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We report on a case of perhexiline maleate-induced hepatitis secondary to a long-term administration of recommended daily dosages of 300 mg. The patient had a spectacular weight loss of 29 kg. He developed hepatitis, which subsided after drug withdrawal. Our electron-microscopic findings with the typical inclusion bodies and impaired hydroxylation capacity point to an underlying metabolic disorder as the pathogenetic mechanism.

The authors describe a case of cirrhogenic hepatitis due to Pexid which was given for 8 months at 400 mg/day for a severe angina pectoris. We find here the anatomo-clinical profile of perhexiline maleate hepatiits already described in approximately 20 cases. There was a cirrhogenic evolution in our case as in 5 others : but here cirrhosis was revealing and seems stabilized since the treatment was stopped. The cirrhogenic evolution could be due to a cumulative effect of the drug and/or to an immuno-allergic mechanism as in alcoholic cirrhosis which is very similar, especially from an anatomical point of view. However cirrhogenic hepatitis differs by a characteristic lysosomal overload : brown pigment under microscopic observation and lipolysosomes with in some cases a lamellar structure under electron microscopic observation. The prescription of such a drug should be limited to cases of refractory angina pectoris and needed a regular clinical and biological survey.

Case report of polyneuritis and liver dysfunction induced by perhexiline maleate in a 64 years old male patient. The ultrastructural study of nerve, liver, muscle and skin biopsies shows polymorphous, membrane bound, often multilamellar, lysosome-like inclusions, the content of which is probably complex lipids. The histochemical study of liver reveals a lipid storage, consisting mainly of triglycerides and of smaller amount of phospholipids and free fatty acids, the pattern of which is abnormal. The biochemical study of nerve tissue shows a decrease of phospholipids levels and some qualitative disturbances in gangliosides. These changes, some of which are similar to those reported in amphiphilic drug intoxications, are prevalent in high lipid metabolism cells such as hepatic and Schwann cells.

A patient developed papilloedema and hepatic dysfunction while being treated with perhexiline maleate. These later regressed when the drug was withdrawn. Patients should be monitored for these potentially serious side-effects while on this drug.

5 patients treated with perhexiline maleate, 200-400 mg/day for at least 6 months, exhibited evidence of hepatitis. The picture was very similar to acute alcoholic hepatitis, clinically, biologically and histologically with presence of necrosis, Mallory's hyaline, polynuclear infiltration and to a lesser degree, steatosis. Association with peripheral neuropathy, hypoglycemia, and renal failure appears strikingly frequently. The evolution was severe since 3 patients died within 6 months, even after treatment withdrawal. Further studies are to be done to understand the mechanisms of hepatic and neurologic toxicity, and to measure the hazards of this drug. These studies could bring a new insight to alcohol toxicity.

Two patients who developed biochemical and histological evidence of hepatitis while taking the anti-anginal drug perhexiline maleate are described. The pathological changes were those of mild to moderate fatty change together with a hepatitis which resembled alcoholic hepatitis, including in one patient the presence of material which by light microscopy was indistinguishable from Mallory's alcoholic hyalin. However, the predominantly periportal location of this material contrasted with the centrilobular distribution of Mallory's hyaline. One patient showed, in addition, severe atypia of the hepatocytes which was still present in less pronounced form 10 weeks after stopping perhexiline. The other patient had advanced hepatic fibrosis.

The authors report the cases of 2 patients who died from cirrhosis after receiving perhexiline maleate, a drug widely used in Europe for the treatment of angina pectoris. Perhexiline maleate had been ingested for 24 and 28 mo, respectively. Manifestations of cirrhosis included jaundice, hepatic encephalopathy, ascites, and portal hypertension. Associated manifestations of intolerance to perhexiline maleate included peripheral neuropathy in 1 patient and marked weight loss in both. Histologic lesions resembled those observed in patients with alcoholic liver disease. Ultrastructural lesions included numerous enlarged lysosomes containing myeloid figures. Histochemical stains demonstrated increased phospholipid content of the hepatocytes. These findings are consistent with the view that prolonged administration of perhexiline maleate may induce both histologic lesions resembling those of alcoholic liver disease and ultrastructural and histochemical lesions resembling those of phospholipidosis.