Evaluation of Abnormal Liver Tests

January 5, 2002

NOTE: To view the article with Web enhancements, go to:

http://www.medscape.com/ExcerptaMed/ClinCornerstne/2001/v03.n06/clc0306.02.roch/\

clc0306.02.roch-01.html.

Evaluation of Abnormal Liver Tests

Fedja A. Rochling, MD, Assistant Professor of Medicine, Division of

Gastroenterology and Hepatology, University of Arkansas for Medical

Sciences and Central Arkansas Veterans Healthcare System, Little Rock,

Arkansas

Abstract

Serum liver tests are important but often problematic in evaluating

patients with and without symptoms of hepatic disease. The common term

" liver function tests " is misleading because most tests used in clinical

practice measure hepatocellular damage not function. True liver function

tests are those that measure synthesis of proteins made by the liver

(albumin, clotting factors) or the liver's capacity to metabolize drugs. A

commonly ordered panel of automated tests includes bilirubin,

aminotransferases, alkaline phosphatase, and -glutamyl transpeptidase.

This article reviews patterns of elevated enzyme values encountered in

liver diseases and their diagnostic limitations and provides an algorithm

for evaluating abnormal liver test results.

Evaluation

Although as many as 6% of normal asymptomatic people may have abnormal

liver enzyme levels, the overall prevalence of liver disease in the

general population is only ~1%. Inherent to the definition of " normal

range, " 5% of all test results from normal persons fall outside this

range; hence, some abnormal liver tests are not truly abnormal. A

practical approach to an isolated elevation of an aminotransferase level

is to repeat the test, with further evaluation only if >2-fold elevation

persists (Table I).

Initial evaluation of the patient with abnormal liver test results should

include a physical examination and the patient's history with an emphasis

on risk factors for viral hepatitis, medication used in the preceding 6

months, consumption of herbal and alternative remedies, and occupational

exposure to toxins. Liver disease may exist even in the absence of obvious

risk factors. Figure 1 shows an approach to the evaluation of asymptomatic

patients with an abnormal liver test. Management of abnormal liver tests

in the absence of liver risk factors should involve repeating the test

once. Risk factors or underlying conditions such as viral hepatitis,

autoimmune hepatitis, hemochromatosis, 's disease (WD),

alpha1-antitrypsin deficiency, and medications should have been excluded.

If continued elevation of the enzyme values of >2 x the upper limit of

normal for the reference laboratory is encountered, then further

diagnostic evaluation with imaging studies and a liver biopsy is

indicated. Recent publications point to the role of chemical agents such

as dimethylformide, hydrazine derivatives, and hydrochlorofluorocarbons as

etiologic agents for the development of abnormal liver blood tests in

otherwise healthy individuals.

Figure 1. Suggested approach to using liver tests to evaluate asymptomatic

patients. HBsAg = hepatitis B surface antigen; anti-HBc = antibody to

hepatitis B core antigen; anti-HCV = antibody to hepatitis C virus; AP =

alkaline phosphatase; AST = aspartate aminotransferase; ALT = alanine

aminotransferase; TF = transferrin; CT = computed tomography; US =

ultrasound; MR = magnetic resonance; ERCP = endoscopic retrograde

cholangiopancreatography. Modified from Bach N, Koff RS, Maddrey W. When

and how to screen for liver disease. Intern Med. 1999;20:49, with

permission.

Bilirubin Levels

Normal serum bilirubin values represent a balance between production

(degradation of hemoglobin) and hepatic elimination. Normal total serum

bilirubin levels are 6 mg/dL. In complete bile duct obstruction, the

maximum observed bilirubin level is ~30 mg/dL because the kidneys continue

to excrete conjugated bilirubin.

Bilirubin levels of 25 to 30 mg/dL indicate severe hepatic parenchymal

disease associated with hemolysis or renal disease (Table III). History,

physical examination, and imaging studies such as transabdominal

ultrasonography are needed to further determine the cause of jaundice. The

threshold value of the serum bilirubin associated with jaundice is

variable, but in general icterus is clinically detectable at 2 to 3 mg/dL.

Serum Aminotransferases

Serum aminotransferases are enzymes that act as sensitive indicators of

hepatocellular damage. The less specific aspartate aminotransferase (AST)

is localized in heart, skeletal muscle, kidney, brain, pancreas, lungs,

leukocytes, and erythrocytes. Alanine aminotransferase (ALT) is limited to

the liver.

Aminotransferase levels are elevated in acute and chronic hepatitis,

cirrhosis, hepatic congestion, and infiltrative diseases such as infection

or cancer (Table IV). The degree of enzyme level elevation does not

correlate with eventual outcome, even when aminotransferase values reach

the several thousands range. In contrast, patients with acute alcoholic

hepatitis may have severe liver dysfunction despite elevated

aminotransferase levels only in the 200 to 400 IU/L range. In drug

toxicity or acute viral hepatitis, a full recovery is usually seen.

Declining AST and ALT levels generally indicate recovery; however,

although rare, a rapid decline may portend a poor outcome because of mass

hepatocyte death. In some patients a rapid decline of transaminases may be

accompanied by a progressive coagulopathy, hypoglycemia, and infection,

thus resulting in death.

In alcoholic liver disease, ALT levels tend to be normal or minimally

elevated. The AST to ALT ratio is useful diagnostically in patients with

alcoholic liver disease, 70% of whom have a ratio >2. Low AST levels may

be seen in hemodialysis and pyridoxine-deficient patients.

Isolated, persistently elevated aminotransferase levels, with negative

viral markers and an absence of alcohol abuse, usually signify fatty liver

or nonalcoholic steatohepatitis. Initially, when an isolated elevation of

an aminotransferase level is reported, the test should be repeated.

Further evaluation is indicated only if a persistent, >2-fold elevation is

observed.

Elevation of immunoglobulin (Ig)-complexed AST levels ( " macro-AST " )

detected on routine blood testing may falsely imply hepatic dysfunction.

The elevated AST values can persist for many years. Liver and muscle

disease can be excluded by the finding of normal serum levels of ALT and

creatine phosphokinase. Evaluation for a macroenzyme should be pursued

only when a single enzyme level is elevated and more common causes of

abnormal liver test results have been excluded. The presence of macro-AST

can be determined by exclusion chromatography, electrophoresis, activation

assays with pyridoxal-58-phosphate, or measurement of urinary excretion.

No literature is available that describes one methodology as preferable to

another.

Alkaline Phosphatase

Alkaline phosphatase (AP) comprises a family of enzymes located in liver,

bone, placenta, and intestine that hydrolyze phosphate esters at alkaline

pH. In healthy subjects, circulating AP is derived from bone and liver; in

those with blood group O, AP is primarily of intestinal origin. There is a

direct correlation between serum AP levels and body weight and frequency

of cigarette smoking and an indirect correlation with height.

In the third month of pregnancy, AP levels are elevated to 2 x the upper

limit of normal. Other extrahepatic causes of elevated AP levels include

hyperthyroidism, cardiac failure, lymphoma, hypernephroma, and Paget's

disease of the bone. Infiltrative or granulomatous hepatic disease such as

tuberculosis, sarcoidosis, fungal infections, and lymphoma can elevate AP

levels disproportionately to bilirubin.

Determining whether an isolated elevation of AP levels indicates liver or

biliary disease can be approached by electrophoretic fractionation of AP

or by measurement of -glutamyl transpeptidase (GGT), 58 nucleotidase, or

leucine aminopeptidase. In nonpregnant patients, increased GGT levels

indicate that the elevated AP levels are of hepatic origin. In £ one third

of cases, elevated levels of hepatic AP are nonspecific. The degree of

elevation of AP levels does not help differentiate between extrahepatic

and intrahepatic cholestasis.

Low to undetectable levels of AP can be seen in fulminant WD,

hypothyroidism, pernicious anemia, congenital hypophosphatasia, zinc

deficiency, and in blood samples anticoagulated with oxaloacetate. Figure

2 provides an evaluation approach for elevated AP levels.

Figure 2. Approach to elevation of alkaline phosphatase (AP) levels. GGT =

-glutamyl transpeptidase; ERCP = endoscopic retrograde

cholangiopancreatography; AMA = antimitochondrial antibody. From Kamath

PS. Clinical approach to the patient with abnormal liver test results.

Mayo Clin Proc. 1996;71:1089-1095, with permission.

Gamma-glutamyl Transpeptidase

Elevation of GGT levels may be associated with liver, biliary or

pancreatic disease, myocardial infarction, renal disease, chronic lung

disease, and diabetes. Elevation of GGT levels is a sensitive but

nonspecific indicator of biliary disease. The major use of GGT is to

confer additional liver specificity in evaluating elevated AP levels.

GGT, a microsomal enzyme, provides an indirect but nonspecific approach to

assessment of mixed-function oxidase activity, including cytochrome P-450.

Agents such as ethanol and phenytoin, which induce these enzymes, cause

elevation of GGT levels.

In a large study conducted in Norway, GGT levels were measured in >21,000

healthy people. A sex-specific multiple regression analysis showed a

strong association between GGT levels and body mass index, alcohol use,

and total serum cholesterol and a somewhat weaker association with serum

triglycerides, high-density lipoprotein cholesterol, heart rate, blood

pressure, use of analgesics, and time since last meal. The association of

high levels of GGT (and other liver enzymes) with moderate obesity in

nonalcoholic, nondrinking men has been attributed to hepatic steatosis.

Familial idiopathic elevation of GGT levels has been reported and should

be considered only when other common causes of elevated GGT levels have

been excluded.

Tests of Liver Function

Although the tests discussed earlier are often termed " liver function

tests, " the term is a misnomer; most liver tests used in clinical practice

measure hepatocellular damage rather than liver function. True liver

function tests measure the liver's synthesis of proteins (albumin,

clotting factors) or its capacity to metabolize drugs (galactose or

aminopyrine clearance). The latter are rarely used in general practice and

are not reviewed here.

Albumin

Measurement of serum albumin levels is useful in chronic liver disease and

is a component of grading systems (eg, Childs-Turcotte-Pugh, Mayo Endstage

Liver Disease Score). The protein is not a good indicator of hepatic

synthetic function in acute liver disease due to its half-life of 20 days.

The patient with alcoholic liver disease, protein malnutrition, or chronic

hepatitis may experience downregulation of albumin synthesis. Patients

with ascites may have upregulated albumin synthesis but exhibit low serum

levels due to the larger volume of distribution.

Prothrombin Time

Prothrombin time (PT), a universal indicator of liver failure, is

prolonged in cholestasis or severe hepatocellular disease. Correction of

the PT after parenteral administration of vitamin K may help distinguish

cholestasis from hepatocellular disease. (When the PT is prolonged,

vitamin K is given 5 to 10 mg/d for £3 days; if the PT improves by 30% or

normalizes within 24 hours of vitamin K administration, then hepatic

function is intact with regard to clotting factor production and PT

prolongation was probably due to vitamin K deficiency.)

In acetaminophen-induced fulminant hepatic failure, PT is an important

early predictor of outcome and may assist with timely referral to a liver

transplant facility. Due to variability among thromboplastin reagents,

there are large interlaboratory differences in PT results. Nevertheless,

PT standardization in patients with liver failure using the international

normalized ratio (INR) has been misleading. Some authorities discourage

the use of INR to assess prognosis in hepatic failure.

Immunoglobulins

Individuals with cirrhosis may demonstrate elevated levels of Igs due to

impaired function of the hepatic reticuloendothelial system (Kupffer's

cells) and portovenous shunting of blood. Various diseases are associated

with distinctive Ig patterns. The pattern of Igs in antimitochondrial

antibody (AMA)-positive primary biliary cirrhosis (PBC) is characterized

by elevated IgM levels with normal IgA levels. In rare cases of

AMA-negative PBC, IgG levels are elevated whereas IgM levels are usually

normal.

Persistent hypergammaglobulinemia suggests chronic active hepatitis,

usually due to an autoimmune etiology. In autoimmune hepatitis, the

response to immunomodulatory therapy can be monitored by following serum

aminotransferase levels and quantitative Ig values.

Drug- and Toxin-Induced Elevation of Liver Enzyme Levels

Many drugs and industrial toxins affect the liver and cause either

hepatocellular or cholestatic injury, as evidenced by elevated liver

enzyme levels (Table V). Drug-induced liver injury accounts for >30% of

acute liver failure and 2% to 20% of hospitalized jaundiced patients.

Monitoring both ALT and AST levels is recommended for drugs with

hepatotoxic potential. ALT level elevations 80% of phenotypic HH patients.

HH should be suspected when patients present with symptoms or physical

findings such as abnormal liver enzymes, a family history of HH, or

abnormal iron studies indicative of liver disease.

Early diagnosis and treatment reduce morbidity and mortality. However,

serum iron studies are associated with false-positive and false-negative

results. Reliance on these alone to diagnose HH can be misleading. HFE

gene testing is a reasonable step after repeat-fasting elevated

transferrin levels (>50%) or elevated serum ferritin levels (>500 mg/L).

However, £20% of patients with clinical HH do not have HFE mutations.

For the individual 30% of acute liver failure and £20% of hospitalized

jaundiced patients. Monitoring aminotransferase levels is recommended for

drugs with hepatotoxic potential. ALT level elevations 3 x upper normal

limits.

Sidebar: Dialogue Box

ADVISORY BOARD

What is your management of the patient with a mild elevation, that is less

than 2-fold, of AST and ALT levels?

RAUFMAN

In the asymptomatic patient I would repeat the test in 1 to 3 months.

Since it is common in a patient with hepatitis C for serum transaminase

levels to fluctuate back and forth from normal, I would also do a

hepatitis C antibody test. If that test is negative and the ALT levels

remain 2-fold or less elevated, I would check the levels again in 6 to 9

months. I definitely wouldn't ignore it, but I wouldn't feel compelled to

evaluate the patient further. Sometimes you see patients who don't feel

comfortable with this approach and have to know what the precise cause of

the elevation is regardless of how mild the abnormality. In such a

situation, you're going to have to decide whether a more aggressive

diagnostic approach, possibly even a liver biopsy, is reasonable in an

effort to allay the patient's anxiety.

ADVISORY BOARD

In a patient found to have an unconjugated hyperbilirubinemia, what is the

minimum workup required to make the diagnosis of GS?

RAUFMAN

Provided the patient is relatively young and the serum bilirubin level is

no higher than 5 mg/dL, I would require only that the patient have normal

liver tests, that is, normal transaminase levels and normal alkaline

phosphatase levels, with no evidence of hemolysis or coagulopathy and a

normal complete blood cell count. In the asymptomatic patient with normal

liver tests, I would feel secure with the diagnosis and would simply

follow the patient.

ADVISORY BOARD

What do you mean by " follow the patient " ?

RAUFMAN

I would repeat the bilirubin test periodically, assuming this is a patient

I see in practice, and tell the patient to call if any signs or symptoms

of anything develop. I would then repeat the test in 1 or 2 months to make

sure there was no upward trend. For example, if the bilirubin level went

up and there was no evidence that the patient had been stressed, I would

be more concerned about another cause for the increased bilirubin.

ADVISORY BOARD

What can be expected in a patient with GS subjected to the stress of the

postoperative period?

RAUFMAN

For most patients, uncomplicated surgery should not make a difference if

the patient is kept adequately hydrated and there isn't significant

third-spacing of blood. A minor 1- to 2-mg/dL rise of bilirubin might be

seen during the perioperative period, but that really shouldn't be a

problem. The liver synthetic function in terms of clotting should remain

perfectly normal.

ADVISORY BOARD

In the acute setting in the emergency room, if someone came in with a

hepatocellular injury such as acute viral hepatitis, what parameters would

you use to determine the severity and whether the patient requires

admission?

RAUFMAN

I would evaluate several parameters. Findings that would warrant hospital

admission include the presence of coagulopathy with a prolonged INR,

mental status abnormalities suggesting hepatic encephalopathy, the

presence of hypoglycemia, and, particularly with the patient with viral

hepatitis, inability to tolerate oral intake, electrolyte abnormalities,

or significant dehydration.

ADVISORY BOARD

In the workup of a patient with elevated ALT and AST levels, what

laboratory tests do you order to exclude the possibility of autoimmune

hepatitis?

RAUFMAN

I generally order the antinuclear antibody (ANA) and anti-smooth muscle

antibody tests. For the patient with whom I have a higher index of

suspicion, for example a woman with rash and arthralgias, I would also

order more specialized tests such as a liver-kidney microsomal antibody.

Otherwise a normal ANA and normal smooth muscle antibody should rule out

autoimmune hepatitis most of the time.

ADVISORY BOARD

In what settings would a patient likely be exposed to hepatotoxic

chemicals such as dimethyl-fluoride hydralazine derivatives and

hydrochlorofluorocarbons?

RAUFMAN

Situations where there is risk of exposure to industrial solvents. For

example, patients involved in the dry cleaning business or who work as

janitors can be exposed to fumes from these solvents and develop liver

disease over time.

ADVISORY BOARD

What is the value of including the AST in the screening panel?

RAUFMAN

For detecting alcoholic liver disease. The ALT/AST ratio can be really

helpful at times in discriminating alcoholic liver disease from other

causes of elevated transaminase levels, such as viral hepatitis. Although

the AST is nonspecific and can come from a lot of different organs, such

as muscle, it can be of value as an early indicator of alcoholic liver

disease.

ADVISORY BOARD

Do you think that AST is a better marker for alcoholic injury than the

GGT?

RAUFMAN

Yes. They look at different things, but in terms of actual injury, the AST

is better at detecting the development of alcoholic hepatitis. GGT levels

do go up in alcoholic liver disease, but they also go up in other disease

states such as cholestatic liver disease. I don't think GGT is as helpful

as AST because it isn't quite as specific as we would like to think. I

find the real value of the GGT to be in the workup of elevated AP levels

-- if the GGT levels are elevated then the elevated AP levels are likely

hepatobiliary in origin; if they are normal, then the elevation is likely

coming from bone.

ADVISORY BOARD

How do you screen for hemochromatosis?

RAUFMAN

I usually screen by ordering the transferrin saturation. If the iron

saturation is 30 mg/dL 50% >50% >50%

Alanine

aminotransferase Normal >5-fold increase 2- to 5-fold increase 3- to 5-

fold increase with cholangitis

Alkaline phosphatase Normal 3- to 5-fold increase >3- to 5-fold increase

Prothrombin time Normal Prolonged Prolonged Prolonged

Corrected by vitamin K - No Variable Yes

Ultrasonography of liver

Biliary dilatation No No No Yes

Endoscopic retrograde cholangiopancreatography Not necessary Not necessary

Usually not necessary Usually necessary

*May or may not be present. Reprinted with permission from Kamath PS.

Clinical approach to the patient with abnormal liver test results. Mayo

Clin Proc. 1996;71:1089-1095.

Table IV. Typical Rangeof Elevated Aminotransferase Levels (AST AND ALT)

in Various Liver Diseases

Mild Elevation ( 20-fold)

Viral hepatitis

Drug- or toxin-induced hepatitis

Ischemic hepatitis

AST = aspartate aminotransferase; ALT = alanine aminotransferase.

Table V. Agents Reported to Cause Elevations in Liver Enzyme Levels

Medications

Antibiotics

Antiepileptic drugs

HMG-CoA reductase inhibitors

Sulfonylureas

NSAIDs

Herbs and Alternative Remedies

Chaparral

Chinese herbs

Gentian

Scutellaria (skullcap)

Germander

Alchemilla

Senna

Shark cartilage

Substances of Abuse and Toxins

Anabolic steroids

Cocaine

58 Methoxy-3,4 methylenedioxy

Methamphetamine hydrochloride

(Ecstasy)

Phencyclidine hydrochloride

(angel dust)

Glues and solvents containing toluene

Trichloroethylene, chloroform

Amanita phalloides toxin

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NSAIDs = nonsteroidal

anti-inflammatory drugs. Modified from Pratt DS, Kaplan MM. Evaluation of

abnormal liver-enzyme results in asymptomatic patients. N Engl J Med.

2000;342: 1266-1271, with permission.

Suggested Reading

Bach N, Koff RS, Maddrey W. When and how to screen for liver disease.

Intern Med. 1999;20:49.

Bacon BR. Iron overload states. Clin Liver Dis. 1998; 2:63-75.

Borer WZ. Reference intervals for the interpretation of laboratory tests.

In: Rakel RE, ed. Conn's Current Therapy. Philadelphia, Pa: WB Saunders

Co; 1996:1197-1198.

Friedman LS, P, Munoz SJ. Liver function tests and the objective

evaluation of the patient with liver disease. In: Zakim D, Boyer TD, eds.

Hepatology: A Textbook of Liver Disease. 3rd ed. Philadelphia, Pa: WB

Saunders Co; 1996:791-833.

Gopal DV, Rosen HR. Abnormal findings on liver function tests.

Interpreting results to narrow the diagnosis and establish a prognosis.

Postgrad Med. 2000;107: 100-114.

ston DE. Special considerations in interpreting liver function tests.

Am Fam Phys. 1999;59:2223-2230.

Kamath PS. Clinical approach to the patient with abnormal liver test

results. Mayo Clin Proc. 1996;71: 1089-1095.

Kew MC. Serum aminotransferase concentration as evidence of hepatocellular

damage. Lancet. 2000;355: 591-592.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. N Engl J Med. 2000;342:1266-1271.

Pratt DS, Kaplan MM. Evaluation of the liver: laboratory tests. In: Schiff

ER, Sorrell MF, Maddrey WC, eds. Schiff's Diseases of the Liver. 8th ed.

Philadelphia, Pa: Lippincott & Wilkins Inc; 1999:205-244.

Whitehead MW, Hawkes ND, Hainsworth I, Kingham JG. A prospective study of

the causes of notably raised aspartate aminotransferase of liver origin.

Gut. 1999; 45:129-133

__________________________________________________

January 5, 2002