1546

ALLOPURINOL HEPATOTOXICITY CASE REPORT AND LITERATURE REVIEW S. K . C H A W L A , H . D. PATEL, G . R. P A R R I N O , J . SOTERAKIS, P. A. LOPREST1,and W . A. D'ANGELO

Allopurinol was introduced into clinical medicine in 1962 and several adverse effects have been reported with its widespread use. T h e side effects have usually been mild (gastrointestinal distress, diarrhea, headache, pruritis, fever, and maculopapular rash) and have subsided promptly after withdrawal of the drug. T h e reports of more serious and fatal reactions, such as agranulocytosis ( 1 ), exfoliative dermatitis (2), and acute vasculitis (3), are being recorded with increasing frequency. Rarely, adverse reactions from allopurinol a r e associated with signs of hepatic injury with or without jaundice (4);in a few cases, significant hepatotoxicity has been reported (4-7). This report describes a case of allopurinol hepatotoxicity and reviews the literature concerning this complication associated with the use of allopurinol.

CASE REPORT A 44-year-old white male with gouty arthritis was admitted with chief complaints of diplopia, left upper quadrant fullness, and pain of 3-day duration. He had been receiving 300 rng of allopurinol daily for I week prior to admission. He denied any history of heavy alcohol intake, nausea, vomiting,

or pruritis. On physical examination vital signs were normal. The liver was enlarged with a vertical span of 19 crn in the midclavicular line and was smooth, soft, and nontender. The spleen was palpable four finger breadths below the left costal margin and there were no stigmata of chronic liver disease. Table 1 shows the pertinent laboratory data. Hospital Course. On the day of admission, allopurinol was discontinued, following which the patient showed prompt improvement in his clinical symptoms and signs. The ocular symptoms were the first to disappear followed by subsidence

Table 1.

From the Department of Medicine, Catholic Medical Center Affiliation, Queens Hospital Center, Jamaica, New Y ork. S. K . Chawla, M.D.; H. D. Patel, M.D.; G . R. Parrino. M.D.; J. Soterakis, M.D.; P. A. LoPresti, M.D., F.A.C.P.; W . A. D'Angelo, M.D., F.A.C.P.: all Department of Medicine, Catholic Medical Center Affiliation, Queens Hospital Center, 82-69 164th Street, Jamaica, New York 11432. Address reprint requests to Satish K. Chawla, M.D., Catholic Medical Center Affiliation, Queens Hospital Center, 82-68 164th Street, Jamaica, New York 11432. Submitted for publication May 26, 1977; accepted June 10. 1977. Arthritis and Rheumatism, Vol. 20, No. 8 (November-December 1977)

Normal Values SCOT 7-40 mU/ml Alkaline phosphatase 30-85 mU/ml Total bilirubin 0.15-1 .O mg % Eosinophil count Total eosinophil count

On Admission

Eighth Hospital Day

50 mU/ml 98 mU/ml I .8 mg % 8% 1,024

40 mU/ml 89 mU/ml 0.8 mg '70 2% I80

ALLOPURINOL H EPATOTOX IClTY

1547

Fig 1. Liver biopsy following allopurinol showing fatty changes. focal necrosis, and scattered noncaseating granuloma.

of left upper quadrant heaviness and pain. Four weeks tollowing the withdrawal of allopurinol, the liver and spleen were no longer enlarged and palpable. Liver biopsy obtained on the day after admission (Figure 1 ) revealed fatty changes, focal necrosis, and noncaseating granulomata with scattered eosinophils. These changes could be interpreted as being due to alcohol abuse, but the lack of alcohol intake in the patient suggested some other etiologic agent. The following special studies were within normal limits: roentgenogram of the chest, PPD, serum ANA, and LE cell test. A systematic work-up consisting of skin testing and bacteriologic and radiographic failed to studies to determine the cause of the granulomata reveal an .etiologic agent.

DISCUSSION There is sufficient clinical and laboratory evidence to suggest that the patient herein reported developed an adverse reaction to allopurinol. Although there is no direct proof (i.e., rechallenge with allopurinol and followup liver biopsy) that allopurinol caused a granu~omatoushepatitis, the rapid resolution of both and biochemical findings, without specific therapy exCePt for the discontinuation of a l b u r i n o l , strongly favors the cause and effect relationship between the allo-

Table 2. Group I (Allopurinol) Before Therapy Serum Bilirubin

Alkaline Phosphatase (mean level) SGPT SCOT

Normal

During Therapy

Minor elevations in 3 patients (between 1-2/mg) 8.8 Units 10.9 Units (range: 5-19) (range: 6-17) mean increase 2.1 Units Normal Minor elevations in 4 patients Within normal limits-with

Group 11 (Uricosuric) Before Therapy

During Therapy

Normal

Minor elevations in I patient

7.9 Units (range: 4-13)

8.4 Units (range: 5-12)

Normal

Minor elevations in 1 patient no alterations in both groups

Data from Scott JT, Hall AP, Grahame R: Allopurinol in treatment ofgout. Br Med J 2:321-327, 1966.

CHAWLA ET AL

1548

purinol and the clinical findings. This patient was not rechallenged with allopurinol because of the following considerations: 1 ) The patient presented with severe ocular and abdominal symptoms and we were reluctant to risk the precipitation and possible exacerbation of the original symptoms; 2) the patient was reluctant to undergo a rechallenge and subsequent liver biopsy. The mechanism of allopurinol-induced hepatotoxicity is unknown. However, various reports of hypersensitivity reaction to allopurinol have been recorded in the literature. The two recorded cases of granulomatous hepatitis following allopurinol administration had associated clinical findings suggestive of drug-induced hypersensitivity (5,6). Lidsky and Sharp (7) observed increased susceptibility of patients with renal insufficiency

to the hepatotoxic effect of allopurinol. In their group of 14 allopurinol-treated patients, significant hepatic abnormalities were observed. Two patients with renal impairment developed intrahepatic cholestatic jaundice and another developed an elevation of alkaline phosphatase only. In another patient in this series who had no evidence of renal impairment, elevation of serum-alkaline phosphatase and of transaminase levels was noted. These data suggest that patients with renal impairment may need adjustments to their allopurinol dosage to avoid hepatotoxicity. Scott .(8) and his colleagues studied 40 patients with gout, treated with either allopurinol or uricosuric drugs. Twenty-one patients (Group I ) were started on allopurinol and 19 patients (Group 11) received urico-

Table 3. Authors

Sex/Age

Daily Dose

Clinical Findings/Diagnosis

Laboratory Data

Histopathology (Liver Biopsy)

Butler (12)

F/28

NM

Generalized pruritis, urticaria, fever, and erythematous rash Diagnosis: hyperuricemia

W BC-2500 Eosinophil count-45% SCOT-880-2320 m U / m I Alkaline phosphatase-I88 mU/ml Bilirubin-4.6-13.1 mg O/o Serum creatinine-I 1.0 mg%

At autopsy: panlobular necrosis with scattered islands of surviving hepatocytes accompanied by infillrates ol’ eosinophils. neutrophils. plasma cells, and lymphocytes

Espiritu (6)

M/55

NM

Arthralgias, myalgias and fever Diagnosis: hyperuricemia

T Bilirubin-0.4-0.9 mg% SCOT- 100- I40 mU/ml Alkaline phosphatase-600900 m U / m l

Presence of small granulomas scattered throughout the hepatic lobules but sparing portal tracts. Also, few scattered eosinophilic granulocytes. A repeat biopsy later shomed resolution

Simmons ( 5 )

M/50

300 mg Fever, myalgia, dark urine, and enlarged liver Diagnosis: acute renal failure

Bilirubin--1.5 mg % Alkaline phosphatase-240 mU/ml Eosinophil count-l2%

Multiple, noncaseating epitholoid granulomas. chiefly in or adjacent to portal tract, focal necrosis. and mild fatty metamorphosis. Repeat biopsy showed resolution

Mills (4)

M/52

200 mg Fever, pruritic dermatitis, myalgia and arthralgia, enlarged liver Diagnosis: acute gouty arthritis

N o mention of liver chemistries

Periportal infiltration with mononuclear cells and eosinophils

Klatskin (13)

NM

NM

Elevated alkaline phosphatase and transminases following two weeks of allopurinol therapy (values not mentioned)

Bile stasis. central necrosis, rate acidophilic bodies, mild lymphocytic inflammatory reaction i n portal triads

Lidksy and Sharp (7)

NM

200 mg Jaundice compatible with intrahepatic cholestasis in two patients receiving allopurinol Diagnosis: Primary gout

Liver function studies not described

Liver biopsy on one patient disclosed periportal inflammator) intiltrates containing eosinophils

NM-not

mentioned.

Jaundice, pruritis Diagnosis: not mentioned

ALLOPURINOL HEPATOTOXICITY

suric treatment. The various tests of liver function obtained are outlined in Table 2 . None of the patients showed any clinical evidence of liver disease. The authors concluded that the abnormalities in both groups were insignificant and that, based on this, allopurinol could not be incriminated as a hepatotoxic drug. They suggested further studies for evaluation of hepatotoxicitv. Rundles, Metz, and Silberman (9) studied 46 patients receiving allopurinol in whom no adverse effects were noted when screened by an extensive series of biochemical tests. In 2 patients with gout secondary to hematoictic disorders, reported by Yii and Gutman (lo), the cephalin floculation test became strongly positive coincident with the administration of allopurinol. Blechman (1 1 ) and his group observed 22 patients who were treated with allopurinol for a period of up to 16 months and recorded hepatotoxicity in two patients. These patients developed hepatomegaly without significant abnormalities in liver function studies. The hepatomegaly in 1 patient subsided spontaneously despite the continued use of allopurinol. Although early investigation failed to reveal any significant hepatic toxicity associated with the use of allopurinol, recent case reports of jaundice and significant hepatotoxicity have appeared in the literature. Butler (12) and coauthors reported a patient taking allopurinol who developed massive hepatic necrosis. Review of the English literature reveals 6 documented cases of allopurinol-induced liver disease, in whom liver biopsies revealed abnormal histopathology. A review of pertinent clinical settings and histopathologic findings of these six cases are outlined in Table 3. I n earlier studies, the role of allopurinol in the production of an enlarged liver and minimally abnormal liver function (alkaline phosphatase, in particular) is unclear because biopsies were not obtained. The recent recording of these 6 cases (Table 3) suggests that, indeed, allopurinol is hepatotoxic and can induce mild to severe hepatic damage with varying histologic findings. When liver function test abnormalities occur following the use of allopurinol, the drug should be suspected as the causal agent. This review emphasizes that allopurino1 hepatotoxicity may be a more serious disorder than has been previously recognized.

SUMMARY Significant hepatotoxicity due to allopurinol seems to be rare. Only 6 such cases have been recorded in the literature. The clinical and histopathologic find-

1549

ings of allopurinol-induced liver injury are variable in the previously reported cases. Described herein is another patient with allopurinol hepatotoxicity. Of interest is the similar histopathology between the present case and the two previously reported cases of allopurinolinduced granulomatous hepatitis; thus this is the third such recorded case. Allopurinol should be suspected when liver abnormalities occur following use of this drug.

ACKNOWLEDGMENTS The authors wish to thank and gratefully to acknowledge the many helpful suggestions of Dr. Peter Nuccio and Ms. Linda Maurer in the preparation of this manuscript.

REFERENCES I . Greenberg MD, Zambrano SS: Aplastic agranulocytosis after allopurinol therapy. Arthritis Rheum l5:4 13-41 6, 1972 2. Stratigos JD, Bartsokas SK, Capetanakis J: Further experience of toxic epidermal necrolysis incriminating allopurinol, pyrazolone and derivates. Br J Dermatol 86: 564-567, 1972 3. Jarzohski J , Ferry J. Womholt D , Fitch DM. Egan JD: Vasculitis with allopurinol therapy. Am Heart J 79: 1 16121, 1970 4. Mills RM Jr: Severe hypersensitivity reactions associated with allopurinol. JAMA 216:799-802, 1971 5. Simmons F, Feldman B, Gerety D: Granulomatous hepatitis in a patient receiving allopurinol. Gastroenterology 62:101-104, 1972 6. Espiritu CR, Alalu J, Glueckaf LG, Lubin J: Allopurinolinduced granulomatous hepatitis. Am J Digest Dis 21: 804-805, 1976 7. Lidsky MD, Sharp JT: Jaundice with the use of 4hydroxyprazolo pyrimidine. Arthritis Rheum 10:294. 1967 8. Scott JT, Hall AP, Grahame R: Allopurinol in treatment of gout. Br Med J 2:321-327. 1966 9. Rundles RW, Metz EN, Silberman HR: Allopurinol i n the treatment of gout. Ann Int Med 64:229-258, 1966 10. Yii TF, Gutman AB: Effect of allopurinol on serum and urinary uric acid in primary and secondary gout. Am J Med 37:885, 1964 1 1 . Blechman WJ, Rosenberg DG, Hilf P: Use of allopurinol in gout, hyperuricemia and uric acid lithiasis. South Med J 6(2), 215-218, 1967 12. Butler RC, Shah M, Grunow WA, Tenter EC Jr: Massive hepatic necrosis in a patient receiving allopurinol. JAMA 231(5):413-474, I977 13. Klatskin G: Toxic and drug induced hepatitis, Diseases of the Liver. Edited by L Schiff. Fourth edition. Philadelphia, JB Lippincott Co, 1975, chap 20, p 640