ACUTE SUBMASSIVE HEPATIC NECROSIS DUE TO METHYLDOPA

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1 GASTROENTEROLOGY 66:120: Copyright 1974 by The Williams & Wilkins Co. Vol. 66. :-./0. i Printed in U.S.A. ACUTE SUBMASSVE HEPATC NECROSS DUE TO METHYLDOPA A case demonstrating possible initiation of chronic liver disease RVN L. SCHWETZER, M.D., AND ROBERT L. PETERS, M.D. Departments of Medicine and Pathology, University of Southern California, School of Medicine-John Wesley County Hospital, Los Angeles. California Acute submassive hepatic necrosis in a patient who had received methyldopa for 10 weeks is described. The liver lesion was associated with a positive lupus erythematosus preparation, a positive direct Coombs test, and transient portal hypertension. Causal relation between methyldopa and the hepatic necrosis was established by an unequivocal response of transaminase activity to readministration of the drug. The most striking histological feature during the acute phase of the disease was extensive necrosis of liver cells in the periportal areas. The initial illness improved rapidly, and the patient has since remained asymptomatic. However, the following subsequent observations suggest that hepatic necrosis due to methyldopa may have initiated chronic liver disease: (1) the left lobe of the liver became persistently enlarged and firm after recovery from the acute liver injury; (2) liver scans 6 and 9 months after the acute episode revealed generalized mottling and a hypertrophied left lobe; (3) the liver tests did not return to normal for a period of 9 months; and (4) follow-up liver biopsies revealed broadened periportal fibrosis at 6 months and collapsed stroma at 10 months after the acute submassive necrosis, although there was insignificant inflammatory activity at the time of the biopsy. Since the introduction of methyldopa for the treatment of hypertension in 1960, there have been several reports of adverse hepatic reactions associated with its use. Most reactions may be classified as (1) slight and usually transient abnormalities in liver tests with no clinical symptoms or signs; or (2) significant hepatic cell injury producing a syndrome with clinical, biochemical, and histopathological changes resembling acute viral hepatitis. Received September 6, 197:3. Accepted December Address reprint requests to: Dr. rvin L. Schweitzer. Liver Service. John Wesley County Hospital, 2826 South Hope Street, Los Angeles, California This investigation was supported in part by Account 6001 of the John Wesley Hospital Attending Staff Association More than 35 cases of hepatic cell injury associated with methyldopa have been recorded in the English literature, but proof of a specific cause-effect relation is frequently lacking. However, there are at least six case reports 1-5 in which (1) liver biopsy during the acute illness showed definite changes of necrosis and inflammation; and (2) readministration of the drug produced biochemical signs of transient liver cell injury. The evidence that hepatic damage was the direct result of methyldopa in such patients seems indisputable. n these cases, the illness began after a 2-month median period of drug administration and consisted of fatigue, anorexia, nausea, vomiting, abdominal discomfort, and jaundice. Serum glutamic oxaloacetic transaminase (SGOT) elevations of at least

2 1:204 SCHWETZER AND PETERS Vol. 66. No. 6 7 times normal were recorded in 4 cases 2-5 and a positive lupus erythematosus (LE) preparation was detected in 1. 5 There were no cases in which a positive direct Coombs test was described. Goldstein et a1. 6 described 21 consecutive patients who presented with histological criteria of active chronic hepatitis. in 5 of whom the disease was thought to be induced by Aldomet. These patients had taken the drug for from 2 months to 3 years. and 1 had had an attack of Aldomet-related hepatitis 2 years before. A fatal case of methyldopa-induced submassive hepatic necorsis was reported by Rehman et a1. 7 This patient developed hepatic necrosis after two separate administrations of the drug; the second episode developed after 9 weeks of medication and resulted in death with hepatic coma. This report describes a patient with methyldopa-induced liver injury consisting of acute sub massive hepatic necrosis with transient portal hypertension. a positive LE phenomenon, and a positive direct Coombs test. Readministration of the drug produced a transient increase in both SGOT and serum glutamic pyruvic transaminase (SGPT) activity. Follow-up for 1:2 months after the onset of illness is suggestive of chronic liver disease. Case Report M. R, a 49-year-old female who was known to have essential hypertension for at least 15 years and diabetes mellitus for at least 4 years, was feeling well until about April :2, when she developed fatigue, anorexia, nausea. and vomiting. These symptoms persisted, and slight diarrhea and feverishness ensued a few days later. On about April 10 the patient noted that her urine was very dark and that her eyes were yellow. There was no high fever, chills, abdominal pain, rashes. or joint swelling. She denied unusual somnolence. confusion, agitation. or disorientation. The patient had no injections of blood products, surgical or dental procedures, exposure to persons with jaundice or hepatitis. travel outside the Los Angeles area, or ingestion of raw clams or shellfish in the past :2 years. She denied ever using illicit parenteral drugs or having contact with drug users. Treatment for essential hypertension consisted of hydrochlorothiazide from 1968 through and reserpine from,january 1971 to,january :2. On.January 16, 197:2. reserpine was discontinued and methyldopa. :250 mg three times a day, was begun. Other medications included diazepam. 5 mg twice a day. for over:2 years. indomethacin, :25 mg as needed for back pain since February : :2 (it was estimated that 60 capsules were taken during this period). and daily neutral protamine Hagedorn insulin injections for over ; years. She received blood transfusions on two occasions associated with cesarean sections in 1949 and again in 195:2. n she had an episode of abdominal pain with no sljecific cause being found. A cholecystogram, upper gastrointestinal X-ray studies. intravenous urogram, and a serum bilirubin were normal. She had at least two extensive evaluations for a specific etiology for hypertension during the past 10 years. Tests for thyroid disorders, pheochromocytoma, renal disease, and other causes of elevated blood pressure were within normal limits. The patient was admitted to the Los Angeles County-University of Southern California Medical Center on April 1:3. 197:2. at which time she was found to be markedly jaundiced with some upper quadrant tenderness and a blood pressure of 160/ 1:20. Laboratory studies included a normal hemogram and urinalysis except for bilirubinuria and 4 glycosuria. Serum albumin was 3.3 g per 100 ml, globulin was 5.5 g per 100 ml, total bilirubin was 22,1 mg per 100 ml with a direct fraction of alkaline phosphatase was 11 Bessey Lowry units per ml (normal 1 to 3). SGOT was 3590 Karmen units per m!. SGPT was 1860 Karmen units per ml, and the prothrombin time was 59%. A diagnosis of acute viral hepatitis was made, and on April 17, 1972 she was transferred to the Hepatitis Unit of John Wesley County Hospital for further care and evaluation. On arrival at the.john Wesley County Hospital the patient was markedly icteric. but she did not appear critically ill. Her weight was kg. temperature 98 F, pulse 92 beats per min. respirations 28 per min, and blood pressure 1:20/90 mm Hg. Positive physical findings were marked jaundice. diabetic retinopathy. with multiple microaneurysms and a few exudates. a grade 2/6 systolic murmur at the apex, an ancient vertical lower midline surgical abdominal scar, and slight tenderness beneath the right subcostal margin. There were no palpable masses or organs in the abdomen, and there were no stigmata of chronic liver disease. Neurological examinations were normal, pulses were adequate in all extrmities, and there was no peripheral edema. Laboratory examinations included a normal urinalysis except for the

3 June 1974 METHYLDOPA HEPATC NECROSS 1205 presence of bilirubin. The hemoglobin was 16 g per 100 m!. the white blood count was 7300 with 60 segmented neutrophils, three bands, and 37 lymphocytes, and the reticulocyte count was 2.:i%. The serum albumin was 3.1 g per WO m!, the globulin was 5.8 g per 100 ml, alkaline phosphatase was 11.8 Bessey Lowry units per ml, total bilirubin was 31.9 mg per 100 m!. direct reacting bilirubin was 16.4 mg per too ml, SGOT was :3120 Karmen units per ml. SGPT was 1950 Karmen units per ml. and the prothrombin time was 80');. The blood urea nitrogen was 18 mg per too ml. the serum creatinine was 1.7 mg per 100 ml, and the fasting glucose was 268 mg per 100 m!. Serum electrolytes were within normal limits, the serum amylase was 115 Somogyi units. and the monos pot test was negative. The hepatitis B (by radioimmunoassay) and antibody (by passive hemagglutination), the smooth muscle antibody. and the mitochondrial antibody were all negative. The LE preparation was positive, and antinuclear antibodies were present. The direct eoom bs test was positive. A chest X-ray and electrocardiogram were within normal limits. A wedged hepatic vein pressure was 8 mm Hg (normal 1 to 4 mm Hg) above inferior vena caval pressure. All medications except insulin were stopped, and the patient was treated conservatively with rest, a nutritionally adequate diabetic diet, and multivitamins. On April 24, a complete blood count revealed a hematocrit of 43 volume,; per 100 ml with a hemoglobin of 14.7 g per WO m!, a white blood count of 7000 with 59 segmented neutrophils, two bands, 3:3 lymphocytes, one monocyte, three eosinophils, and two basophils. The peripheral smear was normal. and the collected reticulocyte count was 40(. The LE prep and the direct Coombs tests were still positive. She improved steadily, and on May 2, 1972, a Menghini needle liver biopsy was taken. Histological examination revealed extensive periportal areas of destruction of the liver parenchymal cells. The portal structures, arterioles, portal vein radicles, and interlobular ducts were surrounded by lymphocytes (fig. 1). The limiting plate was destroyed. The poorly defined portal areas were surrounded by broader areas of collapsed stroma in which there was plasmacytic hyperplasia, occasional eosinophils. and a congested vascular bed (fig. 2). The hepatocytes in the remainder of the lobule were swollen and plantlike with a general lack of the cord architecture. The liver cell nuclei were FG. 1. Liver lobule showing central vein at bottom and portal area at upper left. ote the hepatocellular destruction around the portal region and the swollen hepatocytes and deranged cord pattern elsewhere (H & E,, 96),

4 1206 SCHWETZER AND PETERS Vol. 66, No.6 FG. 2. On higher magnification, the portal area of the lower left corner is surrounded by collapsed stroma in the remainder of the photograph!h & E. 160). markedly enlarged and vesicular with a fine but sharp nuclear membrane and very prominent nucleoli. There were occasional canalicular bile plugs. The central vein and centrolobular hepatocytes were not involved by the destruction (fig. 3). but almost all of the cells in the lobule were swollen. There was no nodular regenerative activity. and Kupffer cells were somewhat increased. n areas away from the collapse there were relatively few inflammatory cells. The layer of hepatocytes just peripheral to the area of collapse was the most greatly swollen, and many of the cells had nuclei undergoing mitosis. A third complete blood count was performed on May 8, at which time a hematocrit was 41 volumes per 100 ml, the hemoglobin 13.6, the white blood count 5800 with 50 segmented neutrophils, five bands, 42 lymphocytes, two monocytes, and one basophil. At this time the LE prep and direct Coombs test were both still positive. By May 12, the patient was feeling very well. Her total bilirubin had fallen to 8.2 mg' per 100 m!, with an SCOT of 1200 Karmen units per ml and an SCPT of 720 Karmen units per ml. She was discharged from the hospital to convalesce at home with a 250-mg sodium, diabetic diet, insulin, and rest. Pertinent laboratory tests during the acute illness and early convalescence are shown in figure 4. After discharge the patient remained essentially asymptomatic and jaundice gradually disappeared. Her blood pressure remained below 140/90 mm Hg with rest and sodium restriction during this period. On September 10, after all tests had become nearly normal, the patient was hospitalized for reevaluation. Blood pressure was 160/110 mm Hg, and there was no jaundice or other change in the physical examination: stigmata of chronic liver disease and hepatomegaly and splenomegaly were not detected. The direct Coombs test was still positive, the hemoglobin was 14 g per 100 ml, and the reticulocyte count was 1.5%. The serum albumin was 3.9 g per 100 ml, globulin was 4.4 g per 100 ml, alkaline phosphatase was 7.4 Bessey Lowry units per ml, total bilirubin was 1.1 with a direct fraction of 0.3 mg per 100 ml, SCOT was 60 Karmen units per ml and SCPT was 25 Karmen units per ml. The prothrombin time was 100%, the fasting glucose was 117 mg per 100 ml, and bromosulfophthalein retention at 45 min was 15%. The LE preparation, smooth muscle antibody, antinuclear antibody, and direct Coombs test were negative. Hepatic scan was abnormal, with a mottled appearance of the liver and a hypertrophied left lobe. Wedged hepatic vein pressure was 4 mm above inferior vena caval pressure.

5 June 1974 METHYLDOPA HEPATC NECROSS 1207 FG. 3. Higher power photomicrograph of central vein area shows little destruction but distortion of liver cord pattern by regenerating hepatocytes (H & E, A 320) ,., ! co co 0 0 """,::: 'i=' 'i=' 0 Q '" '" D i t'ect Coombs Test l.e. Preparat i on......, _ e.... \\ 4/14 4/20, \,,, / " " -... " /10 5/20 5/30 6/ r r !, , D " FG. 4. Biochemical and immunological tests during the acute phase of methyldopa-induced hepatic necrosis. SCOT, serum glutamic oxaloacetic transaminase; SCPT, serum glutamic pyruvate transaminase; LE, lupus erythematosus. " '"

6 1208 SCHWETZER AND PETERS Vol. 66, No.6 A second needle liver biopsy taken on September 12, 1972, was somewhat fragmented and still showed broadened fibrous areas around the portal structures. Central veins were normal, but the hepatocytes were slightly swollen in a uniform fashion throughout. The liver cell nuclei, although still somewhat enlarged over normal, were much less striking than in the earlier biopsy. Occasional mitosis could still be found. Kupffer cells were no longer hyperplastic, and the portal cellular component consisted principally of proliferating connective tissue cells. Because of the uncertainty of her liver disease, drug challenge was proposed, and the patient consented to readministration of methyldopa as a diagnostic test. On September 12, 1972, methyldopa, 250 mg three times a day, was begun. The patient had a temperature of 99.9 F the morning after the initiation of the medication but was afebrile thereafter. She remained entirely asymptomatic and left the hospital on September 15, 1972, to be followed as an outpatient every other day. Eight days after beginning methyldopa, her SGOT rose to 325 Karmen units per ml and SGPT to 500 Karmen units per m!. The medication was stopped immediately, and transaminase activity gradually returned to pretreat ment levels (fig. 5). The patient has since been asymptomatic, and her blood pressure has been easily controlled with 50 mg of hydrochlorothiazide and 50 mg of triamterine daily. However, from October 1972 through December 1972, her SGOT ranged from 50 to 103 Karmen units per ml and her SGPT from 49 to 85 Karmen units per m!. During this period the liver was found to be palpable; the edge descended 2 cm below the costal margin at the right anterior axillary line and 4 cm below the xiphoid process during inspiration with a moderately firm consistency. On December 29, albumin was 4.5 g per 100 m!. globulin was 4.0 g per 100 ml, alkaline phosphatase was 10.:3 Bessey Lowry units per ml, SGOT was 103 Karmen units per ml, and SGPT was 85 Karmen units per m!. There was 18% bromosulfophthalein retention, and a repeat liver scan was still grossly abnormal with no change from that of September 18, From January 1973 through April 197:3, all liver tests were normal, including SGOT and SGPT which remained consistently less than 35 Karmen units per m!. On February 20, 1973, a follow-up needle liver biopsy was taken. The specimen was fragmented. Most fragments revealed uniform hepatocytes without necrosis or inflammation but were of insufficient size to see an entire lobule (fig. 6). There was no evidence of continuing necrosis or cell damage, but there were a few tiny segments of collapsed liver stroma (fig. 7). Discussion There seems no doubt that the hepatic necrosis which occurred in this patient was due to methyldopa. The induction time between beginning the drug and the onset E E 400 " 350 "" c "" c '" " ,\\, c c '"' " coo ;:- ;:- 0 "-, 'c- SO-.." V> V>...- '" 100- '. '. ' ;::..:., ' J :: : _...,..., :.::::-.:::.:. ": -9.0 E 0-8,0-7.0 E -6.0 'C g '" E <f) -1.0 Methy dopa Bromsul fa e in Retent ion (45 m; n.) 15% 28% FG. 5. Response of biochemical hepatic tests to readministration of methyldopa. SCOT, serum glutamic oxaloacetic transaminase: SCPT, serum glutamic pyruvate transaminase.

7 June 1974 METHYLDOPA HEPATC NECROSS 1209 FG. 6. Fragments of liver taken after recovery show a cobblestone pattern of hepatocytes, suggesting continued regenerative activity (H & E, 'X 96). FG. 7. A few fragments of the biopsy shown in figure 4 show collapsed stroma only' (H & E.. 160).

8 1210 SCHWETZER AND PETERS Vol. 66, No.6 of symptoms, the clinical syndrome of malaise, gastrointestinal symptoms, and jaundice, and biochemical tests indicating acute liver cell injury were similar to previously reported proved cases. The presence of a positive LE phenomenon and a positive direct Coombs test is compatible with an abnormal immune response and has previously been described in association with the administration of methyldopa. Most significantly, the response to readministration of methyldopa demonstrated an unequivocal relation between the drug and liver cell injury. The patient had received indomethacin and diazepam for varying periods before illness, and although hepatic damage has been reported with these drugs, 8-11 they do not seem to be a likely cause of liver injury in this case. The morphological features of nonfatal hepatic necrosis after methyldopa therapy have been described by other investigators as indistinguishable from viral hepatitis or as nonspecific. 1 5 n the liver of our patient, the lesion was sharply zonal, unlike viral hepatitis where the necrosis is more severe centrally, but without sharp zonal margins. Similar to viral hepatitis, the liver did have the hyperplasia of the lymphoreticuloendothelial components characterized by Kupffer cell hyperplasia and portal lymphoid hyperplasia. n addition, the hepatocytes had the swollen cytoplasmic character and more primitive nuclear chromatin pattern of regenerating cells. like that seen in viral hepatitis and other conditions with recent hepatocellular necrosis. n contrast to either viral hepatitis or most drug-associated hepatic necroses, the zonal necrosis was periportal. The lymphoproliferative changes occurring simultaneously with fairly acute hepatocellular necrosis resulting in certain histological similarities to viral hepatitis suggest that either a hypersensitivity response or response to a metabolic product of methyldopa should receive consideration. The periportal zonal necrosis, liver cell regenerative changes, and inflammatory hyperplasia that give the liver of this single patient a distinctive histological appearance should not be extrapolated to other cases of liver disease after methyldopa, but the periportal character of the major hepatocyte damage should be looked for in other cases of liver necrosis after use of that agent. The hepatic injury with the syndrome of acute icteric hepatitis due to methyldopa meets the criteria for a hypersensitivity reaction. The hepatitis is not related to the dose or duration of administration of the drug; it is frequently accompanied by other signs of hypersensitivity; it occurs in only a minute proportion of treated patients; it cannot be predictably reproduced in experimental animals; and it usually recurs after readministration of the drug. Elkington et al. 2 reported a patient in whom three exposures to methyldopa produced relapses which were successively less severe. They suggested that this might represent desensitization of the patient to the drug. The presence of a positive LE preparation during the acute phase of the illness in our patient is of special interest. There have been reported cases of methyldopa induced LE reactions associated with Coombs-positive hemolytic anemia,12 and 1 case with the LE preparation being positive during the acute phase of methyldopa hepatitis. 5 Other drugs such as procaine amide, 13 isoniazide, 14 and hydralazine 15 are known to produce lupus-like syndromes. However, only oxyphenisatin has been shown to produce liver cell injury associated with a positive LE cell phenomenon. Reynolds et al. 16 found either a positive LE cell preparation and/or antinuclear anti bodies in 4 of 6 patients with chronic active hepatitis caused by this drug. The presence of a positive direct Coombs test associated with methyldopa hepatitis has not been previously reported, despite the fact that the test is positive in 10 to 20% of all patients who receive the drug. 17 Most cases of methyldopa hepatitis occur within 4 months of beginning the drug, and the occurrence of a positive direct Coombs test is rare in patients taking the drug for less than 6 months. Furthermore, the incidence of a positive direct Coombs test is related to the dose, with its occurrence being twice as frequent in patients receiving 1.25 to 2 g

9 June 1974 METHYLDOPA HEPATC NECROSS 1211 than in those receiving less than 1 g daily. Hence, the positive direct Coombs test in our patient who received only 0.75 g of methyldopa daily for 10 weeks is extraordinary and suggests an unusually prompt and marked immune response. The fact that the test has remained positive for 9 months after discontinuing the medication is, in itself, of uncertain significance in that such a prolonged response has been reported in several asymptomatic patients. Many features of this case suggest that hepatic necrosis due to methyldopa may result in chronic liver disease. (1) The left lobe of the liver became palpably enlarged with a firm consistency after recovery of the acute illness, and this finding has persisted to date. (2) Liver scans done 6 and 9 months after the acute episode were abnormal in that there was a mottled appearance of the liver and an unusual configuration compatible with a hypertrophied left lobe. (3) The biochemical hepatic tests did not return to normal for 9 months. (4) Liver biopsy still showed tiny segments of collapsed stroma 10 months after the acute liver injury. REFERENCES 1. Gilmore BL, Freis ED: Methyldopa in the treatment of hypertension. Med Ann DC 34: Elkington SG, Schreiber WM, Conn HO: Hepatic injury caused by L-alpha methyldopa. Circulation 40: , Morin Y, Turmel L, Fortier J; Methyldopa: clinical studies in arterial hypertension. Am J Med Sci 248: , Tysell JE Jr, Knauer CM: Hepatitis induced by methyldopa (Aldomet). Dig Dis 16: , Eliastam M, Holmes A W: Hepatitis, arthritis and lupus cell phenomena caused by methyldopa. Dig Dis 16: , Goldstein GB, Lam KC, Mistilis SP: Druginduced active chronic hepatitis. Dig Dis 18: , Rehman OU, Keith TA, Gall EA: Methyldopainduced submassive necrosis. JAM A 224: , Kelsey WM, Scharyj M: Fatal hepatitis probably due to indomethacin. JAM A 199: , Fenech FF, Bannister WH, Grech JL: Hepatitis with biliverdinaemia in association with indomethacin therapy. Br Med J 2: , Jacobs JC: Sudden death in arthritic children receiving large doses of indomethacin. JAM A 199: , Cook GC, Sherlock S: Jaundice and its relation to therapeutic agents. Lancet 1: , Sherman JD, Love DE, Harrington JF: Anemia, positive lupus and rheumatoid factors with methyldopa. Arch ntern Med 120: , Ladd AT: Procainamide-induced lupus erythematosus. N Engl J Med 267: , Bickers N, Buechner HA, Hood BJ, et al: Hypersensitivity reaction to antituberculosis drugs with hepatitis, lupus phenomenon and myocardial infarction. N Engl J Med 265: , Kaufman M; Pancytopenia following use of hydralazine ("Apresoline"): report of a case. JAMA 151: , Reynolds TB, Peters RL, Yamada S: Chronic active and lupoid hepatitis caused by a laxative. oxyphenisatin. N Engl J Med 285: , Carstairs KC, Breckenridge A, Dollery CT, et al: ncidence of a positive direct Coombs test in patients on alpha-methyldopa. Lancet 2: , 1966