CONTEXT:Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.OBJECTIVE:To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.DESIGN:Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.RESULTS:The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.CONCLUSION:Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT, Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mite with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestions of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain, Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.

Sarcoidosis often involves the liver with mild elevation of serum enzymes and granulomas histologically. Rarely, chronic cholestasis, portal hypertension, cirrhosis, or nodular hyperplasia may be found. The pathogenesis of the portal hypertension and of the cirrhosis are not understood. In part because large samples of tissue have seldom been described. We describe the clinical and anatomic findings of four patients with sarcoid liver disease in whom the whole livers were available for examination. One patient had cirrhosis, one had diffuse nodular hyperplasia, and two had small regions of parenchymal fibrosis. The first two of these had a history of variceal bleeding and healed portal vein thrombosis. One had chronic cholestasis without cirrhosis. We suggest that the cirrhosis and focal fibrosis were caused by ischemia secondary to primary granulomatous phlebitis of portal and hepatic veins. The portal hypertension in two patients was likely secondary to portal vein thrombosis, because cirrhosis was absent at the onset of variceal bleeding.

Ribavirin therapy was initiated at a median of 181 days after liver transplantation in 18 patients with persistent elevation of alanine aminotransferase values and biopsy-proven hepatitis, and continued for 23 months (12-44 months). All patients had a prompt biochemical response, with alanine aminotransferase decreasing by 69%; complete normalization occurred in 5 (28%). Serum hepatitis C virus RNA levels did not change during therapy. Liver biopsies obtained after 17 months (9-38 months) of therapy showed no improvement in necroinflammation. However, worsening of fibrosis occurred in 12 patients; and cirrhosis developed in 5 patients (28%), with 3 patients progressing to graft failure. Biopsies from 27 untreated patients who did not fulfill treatment criteria (median follow-up, 38 months) and 4 patients who received 3 months of ribavirin (44 months) showed cirrhosis in 11 and 75%, respectively. Patient and graft survival rates for treated and untreated patients were similar. Although ribavirin improves alanine aminotransferase, it does not prevent the development or progression of fibrosis in patients with recurrent hepatitis C virus.

This study documents the hepatic morphology and the ultrastructure of a model of hepatic fibrosis in rabbits. Rabbits were given a cholesterol-supplemented diet (1%), a stilbestrol diet (10 mg subcutaneously twice a week), or both treatments simultaneously for 7 weeks. Rabbits given the combined treatment developed sinusoidal and portal fibrosis with only a mild disturbance of acinar vascular relationships. Ultrastructurally, there was marked widening of the spaces of Disse by collagen fibers, basement membrane material adjacent to endothelial cells and hepatocytes, blunted hepatocellular microvilli, activated stellate cells, lipid droplets in endothelial cells and hepatocytes, and degranulated platelets in sinusoids. The hepatic hydroxyproline content was markedly increased (12.0 +/- 5.2 vs. 4.8 +/- 1.5 mmol/g of liver dry weight; P < .001). Plasma bile acids were markedly increased (222 +/- 180 vs. 12 +/- 5 in controls; P < .001). Dipyridamole (25 mg every 12 hours) that was given in addition to cholesterol and stilbestrol decreased the hepatic collagen content (-49% and -48%, in two experiments; P < .05 in both) and splenomegaly. This model provides a reliable method for the production of extensive sinusoidal fibrosis with capillarization of sinusoids. Hepatocellular degeneration is only mild to moderate, and fibrosis occurs slowly without the sudden pathological changes that occur with other models of hepatic fibrosis, such as with the administration of CCl4 or galactosamine. The mechanism of injury may involve the accumulation of bile salts or the generation of free radicals from cholesterol oxidation products. The possibility that the sinusoidal release of platelet-derived factors may have a role in the activation of stellate cells (lipocytes) is supported by the suppression of fibrogenesis by dipyridamole.

Lipiodol has been used to increase the detectability of small primary neoplasms in the liver. We report a patient who was found to have lipiodol deposits in the liver one month after intra-arterial injection. The region was resected, under ultrasound control, because of the impression that the lesion was malignant. The specimen contained two small hemangiomas as well as many small dysplastic nodules (adenomatous hyperplasia) in a noncirrhotic parenchyma. To locate the lipiodol deposit in this case, the tissue was radiographed, postfixed in osmium tetroxide, and embedded in paraffin. Black osmium-stained deposits were found within the cavities of the hemangiomas but not in the dysplastic nodules. Most of the deposits were extracellular multivesiculated bodies with a small focus of lipid droplets engulfed by multinucleated foreign-body type giant cells. This report reinforces that hepatic lipiodol retention is not specific for hepatocellular carcinoma. We present, for the first time, the histologic appearance of lipiodol accumulation in an hemangioma. The value of osmium tetroxide postfixation for the detection of lipiodol is also demonstrated.

Focal nodular hyperplasia (FNH) is usually a stable lesion that does not enlarge when studied for long periods of time; recurrence after resection has not been reported. We present a patient with a solitary FNH lesion that enlarged, was resected, and then recurred. A second resection was performed because of abdominal pain and disclosed multiple lesions, two of which were acutely infarcted. Thirty-two months later there was ultrasound evidence of further recurrence. Histology of the lesions showed the usual appearance of FNH with ducts and ductules in the central stalk regions but also some areas with minimal ductular differentiation and scanty connective tissue. Because of the clinical and histological appearance, the lesions in this patient were distinct from the usual type of FNH and merit the name “focal nodular hyperplasia, progressive type.”

Two patients with hepatic injury after ingestion of chaparral leaf are presented. The first patient, a 71-yr-old man, developed biopsy-proven hepatitis 3 months after ingesting chaparral leaf daily. His illness resolved with discontinuation of the herb and later recurred with rechallenge. The second patient is a 42-yr-old woman who developed hepatitis 2 months after chaparral leaf ingestion and recovered completely after discontinuation of the compound. Both patients have remained well with abstinence from chaparral. These reports provide evidence of the hepatotoxicity of this herb and stress the need for awareness of the potential harm from such nonprescription remedies.

The pathogenesis of congestive cirrhosis is generally thought to be a reaction of the hepatic stroma to hypoxia, pressure, or necrosis. This does not explain the poor correlation between symptoms and severity of fibrosis and the irregular distribution of fibrosis within the liver. We have observed healed hepatic vein (HV) thrombosis in patients with congestive heart failure (CHF). The purposes of this study were to document hepatic vascular lesions in autopsy livers of patients with chronic CHF, to determine the role of these lesions in the pathogenesis of congestive cirrhosis, and to refine the definition of congestive cirrhosis. Twenty-five livers were studied, 13 with multiple large blocks 4 x 5 cm. Sections were graded for parenchymal fibrous septa, sinusoidal fibrosis, and intimal fibrosis of portal veins (PVs) and HVs. Fibrous septa were found in livers of 7 of 13 patients with CHF and in none of 12 controls without CHF (P = .007). Parenchymal fibrosis was highly variable in distribution, often with severe septation in some areas and nearly normal morphology in others. Intimal fibrosis and obstruction of small- and medium-HVs were found only in livers of patients with CHF. The vascular lesions were confined to regions with fibrous septation and had morphology suggestive of organized thrombosis. Acute thrombi in sinusoids were noted in livers of 4 patients with CHF and in livers of 2 patients without CHF. These findings support the hypothesis that congestive cirrhosis is a response to intrahepatic thrombosis. The pattern of disease suggests that thrombus begins in sinusoids, occasionally propagates to HVs, and causes secondary local PV thrombosis, ischemia, parenchymal extinction, and fibrosis.

Objective: To describe the hepatotoxicity associated with ingestion of the Chinese herbal product Jin Bu Huan Anodyne Tablets (Lycopodium serratum) and to propose possible mechanisms of injury.Design: Retrospective analysis.Setting: Academic hepatology units and private practice facilities.Patients: Seven previously healthy patients.Measurements: Clinical, laboratory, radiologic, and histologic studies.Results: Acute hepatitis occurred after a mean of 20 weeks (range, 7 to 52 weeks) of Jin Bu Huan ingestion and resolved in six patients within a mean of 8 weeks (range, 2 to 30 weeks); another patient is currently improving. Hepatitis was associated with symptoms of fever, fatigue, nausea, pruritus, and abdominal pain and with signs of jaundice and hepatomegaly. Biopsy specimens showed that one patient had hepatitis with eosinophils (consistent with a drug reaction) and the other had mild hepatitis, moderate fibrosis, and microvesicular steatosis. Decreasing the Jin Bu Huan dose in one patient improved liver test results. Reusing Jin Bu Huan in two other patients caused abrupt recrudescence of hepatitis.Conclusion: Jin Bu Huan can cause liver injury. Although the hepatotoxic mechanisms are not defined, they may include hypersensitive or idiosyncratic reactions or direct toxicity to active metabolites. Hepatotoxicity caused by herbal products underscores the importance of national surveillance programs and quality control of the manufacture of these products.