Liver Enzyme Abnormalities:What to Do for the Patient

March 1, 2006

You routinely order laboratory screeningpanels, including serum liver enzymemeasurements, for nearly everypatient who has a complete physicalexamination or who is seen for any ofa host of other complaints. If you findabnormal liver enzyme levels, your familiaritywith the common causes andthe settings in which they occur mayenable you to avoid costly diagnosticstudies or biopsy.

You routinely order laboratory screeningpanels, including serum liver enzymemeasurements, for nearly everypatient who has a complete physicalexamination or who is seen for any ofa host of other complaints. If you findabnormal liver enzyme levels, your familiaritywith the common causes andthe settings in which they occur mayenable you to avoid costly diagnosticstudies or biopsy.

In this article, I present brief casehistories of patients who have similarliver enzyme abnormalities but quitedissimilar clinical backgrounds. Thesedifferences can help guide you in theinterpretation of laboratory findings inyour own patients.

AN APPROACHTO INTERPRETING LIVERENZYME ELEVATIONS
I find it helpful to divide patientswith liver enzyme deviations into 2 categories,according to the predominantelevation: alkaline phosphatase or thetransaminases--aspartate aminotransferase(AST) and alanine aminotransferase(ALT). When alkalinephosphatase elevations are the mainfeature, patients generally have eithercholestatic disease (with bile duct injuryor obstruction) or infiltrative disease--neoplastic or granulomatous(eg, sarcoidosis or tuberculosis).When transaminase elevation is thepredominant abnormality, the usualcause is hepatocellular injury--typifiedby viral hepatitis, autoimmune hepatitis,or injury from medications or toxins(eg, halothane, acetaminophen, orpoisonous mushrooms).

An alkaline phosphatase elevationcan be induced by liver or bone disease.When it arises from the liver, theother liver enzymes, such as AST andALT, are usually mildly elevated aswell; it is unusual for them to be completelynormal. Bone disease, however,cannot account for even mild AST orALT elevation.

γ-Glutamyl transpeptidase (GGT)levels tend to parallel alkaline phosphataseelevations that stem from theliver. Measurement of GGT can be auseful confirmatory test, but it is an inducibleenzyme. Its levels rise (in theabsence of liver disease) in personswho are accustomed to drinking excessivequantities of alcohol or whotake certain medications, such as phenobarbitalor phenytoin.1,2 Some patientshave a mixed (cholestatic andhepatocellular) injury, but most can becategorized in the above manner.

PREDOMINANTALKALINE PHOSPHATASEELEVATION
Let us consider the cases of 8 patients,all of whom have the same abnormalliver enzyme levels: AST, 75U/L (normal, 5 to 35 U/L); ALT, 90U/L (normal, 5 to 40 U/L); and alkalinephosphatase, 450 U/L (normal,less than 85 U/L). (These values areconsidered the norm in my laboratory.)With the exception of one, all patientshave total bilirubin levels of 1.3 mg/dL(normal, up to 1.1 mg/dL). This is atypical pattern in which the alkalinephosphatase concentration is the predominantabnormality. The mild or trivialtransaminase elevations stronglysuggest that the increased alkalinephosphatase level is from liver ratherthan bone.

Because this liver enzyme patternis inconsistent with primary hepatocellularinjury, such as that typicallyseen in viral hepatitis, it would be awaste of money to order hepatitis serologictests. Nevertheless, you mustconsider a differential diagnosis thatincludes a wide range of cholestaticand infiltrative disorders (Table).

 Table - Common causes of hepatic alkaline phosphatase elevation
Extrahepatic obstruction 

Intrahepatic cholestasis 

Infiltrative disorders 

Not every patient, of course, requiresextensive evaluation with invasiveradiologic studies or liver biopsy.Consider first the clinical setting inwhich the abnormalities occur. Informationgarnered from the history andphysical examination will enable you tofocus on the likely diagnosis, and onlyone or two confirmatory tests may berequired.

Case 1:
Young, Asymptomatic Woman

During the course of a routinephysical examination, a 30-year-oldAfrican American woman is found tohave the following liver enzyme levels:AST, 75 U/L; ALT, 90 U/L; alkalinephosphatase, 450 U/L. Her serum bilirubinlevel is 1.3 mg/dL. She is asymptomaticand is taking no medications.

An infiltrative disorder, such assarcoidosis, rarely causes symptoms,yet it often produces this enzyme pattern.In this setting, obtain a chest film.The finding of bilateral hilar adenopathymight suffice to diagnose sarcoidosis(which occurs 10 times more frequentlyin black persons). Some physiciansmight also look for an elevation inserum angiotensin-converting enzyme.If still in doubt, they might perform aliver biopsy; in the case of sarcoidosis,this would almost certainly show noncaseatinggranulomas (Figure).

If the chest film shows no abnormalities,consider the possibility of theearliest stage of primary biliary cirrhosis--a rare disorder found moreoften in middle-aged women (see Case5). Abnormal liver enzyme concentrations(predominantly an increase in alkalinephosphatase) in a young womanwho is asymptomatic is now a commonpresentation for primary binarycirrhosis. A positive test for antimitochondrialantibodies would stronglysupport this diagnosis.

Case 2:
Ill, Feverish College Student

A 20-year-old college student isfeverish and has a sore throat and cervicallymphadenopathy. Serum levelsinclude AST, 75 U/L; ALT, 90 U/L; alkalinephosphatase, 450 U/L; and bilirubin,1.3 mg/dL.

In this setting, the diagnosis is almostcertainly mononucleosis or a re-lated viral disease, such as cytomegalovirus(CMV) infection. You mayfind that her spleen is palpable, andyou should expect to see atypical lymphocyteson a peripheral smear.A spot test for mononucleosis or anEpstein-Barr virus titer should bediagnostic.

Mononucleosis commonly producesthis liver enzyme pattern. Thecharacteristic predominant alkalinephosphatase elevation is presumed tobe caused by sinusoidal infiltrationwith atypical lymphocytes.3 No additionalstudies should be necessary.

Case 3:
Woman With AcuteAbdominal Pain

A 40-year-old woman seen in theemergency department has had severeright upper quadrant pain for thepast 3 hours. Her blood studies revealAST, 75 U/L; ALT, 90 U/L; alkalinephosphatase, 450 U/L; and bilirubin,1.3 mg/dL.

Numbers 1, 2, and 3 on your differentialdiagnosis should be cholelithiasis,which should be confirmed withan ultrasonogram. If no gallstones arevisualized (small stones may bemissed on the ultrasonogram or CTscan), but this patient continues tohave similar attacks, cholecystectomy--with operative cholangiogram orpreoperative endoscopic retrogradecholangiopancreatography (ERCP)--will still be necessary.

Case 4:
HIV-positivity, Low-grade Fever,Weight Loss
A 30-year-old man who is HIVpositivehas had a low-grade fever andweight loss for several weeks. His liverenzyme studies are as follows: AST, 75U/L; ALT, 90 U/L; alkaline phosphatase,450 U/L. His serum bilirubinlevel is 1.3 mg/dL.

Until it is proved otherwise, abnormalliver enzyme levels in an HIVpositivepatient are consicaused by an opportunistic infection(eg, tuberculosis, candidiasis, CMVinfection), which may involve theliver. A drug reaction must also beconsidered.

Moreover, HIV-positive patientsare susceptible to bile duct infectioncaused by Microsporidia, Cryptosporidium,or CMV.4,5 Obtain a CT scanto search for focal lesions in the liverand bile duct dilation. A liver biopsymay be necessary to identify thepathogen.

Case 5:
Middle-aged Woman WithPruritus and Xanthelasma

A 40-year-old woman complainsof pruritus, and you note that she hasxanthelasma. Her serum values includeAST, 75 U/L; ALT, 90 U/L; alkalinephosphatase, 450 U/L; and bilirubin,1.3 mg/dL.

This is the classic presentation ofprimary biliary cirrhosis. As previouslymentioned, this almost always affectsmiddle-aged women. You wouldexpect this patient to test strongly positivefor antimitochondrial antibody. Ifthis antibody is absent, have her bileducts evaluated by means of ERCP orpercutaneous transhepatic cholangiography.Patients with primary biliary cirrhosisbenefit from therapy with ursodeoxycholicacid.6

Case 6:
Enlarged, Nodular Liver andAnemia in Older Man

A 60-year-old man complains ofdecreased energy. His liver is large,hard, and nodular. His hematocrit is29%; mean corpuscular volume, 60 fL;stool test, positive for occult blood. Thepatient's liver enzyme levels are AST,75 U/L; ALT, 90 U/L; alkaline phosphatase,450 U/L. His serum bilirubinlevel is 1.3 mg/dL.

These findings immediately suggestcolon cancer with metastasis tothe liver. Cancer in the cecum andright side of the colon commonly presentswith occult blood in the stoolsand iron deficiency anemia. This patient'sliver enzyme pattern is typical ofmetastatic infiltration of the hepaticparenchyma. The diagnosis can beconfirmed with colonoscopy.

Case 7:
Young Man WithUlcerative Colitis
A 30-year-old man with ulcerativecolitis in remission is receiving sulfasalazinemaintenance therapy. Hisserum values include AST, 75 U/L;ALT, 90 U/L; alkaline phosphatase,450 U/L; and bilirubin, 1.3 mg/dL.

This is a textbook case of sclerosingcholangitis. Although it isseen in association with ulcerativecolitis, this condition does not correlatewith the activity or extent of colitis.The diagnosis can be confirmedwith ERCP.

Case 8:
Elderly Woman With Jaundice

Painless jaundice develops in a70-year-old woman. She had a sinus infectiona month earlier, for which shewas given amoxicillin-clavulanate. Herliver enzyme values are AST, 75 U/L;ALT, 90 U/L; and alkaline phosphatase,450 U/L. Her serum bilirubinlevel is 6 mg/dL.

When you find clinical and laboratoryevidence of cholestasis in an elderlypatient, you must consider malignancyas well as drug-inducedcholestasis. Painless jaundice associatedwith this liver enzyme profile constitutesa classic presentation of cancerof the head of the pancreas.

Remember, however, that medications(typically phenothiazines) mayalso produce this clinical and laboratorypicture. Amoxicillin-clavulanate occasionallycauses intrahepatic cholestasis,which may appear even after thedrug is discontinued.7 Obtain an ultrasonogramor CT scan of the liver andpancreas to exclude tumor in the headof the pancreas and/or bile duct dila-tion. If there is any doubt, ERCP maybe necessary.

PREDOMINANTTRANSAMINASEELEVATION
AST and ALT elevations can bemarked or mild. Very high levels usuallyindicate acute hepatocellularnecrosis, as seen in viral- or drug-inducedhepatic injury. Extremely highlevels (5000 to 10,000 U/L or higher)suggest an overdose of acetaminophen.8 As you will see in the following4 cases, the laboratory data and theclinical history often point to the correctdiagnosis.

Case 9:
Sudden Illness in Day-care Teacher

A 30-year old teacher in a day-carecenter abruptly becomes feverish, witha temperature of 38.9C (102F); she suffersheadache and myalgias, followed bynausea and anorexia. The fever subsidesafter 48 hours and she feels better,but then she notices that her urine isdark and her scleras are yellow. Herliver enzyme levels are AST, 1200 U/L;ALT, 1500 U/L; and alkaline phosphatase,150 U/L. Her serum bilirubinconcentration is 5 mg/dL.

This is a truly representative caseof hepatitis A, epidemics of which havebeen reported in day-care centers. Incontrast to other forms of viral hepatitis,hepatitis A typically presents withthe sudden onset of a flu-like illnessfeaturing headache, fever, and myalgias.The appropriate confirmatory testis IgM antibody to hepatitis A, an acutephase reactant. Other hepatitis serologictests would be superfluous.

Case 10:
Arthritis, Nausea, and Anorexiain Homosexual Man

A 30-year-old man describes therecent occurrence of arthritis in his fingersand knees and a rash on his legs.Over the following 2 weeks, he experiencesan insidious onset of nausea andanorexia. The patient then notes thathis urine is dark and the whites of hiseyes are yellow. His serum values includeAST, 1200 U/L; ALT, 1500 U/L;alkaline phosphatase, 150 U/L; andbilirubin, 5 mg/dL.

Here we see a typical case of hepatitisB, which may be sexually transmittedand is frequently encounteredamong male homosexuals. Extraintestinalmanifestations, such as arthritisand vasculitis, are common in thelate incubation period. The diagnosis isconfirmed by detection of the hepatitisB surface antigen.

Case 11:
Arthralgias and Amenorrheain Young Woman

A 30-year-old woman complainsof arthralgias and amenorrhea. Herliver enzyme pattern includes AST, 200U/L; ALT, 200 U/L; and alkaline phosphatase,120 U/L. Her serum bilirubinconcentration is 1.2 mg/dL.

The cause of such moderatetransaminase evaluation should beidentified if possible, whether or notthe patient has symptoms. The abnormalityis usually chronic. Documentthese abnormal transaminase levels ifthey persist for more than 3 months.

In this patient, the diagnosis is autoimmunechronic hepatitis, which generallyoccurs in young women and commonlypresents with arthralgias and/oramenorrhea. Hyperglobulinemia iscommon, and hypersplenism may bepresent. Tests for fluorescent antinuclearantibodies and smooth muscle antibodiesare likely to be positive. Corticosteroidtherapy, often combined withazathioprine, may be lifesaving.9 Thedifferential diagnosis includes chronichepatitis C, drug-induced liver injury,and such hereditary metabolic disordersas Wilson disease, hemochromatosis,and α1-antitrypsin deficiency.

Case 12:
Alcohol-induced Liver Injury

A 35-year-old bartender undergoesroutine blood studies. Values includeAST, 150 U/L; ALT, 60 U/L; al-kaline phosphatase, 85 U/L; and GGT,300 U/L (normal, 5 to 40 U/L).

Although the patient deniesdrinking heavily, alcohol-induced liverinjury is the obvious diagnosis. Inmost patients thus affected, the ALTvalue is normal or only minimally elevated.The AST level is usually morethan twice that of the ALT, but it isbelow 300 U/L in over 95% of cases.10,11The GGT elevation is induced by alcoholand is invariably marked. Theseliver enzyme values suffice for the diagnosis;it is unnecessary to order aliver biopsy or any other tests.

References:

REFERENCES:


1.

Whitfield JB, Moss DW, Neale G, et al. Changesin plasma

y

-glutamyl transpeptidase activity associatedwith alterations in drug metabolism in man. BrMed J. 1973;1:316-318.

2.

Davidson DC, McIntosh WB, Ford JA. Assessmentof plasma

y

-glutamyl transpeptidase activityand urinary D-glucaric acid excretion as indicesof enzyme induction. Clin Sci Mol Med. 1974;47:279-283.

3.

Shuster F, Ognibene AI. Dissociation of serumbilirubin and alkaline phosphatase in infectiousmononucleosis. JAMA. 1969;209:267-268.

4.

Cello JP. Acquired immunodeficiency syndromecholangiopathy: spectrum of disease. Am J Med.1989;86:539-546.

5.

Beaugerie L, Teilhoc MF, Deluol AM, et al. Cholangiopathyassociated with Microsporidia infectionof the common bile duct mucosa in the patient withHIV infection. Ann Intern Med. 1992;117:401-402.

6.

Poupon RE, Poupon R, Balkau B, et al. Ursodiolfor the long-term treatment of primary biliary cirrhosis.N Engl J Med. 1994;330:342-347.

7.

Reddy KR, Brilliant P, Schiff EF, et al. Amoxicillin/clavulanic acid potassium-associated cholestasis.Gastroenterology. 1989;96:1135-1141.

8.

Zimmerman HJ. Hepatotoxicity. New York: Appleton-Century-Crofts; 1978:288.

9.

Johnson PJ, McFarlane IG, Williams R. Azathioprinefor long-term maintenance of remission in autoimmunehepatitis. N Engl J Med. 1995;333:958-963.

10.

Bradus S, Korn RJ, Chomet B, Zimmerman HJ.Hepatic function and serum enzyme levels in associationwith fatty metamorphosis of the liver. Am JMed Sci. 1963;246:69-75.

11.

Zimmerman HJ, Seeff LB. Enzymes in hepaticdisease. In: Coodley EL, ed. Diagnostic Enzymology.Philadelphia: Lea & Febiger; 1970:1-38.