The effect of PG on patients with fulminant and subfulminant viral hepatitis (FHF) was studied. 17 patients presented with FHF secondary to hepatitis A (n = 3), hepatitis B (n = 6), and non-A, non-B ...(NANB) hepatitis (n = 8). 14 of the 17 patients had stage III or IV hepatic encephalopathy (HE). At presentation the mean aspartate transaminase (AST) was 1,844 +/- 1,246 U/liter, bilirubin 232 +/- 135 mumol/liter, prothrombin time (PT) 34 +/- 18, partial thromboplastin time (PTT) 73 +/- 26 s, and coagulation Factors V and VII 8 +/- 4 and 9 +/- 5%, respectively. Intravenous PGE1 was initiated 24-48 h later after a rise in AST (2,195 +/- 1,810), bilirubin (341 +/- 148), PT (36 +/- 15), and PTT (75 +/- 18). 12 of 17 responded rapidly with a decrease in AST from 1,540 +/- 833 to 188 +/- 324 U/liter. Improvement in hepatic synthetic function was indicated by a decrease in PT from 27 +/- 7 to 12 +/- 1 s and PTT from 61 +/- 10 to 31 +/- 2 s, and an increase in Factor V from 9 +/- 4 to 69 +/- 18% and Factor VII from 11 +/- 5 to 71 +/- 20%. Five responders with NANB hepatitis relapsed upon discontinuation of therapy, with recurrence of HE and increases in AST and PT, and improvement was observed upon retreatment. After 4 wk of intravenous therapy oral PGE2 was substituted. Two patients with NANB hepatitis recovered completely and remained in remission 6 and 12 mo after cessation of therapy. Two additional patients continued in remission after 2 and 6 mo of PGE2. No relapses were seen in the patients with hepatitis A virus and hepatitis B virus infection. Liver biopsies in all 12 surviving patients returned to normal. In the five nonresponders an improvement in hepatic function was indicated by a fall in AST (3,767 +/- 2,611 to 2,142 +/- 2,040 U/liter), PT (52 +/- 25 to 33 +/- 18 s), and PTT (103 +/- 29 to 77 +/- 44 s), but all deteriorated and died of cerebral edema (n = 3) or underwent liver transplantation (n = 2). These results suggest efficacy of PGE for FHF, and further investigation is warranted.
Obliterative lesions in portal veins (PVs) and hepatic veins (HVs) of all sizes are known to occur in cirrhotic livers. PV lesions have generally been attributed to thrombosis, but the pathogenesis ...of the HV (veno-occlusive) lesions is unknown. We have studied 61 cirrhotic livers removed at transplantation to clarify the prevalence, distribution, and pathogenesis of venous lesions, as well as the association of these lesions with other morphological features and clinical morbidity. Intimal fibrosis that is highly suggestive of healed HV or PV thrombosis was found in at least 70% and 36% of livers, respectively. The distribution of HV lesions was patchy and largely confined to veins between 0.1 and 3 mm in diameter, suggesting multifocal origin in small veins. PV lesions were more uniform throughout the liver, suggesting origin in large veins with propagation to the small veins. HV lesions were associated with regions of confluent fibrosis (focal parenchymal extinction), and PV lesions were associated with regional variation in the size of cirrhotic nodules and a history of bleeding varices. These observations suggest that thrombosis of medium and large PVs and HVs is a frequent occurrence in cirrhosis, and that these events are important in causing progression of cirrhosis.
Treatment of patients with primary biliary cirrhosis (PBC) using ursodeoxycholic acid (UDCA) leads to a reduction in serum bilirubin. The first objective of this study was to assess the performance ...of certain prognostic indicators for PBC after the introduction of treatment with UDCA. Serum bilirubin is an important prognostic indicator for PBC and an important component of the Mayo model for grading patients into risk categories. In an analysis of patients enrolled in the Canadian multicenter trial, the Mayo score was calculated before and after treatment with UDCA. After treatment, the Mayo score continued to divide patients with PBC into groups with varying risk. In addition, the serum bilirubin alone was shown to do the same even after the introduction of treatment with UDCA. A second objective was to establish whether UDCA had an effect on long‐term (2‐ to 6‐year) survival in patients with PBC.
Primary nonfunction following orthotopic liver transplantation is characterized by rapidly rising serum transaminases, minimal bile production, and severe coagulopathy, which can progress to ...hypoglycemia, hepatic encephalopathy, and acute renal failure. Untreated it has a mortality of over 80% and to date the only treatment has been retransplantation. As a result of the beneficial effect of Prostaglandin E1 infusion in patients with fulminant hepatic failure, this trial was conducted to determine whether PGE1 would be of value in primary nonfunction. We have encountered 16 cases of primary nonfunction in 94 liver transplants, an incidence of 17%. Initially in the program, there were 6 occurrences of nonfunction that did not receive PGE1; 3 underwent retransplantation (2 survivors), 2 died awaiting another liver, and in one recovery of hepatocellular function occurred with supportive care but the patient died of cytomegalovirus infection. Ten patients received PGE1 within 4-34 hr of transplantation. Within 12 hr of treatment, 8 patients responded with a significant fall in the AST (129 U/hr) whereas, in the untreated group, the AST continued to rise (267 +/- 102 U/hr) at the same rate as prediagnosis (337 +/- 95 U/hr). At the conclusion of the infusion (4-7 days) in the 8 responders, there were significant decreases in AST (4386 +/- 546 U/L to 102 +/- 21 U/L), prothrombin time (22 +/- 2 to 12 +/- .4 sec) and partial thromboplastin time (45 +/- 3-29 +/- 4 sec), and significant increases in coagulation factor V (26 +/- 8 to 95 +/- 12%) and factor VII (10 +/- 5 to 61 +/- 4%). No serious side effects occurred, although 2 patients developed diarrhea, and abdominal cramps. Two patients treated with PGE1 were retransplanted at 10-36 hr and were considered nonresponders. Graft survival was 80% in the PGE1-treated group and 17% in the untreated group (P less than 0.05) and patient survival was 90% and 33%, respectively. This study suggests a potential benefit of PGE1 in the treatment of primary nonfunction.
Modifying the rate of absorption has been proposed as a therapeutic principle of specific relevance to diabetes. To demonstrate clearly the metabolic benefits that might result from reducing the rate ...of nutrient delivery, nine healthy volunteers took 50 g glucose in 700 ml water on two occasions: over 5-10 min (bolus) and at a constant rate over 3.5 h (sipping). Despite similar 4-h blood glucose areas, large reductions were seen in serum insulin (54 +/- 10%, P less than 0.001) and C-peptide (47 +/- 12%, P less than 0.01) areas after sipping, together with lower gastric inhibitory polypeptide and enteroglucagon levels and urinary catecholamine output. There was also prolonged suppression of plasma glucagon, growth hormone, and free-fatty acid (FFA) levels after sipping, whereas these levels rose 3-4 h after the glucose bolus. An intravenous glucose tolerance test at 4 h demonstrated a 48 +/- 10% (P less than 0.01) more rapid decline in blood glucose (Kg) after sipping than after the bolus. Furthermore, FFA and total branched-chain amino acid levels as additional markers of insulin action were lower over this period despite similar absolute levels of insulin and C-peptide. These findings indicate that prolonging the rate of glucose absorption enhances insulin economy and glucose disposal
We have shown, in animal models as well as in retrospective human study, that some degree of decreased thyroid function is beneficial for subjects with liver damage of various etiologies. Therefore, ...we herein present the results of a cohort population study. Between 1991 and 1994, 18 patients (12 women and 6 men; mean age, 59 ± 24 years) with both biopsy-proven active cirrhosis (5 hepatitis C virus, 4 hepatitis B virus, 1 immunocompromised host, 2 primary biliary cirrhosis, 1 alcoholic, and 5 cryptogenic; Child's-Pugh criteriaA-8, B-8, C-2) and primary or induced (by either drug or surgery) thyroxine-treated hypothyroidism were prospectively followed. Each patient was examined at least twice yearly and served as their own control. The thyroid of the profiled patients ranged between euthyroidism and subclinical hypothyroidism. Liver function tests were evaluated and compared in states of normal versus increased thyroid-stimulating hormone (TSH) blood levels. A significant improvement in alanine aminotransferase (p < 0.001), alkaline phosphatase (p < 0.0001), albumin (p < 0.001), and bilirubin (p < 0.01) was found in the increased TSH group. Prothrombin time was also found to be significantly better (p < 0.001). We conclude that euthyroid patients with liver cirrhosis might benefit from a controlled hypothyroidism.
Propylthiouracil has been shown experimentally to protect against alcohol-induced hepatocellular necrosis in hypoxic conditions. An earlier, short-term study of patients with alcoholism and liver ...disease indicated clinical improvement with propylthiouracil, but the effect on mortality could not be assessed. In the present study, we investigated the effect of propylthiouracil on mortality in patients with alcoholic liver disease in a long-term, double-blind, randomized clinical trial involving 310 compliant patients who received propylthiouracil (n = 157) or placebo (n = 153) for a maximum of two years. There were no differences between the two groups in demographic and clinical characteristics and biopsy-confirmed diagnoses at randomization, or in daily urinary alcohol levels during the study. The cumulative dropout rate over two years was not significantly different (propylthiouracil group, 0.68; placebo group, 0.60). The group receiving propylthiouracil (300 mg per day) had a cumulative mortality rate half that in the group receiving placebo (0.13 vs. 0.25 P less than 0.05 in the total sample, and 0.25 vs. 0.55 P less than 0.03 in a subgroup of severely ill patients propylthiouracil group, n = 56; placebo group, n = 41). Proportional-hazards stepwise regression analyses indicated that only propylthiouracil treatment, prothrombin time, hemoglobin levels, and mean daily urinary alcohol levels significantly affected mortality. The hazards ratio for the complete group indicated that mortality in the propylthiouracil group was 0.38 (95 percent confidence interval, 0.20 to 0.83) that of the placebo group. Protection by propylthiouracil was not observed in patients with high morning urinary alcohol levels. No clinically important side effects of propylthiouracil were observed at the dose used. We conclude that the administration of propylthiouracil can reduce mortality due to alcoholic liver disease.
To determine if central sympathetic outflow is increased in patients with cirrhosis and ascites.
Eleven patients with cirrhosis and ascites, 8 patients with cirrhosis but without ascites, and 7 ...age-matched and 8 young healthy volunteers.
With subjects supine, direct microneurographic recordings of efferent post-ganglionic muscle sympathetic nerve activity were obtained from the peroneal nerve, and sympathetic burst frequency was compared with subjects' blood pressure, heart rate, sodium excretion, catecholamines, and plasma renin activity. All patients with cirrhosis were studied at least 5 days after withdrawal from all medications and after 7 days of a 20 mmol/d sodium, 1-L fluid-restricted diet. Age-matched volunteers were studied after 7 days of 20 mmol/d sodium intake and young healthy volunteers after 7 days of 150 mmol/d sodium intake.
Sympathetic nerve activity in ascitic patients (65 +/- 15 bursts/min; mean +/- SD) was markedly increased, whether compared with patients with cirrhosis but without ascites (34 +/- 16 bursts/min; P less than 0.001), age-matched healthy volunteers on similar sodium intake (27 +/- 22 bursts/min; P less than 0.001), or young healthy subjects (21 +/- 10 bursts/min; P less than 0.001). The frequency of muscle sympathetic nerve discharge was directly related to plasma norepinephrine and epinephrine concentrations, plasma renin activity, and heart rate, all of which were increased in those patients with cirrhosis and ascites, and inversely related to 24-hour urinary sodium excretion, the fractional excretion of sodium, and subjects' pulse pressures. Sympathetic nerve activity fell from 78 to 6 bursts/min in one patient after liver transplantation.
This study provides the first direct evidence that elevated plasma norepinephrine concentrations in patients with cirrhosis and ascites are due to increased central sympathetic outflow. Sympathetic nerve activity is not increased in patients with cirrhosis but without ascites. Because there were direct positive correlations of sympathetic nerve activity with plasma norepinephrine concentrations, plasma epinephrine concentrations, plasma renin activity, and heart rate, the increase in central sympathetic outflow in patients with cirrhosis and ascites appears generalized and not restricted to muscle nerves. The anti-natriuretic effects of parallel increases in renal and muscle sympathetic nerve activity could account for the inverse correlation between muscle sympathetic nerve activity and sodium excretion.
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