Willis C. Maddrey

Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial.

A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.

Serial Studies of Hepatitis-Associated Antigen and Antibody in Patients Receiving Antitumor Chemotherapy for Myeloproliferative and Lymphoproliferative Disorders

The effects of antitumor chemotherapeutic agents on hepatitis B antigen (HBAg) and antibody (HBAb) were studied serially in 25 patients with myeloproliferative and in 60 patients with lymphoproliferative disorders. HBAg was detected at some time in 17 patients, and HBAb in 40 patients. Seventeen patients who had HBAb detected immediately pretreatment had a decrease in HBAb titer which paralleled the fall in white blood cell count. In 5 of these patients, HBAg appeared when HBAb titers fell. In 3 of the 5 patients, a reappearance of HBAb was observed with disappearance of HBAg from the serum, and in the 2 other patients HBAg persisted once it appeared. In all 3 patients who had HBAg at the time of initiation of chemotherapy, bone marrow suppression was associated with a marked increase in HBAg titer. The increase in HBAg titer was associated with hepatocellular damage, as manifested by an elevation in serum transaminase enzymes. These observations suggest that antitumor chemotherapeutic agents reduce HBAb titers. In some patients, HBAg appears after a decrease in HBAb titers. In patients with preexisting HBAg, such therapy leads to large increases in HBAg titer. Whether this appearance or increase of HBAg is related to an inhibition of antibody formation, allowing expression of preexisting antigen, or to an inhibition of cellular immunity, allowing viral proliferation, is uncertain.

Bone Disease in Primary Biliary Cirrhosis: Histologic Features and Response to 25-Hydroxyvitamin D

Fifteen female patients with primary biliary cirrhosis were evaluated for vitamin D status and evidence of metabolic bone disease. Full-thickness iliac crest bone biopsy specimens with histomorphometric analysis after double tetracycline labeling were performed before and after 1 yr of treatment with oral 25-hydroxyvitamin D (100 micrograms/day). Initially, serum 25-hydroxyvitamin D levels were low (less than 15 ng/ml) in 11 of the 15 patients and were increased to normal (greater than 25 ng/ml) in all patients within 3 mo. Serum parathyroid hormone levels were low normal or not detectable in all patients and did not change with therapy. No patient had a fracture during the treatment. No evidence of osteomalacia was found initially or in follow-up study in any patient. Follow-up histomorphometric analysis at the end of the 1-yr treatment showed that bone volume decreased during the study interval despite therapy (p less than 0.001). Photon beam densitometry confirmed the loss in trabecular density of the radius over the study interval (p less than 0.03). The mean fractional osteoid surface was not increased initially and did not change with therapy. The mean linear bone appositional rate as measured by double tetracycline labeling was not decreased initially and did not change with therapy. It was concluded that in moderate to severe primary ciliary cirrhosis, initial 25-hydroxyvitamin D levels are low and are rapidly corrected by oral 25-hydroxyvitamin D. These patients have significant osteoporosis which progresses despite 25-hydroxyvitamin D.

Routine Use of Penicillin Skin Testing on an Inpatient Service

Abstract The routine use of prospective penicillin skin testing on hospitalized patients was evaluated over a six-month period. Patients with clinical indications for the use of penicillin drugs we...

The Budd-Chiari syndrome. Treatment by mesenteric-systemic venous shunts

Twelve patients with the Budd-Chiari syndrome have been managed surgically. Ten of the patients were female, two were male, with a mean age of 40 years. Three of the patients had polycythemia vera, two had pre-existing cirrhosis, one had ingested estrogens, one had an occult tumor, and in four there were no associated factors. Ten patients presented with ascites and two with bleeding esophageal varices. The diagnosis was confirmed in all 12 patients by liver biopsy and hepatic vein catheterization. Inferior vena cavography revealed the abdominal vena cava to be thrombosed in six patients. The superior mesenteric vein was used to decompress the congested liver in all 12 patients. In five patients, a mesocaval shunt (MCS) was performed and in seven patients, a mesoatrial shunt (MAS) was carried out. There were four hospital deaths (two MCS, two MAS). One late death (MAS) occurred from liver failure following shunt thrombosis. Two additional patients (one MCS, one MAS) re-developed ascites immediately following surgery and angiography revealed a thrombosed shunt. Ascites has been controlled with a LeVeen shunt in these two patients, but liver biopsies showed progression to cirrhosis. The remaining five patients (three MAS, two MCS) did well, and angiography revealed patent shunts. Two of these patients, however, re-developed ascites at 4 and 10 months following MAS and required a second MAS. Follow-up ranges from 6 to 68 months. In three of the patients (two MCS, one MAS) with patent shunts, liver biopsy shows a remarkable return toward normal liver architecture and histology.

The Use of Ornithine Salts of Branched-Chain Ketoacids in Portal-Systemic Encephalopathy

In eight patients with chronic portal-systemic encephalopathy who were symptomatic despite protein restriction and lactulose, a double-blind crossover comparison was conducted of branched-chain amino acids (68 mmol/d) versus ornithine salts of branched-chain ketoacids (34 mmol/d), both mixtures being administered orally for 7 to 10 days, after control periods, during a single hospitalization. Ornithine salts of branched-chain ketoacids markedly improved electroencephalographic abnormalities and clinical grade of encephalopathy; branched-chain amino acids had significantly lesser effects, which were of borderline statistical significance. To ascertain whether ornithine or branched-chain ketoacids were responsible for the improvement observed, we administered to six patients calcium salts of branched-chain ketoacids (34 mmol/d) after control periods; only slight improvement was seen.. Four patients received a daily dose of ornithine alpha-ketoglutarate containing the same quantity of ornithine; one did not change and three deteriorated rapidly. We conclude that the combination of ornithine and branched-chain ketoacids improves chronic portal-systemic encephalopathy more than its components given separately and more than branched-chain amino acids at twice the molar dose.

Severe hepatitis from methyldopa.

Severe hepatitis secondary to methyldopa therapy for hypertension was encountered in 6 patients over a 2-year interval. The drug was inadvertently readministered to 1 patient with recurrence of hepatitis within 1 week. One patient died with massive hepatic necrosis. Liver biopsy in the 5 survivors revealed that 4 of them had severe hepatitis with histological patterns indistinguishable from early active stages of chronic aggressive hepatitis. However, all rapidly improved after discontinuation of the drug. The severity of the hepatitis should be considered whenever a person taking the drug develops constitutional symptoms compatible with a hepatitis prodrome, and the drug should be promptly discontinued if chemical evidence of hepatitis is found. A possible drug etiology must be sought in all patients with a histological picture suggesting chronic aggressive hepatitis.

Mesoatrial shunt: a new treatment for the Budd-Chiari syndrome.

A patient is presented with the Budd-Chiari Syndrome. Because of a thrombosed inferior vena cava, none of the standard portal-systemic shunts could be utilized for decompression of the engorged liver. A new shunt constructed by interposing a Daeron® graft between the superior mesenteric vein and the right atrium was performed. Portal pressure was reduced hy the shunt from 30 cm of H2O to 10 cm of H2O. Patency has been confirmed post-operatively by cathelerization and with angiography. The patient is asymptomatic with normal liver function fests, nine months following the procedure, A surgical approach is outlined for symptomatic patients with the Budd-Chiari Syndrom.

EFFECTS OF KETO ANALOGUES OF ESSENTIAL AMINO ACIDS IN PORTAL-SYSTEMIC ENCEPHALOPATHY

Keto analogues of five essential amino acids (valine, leucine, isoleucine, methionine, and phenylalanine) were given either parenterally or orally in varying proportions to 11 patients with portal-systemic encephalopathy and hyperammonemia. Plasma concentrations of amino acids corresponding to the infused analogues, including alloisoleucine, increased significantly after infusions. Plasma tyrosine and glycine, which were abnormally elevated in control samples, fell after the infusions. After one to five daily infusions, the ratio of essential to nonessential amino acids in fasting plasma was increased toward normal, suggesting improved protein nutrition. Arterial blood ammonia and glutamate did not change immediately after infusions, but a pronounced decrease in glutamine (42%) was observed. Eight nitrogen balance studies performed in 5 patients during 3 to 12 days of oral or intravenous keto acid therapy failed to show consistent improvement in balance as compared with control periods. After five courses of oral therapy there was again significant improvement in the ratio of essential to nonessential amino acids. No toxicity from keto analogue administration was found, and clinical improvement, as assessed by mental status and psychological testing occurred in 8 of 11 patients. These studies suggest keto analogues of essential amino acids are converted to the corresponding amino acids in patients with portal-systemic encephalopathy, and that such therapy may be of benefit.

Hepatic collagen proline hydroxylase activity in alcoholic liver disease

The activity of hepatic collagen proline hydroxylase was examined in biopsy samples as a factor in collagen synthesis in 77 patients with alcoholic liver disease. The urinary excretion of peptide bound hydroxyproline was also measured in most of the patients, as an index of collagen degradation. The highest activities of collagen proline hydroxylase were found in the patients with alcoholic hepatitis. Enzyme activity was markedly increased in patients with non-specific changes on liver biopsy, whereas, patients with fatty infiltration had only mild elevations, and those with inactive cirrhosis had normal enzyme activity. Urinary hydroxyproline was elevated only in patients with alcoholic hepatitis and inactive cirrhosis. Follow-up determinations in 16 patients with alcoholic hepatitis, after 4 to 5 weeks, revealed a decrease in enzyme activity, but no change in urinary hydroxyproline. We conclude that among the types of alcohol-related liver diseases, alcoholic hepatitis is associated with the greatest turnover of hepatic collagen.