Hepatic toxicity associated with gold therapy.

Three patients with rheumatoid arthritis developed jaundice after initiation of chrysotherapy. Gold sodium thiomalate had been administered in dosages of 37.5, 60, and 110 mg in these patients before the onset of jaundice. Liver function studies indicated a cholestatic jaundice in all subjects. One patient underwent exploratory laparotomy because of progressive jaundice. Liver biopsy was done in two patients. In one patient significant bile stasis and thrombi were seen in the biliary tree. In another patient liver biopsy showed ballooning of hepatocytes with minimal cholestasis. All patients recovered spontaneously. Awareness of this rare complication may prevent unnecessary diagnostic and surgical procedures in patients with rheumatoid arthritis who may develop jaundice while receiving chrysotherapy.     

Jaundice in Multiple Myeloma: The Role of Oxymetholone

Jaundice complicated the course of disease in 11 (41%) of 27 consecutive patients with multiple myeloma. In only one patient was myeloma cell infiltration of the liver the sole cause of jaundice. One patient was found to have carcinoma of the pancreas. In nine jaundice developed during therapy with the bone marrow stimulant oxymetholone. Liver histology in six of the nine showed cholestatic hepatitis or a predominantly cholestatic reaction; clinical events were consistent with oxymetholone-induced cholestasis in the remaining three. In addition to oxymetholone all patients were receiving intermittent therapy with melphalan, prednisolone and procarbazine, but such therapy was not temporally related to the onset of jaundice. All jaundiced patients were HB_sAg negative. Of the 19 patients treated with oxymetholone for refractory anaemia, nine (47%) developed jaundice. The reason for such a high complication rate is obscure. Three of these patients, who showed a severe cholestatic hepatitis, died in acute liver failure. These results indicate that high doses of oxymetholone should be used with great care in the therapy of refractory anaemia in multiple myeloma.     

Idiopathic adulthood ductopenia: case report and review of the literature

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.     

Cholestasis secondary to hyperthyroidism made worse by methimazole

A 28-year-old man presented with weight loss, jaundice, and pruritis. This was diagnosed to be secondary to Graves disease and the patient was prescribed methimazole. He returned 2 weeks later with worsening of his jaundice. Further investigation, including liver biopsy, indicated that there was superimposed methimazole-induced cholestasis. Discontinuation of methimazole and treatment of hyperthyroidism with lithium followed by radioactive iodine therapy resulted in resolution of his symptoms. This case highlights the fact that worsening cholestasis after therapy for Graves disease should raise the possibility of thionamide-induced exaggeration of liver cholestasis.     

Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes

Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.     

Reversible cholestasis with bile duct injury following azathioprine therapy. A case report

A 67-year-old patient, with primary polymyositis and without previous evidence of liver disease, developed clinical and biochemical features of severe cholestasis 3 months after initiation of azathioprine therapy. Liver biopsy showed cholestasis with both cytological and architectural alterations of interlobular bile ducts. Azathioprine withdrawal resulted after 7 weeks in the resolution of clinical and biochemical abnormalities. It is believed that this is the first reported case of reversible azathioprine-induced cholestasis associated with histological evidence of bile duct injury.     

Prochlorperazine-induced chronic cholestasis

A patient with prochlorperazine-induced cholestasis that persisted for more than 2 years is reported. The timing of the onset of jaundice, the clinical, biochemical and histological findings and the subsequent course of this patient were typical of chlorpromazine-induced chronic cholestasis. Despite subsequent resolution of jaundice, liver biopsy performed 2 years after the onset of clinical disease showed fibrous expansion of the portal tracts with focal porto-portal and centro-portal bridging fibrosis, and paucity of inter-lobular bile ducts, a picture simulating that of primary biliary cirrhosis. Long-term follow-up is required to determine whether this patient will progress to frank cirrhosis.     

Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report

We report a case of fosinopril-induced prolonged cholestatic jaundice and pruritus in a 61-year-old man, with no previous hepatobiliary disease, who presented with asthenia, jaundice and itching 3 weeks after starting fosinopril therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. Liver biopsy showed cholestasis without bile duct damage. The disease ran a severe course during the 2 months of hospitalization, with prolonged itching for 6 months, eventually controlled with oral naltrexone. Jaundice subsided after 4 months, with anicteric cholestasis persisting for more than 18 months. Similar occurrences have been reported with other inhibitors of angiotensin-converting enzyme (mostly captopril), but this is the first case of an important adverse reaction to fosinopril.     

Biliary Complications Associated with Selective Internal Radiation (SIR) Therapy for Unresectable Liver Malignancies

Selective internal radiation (SIR) therapy using (90)yttrium microspheres is effective for treating selected cases of unresectable liver malignancies with little morbidity. We herein report two cases illustrating a very rare complication of SIR. A 68-year-old patient with inoperable recurrent hepatocellular carcinoma received one treatment of SIR with (90)yttrium microspheres and 4 months later presented with obstructive jaundice. Percutaneous transhepatic cholangiography revealed diffusely dilated intrahepatic ducts with multiple biliary strictures. Hepatic angiography showed normal hepatic arterial branches with no evidence of vascular insufficiency. Liver biopsy finally revealed cholestasis, cholangitis, and fibrosis, consistent with radiation-induced damage. Another 56-year-old patient with unresectable colorectal liver metastases presented with cholangitis 4 weeks after SIR. Ultrasonography showed no biliary dilatation, and endoscopic retrograde cholangiopancreatography demonstrated a normal biliary tree. Liver biopsy subsequently confirmed radiation-induced cholangitis.     

Cholestasis and alcoholic liver disease

Histologic cholestasis and clinical jaundice may be seen in all stages of alcoholic liver disease. In rare cases, isolated cholestasis without significant steatosis, hepatitis, or cirrhosis is identified in an alcoholic patient. The mechanisms of ethanol-induced cholestasis are not well studied but may involve compression of intrahepatic biliary radicals or interference with basolateral uptake and intracellular transport of bile acids. In the evaluation of the jaundiced alcoholic patient, clinical, biochemical, and radiologic data are usually sufficient to distinguish alcohol-induced liver disease from extrahepatic biliary obstruction. In cases where the diagnosis is not readily apparent, more invasive studies such as liver biopsy or ERCP may be necessary. The risk of these invasive studies is directly related to the degree of underlying hepatic dysfunction.     

Clinical and histological recovery from “life-threatening” severe acute alcoholic hepatic failure with complete hepatofugal portal blood flow

A 25-year-old man who was a heavy alcohol drinker was admitted to our hospital after presenting with general malaise, dyspnea, abdominal distension, systemic edema and jaundice. His liver function tests showed hyperbilirubinemia and prolonged prothrombin time, and a computed tomography scan and ultrasound showed liver atrophy and massive ascites. Furthermore, Doppler ultrasound revealed complete hepatofugal portal blood flow in the portal trunk and intrahepatic portal branches. Causes other than alcohol were excluded, and he was diagnosed as having severe acute alcoholic hepatic failure (Maddrey’s discriminant function score 43.3, MELD score 21), although not clinically typical. He was treated with anti-coagulation therapy according to the precise evaluation of portal blood flow by Doppler ultrasound, and marked clinical, biochemical and hemodynamic improvements were observed. Liver biopsy performed 2 months after onset showed submassive necrosis with pericellular fibrosis. Liver biopsy performed three years after onset showed mild portal fibrosis with a marked improvement. Doppler ultrasound is an indispensable tool for evaluating patients with severe acute hepatitis.     

Case report: fulminant hepatic failure involving duloxetine hydrochloride.

BACKGROUND AND AIMS: Duloxetine hydrochloride was approved by the Food and Drug Administration in August 2004 for the treatment of major depressive disorder and diabetic peripheral neuropathic pain. Initial product labeling contained a precaution regarding the risk for increases in liver function test results. Recently, postmarketing research has revealed episodes of cholestatic jaundice and increases in transaminase levels to greater than 20 times normal in patients with chronic liver disease. METHODS: In this case report, we describe a patient with non-Hodgkin's lymphoma in remission and depression treated with duloxetine and mirtazapine. RESULTS: Approximately 6 weeks after increasing her duloxetine dose from 30 to 60 mg daily, she became jaundiced and presented with fulminant hepatic failure. Liver function tests immediately before initiating duloxetine were not available, although the patient carried no prior history of chronic liver disease. A complete work-up for alternate causes failed to reveal another explanation for the patient's clinical presentation. A liver biopsy examination showed histologic changes of subacute injury and the patient's clinical course was consistent with drug-induced liver injury. Despite aggressive measures, the patient's condition deteriorated and the decision was made to withdraw care. CONCLUSIONS: This report shows a case of fulminant hepatic failure and death involving duloxetine use. Given recent reports of severe hepatotoxicity associated with the use of duloxetine in patients with pre-existing liver disease, further investigation into the safety of this compound is warranted.     

Carbamazepine hepatitis: the clinicopathological spectrum

Abstract Despite 20 years of widespread use, carbamazepine has rarely been implicated as causing hepatic drug reactions. The observation of eight cases of carbamazepine hepatitis during a 3-year period afforded an unusual opportunity to describe the clinicopathological spectrum of this reaction. The eight patients (four males, four females, aged 44–83 years) presented with fever, anorexia and malaise within 12 weeks of starting carbamazepine. Clinical features included swinging fever, jaundice (six cases) and right upper quadrant abdominal pain and tenderness which frequently led to a clinical diagnosis of cholangitis; rash and eosinophilia were not present. Serum transaminase and alkaline phosphatase values variably suggested cholestasis (three patients), predominantly hepatocellular injury (one patient) or were mixed (four patients). However, in all four patients subjected to liver biopsy, the histological picture was a granulomatous hepatitis.
Cessation of carbamazepine resulted in rapid resolution of symptoms with normalization of biochemical abnormalities within 4 weeks. In two patients who were rechallenged with carbamazepine, symptoms and abnormal serum biochemistry recurred within 24 h. It is suggested that carbamazepine causes hepatic drug reactions more commonly than has been previously recognized. Although the clinical and laboratory picture may suggest cholangitis, the usual histological finding is a granulomatous hepatitis. Prompt resolution can be expected in the majority of cases upon withdrawal of the drug.     

Severe intrahepatic cholestasis,erythrocytosis and hypoglycemia: Unusual presenting features of systemic AL amyloidosis

We report the case of a 68-year-old African woman who presented with jaundice, hepatomegaly and anasarca. Clinical investigation disclosed severe intrahepatic cholestasis, nephrotic syndrome, erythrocytosis and hypoglycemia. Diagnosis of systemic AL amyloidosis was established by percutaneous liver biopsy. Bone marrow biopsy showed 32% of myeloma cells. The patient started treatment with melphalan and prednisolone, but liver function deteriorated and she died in hepatic failure complicated by septic shock three weeks after the diagnosis. We present possible explanations for the unusual clinical and laboratory findings, which required a multidisciplinary approach and posed challenging problems in differential diagnosis and management.     

Cholestatic hepatitis related to use of irbesartan: a case report and a literature review of angiotensin II antagonist-associated hepatotoxicity

We report a patient who developed cholestatic hepatitis shortly after starting therapy with irbesartan, one of the new, recently marketed angiotensin II antagonists. Serological studies and ultrasonography ruled out viral hepatitis and extrahepatic obstructive jaundice, respectively. A percutaneous liver biopsy showed a portal inflammatory infiltrate with eosinophils and marked cholestatic features in the perivenular area. Irbesartan was discontinued and the patient's jaundice resolved slowly over a period of several weeks, although mild biochemical cholestasis lasted for more than 1 year. There have been seven prior cases of angiotensin II antagonist-induced hepatotoxicity reported in the literature. A class warning for hepatotoxicity for these compounds should probably be considered.     

Severe intrahepatic cholestasis, erythrocytosis and hypoglycemia: unusual presenting features of systemic AL amyloidosis

We report the case of a 68-year-old African woman who presented with jaundice, hepatomegaly and anasarca. Clinical investigation disclosed severe intrahepatic cholestasis, nephrotic syndrome, erythrocytosis and hypoglycemia. Diagnosis of systemic AL amyloidosis was established by percutaneous liver biopsy. Bone marrow biopsy showed 32% of myeloma cells. The patient started treatment with melphalan and prednisolone, but liver function deteriorated and she died in hepatic failure complicated by septic shock three weeks after the diagnosis. We present possible explanations for the unusual clinical and laboratory findings, which required a multidisciplinary approach and posed challenging problems in differential diagnosis and management.     

Steroid-Responsive Chronic Hepatic Graft-versus-Host Disease without Extrahepatic Graft-versus-Host Disease

A 29-yr-old woman developed severe, progressive cholestasis 5 months after allogeneic bone marrow transplantation. Extrahepatic graft-versus-host disease (GVHD) was absent. Skin biopsy was equivocal 2 months after transplant, rash was absent during the period of cholestasis, and cholangiographic abnormalities were absent. Liver biopsy 7.5 months posttransplant revealed chronic hepatic GVHD. Cholestasis dramatically resolved with high dose corticosteroid therapy. Chronic hepatic GVHD occurs in the absence of overt extraintestinal GVHD and respond promptly to therapy. This underscores the importance of aggressive diagnostic evaluation of posttransplant cholestasis.     

Severe penicillin-induced cholestasis in a 91-year-old woman

Summary An elderly woman was admitted for treatment of severe stasis ulceration, associated with varicose veins. One course of cloxacillin was given orally followed by a second course of penicillin-G to eradicate persistant hemolytic streptococcal skin infection. Deep progressive jaundice subsequently developed due to intrahepatic cholestasis and persisted for several weeks before resolution. Having excluded a progressive extrahepatic malignant lesion by appropriate investigations, the diagnosis was substantiated by classical changes present in a percutaneous liver biopsy.     

Hepatic involvement associated with ingestion of metapramine

The authors report the cases of 3 women who developed hepatic injury during administration of metapramine, a tricyclic antidepressant introduced in France in 1984. One patient had jaundice and pruritus; the 2 others had loss of weight. Serum alkaline phosphatase and serum transaminase activities were increased in 3 and 2 patients, respectively. Blood hypereosinophilia was found in one patient; erythrocyte sedimentation rate was elevated in 2 patients. The outcome was favorable after drug withdrawal in the 3 patients. Liver biopsy showed centrolobular cholestasis in the 3 patients. There was no rechallenge; in 2 patients, other drugs than metapramine might be implicated in hepatic injury; however, the similarity of these 3 cases suggests that metapramine, like other tricyclic antidepressants, may be responsible for hepatic injury.