Azathioprine and the liver

CASTROENTEROLOGY

Azathioprine

1984;86:162-5

and the Liver

Evidence Favoring Idiosyncratic, Mixed Cholestatic-Hepatocellular Injury in Humans RONALD

and JAY

A. DePINHO,

CHARLES

S. GOLDBERG,

H. LEFKOWITCH

Departments of Medicine and Pathology, University, New York, New York

College of Physicians

A patient with systemic lupus erythematosus developed jaundice and biochemical evidence of hepatic dysfunction 3 wk after initiation of azathioprine therapy. A liver biopsy specimen was obtained, and it showed canalicular cholestasis and centrilobular ballooning of hepatocytes. Clinical and serologic assessment excluded other causes of hepatic dysfunction, such as viral hepatitis, administration of other drugs, or worsening of the co!lagen disease and the patient was improved 2 wk after azathioprine was discontinued. This case adds further evidence that azathioprine is an idiopathic hepatotoxin with the potential for combined cholestatic and hepatocellular injury in humans. Despite studies of azathioprine (AZ) liver damage in animal models (l-4) and sporadic case reports in humans (5,6), evidence favoring AZ hepatotoxicity in humans remains controversial. The issue has been clouded, in most instances, by failure to exclude other causes of hepatic dysfunction. Concomitant administration of other potentially hepatotoxic drugs or blood products, absent or incomplete serologic data regarding viral infections, and the possibility of hepatic involvement by underlying systemic diseases have led a number of investigators (7,8) to doubt the potential for AZ liver injury. In this report, we describe a patient with systemic lupus erythematosus who developed biochemical

Received March 11, 1983. Accepted July 8, 1983. Address requests for reprints to: Jay H. Lefkowitch, Department of Pathology, College of Physicians & Surgeons, 630 West 168th Street, New York, New York 10032.

Dr. Goldberg is currently located at 96 Gates Avenue, Montclair, New Jersey. The authors thank the members of the housestaff who cared for this patient: Drs. Mark Apfelbaum, Steven Corwin, and Claes Rymond. 6 1984 by the American Gastroenterological Association 0016-5085/84/$3.00

& Surgeons,

Columbia

and histologic evidence of hepatotoxicity 3 wk after initiation of AZ therapy. In this case, exclusion of other possible etiologic factors, together with biochemical and histologic features of a combined cholestatic-hepatocellular injury and clinical improvement after withdrawal of the drug, strongly support an idiosyncratic hepatic reaction to AZ alone. The confounding variables in earlier studies of AZ hepatotoxicity are also reviewed.

Case Report A 22-yr-old black man was admitted to this medical center in November 1981 with an acute exacerbation of systemic lupus erythematosus, characterized by pleuropericarditis and renal failure. During the 8 yr before admission, the patient had numerous episodes of pleuropericarditis, managed symptomatically with nonsteroidal antiinflammatory agents. During an admission for pleuropericarditis in June 1981, complete blood count, urinalysis, and blood chemistries, including tests of liver and renal function, were normal. Serologic studies included positive antinuclear antibodies (1: 160) with a homogeneous pattern, positive lupus erythematosus preparation, anti-deoxyribonucleic acid (DNA) antibodies by FARR

technique at 93%, and negative latex fixation test. Serum hemolytic complement (CH,,) was 126 U (normal 160-210 U). A renal biopsy specimen obtained in July 1981 showed glomerular, mesangial, and paramesangial electron-dense deposits, consistent with lupus nephritis, class IIB. The most recent admission in November 1981 followed poor compliance with medical therapy. Admission physical examination showed normal vital signs, diminished breath sounds, and dullness at the left base. Abdominal exam was normal. A nontender liver edge was palpated 2 cm below the right costal margin, and the liver spanned 10 cm by percussion. Chest x-ray showed a mildly enlarged cardiac silhouette and a small left pleural effusion. A small posterior pericardial effusion was confirmed by echocardiogram. Complete blood count and serum electrolytes, coagulation studies, and tests of liver function were normal. Blood urea nitrogen (BUN) and serum creatinine were

lanuar~

AZATHIOPIWNE

1984

Wo (U) \

SGPT

DB

AP

(mg/dl)

(U/I)

0

I

23456709 WEEKS

Figurr

I.

from a patient Gth systemic lupus er\ thematosus receiving azathioprine (M). The course oi .I% tht:rap~.. time of liver biopsy, and results of hr,patic tests are shown in (B). In (A], improvements in serum hlood urea nitrclgen (BUN) and hemolytic. comliver plr:mr?nt (CM->)) before development at deranged I,C~boratorq

data

fullc:tion are shown. During the subsequent ~-ma peri0~1. bimonthl!: liver func:tion tests were normal. Abbreviations inc:lude: SGPT (serum glutamic: pyruvic: trans~~~ninasr?). normal .cki(l II/L; DB [direct biliruhin), normal e’1.2 mg. tll; XI’ (alkaline phosphatase). normal 3& 1(1(111’1..SW text for further details.

48 mg/dl (normal <20 mg:dl) and 2.1 mg!dl (normal 0.61.3 mg.‘dl). respectively. Anti-deoxyribonucleic: acid antibodies by FIIRR technique were 98%, CH,,, was 110, and sedimentatioli rate was 33 mm/h. the erythrocqte Prednisone therapy. 60 mg daily, was begun. Renal f unction continued to deteriorate as BUN and serum creatinine rose to 106 and 3.6 mg%, respectively. Solumedrol. 1 g daily for 3 successive days, was given intravenously. Prednisone was continued and azathioprine, 50 mg daily (Cl.8 mg:kg day), was added. Several days later, the dose of azathioprine was increased to 100 mg daily (1.6 mg/kg da) ). Over the ensuing 2 wk of therapy. pleuritic chest pain and pleuropericardial effusions resolved. CH,,, normalized to 175. anti-DNrI antibodies decreased to 64%, and BUN and serum creatinine fell to 14 and 0.9 mg’%,, respec:tivel\;. Three weeks after the institution of azathioprine. with continued laboratory and clinical evidence of s\rsternic lupus erythematosus in remission, a routine ser;m test showed an abrupt rise in transaminases, alkaline phosphatase and. subsequentl~~, bilirubin (Figure I]. On physical examination, there was scleral icterus, normal vital signs, clear lungs. and dn unchanged cardiac examination. The abdomen 11.a~ soft anti nontender with normoactive bowel sounds. The liver edge was nontender and descended z cm

HEPAI‘OTOXICITY

163

below the right costal margin with a percussed span of 10 cm. The spleen was not palpable and there was no evidence of ascites. Laboratory data included hematocrit of 42.8%, BUN of 23, serum creatinine of 1.0, and one-stage prothrombin time at control value. Two abdominal ultrasonograms, performed 1 wk apart, showed no evidence of intra- or extrahepatic duct dilatation, gallstones, ascites, or pancreatic disease. A liver-spleen scan demonstrated mild hepatomegaly with no parenchymal defects and no splenomegaly. Serum immunoglobulin M and immunoglobulin G antibodies to hepatitis A virus, hepatitis B surface antigen, and antibodies to hepatitis B core and surface antigen were negative on multiple determinations. Cytomegalovirus titers were negative on separate occasions, 2 wk apart. There was no history of intravenous drug abuse, exposure to chemicals or jaundiced individuals, administration of blood products, or ingestion of shellfish. The patient received clonidine. 0.2 mg twice daily, for hypertension. This drug regimen was continued throughout the entire hospital course and for several months thereafter. Further elevations in serum liver function tests (Figure 1) prompted discontinuation of azathioprine therapy. Liver tests continued to rise for several days, but then gradually normalized over the next 2 wk. Bimonthly serum liver tests remained normal over the next 3 mo of observation despite continuation of clonidine. A percutaneous needle liver biopsy performed 1 wk after the onset of abnormal liver function tests showed striking centrilobular ballooning of liver cells and canalicular cholestasis with liver-cell rosette formation (Figure 2). Occasional central acidophilic bodies were present. The lobular parenchyma showed virtually no inflammatory cell infiltration. Portal tracts contained small numbers of mononuclear cells, but no eosinophils.

Discussion The hepatotoxic potential of AZ in humans has been debated. Experiments employing the canine model (l-4) have demonstrated that AZ administration leads to an acute elevation in serum liver enzymes which, over the course of several weeks, regress to normal despite continuation of the drug. Histologic changes of centrilobular hepatocyte necrosis and intrahepatic cholestasis were shown (2). Simple extrapolation of this animal data to humans has not been feasible, partly due to species variation and also because of controversial features of reports of AZ hepatotoxicity in humans. In earlier investigations of AZ hepatotoxicity in renal transplant patients and patients with psoriasis (s-19). evidence favoring AZ-induced damage included (a) improvement of liver function tests after discontinuation of the drug or adjustment of dose (9,10,12-14). (b) recurrence of serum enzyme abnormalities after reinstitution of AZ therapy (9), (c) absence of identifiable factors such as other drugs, recent surgery, or anesthesia that could have caused

164

Figure

DEPINHO

ET AL.

2. Needle liver biopsy specimen 1 wk after onset of hepatic dysfunction. There is marked ballooning of hepatocytes near the central vein at top and canalicular cholestasis (arrow] is present. The portal tract at bottom is mildly inflamed. (H&E, x94).

liver dysfunction (5,6), and (d) cholestatic and fibrotic damage demonstrated on liver biopsy (15,161. In most of these studies, however, complicating clinical features obscured the issue, including (a) simultaneous administration or cessation of other drugs with hepatotoxic potential (6,8,9,12), (b) absence of or incomplete serologic studies to exclude hepatitis due to hepatitis A, B, or cytomegalic virus (5,6,10), (c)progression of disease despite discontinuation of AZ (lO,ll), (d) inability to correlate AZ dosage directly with serum biochemical abnormalities (7), (e) inherent risks (in the renal transplant patients) for non-A, non-B, posttransfusional hepatitis (T-9,1214], and (f) administration of blood products (10). In addition, significantly impaired renal function is an important factor relevant to any study purporting to show AZ liver damage because the state of renal function may influence the hepatotoxic potential of AZ (20).The detoxification of 6-mercaptopurine, a metabolite of AZ that can cause both hepatocellular and cholestatic liver injury (21), may be impaired in uremia (20). Perhaps the most compelling evidence supporting AZ hepatotoxicity is found in two studies that em-

GASTROENTEROLOGY

Vol.

86. No.

1

ployed serial liver biopsies in psoriatic patients receiving AZ. Du Vivier et al. (15) followed 29 psoriatic patients who had undergone liver biopsy before treatment, after 6 mo of treatment, and then at yearly intervals. They encountered 2 cases of slight cholestasis and 8 cases of portal fibrosis. A follow-up biopsy in 1 case of mild portal fibrosis revealed no abnormalities at 24 mo despite continuation of the drug. Similar findings were obtained from 29 psoriatic patients studied by Munro (16).In the posttreatment category, 2 cases of minimal cholestasis and 10 cases of minimal portal enlargement and fibrosis were observed, while only 2 cases had some degree of portal fibrosis before AZ administration. The patient described in this report developed severe cholestasis and hepatocellular injury in the setting of systemic lupus erythematosus and lupus nephritis. Our evaluation of the liver disease was that it was uncomplicated by sepsis, viral hepatitis, hemodialysis, blood product or aspirin administration, extrahepatic bile duct obstruction, or the simultaneous withdrawal of another known hepatotoxic drug (clonidine was continued throughout the entire hospital admission). In addition, the activity of the underlying collagen vascular disease was decreasing at a time when liver function began to worsen. The findings on liver biopsy further supported a mixed cholestatic-hepatocellular injury. We agree with Menard and colleagues (22), who in a recent review concluded that “. . . the liver toxicity of AZ probably exists, but it is both rarer and much less severe than that attributed to 6-mercaptopurine.” Our case provides additional evidence that, in humans, AZ is an idiosyncratic hepatotoxin with the potential for cholestatic and hepatocellular liver damage.

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Liver disease in kidney transplant patients receiving azathioprine. Arch Intern Med 1973;132:29-37. Wane AJ. Luby JP, Hallinger 8, et al. Etiology of liver disease in renal transplant patients. Ann Intern Med 1979:91:364-71. Franksson C. Hepatitis and liver damage among patients and staff in a transplantation unit. Transplant Proc 1969:1:20912. Anuras Y, Piros J, Bonney WW, Forker EL, Colville DS. Carry RJ. Liver diseases in renal transplant recipients. Arch Intern Med 1977:137:42-8. Berne TV, Chatterjee SN, Craig JR, Redeker AG. Payne JE. Hepatic dysfunction in recipients of renal altografts. Surg Gynecol Obstet 1975;141:171-5. Corlev CC:. Lessner HE, Larsen WE. Azathioprine therapy of “autoimmune” disease. Am J Med 1966;41:404-12. Malekzadeh MH, Grushkin CM, Wright HT, Fine RN. Hepatic dysfunction after renal transplantation in children. J Pediatr 1972:81:279-85. Du Vivier A, Munro DD, Verbov J, Treatment of psoriasis with azathioprine. Br Med J 1974:1:49-51.

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16. Munro DD. Azathioprine in psori,rsis. Proc K Sac MetI 1973;66:747-8. 17. Sopko J. Anuras S. Liver disease in renal transplant recipents. Am J Med 1978:64:139-46. 18. Briggs WA, Lazarus JM, Birtch AC;, Hampers CL. Hager EB, Merrill JP. Hepatitis affecting hemodi,d!;sis and transplant patients. Arch Intern Med 1973;132:21-8. 19. Starzl TE, Marchioro TL. Porta KA. Llnorrt (:A. Rifkind D, Waddell WK. Renal homotransplalltatiur~, late function anal complications. Ann Intern Med 1964:61:470--97. 20. Berenbaum MC. Immunosuppressive agents and allogeneic: transplantation. J Clin Pathol [Suppi] 1967:20:471. 21. Zimmerman HJ. lshak KG. Hepatic: injury due to drugs ant1 toxins. In: MacSween KNM. Anthony PP. Scheuer PJ, eds. Pathology of the liver. Nevv York: (~hurc.hill I.ivingstonc~. 1979:335-86. 22. Menard DB. Gisselbrecht C. Marts M. Keyes 1;. Dhumeaux D. Antineoplastic agents and the livrsr. (;;lstroorlterologv 1980:78:142-64.