Propranolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment?

Although beta blockers have had significant impact in the treatment of portal hypertension, the question of how long they should be continued for prevention of variceal hemorrhage remains unknown. Prospective studies on beta blockers to prevent variceal hemorrhage lack long-term follow-up, and indefinite administration of beta blockers for primary prevention of variceal bleeding has become standard practice. The aim of this study was to determine the outcomes of patients in whom beta blocker therapy was discontinued. Patients completing a prospective, randomized, double-blind, placebo-controlled trial of propranolol for the primary prevention of variceal hemorrhage were tapered off of propranolol and placebo and followed prospectively for subsequent events. Of the 49 patients in the follow-up study (25 former propranolol, 24 former placebo), 9 experienced variceal hemorrhage (6 former propranolol, 3 former placebo). Following withdrawal of propranolol, the freedom from variceal bleeding was not significantly different between these 2 groups of patients, suggesting that the protective effect of propranolol against variceal hemorrhage, noted previously, was no longer present. Seventeen patients died (12 former propranolol, 5 former placebo) during the follow-up study. Cumulative survival was longer in the placebo group. These trends for EVH and survival were opposite to those observed in the original study population while patients were taking medication. When propranolol is withdrawn, the risk of variceal hemorrhage returns to what would be expected in an untreated population. Patients who discontinue beta blockers experience increased mortality compared with an untreated population. These observations support the current practice of indefinite prophylactic therapy.

Treatment of acute variceal bleeding.

Once the bleeding patient has been resuscitated and the diagnosis of acute variceal hemorrhage established by endoscopy, emergency injection sclerotherapy should be employed as the therapeutic option of choice. Endoscopic band ligation is a promising new technique that may prove to be as effective as sclerotherapy, with fewer complications. Pharmacologic treatment (with vasopressin and nitroglycerin) and balloon tamponade remain important alternative treatments, both as empiric temporizing therapy before sclerotherapy can be arranged and in the approximately 30% of patients who continue to bleed after a single sclerotherapy session. Continued bleeding in many of these patients can be controlled with a second session of sclerotherapy. If active acute bleeding persists after two sclerotherapy treatments, treatment should be considered a failure. Some of these patients may be suitable for surgical treatment with either staple-gun transection of the esophagus or emergency portacaval shunting.

Propranolol in the prevention of the first hemorrhage from esophagogastric varices: A multicenter, randomized clinical trial. The Boston-New Haven-Barcelona Portal Hypertension Study Group.

To assess the effectiveness of propranolol in the prevention of initial variceal hemorrhage, a double-blind, randomized trial was carried out in three centers. Patients with cirrhosis (78% alcoholic), hepatic venous pressure gradients greater than 12 mm Hg and endoscopically proven esophageal varices were randomly assigned to propranolol (51 patients) or placebo (51 patients). Of the 102 patients, 58% were Child's class A, 34% were Child's class B and 8% were Child's class C. Daily dosage was determined by the administration of progressively increasing doses of propranolol with the hepatic vein catheter in place to achieve a 25% decrease in hepatic venous pressure gradient, a decrease in hepatic venous pressure gradient to less than 12 mm Hg or a decrease in resting heart rate to less than 55 beats/min. During a mean follow-up period of 16.3 mo, 11 patients in the placebo group (22%) bled from esophageal varices compared with 2 in the propranolol group (4%) during a mean period of 17.1 mo (p less than 0.01). Three additional patients (6%) in the placebo group bled from portal hypertensive gastropathy compared with none in the propranolol group. Propranolol appeared effective in preventing bleeding from large varices. Eleven deaths (22%) occurred in the placebo group compared with eight deaths (16%) in the propranolol group (NS). The mean dose of propranolol was 132 mg/day, and the median dose was 80 mg/day. Using a compliance index (pill count, clinic attendance, alcohol and propranolol levels and alcohol history), 81% of the propranolol patients and 77% of the placebo patients were considered compliant. Complications severe enough to require cessation of therapy occurred in eight patients (16%) in the propranolol group and four in the placebo group (8%) (NS). We conclude that propranolol effectively prevents the first variceal hemorrhage in patients with alcoholic cirrhosis and large esophageal varices but does not improve survival.

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity.

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.

Osteoporosis in primary biliary cirrhosis: effects of 25-hydroxyvitamin D3 treatment.

Bone histology, bone mineral content, and calcium absorption were evaluated in 10 patients with primary biliary cirrhosis and osteopenia, before and after 1 yr of treatment with oral 25-hydroxycholecalciferol. Before treatment, quantitative histomorphometric analysis of full-thickness iliac crest bone biopsy specimens with double-tetracycline labeling demonstrated that 9 of 10 patients had osteoporosis. None had osteomalacia. Fasting intestinal calcium absorption correlated well with trabecular bone volume (r = 0.85). Bone mineral content measured by 125I-photon absorption was low in 6 of 10 patients, and it correlated poorly with iliac crest trabecular bone volume. After 1 yr of treatment with oral 25-hydroxyvitamin D3, bone mineral content fell in all 8 patients who were restudied. Iliac crest trabecular bone volume increased in 3 patients, 2 of whom had the greatest pretreatment impairment in calcium absorption, but fell in 5. Bone fractures continued to occur in 3 of 5 patients who were alive after 1 yr and developed for the first time in a sixth patient. We conclude that 25-hydroxyvitamin D3 is ineffective in reversing the bone thinning in the majority of primary biliary cirrhosis patients, but it may be helpful in a few selected patients.

A prospective trial of D-penicillamine in primary biliary cirrhosis.

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.

Effect of 25-hydroxyvitamin D3 on vitamin D metabolites in primary biliary cirrhosis.

The osteopenic bone disease associated with primary biliary cirrhosis is thought to be de to a deficiency in vitamin D or its metabolites. However, this has never been proven. Therefore, we measured serum levels of 25-hydroxyvitamin D3 (25-OHD3), 1,25-dihydroxyvitamin D (1,25(OD)2D), and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), before and after a 1 yr treatment with oral 25,OHD3, in 10 patients with primary biliary cirrhosis selected because of documented osteopenic bone disease. Only in 1 patient was the pretreatment serum 25-OHD3 level below normal, less than 4.4 ng/ml. In 8 patients the serum 25,OHD3 level was in the low normal range and in one, was above normal. Serum levels of 1,25(OH)2D, the vitamin D metabolite with the greatest stimulatory effect on intestinal calcium absorption, were normal in 9 patients and elevated in 1. In contrast, serum levels of 24,25-(OH)2D3, a metabolite whose function is not known with certainty, were undetectable in 8 patients, low normal in a ninth, and normal in 1 patient who had been on large amounts of vitamin D2 (50,000 U b.i.w.,) before the start of the study. After 1 yr of treatment with oral 25-OHD3, serum 25-OHD3 rose to above normal in 9 patients. Serum 1,25-(OH)2D levels did not change significantly, while 24,25-(OH)2D3 rose to normal levels or higher in 9 of 10 patients. The bone disease of primary biliary cirrhosis is not due to 25-hydroxyvitamin D deficiency alone and is certainly not due to a deficiency of 1,25-(OH)2D as has been postulated. It may be related to low blood levels of 24,25-(OH)2D3 or to other as yet undefined factors.

Viral hepatitis in homosexual men.

We studied 33 episodes of acute viral hepatitis in homosexual men to determine the type of hepatitis seen in this population. Seventy percent were caused by type A hepatitis, and 30% by type B hepatitis. None were due to non-A, non-B hepatitis. A high proportion of patients presenting with either type of acute hepatitis had evidence of previous infection with the other type: Seventy percent of patients with type B hepatitis had previous infection with type A, and 74% of patients with type A hepatitis had previous infection with type B. This study shows that, in homosexual men, hepatitis A, like hepatitis B, is a sexually transmitted disease.

Hepatic transaminase activity in alocholic liver disease.

Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activity were measured in precutaneous needle biopsy specimens of human liver tissue and compared with transaminase values in serum obtained on the day of biopsy. Hepatic GPT activity was significantly decreased in liver tissue of patients with alcoholic hepatitis and cirrhosis compared with the activity in individuals with normal livers (P less than 0.05) and individuals with primary biliary cirrhosis (P less than 0.05). The decreased hepatic GPT activity was not related to the presence of cirrhosis in biopsy specimens and was not increased by the addition of saturating amounts of pyridoxal phosphate to the assay mixture. Hepatic GOT was also slightly but significantly lowered in individuals with alcoholic liver disease (P less than 0.05). The GOT/GPT ratio in serum and liver tissue was increased only in individuals with alcoholic liver disease, but the increase did not reach statistical significance. The increased GOT/GPT ratio is due primarily to the low activity of GPT in liver and serum. The less than expected elevation of GPT in serum of patients with alcoholic hepatic reflects the diminished hepatic GPT activity and lesser amounts of this enzyme available to leak into serum from damaged hepatocytes.

D-Penicillamine-induced Goodpasture's-like syndrome in primary biliary cirrhosis--successful treatment with plasmapheresis and immunosuppressives.

A 36-yr-old woman with primary biliary cirrhosis developed a Goodpasture's-like syndrome while on D-penicillamine treatment. She responded dramatically to plasmapheresis and immunosuppressive agents. Her illness was felt to be induced by D-penicillamine. This case illustrates the potential toxicity of D-penicillamine in primary biliary cirrhosis. We suggest that this drug be used only in controlled trials until efficacy is demonstrated.

Primary biliary cirrhosis and cold autoimmune hemolytic anemia: effect of partial plasma exchange.

The previously unreported occurrence of primary biliary cirrhosis with cold autoimmune hemolytic anemia is described. Red cell survival studies showed a t1/2 of 11.1 days. Partial plasma exchange increased red cell survival to 15.8 days. Concomitantly, alkaline phosphatase, SGOT, SGPT, and bilirubin was reduced in predictable amounts but rebounded to prepheresis levels quickly. Although partial plasma exchange was effective in increasing red cell survival and in reducing the level of selected abnormal plasma components, the patient died 3 mo after initiation of plasma exchange therapy. Partial plasma exchnage did not appear to have any long-term beneficial effects on either liver disease or the hemolytic process.