206 HEPATIC SINUSOIDAL DILATATION AFTER CHENODEOXYCHOLIC-ACID THERAPY acid
SiR,-Chenodeoxycholic (c.D.c.A.) dissolves gallstones, but several countries have been reluctant to endorse the marketing of this drug until clinical trials demonstrate its safety. Liver toxicity in man is suspected because c.D.C.A. administration to laboratory animals has led to mild to severe functional and morphological liver damage. In man, routine liver-function tests have shown only transient abnormalities during the first few months of C.D.C.A. therapy. The few histological and electron-microscopic studies of liver-biopsy material from c.D.c.A.-treated patients have revealed no specific liver damage attributable to the drug. However, because patients with cholelithiasis often have some degree of structural hepatic lesion it is difficult to prove that any new lesion is a consequence of drug hepatotoxicity, unless serial biopsies are done before and during C.D.C.A. administration. We have done a toxicological study in the course of a clinical trial of C.D.C.A. in the treatment of radiolucent gallstones. Patients were selected if they had functional gallbladders, no visible calcification of the stones, and normal liver-function tests. Pregnant women and women of childbearing age were excluded. From about 60 patients who started in the trial, we selected for study 26 who had taken c.D.c.A. for at least twelve months. The patients took 750-1000 mg C.D.C.A. (RousselUclaf) per day according to body-weight. No special diet or dietary restrictions were prescribed. All patients were examined before, and at six and twelve months during treatment, by X-ray, a battery of liver-function tests and blood studies, and biopsy. Liver biopsy was done under localanaesthesia with a disposable needle (’Trucut’, Travenol). Liver tissues were then processed for histology (Masson’s trichrome, oil-red) and electron microscopy. Histological slides were coded and interpreted by two independent observers. Clinical and laboratory follow-up did not reveal any new problems apart from those previously described (e.g., occasional diarrhoea and transient transaminases increases). Most pre-treatment liver samples showed slight hepatocyte clarification, steatosis, inflammatory infiltration of the lobules, triaditis, intracellular pigments, and sinusoidal congestion. However, sinusoidal dilatation was more common in samples taken during treatment. This abnormality was observed in 9 out of 26 patients pretreatment and in 14/24 and 13/20 after six and twelve months of c.D.c.A. therapy, respectively. 6 patients had only two biopsies. The difference between the frequency of sinusoidal dilatation in the first and third specimens was significant The other lesions observed before treatment (P
SiR,-Chenodeoxycholic (c.D.c.A.) dissolves gallstones, but several countries have been reluctant to endorse the marketing of this drug until clinical trials demonstrate its safety. Liver toxicity in man is suspected because c.D.C.A. administration to laboratory animals has led to mild to severe functional and morphological liver damage. In man, routine liver-function tests have shown only transient abnormalities during the first few months of C.D.C.A. therapy. The few histological and electron-microscopic studies of liver-biopsy material from c.D.c.A.-treated patients have revealed no specific liver damage attributable to the drug. However, because patients with cholelithiasis often have some degree of structural hepatic lesion it is difficult to prove that any new lesion is a consequence of drug hepatotoxicity, unless serial biopsies are done before and during C.D.C.A. administration. We have done a toxicological study in the course of a clinical trial of C.D.C.A. in the treatment of radiolucent gallstones. Patients were selected if they had functional gallbladders, no visible calcification of the stones, and normal liver-function tests. Pregnant women and women of childbearing age were excluded. From about 60 patients who started in the trial, we selected for study 26 who had taken c.D.c.A. for at least twelve months. The patients took 750-1000 mg C.D.C.A. (RousselUclaf) per day according to body-weight. No special diet or dietary restrictions were prescribed. All patients were examined before, and at six and twelve months during treatment, by X-ray, a battery of liver-function tests and blood studies, and biopsy. Liver biopsy was done under localanaesthesia with a disposable needle (’Trucut’, Travenol). Liver tissues were then processed for histology (Masson’s trichrome, oil-red) and electron microscopy. Histological slides were coded and interpreted by two independent observers. Clinical and laboratory follow-up did not reveal any new problems apart from those previously described (e.g., occasional diarrhoea and transient transaminases increases). Most pre-treatment liver samples showed slight hepatocyte clarification, steatosis, inflammatory infiltration of the lobules, triaditis, intracellular pigments, and sinusoidal congestion. However, sinusoidal dilatation was more common in samples taken during treatment. This abnormality was observed in 9 out of 26 patients pretreatment and in 14/24 and 13/20 after six and twelve months of c.D.c.A. therapy, respectively. 6 patients had only two biopsies. The difference between the frequency of sinusoidal dilatation in the first and third specimens was significant The other lesions observed before treatment (P
