William P. Baldus

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis

BACKGROUND/AIMS A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. METHODS Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. RESULTS In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity. CONCLUSIONS UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC.

A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis

Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P less than 0.06) and pruritus worsened in 6 (P less than 0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P less than 0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation.

Trial of Penicillamine in Advanced Primary Biliary Cirrhosis

A total of 227 patients with histologically advanced primary biliary cirrhosis entered a double-blind, randomized, controlled trial to determine whether penicillamine (1 g per day) was therapeutically effective; 111 patients received the drug, and 116 received placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, and histologic features. Penicillamine therapy did not result in an overall improvement in survival as compared with placebo. Clinical symptoms and serial hepatic laboratory values reflected the progressive nature of the disease and were similar in both groups. There were no substantial differences between treatment groups in the morphologic features of sequential biopsy specimens. The development of major side effects led to permanent discontinuation of penicillamine in 22 per cent of the patients taking the drug. We conclude that penicillamine is not useful for patients with histologically advanced primary biliary cirrhosis. The trial is being continued in patients with early histologic disease whose better prognosis necessitates longer follow-up.

Diagnosis of Wilson's Disease Presenting as Fulminant Hepatic Failure

The clinical course, results of standard laboratory tests, parameters of copper metabolism, and hepatic morphology in 9 cases (3 of our own and 6 from the literature) of Wilsons disease presenting as fulminant hepatic failure were compared with the findings in 5 cases of idiopathic fulminant hepatic failure. Patients with Wilsons disease were usually younger, and 7 of the 9 patients had Kayser-Fleischer rings. Patients with idiopathic fulminant hepatic failure had elevated 24-h urinary copper, decreased ceruloplasmin, and low or normal serum copper. Fulminant hepatic failure with Wilsons disease differed from idiopathic fulminant hepatic failure by the following biochemical findings: (a) higher copper levels in serum, urine and liver; (b) less pronounced elevations of transaminase levels; (c) higher concentrations of total bilirubin; and (d) lower hemoglobin values. Serum copper was the most useful biochemical test in diagnosing Wilsons disease before death. At autopsy, only hepatic copper concentrations clearly separated the two groups. Serial serum copper levels (antemortem) and quantitative analysis of hepatic copper (after recovery or postmortem) in patients with fulminant hepatic failure should help to exclude Wilsons disease.

Fulminant Hepatitis: Mayo Clinic Experience With 34 Cases

From 1974 through 1982, fulminant hepatitis was diagnosed in 34 patients at our institution. Of these patients, only two survived (survival rate, 6%). This syndrome was caused by viruses (B and non-B hepatitis and herpes simplex) in 23 patients, hepatotoxic drug in 6, Wilsons disease (hepatolenticular degeneration) in 3, and industrial poisons in 2. Most of the patients died within 10 days after the onset of encephalopathy. The poor prognosis in our group of patients was probably related to the preponderance of older patients and cases caused by non-B hepatitis virus. In our patients, the clinical course was complicated by renal failure, ascites, bleeding, sepsis, pancreatitis, and seizures. The major cause of death was hepatic failure.

Primary Sclerosing Cholangitis and Celiac Disease: A Novel Association

The association of primary sclerosing cholangitis and celiac disease was observed in three patients, an association not previously reported. All three patients were men who presented with chronic cholestatic liver disease at ages 32, 46, and 62 years, respectively. In each patient, endoscopic retrograde cholangiography showed the typical findings of primary sclerosing cholangitis. Histologic features of liver biopsy were compatible with the diagnosis. Two patients had associated chronic ulcerative colitis. All three patients complained of frequent loose stools and weight loss; subsequent testing showed severe steatorrhea (204 to 323 mmol/d of fecal fat on a 100 g fat diet). Total villous atrophy was found in all three patients on histologic examination of the small bowel. Celiac disease was diagnosed at the time of presentation in two patients who had primary sclerosing cholangitis and was diagnosed three years after the onset of primary sclerosing cholangitis in the third patient. The celiac disease responded to a gluten-free diet in each patient whereas the primary sclerosing cholangitis was not affected by dietary treatment. The possibility of a chance association of primary sclerosing cholangitis and celiac disease cannot be accurately assessed but seems unlikely given the rarity of both diseases. The relationship between the two diseases remains unknown, although an immunologic connection is suspected. Celiac disease should be considered in the differential diagnosis of severe steatorrhea in patients with primary sclerosing cholangitis.

Screening for hemochromatosis: A cost-effectiveness study based on 12,258 patients

BACKGROUND/AIMS Current emphasis in hemochromatosis has focused on early detection and treatment to prevent permanent liver damage and hepatocellular carcinoma. Thus far, only normal population and high-risk groups have been screened but not patients seeking medical care. METHODS Serum iron levels were determined in consecutive fasting blood samples collected in the morning from 12,258 Mayo Clinic patients. RESULTS One hundred twenty-seven patients had an initial serum iron concentration > or = 180 micrograms/dL. Eight patients (age, 38-71 years; 7 men and 1 woman) had transferrin saturation > or = 62% (range, 84-99) and serum ferritin value > or = 400 micrograms/L (range, 457-4004) with no other explanation for the abnormal iron test results. Three patients (2 male and 1 female) had markedly elevated hepatic iron concentration (range, 11,080-29,719 micrograms/g dry wt) and hepatic iron index (range, 2.9-8.4) indicative of homozygous hemochromatosis. One patient who refused liver biopsy had 7 g of iron removed by phlebotomy and is likely homozygous. Two patients had hepatic iron indices < 1.5 and are probably heterozygous. The genetic status of 1 patient is indeterminate, and 1 patient with normal hepatic iron concentration and hepatic iron index had chronic active hepatitis. None had cirrhosis, diabetes, or cardiomyopathy. No patients with hemochromatosis would have been detected without this study. CONCLUSIONS The yield in this study, 0.33 cases of 1000 screened, is approximately one tenth of the predicted homozygote frequency by recent estimates. Even at this yield, screening appears cost-effective.

Effects of Dopamine on Renal Function in Patients with Cirrhosis

The effects of dopamine on renal function were studied in 10 patients with cirrhosis and various degrees of impairment of renal function. Dopamine caused a consistent increase in effective renal plasma flow but little change in glomerular filtration rate or sodium and water excretion. The hemodynamic change is attributed to a direct effect on the renal vasculature, resulting in reduction in both preglomerular and postglomerular resistance. Unlike other drugs, dopamine partially corrects the renal hemodynamic disturbance in cirrhosis, although its role as a therapeutic agent is limited.

Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases

Clinical and pathologic features of cardiac hemochromatosis diagnosed by endomyocardial biopsy in six men, aged 32 to 75 years (mean 52), are described. Echocardiography demonstrated left ventricular enlargement and marked global systolic dysfunction in five. Cardiac catheterization demonstrated normal coronary arteries, increased left ventricular end-diastolic pressure and decreased left ventricular systolic function in all five so studied. Stainable iron was present in all endomyocardial biopsy specimens from the five patients with decreased left ventricular systolic function. Histologically, iron was detected only within the sarcoplasm, and its extent varied inversely with ventricular function. Thus, cardiac hemochromatosis represents a storage rather than an infiltrative disease. These results indicate that stainable iron is consistently observed in endomyocardial biopsy specimens from patients with impaired left ventricular systolic function. Iron staining is recommended for endomyocardial biopsy specimens from patients with idiopathic cardiac dysfunction.

Idiopathic portal hypertension; a histopathological study of 26 Japanese cases.

Analysis of 25 liver biopsy specimens and one autopsy specimen from 26 Japanese patients (23 women and three men) with idiopathic portal hypertension revealed findings that collectively appeared diagnostic for the condition. Changes in the portal tract included capillary dilatation, phlebosclerosis, and fibro‐elastosis of the stroma. Many portal veins were dilated and had herniated into the surrounding hepatic parenchyma. Portal vein obliteration and loss of bile ducts were a rare complication. The acinar architecture was disturbed by: 1 capillary and necro‐infiammatory bridging, mostly between portal tracts and terminal hepatic veins; 2 the formation of isolated megasinusoids in a random distribution; 3 displaced and abnormally large hepatic vein branches with or without phlebosclerosis and 4 slender, curved fibrous septa (hairline septa). Early nodular regeneration was found in 25% of the cases. Our review supports the contention that incomplete septal cirrhosis may be a late manifestation of idiopathic portal hypertension. It is not clear whether the biopsy findings in Japanese patients differ only in severity from those in western patients, or whether the conditions differ pathogenetically. Some histopathological findings in the Japanese cases, in particular the necroinflammatory changes, are difficult to reconcile with portal hypertension as a primary haemodynamic abn rmality.