Bernard Portmann

Histological grading and staging of chronic hepatitis

‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology, University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK, “Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

Nomenclature of the finer branches of the biliary tree: Canals, ductules, and ductular reactions in human livers

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field. (HEPATOLOGY 2004; 39:1739–1745.)

Hepatitis B virus reinfection after orthotopic liver transplantation: Serological and clinical implications

The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patients had co-existing HBV and delta virus (HDV) infection. Five patients became HBsAg seronegative after transplantation (four immediately and one after an hepatitic episode). Of the 20 patients with HBV infection alone, 17 had evidence of viral replication after transplantation with markedly increased HBV DNA levels. Five patients with HDV infection had HBV DNA in serum, but in significantly lower amounts than in those with HBV infection alone. Twenty-five episodes of graft dysfunction attributed to recurrent HBV infection occurred in 19 patients (65.5%). Thirteen episodes (in 12 patients) were self-resolving acute hepatitic illnesses. Six patients had a rapidly progressive illness leading to graft loss within 6 weeks, with the distinctive histological features termed fibrosing cholestatic hepatitis (FCH). Liver function tests in these patients showed markedly abnormal serum bilirubin and prothrombin times, but only modest increases in serum transaminase levels. An additional six patients lost their graft as a consequence of HBV recurrence through various pathogenetic mechanisms including possible (but unproven) FCH, chronic active hepatitis or late-onset hepatic failure. Co-existing HDV infection appeared to confer some medium-term protection from graft loss.

De-novo autoimmune hepatitis after liver transplantation.

Summary Background Late graft dysfunction that does not result from recognised causes, such as rejection, infection, or vascular or biliary complications, can occur after liver transplantation. We investigated a particular type of unexplained graft dysfunction that is associated with autoimmune features in children who underwent transplantation at our unit between 1991 and 1996. Methods Seven (4%) of 180 liver-transplant recipients developed an unexplained but characteristic form of graft dysfunction (five boys, two girls; median age at presentation 10·3 years, range 2·0–19·4). The median period after surgery was 24 months (6–45). The indications for transplantation had been extrahepatic biliary atresia (four patients), Alagilles syndrome (one), drug-induced acute liver failure (one), and α1-antitrypsin deficiency (one). Four patients were on triple immunosuppression with cyclosporin, azathioprine, and prednisolone; and three were on tacrolimus. Immunoglobulin measurements, autoantibody studies, serological studies, and HLA typing were undertaken. Liver-biopsy samples were taken. Findings Infectious and surgical complications were excluded. Liver-biopsy samples showed the histological changes of chronic hepatitis, including portal and periportal hepatitis with lymphocytes and plasma cells, bridging collapse, and perivenular-cell necrosis without changes typical of acute or chronic rejection. All patients had high concentrations of IgG (median 22 g/L [range 17·2–34·4]) and high titres of autoantibodies. All but one patient responded to prednisolone 2 mg/kg daily and an increase in or addition of azathioprine (1·5 mg/kg daily) within a median of 32 days (7–316). One responder relapsed owing to poor compliance but went into remission after treatment was restored. All six respondents remain in remission on a reduced dose of prednisolone (5–10 mg/day) and 1·5 mg/kg daily azathioprine at a median of 283 days (range 108–730) follow-up. Interpretation Our data show that symptoms of autoimmune hepatitis, which are responsive to the classical treatment for this condition, can appear in liver-transplant patients while they are on anti-rejection immunosuppression. Whether the liver damage in these patients is a form of rejection or the consequence of autoimmune attack has yet to be established.

CYTOMEGALOVIRUS INFECTION AND DONOR/RECIPIENT HLA ANTIGENS: INTERDEPENDENT CO-FACTORS IN PATHOGENESIS OF VANISHING BILEDUCT SYNDROME AFTER LIVER TRANSPLANTATION

The contribution of cytomegalovirus (CMV) infection and its interrelation with HLA antigens in the development of chronic rejection (vanishing bile-duct syndrome--VBDS) was investigated in 101 patients surviving for at least 3 months after liver transplantation. A 1-2 antigen match for HLA DR antigens (30.9% vs 4.5% for zero DR match; p less than 0.002), a zero match for HLA A/B antigens (27.5% vs 10.9% for 1 or more A/B match; p less than 0.05), and active CMV infection (26.3% vs 4.4% for no CMV infection; p less than 0.005) were independently associated with an increased risk of VBDS. The coexistence of a 1-2 HLA DR match and CMV infection carried the highest relative risk (10.1) of VBDS; these two variables were probably interdependent since either alone was associated with a low relative risk (0.45 and 0.5). The association between VBDS and active CMV infection was not a consequence of alterations in immunosuppressive therapy. The findings would be consistent with precipitation of chronic rejection by CMV-induced HLA antigen expression in patients rendered susceptible by the donor/recipient HLA antigen match.

Recurrence of Primary Biliary Cirrhosis after Liver Transplantation

Three patients who had undergone orthrotopic liver transplantation for primary biliary cirrhosis and were being maintained on immunosuppressive therapy were investigated 31/2 to 41/2 years later because of the redevelopment of pruritus and mild jaundice. In one patient pigmentation was again evident, and all three had a rise in the titer of serum mitochondrial antibody after an initial fall. Liver histology showed features of primary biliary cirrhosis with non-suppurative destructive cholangitis, lymphoid aggregates, and increased deposition of copper-binding protein in the absence of cholestasis. None of these features was found in patients who had received grafts for other conditions and had lived for comparable periods, nor were they found in patients who had had rejection with bile-duct abnormalities. The overall findings indicate a recurrence of primary biliary cirrhosis in the donor organ.

Primary Sclerosing Cholangitis in Childhood

Thirteen children (8 female) with primary sclerosing cholangitis are described, in whom the diagnosis was confirmed by the presence of characteristic changes on endoscopic retrograde cholangiopancreatography. Nine had clinical features of chronic inflammatory bowel disease 1 mo to 5 yr before the onset of primary sclerosing cholangitis (6 patients) or appearing simultaneously with primary sclerosing cholangitis (3 patients). In 4 patients clinical evidence of chronic inflammatory bowel disease was absent but 1 of the 4 was found to have microscopic colitis in colonoscopic biopsy specimens. Biopsies were not performed in the remaining 3 patients. High immunoglobulin G concentrations and positive antinuclear or smooth muscle antibodies were present in all patients except 1 who had been given immunosuppressants. In 7 patients treated with immunosuppressants and followed up for 9 mo to 10 yr there was modest symptomatic improvement. This improvement was accompanied by a fall in transaminase levels in 6 of the patients and histologic improvement in 3 of 4 patients who had undergone biopsy. Greater use of endoscopic retrograde cholangiopancreatography in the last 6 yr led to the identification of 10 of these 13 cases, suggesting a higher incidence of primary sclerosing cholangitis in childhood than would appear from the literature.

Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting.

In a 26-year-old woman who had received an orthotopic liver graft for end-stage autoimmune chronic active hepatitis, signs indicative of the original disease became apparent 18 months after transplantation, at a time when the maintenance dose of prednisolone had been reduced to 3 mg daily. In addition to anorexia, nausea, and weight loss there was a reappearance of spider naevi, serum autoantibodies, and elevated levels of immunoglobulin G. Features typical of chronic active hepatitis were observed on examination of the liver biopsy, and both the clinical and histological pictures were unlike those of other possible causes of liver dysfunction, such as chronic rejection, cyclosporine hepa-totoxicity, and non-A non-B chronic hepatitis. Following substitution of azathioprine for cyclosporine and an increased dose of prednisolone (20 mg daily), there was a rapid improvement in the clinical state and both serum transaminases and immunoglobulins returned to normal values. Histological appearances in a repeat biopsy taken six months later were consistent with chronic active hepatitis in remission. This case provides further evidence of the importance of host factors in the pathogenesis of chronic active hapatitis and emphasizes the necessity for selecting appropriate immunosuppressive therapy in such patients after transplantation.

Cyclosporin a treatment in primary biliary cirrhosis: Results of a long-term placebo controlled trial

BACKGROUND Effective treatment for primary biliary cirrhosis (PBC) resulting in slower progression and improved survival remains elusive. Cyclosporin A (CyA), which has been so effective in preventing human allograft rejection, has shown promise in small numbers of patients in early studies. METHODS Three hundred forty-nine patients with PBC were randomized to receive CyA, 3 mg.kg-1.day-1, or placebo in a multicenter study with follow-up for 6 years. The end point was death or liver transplantation. RESULTS Cox multivariate analysis showed time from entry to death or transplantation was significantly prolonged (by up to 50%) in the CyA-treated group. Liver-related mortality was also significantly lower. However, a univariate analysis of survival showed no statistical differences between the two groups. Biochemical liver indices deteriorated more slowly in the CyA-treated group, but serum creatinine concentration was elevated > 150 mumol/L in 9%, necessitating permanent discontinuation in half of these. A reduction in the dose of CyA was required in 11% because of hypertension. CONCLUSIONS CyA has some therapeutic potential in primary biliary cirrhosis, providing blood pressure and renal function are closely monitored.

Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease.

The records of 52 children with Niemann-Pick disease type C were reviewed to establish whether the disease process and outcome varied with the initial clinical pattern; 34 children (65%) had cholestatic liver disease and hepatosplenomegaly in infancy; 18 were seen at a mean age of 4 years with splenomegaly or neurologic disease or both. Of the 34 children with early cholestatic liver disease, three died in the neonatal period; cholestasis and hepatomegaly subsided in the remaining 31 children, although splenomegaly persisted. Of these 31 children, 15 had persistent liver disease with elevated aminotransferase values. Serial liver biopsy specimens showed that 3 of the 15 children had normal architecture and 12 had hepatic fibrosis, with progression to cirrhosis in 5. No other significant morbidity or additional deaths were associated with the liver disease. The clinical importance of persistent liver disease was overshadowed by the subsequent development of severe neurologic disease. There was no difference in the age at onset of the disease (mean, 4.5 years) or in the pattern of neurologic disease, including supranuclear ophthalmoplegia, whether or not the child had early liver disease. Overt neurologic disease has not yet developed in seven surviving children with liver disease at onset. Sixty-seven percent of children died during the study; the main cause of death was bronchopneumonia. We conclude that the diagnosis of Niemann-Pick disease type C should be considered in patients with unexplained neonatal hepatitis, especially if splenomegaly is a persistent feature. Because liver biopsy specimens may not demonstrate storage cells, bone marrow aspiration to detect the characteristic storage cells is recommended in such patients.