Management of chronic hepatitis C.
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Biomedical subjects
Publications and source records attributed to H F Herlong.
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Post-ischemic hepatic injury is observed commonly following cardiogenic or hypovolemic shock. We evaluated the putative roles of the alpha-adrenergic sympathetic nervous system and the renin-angiotensin axis in the pathogenesis of hepatic injury following cardiogenic shock. Previous studies have characterized the hepatic hemodynamic response to shock, while the relationship of these hemodynamic changes to ischemic hepatic injury has not been defined. Sustained (4 h) periods of pericardial tamponade (after mild hemorrhage) followed by 2 h of resuscitation generated a reproducible model of cardiogenic shock and consequent post-ischemic hepatic injury in anesthetized pigs. In a separate group of pigs, the alpha-adrenergic component of the sympathetic nervous system was ablated with phenoxybenzamine or, in other groups, the renin-angiotensin axis was ablated by either prior nephrectomy or, separately, by confirmed angiotensin converting enzyme inhibition with teprotide. The hepatic injury response in each case was reevaluated. Compared to sham-shocked pigs, those subjected to tamponade alone manifested selective splanchnic vasospasm and consequent biochemical and histological evidence of classic post-ischemic liver injury (centrilobular necrosis involving about a third of each hepatic lobule). These manifestations of splanchnic vasospasm and the consequent ischemic injury were not ameliorated by confirmed alpha-adrenergic blockade, but significantly attenuated by either method of prior ablation of the renin-angiotensin axis. This model of sustained cardiogenic shock and resuscitation generates the manifestations of ischemic hepatic injury associated with selective splanchnic vasospasm, findings consistent with previous, short-term, hemodynamic studies. The major mediator of this response, and the consequent hepatic injury, is the selective hypersensitivity of the mesenteric vasculature to the renin-angiotensin axis.
OBJECTIVE: The current study examines the results of extrahepatic biliary resection, nonoperative endoscopic biliary dilation with or without percutaneous stenting, and liver transplantation in the management of patients with primary sclerosing cholangitis (PSC). SUMMARY BACKGROUND DATA: Primary sclerosing cholangitis is a progressive inflammatory disease leading to secondary biliary cirrhosis. The most effective management of sclerosing cholangitis before the onset of cirrhosis remains unclear. METHODS: From 1980 to 1994, 146 patients with PSC were managed with either resection of the extrahepatic bile ducts and long-term transhepatic stenting (50 patients), nonoperative endoscopic biliary dilation with or without percutaneous stenting (54 patients), medical therapy (28 patients), and/or liver transplantation (21 patients). RESULTS: Procedure-related morbidity and mortality rates were similar between surgically resected and nonoperatively managed patients. In noncirrhotic patients, the serum bilirubin level was significantly (p < 0.05) reduced from preoperative levels (8.3+/-1.5 mg/dL) 1 (1.7+/-0.4 mg/dL) and 3 (2.7+/-0.9 mg/ dL) years after resection, but not after endoscopic or percutaneous management. For noncirrhotic PSC patients, overall 5-year survival (85% vs. 59%) and survival until death or transplantation (82% vs. 46%) were significantly longer (p < 0.05) after resection than after nonoperative dilation with or without stenting. For cirrhotic patients, survival after liver transplantation was longer than after resection or nonoperative dilation with or without stenting. Five patients developed cholangiocarcinoma, including three (6%) of the nonoperatively managed patients but none of the resected patients. CONCLUSIONS: In carefully selected noncirrhotic patients with PSC, resection and long-term stenting remains a good option. Patients with cirrhosis should undergo liver transplantation.
Elevated serum enzyme values are often the earliest indicators of liver injury in asymptomatic patients. Abnormal AST and ALT point to a hepatocyte disorder; abnormal alkaline phosphatase suggests a biliary tract disorder. Selected case histories illustrate how the three enzyme levels, in conjunction with the history and physical examination, can guide the rest of the workup.
BACKGROUND: Currently more than 40% of first-year medical students are female, yet less than 20% of those entering surgical residencies are women. It has been suggested that the surgical environment experienced during medical school clinical clerkships may be perceived as being unfavorable to female students, thus accounting for this disparity. METHODS: One hundred and five medical students at The Johns Hopkins University School of Medicine responded to a questionnaire administered before graduation to assess career choice, the influence of a number of conditions on choice of specialty, the perception of a specialty's attitudes toward their gender, and the students' experiences during clinical rotations. RESULTS: Thirty-four percent of men and 13% of women chose surgery or one of its subspecialties as their career (p < 0.01). Eighty-seven percent of women responding perceived a specialty as unfavorable toward their gender versus 21% of men (p < 0.0001). None of the men believed that surgery was unfavorable toward their gender, whereas 96% of these women believed that surgery was unfavorable (p < 0.00001). Fifty percent of women felt out of place on a clinical service, with 92% of these having this perception on a surgical service. Only 9% of men ever felt out of place on a clinical service (p < 0.0001), and none of the men felt out of place in surgery (p < 0.0001). CONCLUSIONS: Female medical students perceive a gender bias on surgical services, suggesting that an "old boys' club" attitude may still exist in surgery.
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The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 l/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to eat a standard hospital diet. During the month in the hospital, there were six deaths in the treatment group and five deaths in the control group. Nitrogen balance improved in the treated group, but not in the control group. Creatinine-height index, triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups. Serum retinol binding protein increased more in the treatment group than it did in the control group, and transferrin was increased only in the treatment group. Serum bilirubin, type III amino-terminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group, whereas serum AST and prothrombin time improved in the treatment group but not in the control group. Cumulative 2-yr survival rates from the day of entry into the study were 42% and 38% in the treatment and control groups, respectively. Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein, transferrin, bilirubin and prothrombin time. These parameters were unchanged in patients in the control group who died during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
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Plasma tumor necrosis factor alpha (TNF alpha), interleukin 1 alpha (IL-1 alpha), and interleukin 1 beta (IL-1 beta) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discharge. The presence of elevated plasma TNF alpha either at admission or discharge from the hospital was associated with death in 82% (14/17) of patients. By contrast absence of elevated plasma TNF alpha was associated with survival in 100% (6/6). The difference in survival with and without detectable plasma TNF alpha was significant at p = 0.0022. Plasma TNF alpha was not elevated in alcoholic patients without clinically apparent liver disease, with alcoholic cirrhosis, or in nonalcoholic healthy controls. Plasma IL-1 alpha was also significantly increased in alcoholic hepatitis whereas IL-1 beta was not. Neither IL-1 alpha nor beta was correlated with outcome in the alcoholic hepatitis group. It is concluded that the presence of elevated plasma TNF alpha is a significant predictor of decreased long-term survival in patients with severe alcoholic hepatitis.
STUDY OBJECTIVE: To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. SETTING: Four university teaching hospitals. PATIENTS: We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32, calculated using the formula: 4.6 (prothrombin time - control time) + serum bilirubin [in mumol/L]/17.1. Fifty-nine patients (89%) completed the study. Two patients withdrew from the trial. The other 64 patients were hospitalized for the duration of the trial; however, treatment was discontinued in 5 patients because of potential drug toxicity. INTERVENTIONS: Patients were randomly assigned to receive either methylprednisolone (32 mg) or placebo within 7 days of admission. Treatment was given for 28 days. The doses were then tapered over 2 weeks and discontinued. MEASUREMENTS AND MAIN RESULTS: The endpoint of the study was death. Of the 31 recipients of placebo, 11 (35%) died within 28 days of randomization compared with 2 (6%) of the 35 patients given methylprednisolone (P = 0.006). The 95% CI for the difference in mortality was 12% to 70%. In the patients with spontaneous hepatic encephalopathy at entry, 9 of 19 recipients of placebo died (47%) compared with 1 (7%) of the 14 patients given methylprednisolone (P = 0.02). The 95% CI for the difference in mortality was 14% to 66%. The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables (P = 0.004). CONCLUSIONS: Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value.
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Neurologic complications of hepatic disease are not uncommon and involve the CNS more often than the peripheral nervous system or muscles. Progress in the therapy of neurologic disorders associated with hepatic failure has occurred in recent years. Notably, exciting developments in the treatment of hepatic encephalopathy with benzodiazepine antagonists will lead to a better understanding of the pathophysiology of this encephalopathy. The future use of these agents may eventually help reduce the morbidity and mortality of hepatic encephalopathy. The role of this class of drug in other metabolic encephalopathies remains to be established. Furthermore, new therapeutic and surgical alternatives to the treatment of Wilson disease also enhance our therapeutic options. The fate of patients with Wilson disease with fulminant hepatic disease and those patients unable to tolerate or unresponsive to penicillamine therapy has been greatly improved.
Alcohol and dietary intake were determined in alcoholic patients with chronic pancreatitis and alcoholic liver disease. Patients with chronic pancreatitis, alcoholic hepatitis, and cirrhosis ingested approximately 50% of their calories as alcohol, and all had low mean intakes of protein, carbohydrate, and fat as compared with control subjects. Patients with severe alcoholic hepatitis had the lowest intake of nonalcohol calories and protein. Women with chronic pancreatitis had ingested alcohol for a shorter period of time than men whereas women with alcoholic hepatitis and cirrhosis had ingested less alcohol per kilogram body weight per day as compared with men. This study does not support the hypothesis that consumption of a high-protein and high-fat diet is a factor in the development of chronic pancreatitis in the alcoholic patient. The increased susceptibility of women as compared with men to alcoholic liver disease is established.
Thirty-one patients with sclerosing cholangitis underwent reconstruction of their hepatic duct bifurcation and long-term stenting between 1980 and 1987. Indications for surgery were persistent jaundice in 29 and recurrent cholangitis in two. The mean serum bilirubin level before surgery was 10.4 mg/dl. Liver biopsy revealed that 26 patients had varying degrees of hepatic fibrosis, and five patients had progressed to secondary biliary cirrhosis. In 29 patients the major obstructive duct disease was at or near the hepatic duct bifurcation, and in two patients it was in the distal common duct. The operative procedure consisted of: (1) excision of the hepatic duct bifurcation and extrahepatic biliary tree, (2) dilatation of the intrahepatic ducts, (3) insertion of Silastic transhepatic biliary stents, and (4) bilateral hepaticojejunostomies. Two of the five patients (40%) with cirrhosis died after surgery. In contrast, only one of 26 patients (3.9%) with hepatic fibrosis died after operation. The 1-, 3-, and 5-year actuarial survival rates for patients with cirrhosis were 20%, 20%, and 20%, respectively. The only long-term survivor underwent a liver transplant. The 1-, 3-, and 5-year actuarial survival rates for patients with hepatic fibrosis were 92%, 87%, and 71%, respectively. In addition, the mean serum bilirubin levels of patients with hepatic fibrosis at 1, 2, 3, 4, and 5 years were 3.4 mg/dl, 2.9 mg/dl, 4.0 mg/dl, 5.4 mg/dl, and 4.3 mg/dl, respectively. Two of the long-term survivors subsequently underwent a liver transplant. Patients with sclerosing cholangitis, persistent jaundice, and biliary cirrhosis should be referred for consideration of liver transplantation. However, in the absence of biliary cirrhosis, if the major obstructive disease is at the hepatic duct bifurcation, primary biliary reconstruction and long-term stenting should be considered.
Reports of thrombosis rates as high as 40 percent with the mesocaval H shunt led us to review our results with the mesocaval C shunt in 33 consecutive patients. Their ages ranged from 23 to 69 years (mean 50 +/- 12 years). There were 21 male and 12 female patients. The causes of portal hypertension included alcoholic cirrhosis in 13 patients, primary biliary cirrhosis in 6 patients, postnecrotic cirrhosis in 6 patients, cryptogenic cirrhosis in 3 patients, the Budd-Chiari syndrome in 4 patients, and portal vein thrombosis in 1 patient. Twelve patients were in Child's class A, 8 were in Child's class B, and 13 were in Child's class C. Operative mortality was 24 percent (8 of 33 patients) but occurred only in class C patients under nonelective conditions. Shunt patency was determined by one or more of the following: autopsy, angiography, and a lack of recurrent varices or hemorrhage. Autopsies were performed in 12 patients from 1 week to 72 months after operation. All 12 C shunts were widely patent. Angiography was performed in 13 patients from 1 to 38 months postoperatively. All 13 C shunts were patent; however, 2 eventually stenosed and attempts at ballon angioplasty were only moderately successful. Follow-up to time of death or to date was possible in 24 of 25 survivors, and ranged from 3 to 123 months. Evidence of recurrent varices, variceal hemorrhage, or both developed in only two patients (2 of 24, 8 percent), both of whom had stenosed shunts.
Plasma amino acid profiles of alcoholic subjects without clinically apparent liver disease, alcoholic patients with biopsy-proven alcoholic hepatitis, and nonalcoholic controls were compared. Differences in the plasma aminograms of alcoholic subjects with and without liver disease appear to be due predominantly to differences in liver function whereas differences in plasma amino acid levels between the alcoholic subjects and nonalcoholic controls may be related to inadequate dietary-protein intake and pyridoxine deficiency in the alcoholic groups.
Alcoholic beverages contribute an appreciable percentage (4-6%) to the total caloric intake in Western societies. The caloric value of ethanol as fuel may be dose-related. Most evidence suggests that at moderate intake levels of less than 45 g/day (3 drinks) ethanol is efficiently utilized as a fuel by the liver. At high intakes, ethanol calories may not be utilized for cellular synthesis of ATP and maintenance of weight. The exact mechanism for this inefficient utilization remains unknown but may be related, in part, to metabolism of ethanol by the microsomal ethanol-oxidizing system, a reaction that does not contribute to generation of reducing equivalents for ATP synthesis. Although ethanol is utilized for ATP synthesis after single-dose administration, chronic consumption leads to morphological changes in hepatic mitochondria and to decreased ATP synthesis. Reductions in the activities of the enzymes of the mitochondrial electron transport chain have been reported after alcohol feeding and may help to explain decreases in hepatic ATP synthesis. There is some evidence that ATP degradation by "Na-K ATPase" is increased after ethanol feeding and that hepatic O2 consumption is likewise enhanced. However, other studies have failed to demonstrate enhanced O2 consumption. Current evidence suggests that malnutrition alone is not sufficient to explain the pathogenesis of chronic liver disease in alcoholics. Although the daily amount of alcohol consumed and the duration of excessive consumption are clearly important factors in the development of alcoholic hepatitis and cirrhosis, other factors, particularly nutritional deficiencies, may modulate the risk of developing alcohol-related liver damage. The prevalence of malnutrition is exceedingly high in alcoholics with clinically severe liver disease. Nutritional deficiencies are better correlated with a clinical index of severity than with histologic severity of alcoholic hepatitis. Prognosis and outcome of patients with alcoholic liver disease may be affected by nutritional deficiencies, which thus provides a rationale for aggressive nutritional management of these patients.
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