enzymes such as phenytoin (Dilantin) or phenobarbital.15 An elevated GGT level without an increase in the ALP level is most often caused by alcoholic liver damage. Both ALP and
GGT of hepatobiliary origin are also sensitive markers of metastatic liver cancer, which can usually be detected with hepatic
imaging.
CAUSES OF ELEVATED BILIRUBIN LEVELS
An elevated conjugated bilirubin level may have viral, chemical, or alcohol-related causes or be the result of biliary tract
obstruction or cirrhosis.16 Gilbert's syndrome is the most common cause of an elevated unconjugated bilirubin level in an otherwise normal liver test
panel and may be present in about 5% of the population. Hemolysis can be distinguished from Gilbert's syndrome by use of the
CBC, reticulocyte count, and peripheral blood smear. Hemolysis typically causes an elevated reticulocyte count and an abnormal
peripheral blood smear, both of which are normal findings in Gilbert's syndrome.
WHEN TO IMAGE AND BIOPSY
Reserve imaging of the liver for patients with persistently elevated AST or ALT levels whose other blood test results are
normal. Imaging is particularly helpful if the ALP or GGT levels are elevated. The findings can rule out biliary tract obstruction,
whether intrahepatic (liver tumor) or extrahepatic (tumors or stones blocking the bile duct). Liver biopsy should be reserved
for patients with AST or ALT levels that are persistently more than twice the normal values and whose other blood tests and
imaging studies are negative.
This article was written by Anne B. Brown, based on individual interviews with Drs Kaplan and Keeffe, and updated by Drs Kaplan
and Keeffe.
Drs Kaplan and Keeffe disclose that they have no financial relationship with any manufacturer in this area of medicine.
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Drugs mentioned in this article
Amiodarone (Cordarone, Pacerone)
Diltiazem Metformin (Glucophage)
Methotrexate (Rheumatrex, Trexall)
Nifedipine Phenobarbital
Phenytoin (Dilantin)
Pioglitazone (Actos)
Prednisone Rosiglitazone (Avandia)
Tamoxifen Ursodiol (Actigall)
Vitamin E
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