Biomedical subjects
Publications and source records attributed to B Portmann.
Giant cell hepatitis (CGH) with autoimmune haemolytic anaemia (AHA) is a distinct entity with an aggressive course. Immunosuppression may help early disease. A case is reported of a child with GCH and AHA with early disease recurrence after liver transplantation for end stage liver disease.
The comparative efficacy of prednisolone followed by interferon alfa (IFN-alpha) versus IFN-alpha alone in enhancing the rate of antibody to hepatitis B e antigen (anti-HBe) seroconversion has not been evaluated in a large cohort of white children. To determine this, a multicenter-controlled trial was conducted in 95 hepatitis B virus (HBV)-DNA/hepatitis B e antigen (HBeAg)-positive children (median age, 9 years [range, 2-16 years]; 56 boys; 84 [89 percent] white), all having inflammatory changes on liver biopsy. Patients were randomized to receive either prednisolone followed by IFN-alpha (n = 34); placebo followed by IFN-alpha (n = 30); or no treatment (n = 31). The prednisolone/placebo was given on a double-blind basis. Lymphoblastoid IFN-alpha was given at 5 MU/m(2) three times a week for 12 weeks. Baseline clinical, biochemical, and histological features were similar for the three groups. The majority (85 percent) had a baseline aspartate aminotransferase (AST) level < or = 100 IU/L. On follow-up between 12 and 18 months (median, 15 months) after treatment, the loss of HBeAg with anti-HBe seroconversion was more common in patients pretreated with steroids (12 of 34 [35 percent]) or placebo [12 of 30 (40 percent)] as against controls (4 of 31 [13 percent], P< .05). Factors predictive of anti-HBe seroconversion were baseline HBV-DNA concentration of < or = 1,000 pg/mL and a greater degree of portal tract inflammation on pretrial biopsy. Our results show that in white children treatment with IFN-alpha, at the dose and duration used in this study, improves the rate of anti-HBe seroconversion. Steroid priming does not potentiate the effect of IFN-alpha.
Auxiliary liver transplantation (LT) is a special procedure of LT which could be proposed to patients with fulminant hepatic failure (FHF) and has for aim that complete regeneration of the native liver (NL) left in place will allow the graft recipient to resume normal liver function after allograft withdrawal. We report 30 cases of auxiliary LT performed for FHF in 12 European centers. Twenty-five of 30 patients were younger than 50 years. The cause of FHF was hepatitis A virus (HAV) in 4 patients, hepatitis B virus (HBV) in 7, paracetamol overdose in 5, ecstasy in 2, hepatotoxic drugs in 4, autoimmune hepatitis in 2, liver lesions of preeclampsia in 1 and unknown in 5. A postoperative, both clinical and histological follow-up of more than 3 weeks was obtained in 22 patients, enabling us to look for indicators predictive of NL regeneration and outcome. Histological changes observed in the NL included complete regeneration in 68%, incomplete regeneration with obvious fibrous sequelae in 14% and severe liver fibrosis or cirrhosis in 18%, of the 22 patients studied. The percentage and distribution of necrosis observed in tissue samples of the NL at the time of transplantation was not related to the final outcome. Complete NL regeneration was observed in 15 patients, out of whom 14 were younger than 40 years. Patients with complete regeneration were mainly affected by FHF due to HAV, HBV, or paracetamol overdose. After a follow-up of 18/11 (mean/median) months (range, 3 to 67 months), 19 of the 30 patients (63%) survived and 13 of them (68%), i.e., 43% of the 30 patients, had resumed normal NL function, with interrupted immunosuppression, the ultimate goal of emergency auxiliary LT. We conclude that, in patients with FHF, auxiliary LT is a procedure feasible in a number of centers and is associated with a complete regeneration capability of the NL in a majority of survivors, especially in those younger than 40 years. Confirmation of these encouraging preliminary results by large-scale prospective studies is required.
The clinico-pathological features of four cases of pediatric hepatic angiosarcomas are described. One case was initially diagnosed in infancy and underwent resection of a left-sided benign hemangioendothelioma of the liver. Further resection of a lesion in the right liver was followed by malignant transformation. Primary hepatic resection of the tumor was not possible in three other cases, and all received courses of chemotherapy without significant tumor shrinkage. One child underwent liver transplantation but died 4 months later of immunosuppression complications. The remaining three children died of disseminated malignancy. Histological verification of malignancy was difficult in three cases in which there was discrepancy between the rapid growth of the liver tumor and the microscopic features of benign hemangioendothelioma.
The protein encoded by the p53 tumour suppressor gene plays an important part in the regulation of cell growth. Abnormalities of this gene represent one of the most common genetic changes in the development of human cancers. This study investigated the expression of p53 protein in cholangiocarcinoma arising in association with primary sclerosing cholangitis (PSC). Of the 14 patients with cholangiocarcinoma studied, 13 had underlying PSC. The expression of p53 protein was detected immunohistochemically in paraffin wax embedded liver specimens, after microwave pretreatment. The expression of p53 protein was shown in the cholangiocarcinoma tissue of 11 of 14 (78.5%) patients. In five of 10 patients, the accumulation of p53 protein highlighted the presence of neoplastic cells in biliary tissue separate from the main tumour. These cells were mainly located in the septal bile ducts or in the accessory glands, or both, but occasionally also in large portal areas at the periphery of nerves and lymphatics, and in one case in the mucosa of an extrahepatic bile duct. No p53 protein was detectable in liver tissue obtained at the time of transplantation in 15 patients with PSC but not cholangiocarcinoma. These results show that cholangiocarcinoma development in PSC is commonly associated with abnormalities of p53 and that these occur at a late stage in the development of the malignant process. Staining for p53 protein could represent an additional criterion for the diagnosis of cholangiocarcinoma development in patients with PSC.
Eight cases of ecstasy related acute liver damage referred to a specialised liver unit are described. Two patients presented after collapse within six hours of ecstasy ingestion with hyperthermia, hypotension, fitting, and subsequently disseminated intravascular coagulation with rhabdomyolysis together with biochemical evidence of severe hepatic damage. One patient recovered and the other with evidence of hyperacute liver failure was transplanted but subsequently died, histological examination showing widespread microvesicular fatty change. Four patients presented with acute liver failure without hyperthermia. All four fulfilled criteria for transplantation, one died before a donor organ became available, and two died within one month post-transplantation of overwhelming sepsis. Histological examination showed submassive lobular collapse. Two patients presented with abdominal pain and jaundice and recovered over a period of three weeks; histological examination showed a lobular hepatitis with cholestasis. Patients developing jaundice or with evidence of hepatic failure particularly encephalopathy and prolongation of the international normalised ratio, or both, whether or not preceded by hyperthermia, should be referred to a specialised liver unit as liver transplantation probably provides the only chance of recovery.
Fifteen patients with cirrhosis underwent orthotopic liver transplantation for small hepatocellular carcinoma (HCC) and 12 patients with cirrhosis underwent hepatic resection for similar HCC. All tumours were of the non-fibrolamellar variant. The majority of the patients in the transplant group had Child's grade B or C cirrhosis. Median follow-up was 37 months with a minimum of 18 months. Eleven of 12 patients in the resection group had Child's grade A cirrhosis. Median follow-up was 29 months with a minimum of 16 months. Actuarial survival rates at 1 and 3 years for the transplanted patients were 80 and 63 per cent and all were tumour free. Tumour recurrence rate was 15 per cent. The overall 1- and 3-year tumour-free survival rates for patients in the resection group were 61 and 33 per cent. Tumour recurrence rate was 45 per cent. The results show orthotopic liver transplantation to be an important surgical option in cirrhotic patients with small HCC, particularly in those with moderate to severe hepatic decompensation.
This paper documents clinically significant recurrence of hepatitis A virus (HAV) infection in a 63-year-old man transplanted for HAV-related acute liver failure. HAV RNA was documented in the explant and, following early clearance from the blood and graft, was again detected in post-operative biopsies at the time of an acute hepatic illness. Although the clinical and biochemical abnormalities resolved completely, the patient had a second episode of graft dysfunction 6 months later and investigations revealed hepatitis C virus (HCV)-related chronic active hepatitis consistent with acquired HCV infection at the time of transplantation. The possible interaction with hepatitis A may have delayed the appearance of hepatitis C. Administration of HAV immunoglobulin at the time of transplantation should be considered in all cases of HAV-related fulminant hepatic failure.
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Centrilobular necrosis (CLN) is a histological finding often encountered after orthotopic liver transplantation, but its pathogenesis is still unknown. In this study, the significance of CLN was assessed in a series of 227 consecutive liver transplantations performed between January 1989, and December 1991. Seventy-one patients (30.9%) showed CLN on at least one biopsy result, which were obtained because of an increase of aspartate aminotransferase activity. Their liver specimens were reviewed, and 19 histological features were recorded with particular attention given to lobular changes in acinar zone 3, to features commonly attributed to cellular and ductopenic rejection, and to changes suggestive of ischemia. CLN could first be observed either soon (within 4 days) or late (up to 3 years) after transplantation. Only 23 (32.4%) specimens had centrilobular necrosis affecting more than 75% of acinar zones 3. In 60 cases (84.5%) the lesion was limited to acinar zone 3. An important associated feature was sinusoidal congestion in 73.2% of cases. Fifty-one of 71 patients (71.8%) had histological features of cellular rejection before or at the time of CLN, and 13 of these progressed to ductopenic rejection versus 3 of the 156 patients without CLN (P < .0001). Nine patients had a recurrence of CLN, of whom 2 progressed to ductopenic rejection, a recurrence rate of 16.7% in this series. The survival of patients with CLN is worsened by associated ductopenic portal tracts compared with those without ductopenia (P = .0189-Mantel-Cox). This histological combination, irrespective of the serum bilirubin level, may warrant an early conversion to FK506-based immunosuppression.
BACKGROUND/AIMS: Patients with chronic hepatitis B infection have elevated plasma tumor necrosis factor (TNF) alpha levels. Two TNF-alpha receptors have been identified, each responsible for distinct TNF-alpha activities. The aim of this study was to evaluate the biological function of the elevated TNF-alpha in chronic hepatitis B virus infection by examining the two TNF signaling pathways in the evolution of hepatitis B-related liver injury. METHODS: The hepatic expression of the two TNF receptors and the corresponding serum levels of the soluble forms of both TNF receptors were determined and correlated with hepatic inflammation and virus replication in 98 chronic hepatitis B surface antigen carriers. Forty hepatitis B e antigen-positive patients were also studied prospectively, while on interferon alfa treatment, to examine the TNF receptor response during viral clearance. RESULTS: In chronic hepatitis B virus infection, the hepatic expression and serum levels of TNF receptors, in particular 75-kilodalton TNF receptor subtype (TNF-R p75), are significantly enhanced in association with hepatic inflammation and hepatocytolysis but not with hepatitis B virus replication. During interferon alfa treatment, a significant increase of soluble TNF-R p75 always precedes the hepatitis B e antigen antibody against hepatitis B e antigen seroconversion in responders to treatment. CONCLUSIONS: In chronic active hepatitis B infection, there is an up-regulation of the TNF receptor system, preferentially the TNF-R p75 signaling pathway, which suggests that the TNF-alpha/TNF receptor system has an important role in the pathogenesis of liver damage and viral clearance.
BACKGROUND/AIMS: Indian childhood cirrhosis is associated with high liver copper concentrations and progressive liver disease with a high mortality. Early treatment with penicillamine was found to reduce mortality and reverse liver damage. We aimed to define the clinical features of copper-associated liver disease outwith the Indian subcontinent and encourage the earlier consideration of the syndrome in cryptogenic liver disease. METHODS: Three European children presented between 10 and 29 months of age with abdominal distension, pyrexia and hepatosplenomegaly. Over 1-5 weeks their condition deteriorated rapidly due to liver failure. Two died within 2 months of onset and one received a successful liver transplant. In two cases consideration of the diagnosis occurred only on examination of the liver after orthotopic liver transplant or death. Light microscopy was used, with haematoxylin and eosin, reticulin and orcein stains. Tissue, plasma and water copper levels were measured by flame atomic absorption spectrometry. RESULTS: All had micronodular cirrhosis and severe hepatocellular necrosis with Mallory bodies and copious-orcein positive material. Liver copper concentrations ranged from 1100-1310 micrograms/g dry weight. For two patients domestic water with high copper content had been used for the preparation of feeds. No environmental source of excess copper could be identified in the third case. CONCLUSIONS: We suggest that the above condition, which is called Indian childhood cirrhosis in the Indian subcontinent and Copper Storage Disease elsewhere, would be better named 'Copper-Associated Liver Disease in Childhood', emphasising the need to consider this disorder in unexplained liver disease and to seek possible sources of excessive copper intake.
A further series of 41 adult patients with late-onset hepatic failure was investigates with respect to aetiological factors, particularly hepatitis C and E, which have been identified since our earlier report of this condition. The increased use of transplantation and its impact on survival overall is assessed. Comparison is made with 64 patients admitted over the same period with fulminant hepatic failure of non-A, non-B aetiology. Screening for the hepatitis viruses revealed three cases of hepatitis A and one case of Epstein Barr virus hepatitis. There were no cases of hepatitis C or hepatitis E virus detected by enzyme immunoassay and reverse transcriptase/polymerase chain reaction techniques, although three patients had positivity for IgG anti-hepatitis E virus, demonstrating previous exposure. Serum autoantibodies in a titre greater than or equal to 1:40 were present in 29% of samples tested and in three cases, titres of SMA or ANF were greater than 1:320. In a further five cases, a potentially hepatotoxic agent had been given within 3 months of the onset of symptoms, leaving the majority of patients (29) with no identifiable cause for their disease. The frequency of symptoms, however, including nausea, abdominal discomfort with the subsequent development of ascites, encephalopathy and renal impairment suggest a similar disease process in these patients. Analysis of liver biopsy material showed similar patterns on all cases of map-like necrosis with nodular regeneration and without other additional features of aetiological significance. Differences in clinical and histological changes for the non-A, non-B fulminant hepatic failure comparison group reflect the tempo of disease process rather than the nature and cause of the liver damage. The introduction of transplantation has led to a marked improvement in survival (39% overall in the earlier series). In the 21 patients in whom transplantation was carried out, the 1-year actuarial survival is currently 55%. Treatment of late-onset hepatic failure with corticosteroids and the use of Prostaglandin E1 and interferon in individual cases has been disappointing, and the emphasis in management should be placed on teh early referral of such patients to a centre offering transplantation.
Polycystic liver disease is commonly asymptomatic but may present with hepatomegaly, abdominal distension, and dull abdominal pain. Transudative ascites is a rare manifestation in these patients but may occur when portal hypertension is present resulting from associated hepatic fibrosis or after deroofing procedure of a cyst. Exudative ascites might suggest hepatic venous outflow obstruction. Four cases are described where hepatic venous outflow obstruction occurred in patients with polycystic liver disease. Three patients had orthotopic liver transplantation and one had a mesocaval shunt. Of the two patients that survived orthotopic liver transplantation both have shown considerable improvement in their symptoms. None of the patients had any confirmed procoagulant disorder. The mechanism of hepatic venous outflow obstruction in these patients seems to be mechanical compression of hepatic veins by the cysts and associated formation of thrombi in small hepatic vein tributaries. Patients with severe polycystic kidney/liver disease are at risk of hepatic venous outflow obstruction and the onset of this complication is heralded by tender hepatomegaly and presence of exudative ascites.
1. Osbeckia octandra is a plant used in traditional medicine to treat jaundice and other liver disorders. In this study, the effects of Osbeckia leaf extract on paracetamol-induced liver injury were investigated both in vivo in mice and in rat hepatocytes in vitro. 2. Oral administration of Osbeckia extract (330 mg/kg) at the same time as paracetamol (450 mg/kg) to mice, resulted in a significant protection (p < 0.05) against liver damage, as assessed by improvements in the blood Normotest (39.1 +/- 1.9 versus 46.3 +/- 2.0 s), total liver glutathione (730 +/- 39 versus 574 +/- 27 micrograms/250 mg liver), plasma aspartate aminotransferase level (916 +/- 225 versus 1965 +/- 291 iu/l), and liver histopathology at 24 h after paracetamol administration. 3. In experiments to assess the direct effects of Osbeckia extract, significant protection was also found in freshly isolated rat hepatocytes against damage induced by 185 microM 2,6-dimethyl N-acetyl p-quinoneimine (2,6-diMeNAPQI, an analogue of NAPQI, the toxic metabolite of paracetamol) in vitro. When Osbeckia extract (500 micrograms/ml) was added to the incubation medium at the same time as 2,6-diMeNAPQI significant changes in cell viability (78.4 +/- 3.3 versus 47.2 +/- 5.8% of control, p < 0.001), cell reduced glutathione (GSH) level (35.0 +/- 3.1 versus 23.8 +/- 1.5%, p = 0.009), and reduced release of lactate dehydrogenase (129.9 +/- 6.6 versus 224.6 +/- 12.1%, p < 0.001) were demonstrated after 1 h incubation as compared with 2,6-diMeNAPQI alone. 4. Significant protection was still obtained against 2,6-diMeNAPQI in vitro when addition of Osbeckia extract was delayed by 20 min. These results indicate that Osbeckia extract can protect against paracetamol-induced liver injury.
OBJECTIVES AND METHODS: The outcome after liver transplantation for HBsAg-positive liver disease complicated by hepatocellular carcinoma is not clearly defined, and in the present study we analyzed the clinical course in 39 patients transplanted for hepatitis B virus (HBV)-related liver disease (group 1) compared with 16 patients with chronic HBV and hepatocellular carcinoma (group 2) and 52 patients with primary hepatocellular carcinoma seronegative for HBsAg (group 3). RESULTS: Despite similar pretransplant viral serology, HBV recurred more often in patients with tumor (group 2) than in nontumor cases (group 1), with 1-yr actuarial cumulative reinfection rates of 85.4% versus 65.0%, respectively (p < 0.05). In group 2 cases, we observed a more aggressive pattern of HBV-related graft injury with a higher frequency of graft loss (56.3% vs. 12.8%, p < 0.001). Long-term outcome was worse in the group 2 cases, with 5-yr actuarial survival rates of 16.7% compared with 73.2% and 28.2% for groups 1 and 3, respectively. In group 2, recurrence of HBV in the graft, rather than tumor recurrence, was the principal cause of the high mortality observed (56.2% vs. 12.5%), which, in some cases, may have been potentiated by adjuvant chemotherapy. CONCLUSION: The poor outcome of patients transplanted for HBsAg-positive cirrhosis and hepatocellular carcinoma is due to HBV reinfection of the graft, rather than tumor recurrence. Antiviral agents in association with hepatitis B immunoglobulin would be the most promising approach to improving survival in this patient population.
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The role of hepatitis C virus (HCV) infection in severe liver failure (LF) following bone marrow transplantation is still uncertain. We therefore decided to determine the presence of HCV-RNA in 31 patients who died of severe LF after BMT and in 26 matched BMT controls who did not develop LF. HCV-RNA was identified by polymerase chain reaction and anti-HCV by second generation enzyme-linked immunoassay and by 4-band recombinant immunoblotting assay in serum samples obtained before and after BMT. Biochemical and clinical parameters of liver disease were obtained by reviewing clinical records. LF developed at a median interval of 80 days (20-570) from transplantation and was clinically assessed as VOD (n = 7), liver GVHD (n = 5) or hepatitis (n = 19). HCV-RNA was detected, respectively, in 15/31 (48%) and in 12/26 (46%) of LF patients and controls (P = 0.9). Conversely, the risk of dying of LF was 62% and 53% (P = 0.5) respectively, for HCV-RNA positive and negative patients. Anti-HCV profile did not correlate with viremia, nor with type of liver disease. These findings indicate that, despite a 47% prevalence of HCV infection in our series, HCV-RNA positivity was neither a predictor of VOD nor a marker for life-threatening liver disease.