Showing papers in "Hepatology in 1987"

Abstract: To investigate the natural history of compensated cirrhosis, 293 consecutive patients without previous major complications (ascites, jaundice, encephalopathy or gastrointestinal hemorrhage) were studied in terms of morbidity (probability of developing decompensated cirrhosis during follow-up) and survival. Patients were diagnosed by liver histology between 1968 and 1980. Median follow-up was 63 months. Decompensation of cirrhosis was considered when a patient first developed one of the major complications of the disease. Ten years after diagnosis, the probability of developing decompensated cirrhosis and the survival probability rate were 58 and 47%, respectively. A multivariate survival analysis (Cox's regression model) using clinical, biochemical and histological data obtained at diagnosis disclosed seven factors that predicted prognosis: serum bilirubin; serum gamma-globulin concentration; hepatic stigmata; prothrombin time; sex; age, and alkaline phosphatase. According to the contribution of each one of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. The predicting value of this index was validated by a split sample testing technique.

Abstract: Sixty-five patients with histologically proven chronic active hepatitis of unknown cause but associated with the antiliver/kidney microsome antibody type 1, confirmed by immunofluorescence and immunoprecipitation, were selected as forming a special entity. This disease was found to be rare with a prevalence of 5/1,000,000. The female to male ratio was 8:1. The condition occurred at all ages but was most common between the ages of 2 and 14 years. In 22 of the 65 cases, the hepatitis was associated with an autoimmune disease, most commonly insulin-dependent diabetes, autoimmune thyroid disease and vitiligo. The same autoimmune diseases were present in first-degree relatives from seven families. In 36 cases, the onset of disease resembled acute viral hepatitis. Serum biochemical tests showed marked elevation in aminotransaminases and hypergammaglobulinemia. Paradoxically, serum and salivary IgA levels were often normal or low. Histologic findings were multifocal hepatic necrosis with bridging in the acute stage, and aggressive hepatitis with mononuclear cell infiltration or macronodular cirrhosis in the late stages. Serologically, apart from the presence of antiliver/kidney microsome antibody type 1, the disease was characterized by the absence of antiactin, antimitochondria and antinucleus antibodies; however, organ-specific autoantibodies were often present. The clinical course was usually severe: six patients in the acute stage presented with fulminant hepatitis, and all, except two, other patients progressed to cirrhosis. Prolonged treatment with corticosteroids and immunosuppressants was usually effective in rendering the cirrhosis inactive. The cumulative survival rate was 51% at 14 years. We propose to call this entity "anti-LKM1 chronic active hepatitis" or "autoimmune hepatitis type II" to differentiate it from classical "lupoid hepatitis" or autoimmune hepatitis type I.

Abstract: The prevalence of gallstone disease (cholelithiasis and previous cholecystectomy for gallstones) in the population of the town of Sirmione, Italy, examined by ultrasonography, was 6.7% in men and 14.6% in women, ranging from 18 to 65 yr of age (overall prevalence = 11%). The prevalence of cholelithiasis in the same age span was 6.9% (4.5% in men and 8.9% in women). Prevalence of cholelithiasis increased with age in both sexes. Twenty-two percent of gallstone subjects suffered from biliary pain vs. 2% of subjects without gallstones. No difference was observed in the frequency of nonspecific symptoms between subjects with and without gallstones. Of the 132 gallstone subjects, 108 (82%) were not aware of having gallstones prior to the study. Prevalence of gallstone disease was found to be higher in obese and hypertriglyceridemic subjects and to increase with the number of pregnancies.

Abstract: The objective of this study was to assess the prognostic validity of Child-Turcotte classification with regard to short-term (1-year) survival. The Child-Turcotte classification, as modified by Pugh et al., was recorded on admission in 177 cirrhotic patients. The variables that comprise the Pugh modification are ascites, encephalopathy, serum albumin, serum bilirubin and prothrombin time. Using multiple logistic regression, we evaluated the contribution of different models to the likelihood of survival, defining different ways to use the Pugh score. The Pugh score categorized in three strata (5 to 6, 7 to 9 and 10 to 15) captured less variance in the survival than the Pugh score counted from 5 to 15. This, in turn, captured less variance than a model in which the parameters of the Pugh score were analyzed according to their original units. The prediction rule based on the last model was tested in another sample of cirrhotics. The "original unit" model was studied in both training and testing samples, using receiver-operating characteristic curves to evaluate its clinical validity (sensitivity and specificity). The prediction rule based on the "original units" Pugh score allowed for a good discrimination of patients who lived and those who died. (At the point of maximum discrimination, sensitivity and specificity reached a mean of 80%). Validity of the prediction rule was confirmed by the testing sample. The qualities of simplicity, availability, low cost and good discriminating power for a life or death outcome make the Pugh score a very useful method to estimate prognosis in patients with cirrhosis.

Abstract: Fat-storing cells (perisinusoidal stellate cells) were isolated by enzymatic digestion of rat liver and purified by a single-step Nycodenz gradient to yield 11.4 X 10(6) cells per liver, with a purity of 74% and a viability of 76%. Monolayer cultures of fat-storing cells incorporated both [35S]sulfate and [3H]glucosamine into glycosaminoglycans; the rate of incorporation increased with culture time (3-fold between the third and eighth days in culture). About 80% of newly formed glycosaminoglycans were secreted into the medium. Analysis of the types of glycosaminoglycans revealed a different pattern for cells and medium, respectively, which is subject to culture time. Heparan sulfate remains primarily cell-bound and, therefore, has a low fractional secretion rate. Chondroitin sulfate and even more dermatan sulfate are the main types of glycosaminoglycans in the medium. Dermatan sulfate represents about 60% of total medium glycosaminoglycans. In advanced cultures (eighth day), this type becomes the predominant one in the cell layer. The reduction of the molecular weight of native medium-sulfated molecules by papain digestion and beta-elimination and the puromycin-induced inhibition of their synthesis by more than 75% suggest the formation of glycosaminoglycans as complex proteoglycans. It is concluded that fat-storing cells are a major cellular source of dermatan sulfate and chondroitin sulfate in liver connective tissue. Since the pattern of proteoglycans of fat-storing cells closely resembles that found in the fibrotic liver matrix, this cell type might be of pathogenetic significance for the accumulation of chondroitin sulfate and dermatan sulfate in cirrhotic connective tissue.

Abstract: The attempt to divide the large group of chronic HBsAg carriers into "healthy" vs. those with chronic hepatitis of various intensities is sometimes difficult. The major problems are overlap in clinical manifestations, hepatic test results and histologic as well as virologic features. Nevertheless, this separation is not only conceptually important, but may also be useful in patient management, particularly because of the risk of transition to cirrhosis and HCC. Although at least 75% of patients with HCC associated with HBV have cirrhosis, the time point at which the cirrhosis developed is not established, particularly since the vast majority of chronic HBsAg carriers fall into the "healthy" category. Important unanswered questions are, therefore: how often do "healthy" carriers develop cirrhosis and/or HCC, including the time relations between the two? Does the transformation to HCC result from one or several identifiable acute events in the "healthy" carrier (or in mild CPH) or is it a gradual process of progressing chronic hepatitis B in which intercurrent exacerbations may still play a role? Do the quantitative observations as to the relation between persistent HBV infections and HCC in the East apply to Western countries? Our hypothesis concerning pathogenesis is based on pathologic, molecular, clinical and epidemiologic observations and concepts, and is supported by studies of hepadna virus-infected animals. This thesis proposes that integration of HBV DNA into host chromosomes in acute or chronic hepatitis or during the "healthy" carrier state corresponds to an initiation event similar to that described in chemical carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Acetaldehyde, the primary metabolite of ethanol, binds covalently to proteins forming condensation products which have been recently shown to be immunogenic. To assess whether an antibody response against acetaldehyde-modified protein epitopes is associated with alcoholic liver disease, the serum immunoreactivity against proteins modified in vitro by acetaldehyde and against the corresponding unmodified proteins was measured by an enzyme-linked immunosorbent assay in 58 alcoholics with varying degrees of liver damage. Alcoholics showed significantly higher titers against protein-acetaldehyde conjugates than against the unmodified protein, independent of the nature of the carrier protein. The highest titers occurred in alcoholic hepatitis patients. Sera of patients with chronic hepatitis of nonalcoholic origin and of healthy controls also reacted with acetaldehyde conjugates, but their titers were significantly lower than those in alcoholic hepatitis patients. Our data support the idea that binding of acetaldehyde to proteins in humans generates antigenic determinants which trigger a corresponding immune response against such epitopes and suggest that this humoral immune response may be implicated in autoantibody formation and liver damage associated with excessive alcohol consumption.

Abstract: The acute vanishing bile duct syndrome can be defined as an irreversible, rejection-related condition that affects hepatic allografts within 100 days after orthotopic liver transplantation and whose presence requires retransplantation We have observed the acute vanishing bile duct syndrome in 5 of 48 consecutive patients (approximately 10%) who underwent orthotopic liver transplantation In 4 cases, the condition progressed relentlessly within approximately 7 to 11 weeks after orthotopic liver transplantation from mild rejection to severe rejection to acute vanishing bile duct syndrome A fifth patient had severe rejection in the first week and required retransplantation after 17 days because of thrombotic venoocclusive disease complicating the acute vanishing bile duct syndrome Clinically, signs of impending acute vanishing bile duct syndrome included abrupt onset of fever and jaundice and marked elevation of serum bilirubin and alkaline phosphatase levels which persisted despite antirejection treatment Biopsy specimens revealed destructive cholangitis (rejection cholangitis), ductopenia, and, if retransplantation was delayed, presence of noninflammatory, "burnt-out" portal tracts without bile ducts We recommend to base the diagnosis of acute vanishing bile duct syndrome on documentation of severe ductopenia in at least 20 portal tracts which may require several consecutive needle biopsies Rejection arteriopathy which was found in 3 of our 5 cases might have been another important diagnostic clue but could not be recognized prior to retransplantation The pathogenesis of acute vanishing bile duct syndrome is not clear; until the condition had manifested itself, we found no qualitative differences between acute reversible and irreversible rejection(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: The effects of several treatments involving alpha-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an alpha 1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H]thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate. The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, alpha 1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.

Abstract: The fenestration of hepatic sinusoidal endothelial cells in 15 needle biopsies obtained from chronic alcoholics without cirrhosis was studied by scanning electron microscopy. As compared to nonalcoholics, a significant reduction in the number of fenestrae and porosity of the sinusoidal lining wall (fractional area of fenestrae) was observed in acinar Zone 3, both in biopsies with and without Zone 3 fibrosis as judged by light microscopy. A significant reduction of porosity as shown in this study may influence the blood hepatocytic exchange and contribute to the alcohol-induced liver injury.

Abstract: Heavy diffuse bleeding from congested gastric mucosa (congestive gastropathy) was treated by propranolol (dose = 24 to 480 mg per day) in 14 consecutive patients with portal hypertension. Thirteen patients (93%) stopped bleeding within 3 days. Gastric mucosal cherry red spots (a sign of severe gastropathy) were unchanged in 5 patients, became less obvious in 4 and appearances returned to normal in 5. Propranolol was discontinued electively in seven patients after 2 to 6 months; four of these patients rebled from the same lesion and stopped bleeding when propranolol was recommenced. No patient has rebled from congestive gastropathy while receiving propranolol during follow-up of 12 to 42 (median = 23) months. A further 24 patients with nonbleeding congestive gastropathy received 160 mg long-acting propranolol per day in a double-blind placebo controlled cross-over trial. Twenty-two patients completed the study; in nine patients, endoscopic grading of congestive gastropathy improved after propranolol compared to three after placebo (p less than 0.05). Although the mechanism of action is not understood, propranolol appears to have a clinically significant role in the management of nonvariceal gastric bleeding in portal hypertension.

Abstract: In a randomized controlled trial, 41 chronic hepatitis B virus carriers were allocated, by opening numbered computerized randomization envelopes, to receive recombinant interferon-alpha 2A at three different doses: 25; 50, and 100 mU per m2 Thirty-two patients received treatment (6 for 3 months, 26 for 6 months), and 9 patients were controls (received no treatment) Ninety-three per cent of our patients were homosexual, and 41% had anti-HTLV-III in their serum None of the control patients lost HBeAg In contrast, six of the anti-HTLV-III-negative patients (33%) responded to treatment (p less than 002): five of these responders were homosexual (p less than 005) The response rate was greatest (44%) in the anti-HTLV-III-negative patients who received 10 mU per m2 of recombinant interferon-alpha 2A None of the anti-HTLV-III-positive patients responded to treatment The percentage reduction of hepatitis B virus DNA was significantly less in the anti-HTLV-III-positive group in comparison to the anti-HTLV-III-negative group at 1 and 4 months of treatment and at 3 months after the end of treatment (p less than 005) These patients were younger (33 vs 42 years, p less than 002), had lower mean baseline AST values (42 vs 80 IU per liter, p less than 002) and tended to have milder histological disease Homosexual men with HBeAg-positive chronic liver disease who are anti-HTLV-III-positive appear to be less responsive to the direct antiviral and immunomodulatory effects of recombinant interferon-alpha 2A This may be due to the subclinical immunosuppressive effects of co-infection with HTLV-III

Abstract: The incidence, clinicopathological features and etiology of acute exacerbation occurring in patients with chronic type B hepatitis were assessed prospectively among 385 patients who had HBeAg and 279 who had anti-HBe in serum. During an average follow-up of 23.5 months, acute exacerbations occurred in 197 HBeAg-positive patients and in 56 anti-HBe positive patients, with a calculated annual incidence of 28.6 and 10.3%, respectively (p < 0.001). The clinical and laboratory findings of acute exacerbations were similar in the HBeAg-positive and anti-HBe positive patients. The mean serum bilirubin and α-fetoprotein levels were higher in anti-HBe positive patients (p < 0.01), but actual differences were small. The histologic features of acute exacerbations were also similar in the HBeAg-positive patients and anti-HBe positive patients. Lobular alterations were the main histologic findings; in addition, one-fourth of patients had bridging necrosis and one-fourth had piecemeal necrosis. Spontaneous reactivation of hepatitis B was the major cause of these exacerbations in both HBeAg-positive patients (91.5%) as well as anti-HBe positive patients (62.5%). Hepatitis delta virus superinfection accounted for a higher percentage of exacerbations in anti-HBe positive patients (14.3%) than in HBeAg-positive cases (6.5%). Hepatitis A and possibly non-A, non-B virus superinfections also contributed to some episodes of exacerbation. Thus, acute exacerbations of disease occurred more frequently in HBeAg-positive patients than in anti-HBe positive patients with chronic type B hepatitis, but the clinicopathological features and etiologies were similar.

Abstract: The spectrum of liver disease in patients with acquired immune deficiency syndrome (AIDS) and the clinical impact of diagnostic percutaneous liver biopsy in this population were evaluated by a retrospective review of hepatic histology, clinical features and laboratory data in 85 patients (26 biopsies, 59 autopsies). Only 1 (3.8%) biopsy and 9 (15%) postmortem livers were histologically normal. Macrosteatosis and nonspecific portal inflammation were the most common histologic abnormalities. Intrahepatic AIDS-specific opportunistic infections or malignancies were detected in 42% of both biopsy and autopsy groups, with Mycobacterium avium-intracellulare the most frequent pathogen seen. Kaposi's sarcoma, although not detected on biopsy, was the most common postmortem AIDS-related hepatic finding. Intrahepatic lymphoma, cytomegalovirus hepatitis and hepatic mycoses were less frequently observed. In general, hepatic involvement represented part of a previously diagnosed, widely disseminated disease process, and liver biopsy led to new AIDS-specific diagnoses in only two patients. We conclude that while liver biopsy is a useful diagnostic tool in selected patients with AIDS, the information provided by biopsy rarely influences therapy or leads to improved survival.

Abstract: The aim of this study was to determine the prognostic significance of functional changes in the liver during progression of cirrhosis. Liver function was quantitated weekly by the aminopyrine breath test (measuring microsomal function) and the galactose breath test (measuring cytosolic function) in rats made cirrhotic by bile duct ligation (n = 14) and in sham-surgery controls (n = 9). Nine rats died spontaneously of cirrhosis. Both the aminopyrine breath test and galactose breath test were sensitive (89%) predictors of death within 1 week, but the galactose breath test was more specific (83%). Morphometric measurements of livers from surviving cirrhotic animals and controls (n = 5 each) showed that mean hepatocyte mass was maintained in the cirrhotic livers [cirrhosis (17.0 ± 2.0) vs. controls (13.9 ± 0.9 gm)]. The galactose breath test was also maintained, whereas the aminopyrine breath test was significantly decreased in the surviving cirrhotics. The galactose breath test, but not the aminopyrine breath test, correlated with hepatocyte mass (r = 0.67). The aminopyrine breath test correlated with microsomal aminopyrineN-demethylase activity (r = 0.78). Serial use of quantitative liver tests allows prediction of time of death from cirrhosis in this model.

Abstract: Brain edema is a major complication of fulminant hepatic failure and is responsible for death in a large percentage of patients. We previously demonstrated the progressive accumulation of water in grey matter areas of the brain in the rabbit with galactosamine-induced fulminant hepatic failure. We now report the electron microscopic morphology of the brain in the same model of acute hepatic failure following the intravenous injection of horseradish peroxidase, an intravascular tracer which forms an electron-dense reaction product. Rabbits with both mild and severe encephalopathy had normal blood pressures and blood gases at the time of study. Fixation of brain tissue was obtained by whole-body perfusion. Marked swelling of the cytoplasm, perineuronal and perivascular processes of astrocytes were noted in cortical gray, but not white, matter areas; the other cellular components of the brain had normal morphology. Capillary endothelial cells were normal, and there was no evidence of horseradish peroxidase in endothelial cell vesicles, basement membranes or the brain parenchyma, suggesting that the blood-brain barrier was impermeable to large molecules. Histologic evidence of brain edema is seen in this model, with swelling of astrocytes as the primary manifestation of the accumulation of water. Damage to astrocytes or inhibition of their function may contribute to the pathogenesis of hepatic encephalopathy in this model.

Abstract: When a small amount of Gram-negative lipopolysaccharide was intravenously injected into mice which had been injected with heat-killed Propionibacterium acnes 7 days before, massive hepatic cell necrosis was induced and most of the mice died 24 hr later. However, when prostaglandin E1 was administered with lipopolysaccharide, remarkable improvements in the survival rate and in the histological changes of the liver were observed. In order to find out how prostaglandin E1 suppressed the induction of massive hepatic cell necrosis in this experimental model, we studied the effects of prostaglandin E1 on the activation of liver adherent cells, from which the cytotoxic factor is released, and on the protection of hepatocytes from the cytotoxic factor. As a result, prostaglandin E1 not only inhibited the activation of liver adherent cells and suppressed the release of the cytotoxic factor, but it also directly affected the hepatocytes and protected them from the cytotoxic factor.

Abstract: Hepatobiliary and renal elimination of cysteinyl leukotrienes were investigated in a mutant rat strain with a hereditary defect in the hepatobiliary excretion of conjugated bilirubin, dibromosulfophthalein and ouabain. After intravenous injection of [3H]leukotriene C4, the initial half-life of radioactivity circulating in blood was 79 +/- 15 sec (S.D.) in transport mutant rats as compared to 31 +/- 6 sec (S.D.) in normal Wistar rats. The intrahepatic leukotriene radioactivity was increased 5-fold after 1 hr in mutant rats, while the biliary elimination of [3H]leukotrienes was reduced to 1.8% of control. In normal rats, 77 +/- 7% (S.D.) of the administered leukotriene radioactivity were recovered in bile within 1 hr. The total recovery of radioactivity from bile, urine, liver, intestine, stomach, kidneys, muscular system and blood 1 hr after intravenous [3H]leukotriene C4 was 89 +/- 6% (S.D.) in normal rats and 46 +/- 4% (S.D.) in transport mutants. Enterohepatic circulation was studied after intraduodenal administration of N-acetyl-[3H]leukotriene E4, a major cysteinyl leukotriene metabolite in rat bile. In transport mutants, hepatobiliary elimination of the intestinally absorbed [3H]leukotriene was reduced to 5%, whereas urinary excretion was not significantly affected. [3H]Leukotriene metabolites in bile, liver and urine were separated by reversed-phase high-performance liquid chromatography. The proportion of N-acetyl-[3H]leukotriene E4 relative to polar leukotriene metabolites was higher in the bile of transport mutants as compared to control Wistar rats when analyzed within 30 to 60 min after intravenous injection of [3H]leukotriene C4.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Studies of canalicular bile secretion have been limited due to lack of direct access to the canalicular lumen. Isolated rat hepatocyte couplets, consisting of two hepatocytes enclosing a canalicular space, have been proposed as a primary secretory unit that may be useful for direct studies of unmodified canalicular bile secretion. The present study examines their structural characteristics and plasma membrane reorganization. The canalicular space of freshly isolated hepatocyte couplets is freely permeable to ruthenium red, but within 4 hr the junctional borders reseal in most couplets which then exclude ruthenium red from the luminal area. These resealed spaces expand in 61.8 ± 10% of couplets as secretion is elaborated and after 4 hr in monolayer culture, 12.7 ± 4.7% of the canalicular spaces are dilated to diameters greater than 3 μ. Normal-appearing microvilli line these canalicular membranes in the majority of dilated spaces as assessed by electron microscopy. Immediately after isolation, Mg++-ATPase, a histochemical marker for canalicular membranes, is located as a discrete band corresponding to the normal in vivo circumferential distribution of the canalicular membrane domain. However, this pattern of Mg++-ATP-ase staining rapidly diminishes and reorganizes at the remaining canalicular pole within several hours. This membrane reorganization is a microfilament-dependent process, since it is inhibited by cytochalasin D but not by colchicine, an inhibitor of microtubular function or cycloheximide, an inhibitor of new protein synthesis. Thus, 3 to 4 hr after isolation, the isolated hepatocyte couplet has reorganized its canalicular membrane, retaining polarity of its excretory domain only at the remaining junctional contacts between adjacent hepatocytes. Secretion is elaborated into the ruthenium red impermeant canalicular lumen permitting direct studies of canalicular bile secretion by micropuncture, electrophysiologic and quantitative microscopic techniques.

Abstract: The role of liver transplantation in 29 patients with fulminant and subacute hepatic failure due to a variety of different causes was examined by comparing the outcome and a variety of “hospitalization” variables. Transplanted patients (n = 13) were more likely to survive (p < 0.05), were younger (p < 0.05) and spent more time in the hospital (p < 0.025) than did those who were not transplanted (n = 16). Despite spending a much longer time in the hospital, transplanted patients spent less time in the intensive care unit (p < 0.05) in coma (p < 0.01) and on a respirator (p < 0.01) than did those not transplanted. Most importantly, the survival rate for transplanted patients was significantly improved (p < 0.05) as compared to those not transplanted. We conclude that liver transplantation can be applied successfully to the difficult clinical problem of fulminant and subacute hepatic failure. Copyright © 1987 American Association for the Study of Liver Diseases

Abstract: To determine whether bone loss in patients with chronic cholestatic liver disease is the consequence of a high or low bone turnover state, 30 female patients with biopsy-proven primary biliary cirrhosis underwent iliac crest biopsy following double tetracycline labeling. The mean trabecular bone volume was decreased as a result of trabecular plate thinning in both the premenopausal (p less than 0.02) and postmenopausal (p less than 0.05) patients, compared to age- and sex-matched controls. Indications that osteoblastic function was impaired included a significantly lower mean wall thickness (p less than 0.01) and mean osteoid seam width (p less than 0.05), and this in association with a decreased mineral appositional rate and prolonged mineralization lag time was suggestive of a defect in matrix synthesis. Further evidence of impaired osteoblastic activity was the significantly lower bone formation rate at both tissue (p less than 0.001) and basic multicellular unit levels (p less than 0.05) in the postmenopausal patients. Total resorption surfaces and fasting urinary calcium/creatinine ratios were significantly increased (p less than 0.005 and 0.05, respectively) in the premenopausal patients and mean interstitial bone thickness reduced in both pre- and postmenopausal patients, suggesting that increased resorption may also contribute to bone loss in primary biliary cirrhosis.

Abstract: Tissue injury in primary biliary cirrhosis is thought to be mediated by immune mechanisms. Various Class II antigens of the major histocompatibility complex are associated with autoimmune diseases and their differing clinical manifestations. Thus, the aim of this study was to examine the relationship between primary biliary cirrhosis, its clinical manifestations and serologically defined Class II antigens (HLA-DR and HLA-DQ). Typing for these antigens was performed in 114 primary biliary cirrhotic patients and 171 controls by lymphocytotoxicity. There was a 6-fold increase in the frequency of HLA-DRw8 in primary biliary cirrhosis as compared to controls [30.1 vs. 4.7% (p < 0.0001)]. In contrast, HLA-DR5 had a decreased frequency in primary biliary cirrhosis as compared to controls [9.8 vs. 25.2% (p < 0.02)]. We examined the relationship between Class II antigens and the following prognostic indicators in primary biliary cirrhosis: serum bilirubin; 24-hr urine copper; serum albumin; prothrombin time; platelet count; ascites, and histologic stage (I to IV). Patients who are positive for HLA-DRw52 (n = 82) had a 2-fold increase in serum bilirubin compared to those who are negative (n = 32) for this antigen (p < 0.05). Conversely, patients who are positive for HLA-DR2 had less than half the serum bilirubin values of those negative for this antigen (p < 0.02). In conclusion, we found different Class II antigens to be associated with a prognostic indicator in primary biliary cirrhosis (serum bilirubin), while HLA-DRw8 is strongly associated with the disease itself. These data suggest that determining Class II antigens may be important in predicting the course and clinical expression of primary biliary cirrhosis.

Abstract: One hundred and twelve consecutive Child Class A and B cirrhotic patients were included in a prospective controlled trial aimed at investigating the efficacy and safety of endoscopic sclerotherapy vs. distal splenorenal shunt in the elective treatment of hemorrhage from esophagogastric varices. Fifty-seven patients were randomly allocated to splenorenal shunt and 55 to endoscopic sclerotherapy. Since only 4 of the 55 patients assigned to endoscopic sclerotherapy had to be excluded after randomization and before treatment as compared to 14 of the 57 patients assigned to splenorenal shunt, it is suggested that the applicability of endoscopic sclerotherapy is greater than that of splenorenal shunt. One patient in each group died within 30 days of the procedure and two in the endoscopic sclerotherapy group were lost to follow-up just after discharge. Variceal rebleeding during follow-up occurred in 37.5% (18/48) of patients in the endoscopic sclerotherapy group and in 14.3% of those in the splenorenal shunt group (6/42) (p <0.02), whereas hepatic encephalopathy was more frequent in patients submitted to splenorenal shunt (10/42, 24%) than in those treated by endoscopic sclerotherapy (4/48, 8%) (p <0.05). The therapeutic modality was the only variable with independent predictive value for rebleeding during follow-up, whereas for hepatic encephalopathy, the therapeutic modality, and the presence of encephalopathy related to the bleeding episode each showed independent predictive value. Early and long-term mortality, did not differ between the two therapeutic groups, being the 2-year survival was 71% for splenorenal shunt and 68% for endoscopic sclerotherapy. It is concluded that endoscopic sclerotherapy is a good alternative to splenorenal shunt in the elective treatment of esophageal variceal bleeding, especially in patients prone to develop hepatic encephalopathy.

Abstract: Mutant rats (TM rats) with abnormal hepatic excretory function were used to study biliary transport of dibromosulfophthalein, ouabain, tributylmethyl ammonium, cholate and taurocholate. In whole animals, dibromosulfophthalein and ouabain clearance is reduced to 7 and 37% of normal, respectively, due to severely impaired excretion from liver to bile. Initial uptake rates of these agents are relatively little affected. In the isolated perfused liver preparation, dibromosulfophthalein is retained within liver and perfusion medium, and the 60-min recovery on bile is reduced to 1.5 vs 75% in normal controls. Biliary excretion of cholate, taurocholate and the quaternary ammonium cation, [14C]tributylmethyl ammonium, is not impaired. These results provide evidence for a selective defect of organic anion and neutral steroid transport in TM rats and confirm that multiple pathways exist for the hepatobiliary excretion of organic anions, neutral steroids, bile acids and cations. Bile flow in whole animals and in the isolated perfused liver is reduced to 50 and 30% of normal, respectively. This suggests that a normal function of the excretory systems for organic anions and neutral steroids is important for the maintenance of normal bile flow.

Abstract: Mechanisms responsible for disproportional sedation resulting from triazolam administration to patients with cirrhosis were investigated. Ordinary sedative doses (0.25 mg) were given p.o. to 8 cirrhotics and 18 controls. Plasma concentrations of unbound drug were assessed by capillary gas chromatography and equilibrium dialysis. Median apparent oral clearances of unbound triazolam were 14.8 ml per min per kg in cirrhotics and 23.9 ml per min per kg in controls (p less than 0.01). Clearances were significantly correlated with severity of liver disease as assessed by the aminopyrine breath test (Rs = 0.77, n = 17, p less than 0.001). At a time when plasma concentrations of unbound triazolam were the same in both groups, i.e., 2.25 hr after dosing, flicker sensitivity at 5 Hz which was used as an index of CNS performance was impaired by a factor of 3.2 in cirrhotics and 1.4 in controls (p less than 0.01 for group difference). Performance was also significantly lower in cirrhotics with the digit symbol substitution test (p less than 0.05). It is concluded that, in patients with cirrhosis, disproportional sedation after benzodiazepine administration may be due not only to impaired drug elimination, but also to hypersensitivity of the brain.

Abstract: Orthotopic liver transplantation was performed in two groups of dogs; Group I animals consisted of large dogs that served as recipients of livers obtained from smaller dogs while Group II animals consisted of dogs that received liver from donor dogs of nearly the same size. The small-for-size livers transplanted into the Group I dogs rapidly increased in size over the course of 2 weeks until they achieved a size equal to that originally present in the larger recipient dogs. In contrast, the livers transplanted into dogs of the same size as the donors underwent some degree of atrophy. In both groups of animals, plasma levels of insulin and glucagon and hepatic (graft) activities of thymidine kinase and ornithine decarboxylase were followed serially. The only difference between the two groups of animals for these measures was that the ornithine decarboxylase activity rose to a greater degree in the liver that underwent graft enlargement. These data suggest that recipient size determines, at least in part, liver graft size once it is transplanted. These data also suggest that of the parameters followed, only ornithine decarboxylase activity parallels the finding of growth of the transplanted liver.