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From 1990 to present, 14 liver pathologists and 2 clinical hepatologists from 9 countries have met annually to hold thematic 2.5-day meetings centered on case-based discussion. The goal of these meetings has been to identify gaps in knowledge in our field and fuel scholarly effort to address these gaps. The founding principles were worldwide representation, good representation of women, compatibility of participants, commitment to stable membership and regular attendance, mutual education and friendship, and free exchange of ideas. A summary report of the 2.5-day meeting constituted an enduring document that captured the free flow of ideas discussed. These ideas were open to all participants for the pursuit of scholarship back at their home institutions. However, any idea borne out of an Elves meeting merits open invitation for other Elves to participate in, using established standards for meaningful coauthorship. Over 26 consecutive meetings (1990-2015), themes covered the breadth of liver pathology. With retirement of 2 individuals, resignation of 3, and death of 1, six new members were nominated and voted into membership. Over these same 26 years, active members published 2025 articles indexed in PubMEd Central under the topic “liver;” 3% of these articles represented collaborations between members. This international group represents a successful model in a subspecialty of anatomic pathology for open exchange of ideas, mutual education, and generation of topics worthy of scholarly investigation. We conclude that a self-selected group of subspecialty pathologists can meet successfully over 26 years, maintain a high state of engagement through each annual meeting, self-renew as a result of retirement or resignation, and provide a creative stimulus for highly productive academic careers.

The association between autoimmune pancreatitis and sclerosing cholangitis has attracted considerable attention. In contrast to type 1 (IgG4-related) autoimmune pancreatitis, bile duct involvement is uncommon in type 2 autoimmune pancreatitis, a more benign condition characterized histologically by granulocytic epithelial lesions (GELs). Following our recent report on a child with GEL-positive sclerosing cholangitis and excellent response to steroids, we retrospectively reviewed the liver histology of a large number of patients with sclerosing cholangitis to investigate the possible role of type 2 autoimmune pancreatitis in this pathology. Liver biopsies of 103 children with autoimmune sclerosing cholangitis and 142 adults with primary sclerosing cholangitis were reviewed for the presence of neutrophilic bile duct injury. Histologic findings were correlated with clinical features, response to treatment, and outcome. Neutrophilic bile duct lesions similar to GEL were identified in 5 cases (4 children and 1 adult; 4% of autoimmune sclerosing cholangitis and 0.7% of primary sclerosing cholangitis). GEL was more commonly seen in wedge biopsy specimens. One patient had concomitant pancreatitis. Cholangiograms showed diffuse stricturing of bile ducts in all cases. The number of liver tissue IgG4 plasma cells did not increase, and serum IgG4 levels were normal in 3 patients tested. All patients went into remission with prednisolone and/or ursodeoxycholic acid, and their liver function tests remained completely normal without relapses over a follow-up period of 6 to 16 years. Although rare, the diagnosis of sclerosing cholangitis with GEL is important in view of its excellent and apparently sustained response to immunosuppressive treatment.

Sakellariou S, Al-Hussaini H, Scalori A, Samyn M, Heaton N, Portmann B, Tobal K & Quaglia A (2012) Histopathology 60, E58–E65 Hepatocellular adenoma in glycogen storage disorder type I: a clinicopathological and molecular study Aims: Glycogen storage disease type I is a metabolic disorder resulting from deficiency of the glucose-6-phosphate complex. Long-term complications include the development of hepatocellular adenoma (HCA). In this retrospective study, our aim was to reclassify according to geno-phenotypic characteristics nodular lesions identified in hepatectomy specimens of such patients transplanted between 1998 and 2008 at our institution. Methods and results: Clinicopathological data of seven consecutive transplanted patients with glycogen storage disease type I were reviewed. Liver nodules were re-examined histologically and by immunohistochemistry. Molecular analysis was performed additionally in a case with specific features. Four patients had multiple tumours. We concluded that 26 of 38 nodules available for study had features of inflammatory hepatocellular adenomas, seven comprised adenomas not otherwise specified and five were found to be focal nodular hyperplasia. Conclusions: Further studies are needed to clarify the pathogenesis of hepatocellular adenomas in glycogen storage disease; in particular to determine whether they share abnormal metabolic pathways with inflammatory adenomas in the general population. Testing for acute phase proteins may be a helpful tool in the early detection of HCA in such patients. Finally, there is a need to further define their risk of malignant transformation, in relation to age and possible cofactors.

Zen Y, Ishikawa A, Ogiso S, Heaton N & Portmann B (2012) Histopathology 60, 261–269 Follicular cholangitis and pancreatitis – clinicopathological features and differential diagnosis of an under-recognized entity Aims: Biliary and pancreatic ductal systems can be involved in several lymphoplasmacytic inflammatory conditions, including primary sclerosing cholangitis, immunoglobulin G (IgG) 4-related cholangitis and autoimmune pancreatitis. Here in we describe an unusual pancreatocholangitis whose features suggest a distinct disease entity. Methods and results: The study group consists of five adult patients, three with predominantly hilar bile duct stricture and two with a bulky pancreatic head. Four patients were treated surgically for suspected malignancy and one patient underwent liver transplantation with a clinical diagnosis of primary sclerosing cholangitis. Histological examination revealed extensive lymphoplasmacytic inflammation centred on large biliary or pancreatic ducts. Many lymphoid follicles with germinal centres were noted around the affected ducts. Whipple specimens from two patients with a pancreatic head mass showed similar follicular inflammation histologically around bile ducts. In contrast to autoimmune pancreatitis, diffuse infiltration of IgG4+ plasma cells, granulocytic epithelial lesions and obliterative phlebitis were not identified. The postoperative course was uneventful, without evidence of recurrence (follow-up period 17–65 months). Conclusions: This study suggests that a disease entity which can be named follicular cholangitis and pancreatitis exists and may be under-recognized. The disease mainly affects the hilar bile ducts and pancreatic head in adults.

Zen Y, Quaglia A, Heaton N, Rela M & Portmann B (2011) Histopathology 59, 1100–1110 Two distinct pathways of carcinogenesis in primary sclerosing cholangitis Aims: To identify clinicopathological characteristics of cholangiocarcinoma and premalignant lesions arising in patients with primary sclerosing cholangitis (PSC). Methods and results: This study consisted of 25 patients with PSC and bile duct neoplasia [16 with cholangiocarcinoma and nine with biliary intra-epithelial neoplasia (BilIN) equivalent to biliary dysplasia]. Tumour cell morphology, growth patterns, history of inflammatory bowel disease and postoperative survival were recorded. Immunohistochemistry for CK7, CK20, MUC1, MUC2, MUC5AC, MUC6 and CDX2 was performed to characterize cell phenotypes. Cholangiocarcinoma and BilIN were classified into intestinal (n = 14) and non-intestinal classical (n = 11) types. Intestinal-type lesions showed histological features resembling intestinal dysplasia or adenocarcinoma. Intestinal-type cholangiocarcinoma commonly showed intraductal papillary proliferation and mucinous nodule formation. Intestinal-type lesions often had an intestinal immunophenotype that was not detected in classical-type lesions: CK20, 50% versus 0% (P = 0.007); MUC2, 86% versus 0% (P

The aim of this study was to characterize the physiologic expression of "intestinal" features in gallbladders of infants and children. The study group consisted of 56 pediatric (age, 2 weeks to 7 years) and 15 adult (15-25 years) patients who underwent incidental cholecystectomy during surgery for other lesions. All gallbladders examined were histologically unremarkable without inflammation, gallstones, or neoplasia. The presence of goblet cells and the expression of cytokeratin 7, cytokeratin 20, mucin core protein 2, and caudal-related homeobox protein 2 were examined. Intestinal features were frequently detected in the pediatric gallbladders: goblet cells in 34 cases (61%), cytokeratin 20 expression in 25 (45%), mucin core protein 2 expression in 32 (57%), and caudal-related homeobox protein 2 expression in 16 (29%). In contrast, none of these features was identified in adult gallbladders. The expression of mucin core protein 2 was mostly restricted to goblet cells in pediatric gallbladders, whereas cytokeratin 20 and caudal-related homeobox protein 2 were expressed in both goblet and nongoblet cells. Cytokeratin 7 was diffusely and consistently expressed in both pediatric and adult gallbladder epithelium including goblet cells. Intestinal features became less frequent with age and were scarce in children aged 6 to 7 years. Thus, goblet cells were identified in 14 (93%) of 15 children aged

Liver biopsy challenge and clinicopathological correlation Liver biopsy interpretation in inflammatory diseases of the bile ducts or chronic cholangiopathies may be challenging, especially for pathologists working outside referral centres, where there is a limited exposure to relatively uncommon conditions. In view of the importance of sampling errors resulting from the patchy distribution of pathognomonic bile duct injuries and the misleading absence of cholestasis in the early stages, there is a need to recognize surrogate markers and subtle changes, in particular the early periportal deposition of copper and mild biliary interface activity. Such findings may either constitute the first indication of a primarily biliary disorder or be supportive of a clinically suspected diagnosis. Histological changes common to chronic cholangiopathies are reviewed at the variable stages of development that patients may first present to clinicians. As awareness of the protean clinical manifestations is essential for histological interpretation, the major and distinctive anatomoclinical features of primary biliary cirrhosis and primary and acquired sclerosing cholangitis are revisited, together with so-called overlapping syndromes and less common variants and associations, including more recently documented conditions, such as IgG4-related disease and the rarer multidrug resistance 3 deficiency. The review stresses the importance of evaluating histological changes in conjunction with clinical information.

Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment-naive, jaundiced patients presenting to our tertiary unit between 1999-2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 μmol/L versus 262 μmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD-sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD-Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second-line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). Conclusion: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD-Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration. (HEPATOLOGY 2011;)

Zen Y, Quaglia A & Portmann B (2011) Histopathology58, 414–422 Immunoglobulin G4-positive plasma cell infiltration in explanted livers for primary sclerosing cholangitis Aims: To explore whether immunoglobulin (Ig)G4-related sclerosing cholangitis (IgG4-SC) contributes to end-stage primary sclerosing cholangitis (PSC) in the United Kingdom. Methods and results: This study consisted of 41 patients who underwent liver transplantation for advanced PSC. Explanted livers were examined histologically with an emphasis on IgG4-positive plasma cell infiltration. Thirty-nine cases (95%) had minimal or mild infiltration of IgG4-positive plasma cells (≤30 cells/high-power field). In contrast, two cases (5%) showed plasma cell IgG4-positivity in more than 100 cells/high-power field. IgG4-positive plasma cells were accumulated preferentially in a (xantho)granulomatous tissue within large bile ducts. Except for the presence of IgG4-positive plasma cells, there was no significant histological difference between IgG4-positive and negative cases. Both showed sclerosing cholangitis with bile duct erosion and xanthogranulomatous reaction more in keeping with PSC than typical IgG4-SC. Clinically, the two patients differed from typical IgG4-related disease, in that both had associated ulcerative colitis, and one of them was younger than expected for IgG4-SC (28 years old). Conclusions: No classical IgG4-SC could be identified in patients explanted for PSC. The two cases identified with numerous IgG4-positive plasma cells suggest a superimposed immune mechanism of uncertain nature. A prospective study is needed to assess whether such cases will be steroid-sensitive.

The aim of the study was to study the clinical and histological features of Alagille syndrome (AGS) at presentation comparing the value of the various modalities before the implementation of genetic diagnosis.We performed a retrospective analysis of the records of 117 children diagnosed as having AGS after referral to King's College Hospital between 1980 and 2005.Cholestasis was seen in 104 of 117 (89%), characteristic facies in 91 of 117 (77%), posterior embryotoxon in 72 of 117 (61%), butterfly vertebrae in 44 of 117 (39%), heart disease (most often peripheral pulmonary stenosis) in 107 of 117 (91%), and renal disease in 27 of 117 (23%). Serum cholesterol levels of5 mmol/L were seen in 52 of 86 (60.4%). Liver biopsy showed characteristic features of paucity of interlobular bile ducts in 59 of 77 (76.6%) children younger than 16 weeks of age, in 10 of 14 (71.4%) between 16 weeks and 1 year of age, and in 8 of 12 (66.66%) older than 1 year of age. Other biopsy findings were those of nonspecific hepatitis and biliary features. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 21 of 35 (60%), and small/no gallbladder on ultrasound was seen in 29 of 104 (27.8%). Eleven of 117 (9.4%) had a diagnostic laparotomy and operative cholangiography, 2 proceeding to Kasai portoenterostomy before referral to our unit.Clinical features of AGS are not as consistently informative as suggested in the literature. Hypercholesterolaemia is nonspecific but may be a helpful pointer. Histology is not characteristic in 25%; hepatobiliary iminodiacetic acid scan and ultrasound may suggest a false diagnosis of biliary atresia in 60% and 28%, respectively, supporting the concept that infants with liver disease warrant early referral to a specialist centre. The advent of genetic diagnosis will redefine the syndrome with likely effects on the prognosis of the defined group.

Hereditary fibrinogen A -chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 115: 2998–3007, 2010 Arie J. Stangou, Nicholas R. Banner, Bruce M. Hendry, Mohamed Rela, Bernard Portmann, Julia Wendon, Mark Monaghan, Philip MacCarthy, Muriel Buxton-Thomas, Christopher J. Mathias, Juris J. Liepnieks, John O’Grady, Nigel D. Heaton, and Merrill D. Benson Fibrinogen amyloidosis due to mutations in the fibrinogen -chain gene (AFib) localized on chromosome 4 and composed of six exons belongs to the group of nonneuropathic hereditary renal amyloidoses. It is the most common type of all hereditary renal amyloid diseases in the United States and Europe. Like other forms of amyloidosis, AFib amyloidosis is a protein misfolding disorder. Fibrinogen production is exclusively hepatic. Liver transplantation was therefore considered as a logical mode of treatment, whereas isolated renal transplantation was followed by kidney amyloid recurrence in most patients. Stangou et al. have first revisited the current phenotypic description of AFib amyloidosis and second performed a systematic evaluation for liver and kidney transplantation (LKT) in a series of 22 patients (8 women, 14 men). Three of them had been misdiagnosed as primary systemic AL amyloidosis—a diagnostic error already reported (1). The median age at presentation was 55 years (range 33 to 63 years). Proteinuria was the most common presenting feature (median 24-hour urine protein 7.2 g; range 0 to 11.8 g). At the time of assessment, median GFR was 16 ml/min (range 0 to 52 ml/min). Renal biopsy was performed in 21 of 22 patients and revealed amyloidosis in all patients, with enlarged glomeruli replaced by amyloid with minimal or no extraglomerular involvement—a finding suggestive of this type of amyloidosis (1). Twenty of 22 patients progressed to ESRD. Two patients had liver amyloidosis, complicated in one by end-stage liver disease. Coronary atherosclerotic disease was documented in 15 patients (68%), in half of the patients predating evolution of kidney impairment. Twelve patients had severe systemic vascular disease, involving aorta, splanchnic, or carotid arteries. Two patients underwent carotid endarterectomy. Of interest, the excised material contained amyloid purely consistent of mutant fibrinogen A -chain. Cardiac amyloidosis was not a rare localization. Echocardiography was abnormal in 11 of 21 patients (52%). Three of the four endomyocardial biopsies revealed substantial amyloid deposition. One patient developed dilated amyloid cardiomyopathy in association with coronary disease and myocardial amyloidosis, whereas cardiac amyloidosis usually leads to restrictive cardiomyopathy. In addition, cardiac parasympathetic dysfunction and risk of bradycardia were identified in 12 patients. Seven of them had pacemaker insertion. Autonomic involvement of the gastrointestinal tract was a feature in 15 patients. Only 24% of patients had family history of renal disease. However, 81% had family history of systemic or coronary vascular disease. Family members who had such cardiovascular history were indeed carriers of AFib mutations. Spontaneous splenic rupture occurred in four patients (one during hemodialysis and three during transplantation). The excised spleen contained widespread amyloid. Nine of 14 patients accepted on the waiting list received combined liver and kidney allografts. At a median follow-up of 67 months, six of nine patients are alive and well with normal liver function. Five patients have good renal function. Cardiac amyloidosis has not progressed after LKT. I-labeled serum amyloid P component (SAP) scintigraphy showed regression of systemic visceral amyloid deposits as early as at the first annual follow-up scan after LKT, whereas scintigraphy documented progressive amyloid deposition in two patients who had previously undergone isolated kidney transplant. Serial 99mTcDMSA renal scintigraphy after preemptive LKT in two patients demonstrated stable native renal uptake. Four patients with various liver diseases received, after full information, explanted livers from AFib patients. Only one “domino” recipient had SAP scans and echocardiography for up to 5 years with no evidence of de novo amyloid deposition. The study by Stangou et al. extends the clinical scope of AFib amyloidosis. Stangou et al. encourage evaluation of isolated liver transplant early in the course of amyloid nephropathy to prevent systemic deposition and renal progression to ESRD. Amyloid fibrils in AFib contain exclusively variant fibrinogen. Circulating total fibrinogen consists of a mixture of wild-type/ variant fibrinogen in a ratio of 1:1 to 3:2. Wild-type fibrinogen does not perpetuate amyloid disease. After liver transplant, the variant fibrinogen is eliminated and promptly replaced by Published online ahead of print. Publication date available at www.cjasn.org.

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

We studied the clinical features of children with 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7 alpha-dihydroxy-5-cholenoic acid and 3beta-7 alpha-12 alpha-trihydroxy-5-cholenoic acid.Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg x kg(-1) x day(-1) of each), 7 with chenodeoxycholic acid only (7-18 mg x kg(-1) x day(-1)), and 1 with cholic acid (8 mg x kg(-1) x day(-1)) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency.3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.

Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created, but remain independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting with fulminant liver failure who required liver transplant. Patients with AIH and non-AIH etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity, and positive and negative predictive values for scores of ≥6 (probable AIH) and ≥7 (definite AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221 with AIH, 26 with variant syndromes, and 302 with non-AIH). For scores ≥6, sensitivity was 90%, and specificity was 98% with positive and negative predictive values of 97% and 92%, respectively. For scores ≥7; sensitivity was 70%, and specificity was 100% with positive and negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified criteria and 40% for 1999 criteria, respectively. Conclusion: The simplified criteria retain high specificity but exhibit lower sensitivity for scores of ≥7. The explanations for this are unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations. (HEPATOLOGY 2009.)

— Hepatocytes isolated from patients with chronic liver disease are often covered by immunoglobulin. The aim of the present study was to establish whether this surface immunoglobulin (SIg) mediates liver cell damage. Freshly isolated hepatocytes from percutaneous liver biopsy of 16 patients with chronic active hepatitis (CAH) (6 HBsAg positive), 3 with HBsAg-positive chronic lobular hepatitis (CLH), 5 with HBsAg-positive chronic persistent hepatitis (CPH) and 12 with minor histological abnormalities (MHA) (5 HBsAg positive) were divided into two aliquots. One was studied for the presence of membrane-bound immunoglobulin and the third component of complement by direct immunofluorescence and the other was incubated, in an allogeneic cytotoxic assay, with peripheral blood mononuclear cells prepared from healthy volunteers as a source of effectors for antibody-dependent cell-mediated cytotoxicity (ADCC). Liver biopsies were scored for portal and parenchymal inflammatory activity. The percentage of SIg positive hepatocytes was significantly higher in patients with CAH (median 52.5%) than in patients with CLH/CPH (20.5%) or in patients with MHA (1%). Percentages of SIg-positive liver cells were significantly correlated with total liver biopsy scores and with both portal or parenchymal scores considered independently. SIg were found to belong to the IgG class in all groups of patients. When hepatocytes were cultured with normal human lymphocytes, allogeneic cytotoxicity values were significantly higher in patients with CAH (median 34%) than in patients with CLH and CPH (18%) or in those with MHA (12%). Percentage cytotoxicity was positively correlated with total biopsy scores and with portal activity but not with parenchymal activity, suggesting that ADCC might play a damaging role mainly in the portal areas. Our results show that in HBsAg-positive and in HBsAg-negative chronic liver disease IgG on the liver cell membrane is associated with increased susceptibility to in vitro cytotoxicity by killer cells and with increased severity of histological liver damage, suggesting a direct role for these antibodies in the generation of the liver injury.

The cause of cryptogenic ('seronegative') acute liver failure (ALF) is unknown; the presence of non-organ specific autoantibodies (NOSA) may indicate an autoimmune pathogenesis. We investigated the prevalence of autoimmune features including antibodies to soluble liver antigen (anti-SLA) determined by Radioligand assay (RLA) in ALF patients.The prevalence and relationship to the immunoglobulin (Ig) response of NOSA and anti-SLA were determined in 73 ALF patients of different causes. Patients were scored using the revised system for diagnosis of autoimmune hepatitis (AIH).Autoantibodies were present in 23 (32%) patients; 16 had anti-SLA, 6 ANA, 4 ASM and 1 AMA. They were absent in paracetamol-related disease and present in 23 of 53 (43%) of non-paracetamol (NP) cases (p0.0003). Two of 16 (13%) with NP drug-induced (NPDI), 9 of 21 (43%) viral and 5 of 16 (31%) cryptogenic cases had anti-SLA. NOSA and anti-SLA were not associated with liver injury severity or outcome. IgM was higher in those with viral disease (p0.00001). AIH scores classified 50% of cryptogenic cases as 'probable autoimmune hepatitis'.Autoantibodies are common in ALF; cryptogenic cases have features suggestive of an autoimmune pathogenesis. IgM is elevated in viral cases but infrequently in ALF of other causes.

A prospective study was performed to evaluate the outcome of treatment withdrawal in 30 patients with "autoimmune" chronic active hepatitis in remission for periods of 1.5 to 9 years on maintenance corticosteroid and azathioprine therapy. Reactivation of disease, with marked rises in serum aminotransferase level (mean 668 +/- S.D. 458 IU per liter) and accompanied by severe symptoms, occurred in 25 (87%) patients within 52 weeks (median 9 weeks; range 5 to 52) and was associated with the histological features of piecemeal necrosis and lobular hepatitis in all 20 liver biopsies examined. Age, sex, duration of disease and remission, presence of cirrhosis, autoantibody status, or immunoglobulin levels did not differentiate patients who relapsed from those who remained in remission. The response to reinstitution of treatment with prednisolone was satisfactory in 25 patients and clinical and biochemical abnormalities resolved within 10 weeks (median 6; range 3 to 10), death occurred in one patient within 48 hr of readmission to hospital.

We hypothesized that the hepatotoxicity that develops after the induction of oxidative stress (induced by d-galactosamine [GalN]) can be ameliorated by alpha-tocopherol (ATC) and the soy isoflavone daidzein. To test this, we ranked and assigned male Wistar rats into 6 groups, which involved pretreatment (ATC or daidzein) for 1 hour followed by treatment (GalN) for 23 hours. Histopathologic analysis showed that GalN administration induced marked necrosis (P < .001), steatosis (P < .001), both lobular and portal inflammations (P < .001), overall histopathologic score (P < .001), and activation of caspase-3 in the liver (P < .001). Immunohistochemical staining of malondialdehyde-protein adducts, a measure of oxidative stress, was increased in response to GalN (P < .001). Paradoxically, there were increases in total (P < .05) and cytosolic superoxide dismutase (P < .001) activities after GalN administration, indicative of an up-regulation of antioxidant defenses. The concentration of total protein (P < .001), albumin (P < .01), and globulin fractions (P < .001) in the plasma, as well as the activity of aspartate aminotransferase (P < .001), was significantly perturbed after GalN treatment, reflective of overall acute hepatic injury. Administration of daidzein showed a significant amelioration of the Ga1N-induced increase in malondialdehyde-protein adducts (P < .01) and cytosolic superoxide dismutase activities (P < .01) in the liver. However, all other variables were not significantly altered in response to daidzein. In response to ATC pretreatment, the total histopathologic score (P < .05), degree of necrosis (P < .05), and both lobular (P < .05) and portal (P = .05) inflammations were significantly ameliorated. To conclude, both daidzein and ATC protect the liver against oxidative damage possibly via different pathways.

A few reports have suggested that AIH may be less severe in the elderly and may be underdiagnosed, but there is a paucity of data.We have undertaken a systematic analysis of 164 consecutive patients (36 males, 128 females) with definite AIH (median score 23, range 18-28) attending our clinics, comparing those presenting at age60 years (Group 1, n=43) with those presenting at60 years (Group 2, n=121).Median (range) duration of follow-up was 9 years (1-28) in Group 1 and 14 years (1-33) in Group 2. Median ages (ranges) at presentation were: Group 1=65 (60-79) and Group 2=41 (6-59). Group 1 patients had a significantly increased incidence of ascites at presentation (p0.001) and a lower incidence of relapse (42% vs. 70%, p=0.002), but there were no significant differences between the groups with respect to mode of onset (acute, insidious, asymptomatic), other clinical signs at presentation, biochemical parameters, types or titres of autoantibodies, incidence of histological cirrhosis, response to therapy or related side effects. There were also no significant differences in liver-related deaths or transplantation, or the frequencies of HLA DR3 or DR4 - although there was an increased frequency of the A1-B8-DR3/4 haplotype in Group 2 (40% vs. 22%, p=0.138).These findings suggest that AIH often presents in older patients, who frequently have severe disease. Active management in these patients can lead to a normal life expectancy.

Background/Aims The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm. Methods We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6–22) months. All these children were treated in the 6TG-arm. Results The median (range) age at presentation was 6.6 (3.2–11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80IU/l, normal range 10–50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4–36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children. Conclusions 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.

Patients infected with HIV-1 who are heterozygous at HLA class I loci present greater variety of antigenic peptides to CD8+ cytotoxic T lymphocytes, slowing progression to AIDS. A similar broad immune response in chronic hepatitis C (CHC) infection could result in greater hepatic injury. Although specific HLA class II alleles may influence outcome in CHC patients, the role of HLA class I heterogeneity is generally less clearly defined. Our aims were to determine whether HLA class I allelic diversity is associated with disease severity and progression of fibrosis in CHC. The study population consisted of 670 adults with CHC, including 155 with advanced cirrhosis, and 237 non-HCV-infected controls. Serological testing for HLA class I antigens was performed via microlymphocytotoxicity assay. Peptide expression was defined as heterozygous (i.e., a different allele at each locus) or homozygous. Fibrosis staging was determined using METAVIR classification. Heterozygosity at the B locus (fibrosis progression rate [FPR] 0.08 vs. 0.06 units/yr; P = .04) and homozygosity at the A locus (FPR 0.10 vs. 0.08 units/yr; P = .04) predicted a higher median FPR. Age at infection, genotype, and duration of infection were also predictors of FPR. A higher proportion of patients with stage F2-F4 expressed HLA-B18 compared with controls (OR 2.2, 95% CI 1.17-4.23; P = .02). These differences were not observed in patients with advanced cirrhosis. HLA zygosity at 1, 2, or 3 alleles was not associated with fibrosis stage, liver inflammation, or treatment outcome. In conclusion, HLA class I allelic diversity has a minor influence on FPRs and disease severity in CHC.

Background Orthotopic liver transplantation (OLT) plays a pivotal role in the management of selected patients with initial hepatocellular carcinoma (HCC). After disappointing early results and a shortage of cadaveric grafts, patients are currently selected for OLT on the basis of tumour size and number. Limitations of these criteria and the advent of living donation have prompted their re-evaluation. The principal aims of this review were to define the limitations of current transplant criteria for HCC, and to identify potential areas for improvement. Methods A Medline search using the terms ‘liver transplantation’ and ‘hepatocellular carcinoma’ was conducted. Additional references were sourced from key articles. Results and conclusion In patients with HCC, biological properties of the tumour are more accurate than radiological criteria in determining outcome after transplantation. Despite the risks of tumour biopsy, which may have been previously overstated, histological evaluation before transplantation may have a role and warrants further study. By expanding the donor pool and eliminating waiting times, live donor liver transplantation is a valuable resource that has yet to fulfil its potential because of unresolved ethical issues concerning the safety of the donor. The availability of long-term outcome data may help to clarify this in the near future.

Background Steroid-resistant rejection (SRR) results in significant morbidity and mortality from the adverse effects of rescue therapy and in graft loss from chronic rejection. In our knowledge, the efficacy and safety of anti–interleukin (IL) 2r antibodies (daclizumab and basiliximab) for the treatment of SRR in adult liver transplantation has not previously been evaluated. Methods Twenty-five patients received either daclizumab or basiliximab as rescue therapy for SRR. Outcome and biochemical parameters were recorded before and after treatment with an anti–IL-2r antibody. Results The median time from transplantation to SRR was 25 days. Secondary immunosuppression included mycophenolate mofetil in 18 patients. Twelve patients (48%) had complete resolution of SRR. Aspartate transaminase levels normalized at a median of 37 days (range, 1–168 days). In 13 patients (52%) progressive hepatic dysfunction developed. Four of these patients received another transplant, and 6 patients had chronic rejection. Three patients died with graft failure. Of 16 patients with acute cellular rejection, 12 (75%) had resolution, 2 had chronic rejection, 1 required a repeat transplantation, and 1 died with graft failure. In contrast, all 9 patients with established chronic rejection in their pretreatment biopsy continued to have significant graft dysfunction, with 4 having persistent chronic graft dysfunction, 3 requiring repeat transplantation, and 2 dying with graft failure. Conclusion Twelve (48%) of 25 patients who received an anti–IL-2r antibody because of SRR were successfully treated. All successfully treated patients had ongoing acute cellular rejection at liver biopsy (75%), whereas patients with histologic evidence of chronic rejection responded poorly.

Objective To investigate clinical features and to establish optimal management in children with primary immunodeficiency (PID) and liver disease. Study design A retrospective analysis of medical records of 147 children with PID who presented with abnormal liver tests to a tertiary center. Results Clinical evidence of liver disease was documented in 35 (23.8%) patients. Of these, 22 (63%) had hepatomegaly and 14 (40%) had splenomegaly. Sclerosing cholangitis (SC) was diagnosed in 21 children (60%), based on radiological and histological criteria; 4 patients with SC on cholangiography had no biliary changes in the liver biopsy. Ultrasonography demonstrated a dilated biliary system in 14 (67%) children with SC. Of 27 children investigated for Cryptosporidium parvum (CSP), 12 (44%) were positive, including 9 of 12 with SC. Overall, 7 (20%) patients died, including 3 boys with disseminated recurrent CSP infection after successful liver transplantion (LT). Temporary deterioration of liver injury was observed in 2 CSP-positive boys with CD40 ligand deficiency (CD40LD) who were undergoing nonmyeloablative hematopoietic stem cell transplantation (HSCT). Successive liver and HSCT was curative in 1 patient with CD40LD and end-stage liver disease. Conclusion SC is the most common hepatic complication of PID. Mild liver involvement could be arrested by early nonmyeloablative HSCT, whereas advanced disease may warrant combined liver and HSCT.

Sclerosing cholangitis (SC) is a heterogeneous disease entity. Different etiologies such as choledocholithiasis, biliary tumor, or pericholangitis can manifest as SC. Hepatic inflammatory pseudotumor (IP) is rarely associated with SC (sclerosing cholangitis associated with hepatic inflammatory pseudotumor; SC-hepatic IP), but sclerosing pancreatitis (SP) is not infrequently associated with bile duct lesions (sclerosing pancreatitis-associated sclerosing cholangitis; SP-SC). In this study, we compared the histologic changes of hepatic hilar and extrahepatic bile duct lesions of SC (7 cases), SC-hepatic IP (5 cases), SP-SC (5 cases), and typical primary sclerosing cholangitis (PSC) (5 cases). Histologically, all SP-SC cases showed extensive and dense fibrosis with marked lymphoplasmacytic infiltration, many eosinophils, and obliterative phlebitis. Four cases of SC showed bile duct lesions similar to those of SP-SC, whereas other three cases of SC showed milder lymphoplasmacytic infiltration, scant eosinophilic cell infiltration, and no obliterative phlebitis. All SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC. Immunohistochemically, many IgG4-positive plasma cells were found in the bile duct lesions of all SP-SC cases, 4 SC cases with marked lymphoplasmacytic infiltration, and all SC-hepatic IP cases. By contrast, IgG4-positive plasma cells were scarce or hardly found in the remaining 3 SC cases and all PSC cases. In conclusion, 4 SC cases and all SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC, suggesting that these three conditions may be a single disease entity. Their pathogenesis may be similar or closely related to that of SP, and in that respect they may represent an IgG4-related biliary disease. They may respond to steroid therapy as SP does.

There is no accurate method to determine the functional significance of bile duct strictures after liver transplantation, and although biliary reconstructive surgery (Roux-en-Y hepaticojejunostomy, HJ) is the second-line treatment in patients with persistent allograft dysfunction following failed endoscopic therapy, there is no evidence to support this approach. Liver transplant recipients with allograft dysfunction and demonstrable bile duct strictures who had undergone hepaticojejunostomy were identified from a prospective database. Preoperative and follow-up clinical, biochemical, and radiological data were collected. Perioperative liver biopsies were evaluated prospectively by two histopathologists blinded to clinical information. The biopsies were scored according to presence and severity of biliary features, fibrosis, and coexisting diseases. The effects of preoperative factors on postoperative allograft function were analyzed using SPSS statistical software. After hepatico-jejunostomy, graft function returned to normal in 8/44 patients (18%), improved in 16/44 (36%), but remained abnormal in 20/44 (45%), including 4 patients who subsequently underwent retransplantation. Hepaticojejunostomy was more likely to yield a favorable outcome (improved or normal graft function) when performed within 2 years of transplantation. Prolonged duration of biliary obstruction was associated with development of advanced graft fibrosis at the time of surgery, but neither factor significantly influenced postoperative graft function. In conclusion, biliary reconstruction successfully restores graft function in the majority of patients who present with anastomotic strictures within the first 2 years after liver transplantation. In patients presenting with bile duct strictures late after transplantation, surgery should be reserved for selected patients without histological evidence of graft fibrosis (moderate-severe) or significant nonbiliary pathology.

Dehydrated hereditary stomatocytosis (DHSt) is an inherited haemolytic anaemia associated with increased red cell membrane permeability to Na(+) and K(+). It is increasingly recognized that a syndrome of self-limiting perinatal ascites can accompany the haemolysis. The cause of the perinatal ascites is unknown, and it has been argued that this could be due to cardiovascular, hepatic or lymphatic problems. We describe the case of a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. She was extensively investigated at that time. A liver biopsy showed hepatitis and fatty changes. Her ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute haemolysis and was re-investigated. A diagnosis of DHSt was made. Pseudohyperkalaemia, due to ex vivo loss of K(+) from red cells, was present. This study confirms the previously noted association of DHSt, pseudohyperkalaemia and perinatal ascites, and suggests that the latter is of predominantly hepatic origin.

Background There is a detrimental effect of increasing age on the results of the Kasai portoenterostomy for biliary atresia (BA), and some centers routinely advocate primary liver transplantation for the older infant, irrespective of other criteria. This perception that such infants are indeed irretrievable was tested by retrospective analysis. Methods All infants who had undergone surgery for BA during the period 1980 through 2000 aged ≥100 days were reviewed. Actuarial survival was calculated using 2 end-points (death and transplantation). A retrospective review of their ultrasonography (n = 12) and preoperative liver histology (n = 22) was also undertaken to ascertain possible predictive criteria. Results A total of 422 infants had BA diagnosed during this period, of which 35 (8.2%) were ≥100 days at surgery (median [interquartile range], 133 [range, 108 to 180] days). Surgery included portoenterostomy (n = 26), hepaticojejunostomy (n = 7), and a resection and end-to-end anastomosis (n = 1). A laparotomy only was performed in 1. Five- and 10-year actuarial survival rate with native liver was 45% and 40%, respectively. Currently, 12 (35%) patients are alive with their native liver (8 are anicteric), 9 (28%) have undergone transplantation, and 13 have died. Although there were some survival advantages for types 1 or 2 BA and “noncirrhosis” at time of surgery, neither reached statistical significance. Individual histologic features (eg, degrees of fibrosis, giant cell transformation, bile duct destruction) in the retrospective review of available material were not discriminatory. The finding of a “heterogeneous” parenchyma on ultrasonography was predictive of poor outcome but lacked sensitivity. Conclusions The potential for reasonable medium-term survival is present in about one third of infants 100 days or older coming to primary corrective surgery. In the absence of accurate discrimination, the authors continue to favor this option rather than subject all to transplant simply on the basis of age.

Background/Aims In routine examination of liver biopsies isolated ductular hyperplasia (IDH) may be the only histopathological change. Here we describe the clinical and immunophenotypic features of a number of cases retrospectively identified reviewing consecutive liver biopsies from five Italian centers over 4 years. Methods We reviewed 1235 cases biopsied for chronic liver disease (1078 for viral hepatitis). Records of cases fulfilling the inclusion criteria for IDH were reviewed to identify possible aetiologies. Biopsies showing IDH and control biopsies were studied by immunohistochemistry for cytokeratin-7, epithelial-membrane-antigen (EMA), neural-cell-adhesion-molecule (NCAM), Ki-67. Results Out of 70 biopsies fulfilling IDH criteria, 16 (22.8%) were of unknown aetiology. Patients with idiopathic IDH (age 38.2±11 years) were asymptomatic with mild, long-lasting ALT and/or γGT increases. A significant increase of well-differentiated (EMA-positive; NCAM-negative) bile ductules localized at the portal interface and inside the lobule was found in idiopathic IDH. Conclusions Idiopathic IDH was present in 10% of adults biopsied for persistent mild liver function test abnormalities unrelated to viral hepatitis. In contrast with the ductular reaction seen in many forms of liver disease, it is characterized by well-differentiated hyperplastic ductules in absence of significant inflammation, and may represent a non-specific pattern of reaction to mild liver damages.

Patients with cryptogenic cirrhosis (CC) comprise a significant proportion of liver transplant recipients. Poor outcome after transplantation has been reported by some centers, with fibrosis occurring in a significant proportion of patients. Outcome of 46 patients with CC who underwent transplantation between 1989 and 1999 at King's College Hospital London were compared with time-matched recipients who underwent transplantation for hepatitis C virus (HCV) cirrhosis (n = 58) and patients with alcohol-related cirrhosis (AC, n = 53) during the same time period. Mean follow-up was 46 ± 37 months for CC patients, 41 ± 31 months for AC patients, and 49 ± 31 months for HCV patients. No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities. Acute cellular rejection occurred in 30% of CC, 26% of AC, and 37% of HCV patients (P = NS). Overall patient and graft survival at 1 year was 85% and 80% for CC patients, 87% and 81% for AC patients, and 91% and 82% for patients with HCV (P = NS). Five-year patient and graft survival was 81% and 77% for CC patients, 60% and 48% for AC patients, and 79% and 57% for HCV patients (Log rank; P = .369). Twenty-two percent of CC patients had inflammation on last evaluable liver biopsy, compared with 25% of patients who underwent transplantation for AC and 68% of patients who underwent transplantation for HCV. No patient who underwent transplantation for CC had histologic evidence of cirrhosis on last evaluable biopsy, compared with 2% of patients who underwent transplantation for AC and 16% of patients who underwent transplantation for HCV (Chi-squared = 13.053, P = .0015). These results suggest that CC is a favorable indication for OLT and that although a proportion of patients develop inflammation in the liver allograft, this does not result in significant graft dysfunction or loss. (Liver Transpl 2003;9:921-928.)

Aims: Combined hepatocellular ⁄ cholangiocarcinomas have been explained by some investigators as bidirectional differentiation of neoplastic progenitor cell populations. The presence of hepatic progenitor cells has now been confirmed in humans, though whether they can give rise to malignant tumours has not been confirmed. We report four cases of small tumours identified in livers with features of chronic hepatitis which may suggest a role for malignant transformation of hepatic stem cells in hepatic malignancies. Methods: Tumour samples were studied from four patients by histochemistry and immunohistochemistry. Results: Two patients had chronic hepatitis B, one had chronic hepatitis C and chronic alcoholic liver injury, and one had non-B non-C chronic hepatitis. Stages of disease ranged from portal fibrosis to cirrhosis. All tumours contained undifferentiated cells with morphological and immunohistochemical features that would be expected of hepatic progenitor cells. These cells merged with both hepatocellular carcinoma and cholangiocarcinoma components as well as with mature appearing hepatocytes within the tumours. Conclusion: We suggest that these tumours are of hepatic progenitor cell origin, supporting the concepts that human hepatocarcinogenesis can be based on transformation of progenitor cells and that such a process may underlie development of some mixed hepatocellular ⁄ cholangiocarcinomas and dysplastic nodules.

To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression.A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4).The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10-0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07-0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p0.001). A CD4 cell countor =250 x 10(6)/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26-22.79)) and was also correlated with a higher histological index (r=-0.42, p=0.002).HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.

Objective The natural history of hepatitis C virus (HCV) infection in patients with normal liver biochemistry remains poorly characterized. We performed a retrospective review of patients with chronic HCV infection and persistently normal ALT to compare clinical and histological features with those in patients with abnormal liver biochemistry. Methods Ninety-one HCV RNA-positive patients with persistently normal ALT who had a liver biopsy between 1993 and 1999 were identified. Clinical, histological, and epidemiological features in this group were compared with those found in 94 patients with abnormal ALT. Biopsies were assessed using Ishak’s scoring system and fibrosis progression rate calculated from the likely time of infection. Results Although overall necroinflammatory score and fibrosis were significantly lower in those with normal ALT, none had normal liver histology, and 15 (16%) patients with normal ALT were found to have significant necroinflammation with a score of 5 or greater and/or significant fibrosis staged at 3 or 4. No clinical, epidemiological, or virological predictors of severe histological disease were found. Conclusions One in six patients with HCV infection and persistently normal ALT will have evidence of significant, progressive liver disease that can only be identified on liver biopsy.

Background Antimitochondrial antibody-negative primary biliary cirrhosis, or autoimmune cholangitis, may be indistinguishable clinically and histologically from antimitochondrial antibody-positive primary biliary cirrhosis. Aims We aimed to compare the phenotypic markers of the portal and acinar infiltrates in autoimmune cholangitis and antimitochondrial antibody-positive primary biliary cirrhosis. Patients and methods Formalin-fixed, paraffin-embedded liver sections were identified from 32 patients with a clinical and histological diagnosis of primary biliary cirrhosis. Thirteen were antimitochondrial antibody-negative (autoimmune cholangitis group) and 19 were antimitochondrial antibody-positive. The groups were well matched for age, histological stage, liver biochemistry and drug treatment. Immunohistochemical staining was performed using monoclonal antibodies against CD3 (pan T cell), CD8 (cytotoxic), CD45RO (memory), CD45RA (naive), CD68 (macrophages) and against the secreted form of eosinophilic cationic protein (EG2). Results In autoimmune cholangitis, both portal and acinar CD3 cell counts were significantly higher than in antimitochondrial antibody-positive primary biliary cirrhosis (median portal count 421 vs 257 cells/graticule, P < 0.03; median acinar count 18 vs 9 cells/graticule, P < 0.02). There were no differences between the groups in portal or lobular CD8, CD45RO, CD45RA, CD68 or EG2. Of the total group (antimitochondrial antibody positives and negatives), there were significantly more CD45RA cells in early (stage 1) compared with cirrhotic (stage 4) disease (median 19.3 vs 14 cells/graticule, P < 0.03). EG2 staining was found in eight of the 32 sections overall, but not in the patients with stage 1 disease (P< 0.04). Conclusion CD3 counts are higher in autoimmune cholangitis than in antimitochondrial antibody-positive primary biliary cirrhosis in both portal and acinar areas. However, there are no significant differences in memory/ naive T-cell subsets between both conditions and, in both, loss of naive T lymphocytes and secretion of eosinophilic cationic protein occur with disease progression. This implies that the effector pathways of bile duct destruction are similar in autoimmune cholangitis and primary biliary cirrhosis.

Auxiliary partial orthotopic liver transplantation is an alternative therapeutic modality in acute liver failure, wherein the capacity of native liver to regenerate is preserved. A case of acute liver failure due to hepatitis B in an 18-year-old male patient treated with an auxiliary left lateral segment graft is described. There was no recurrence of hepatitis B in the auxiliary graft and the patient cleared the virus after 9 months whilst receiving lamivudine. Immunosuppression was withdrawn at 14 months, and the auxiliary graft atrophied secondary to hepatic arterial conduit thrombosis, possibly precipitated by immunosuppression withdrawal. The native liver regenerated completely, and the patient is well and off immunosuppressive and antiviral therapy 3 years after transplantation. Auxiliary partial orthotopic liver transplantation is an attractive treatment option in acute liver failure due to hepatitis B infection and allows a life free of long-term immunosuppression.

Prevalence and clinical relevance of antibodies to soluble liver antigen (tRNP((Ser)Sec)/SLA) in autoimmune hepatitis (AIH) have been investigated using partially purified or prokaryotically expressed antigen. The aim of this study was to improve the detection of anti-tRNP((Ser)Sec)/SLA by establishing an immunoassay that was able to identify antibodies directed to conformational epitopes and to investigate the clinical implication of this autoantibody in autoimmune liver disease. By using eukaryotically expressed tRNP((Ser)Sec)/SLA as target in a radioligand assay (RLA), 81 patients with autoimmune liver disease (AILD) (33 type 1 AIH, 31 type 2 AIH, and 17 autoimmune sclerosing cholantitis [ASC]), 147 pathologic, and 56 healthy controls were investigated. RLA results were compared with those obtained using a commercial enzyme-linked immunosorbent assay (ELISA) and immunoblot. Reactivity to tRNP((Ser)Sec)/SLA was present in 58% of patients with type 1 and type 2 AIH, 41% with ASC, but in only 3 pathologic controls. RLA was similarly disease-specific but remarkably more sensitive than ELISA and immunoblot. A prospective study showed that anti-tRNP((Ser)Sec)/SLA-positive patients run a severe clinical course, having worse histology, needing longer to achieve remission, relapsing and requiring liver transplantation or dying more frequently than anti-tRNP((Ser)Sec)/SLA negative patients. Anti-tRNP((Ser)Sec)/SLA production was favored by the possession of DR3 and A1-B8-DR3 in AIH type 1 and ASC, and prevented by the possession of A2 in all 3 types of AILD, particularly in type 2 AIH. In conclusion, anticonformational tRNP((Ser)Sec)/SLA reactivity is frequent in type 1 and type 2 AIH and ASC, defining patients with a worse prognosis.

Background. Budd-Chiari syndrome (BCS) is a clinical condition characterized by hepatic venous outflow obstruction secondary to an underlying systemic predisposition to thrombosis. Methods. We reviewed our experience of 19 adult patients who underwent orthotopic liver transplantation for BCS from April 1988 to May 1999 to assess their long-term outcome and specific complications related to this procedure. Results. Of these patients, 13 presented with chronic and 6 with acute liver failure. At presentation predisposing factors included polycythemia rubra vera in five, an undefined myeloproliferative disorder in four, essential thrombocythemia in two, presence of lupus anticoagulant in one, antiphospholipid antibody positivity in one, postgestational in one, oral contraceptive pill in one, and idiopathic in four. Five patients had undergone previous porto-systemic shunt. Of the 19 patients, 16 are alive at a median follow-up of 89 months (range 1-119) with 2 patients developing disease recurrence at 4 months and 7 years posttransplant, respectively. Four patients have been retransplanted: one for progressive graft dysfunction due to nodular regenerative hyperplasia secondary to azathioprine toxicity, two for hepatic artery thrombosis (one soon after and the other 47 months posttransplant), and one for recurrent BCS. Three patients have died: one from an intra-abdominal bleed secondary to acute hemorrhagic pancreatitis 8 years posttransplant, another from acute myeloid leukemia at 6 years posttransplant, and the third patient from graft failure secondary to severe rejection 1 month posttransplant. Conclusion. Liver transplantation for BCS provides good long-term survival with acceptable morbidity. Long-term survival may be prejudiced by progression of the underlying hematological disorders.

Anti-mitochondrial antibody is the diagnostic hallmark of primary biliary cirrhosis. Its role in the aetiology of primary biliary cirrhosis is controversial.Two cases of neonatal hepatitis seropositive for anti-mitochondrial antibody are described. Anti-mitochondrial antibody Ig isotype and epitopic specificity were investigated by immunofluorescence and enzyme immunoassays.In both infants anti-mitochondrial antibody was of the G class, mainly G1 and G3 subclasses, and reacted with two synthetic peptides reproducing major M2 epitopicregions: innerlipoyl domain pyruvate dehydrogenase complex (PDC)-E2(162-176) and PDC-E3 binding protein (PDC-E3BP)86-100. One infant also reacted with outer lipoyl domain PDC-E2(35-49), and 2-oxoglutarate dehydrogenase complex (OGDC)-E2(99-113). An identical pattern of reactivity was present in their mothers, indicating the maternal origin of the antibodies. Anti-mitochondrial antibody disappeared in the infants with the disappearance of the liver pathology.The simultaneous disappearance of hepatitis and anti-mitochondrial antibody in the infants suggests a possible causal link between the two.

In children, a type of graft dysfunction associated with autoimmune features has been described. We have identified 7 adult liver-transplant (LT) recipients from a series of over 1,000 consecutive transplant recipients who presented between 0.3 years and 7.2 years following transplantation with characteristic symptoms, autoantibody profiles, and histologic findings of autoimmune disease. The indications for transplantation were Ecstasy overdose, alcohol-related cirrhosis, primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis (PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns of de novo autoantibody development were noted; anti–liver-kidney-microsome (LKM) antibody development at high titer in association with an aspartate transaminase (AST) > 500 and antinuclear (ANA) and antismooth muscle (AMA) antibody development at titers >1/80 with lower AST levels. All cases had elevated IgG. Liver biopsies showed changes of an autoimmune-type hepatitis with portal and periportal hepatitis in association with a marked infiltrate of plasma cells, lymphocytes, and bridging collapse. Two patients lost their grafts because of the disease. Patients were treated with reintroduction of steroids and azathioprine in cases in which it had been withdrawn. Major histocompatibility class I and II mismatching did not incur risk. Eight of 12 liver allografts were acquired from either DRB*0301- or DRB*0401-positive donors, and 4 recipients were DRB*0301-positive. This series illustrates that both symptoms and histologic findings of graft dysfunction compatible with autoimmune hepatitis (AIH) exist in adult LT recipients. Graft loss may be a consequence. This entity may represent a specific type of rejection that should currently be classified as “graft dysfunction mimicking autoimmune hepatitis.” (HEPATOLOGY 2001;34:464-470.)

Background/aims Haematological malignancies seldom cause clinically significant liver disease. Acute liver failure as the initial manifestation of acute leukaemia is very rare and carries a very poor prognosis. Methods/results Three cases of acute liver failure secondary to acute leukaemia are described. Each case presented initially as acute liver failure of uncertain cause. Specific treatment for the leukaemia was instituted; however, all three patients died as a consequence of the liver failure. We describe the clinical course and relevant investigations of these patients and discuss possible mechanisms of acute liver failure in this setting. Conclusion Acute leukaemia presenting as acute liver failure has a very poor prognosis. Although a rare cause of acute liver failure, it should be considered in any patient presenting with acute liver failure with prodromal symptoms and a raised peripheral white cell count, lactate dehydrogenase and uric acid.

Alpha-1-antitrypsin deficiency (alpha1ATD) is the commonest metabolic disease leading to liver transplantation (LT) in children. Approximately 10-15% of the PiZZ population develops liver disease. Five percent of them will require LT within the first 4 years of life. This study aimed to investigate the prognosis of the liver disease associated with PiZZ alpha1ATD in the era of liver transplantation and to determine predictors of outcome.We reviewed retrospectively the clinical notes of 97 consecutive patients referred from January 1989, when LT became routinely available in our Unit, to July 1998.Of 26 (27%) patients who developed end-stage liver disease, 24 have been transplanted and two are waiting for LT. Twenty-one (81%) of these patients presented with neonatal hepatitis at a median age of 2.1 months. Of 71 (73%) children who have not required LT, 61 (86%) presented with neonatal hepatitis at a median age of 1.6 months. Among infants with neonatal hepatitis who required LT, 18 out of 21 (86%) had jaundice for more than 6 weeks compared with 34 of 61 (56%) who survived without LT (p0.01). Children requiring LT had higher aspartate aminotransferase (AST) at presentation (p0.0001) and both higher AST and gamma-glutamyl transferase (GGT) at 6 months (p0.001), 1-year (p0.0003) and 5-year (p0.01) follow up when compared to those who are well without LT. Furthermore, children who developed end-stage liver disease more frequently had severe bile duct reduplication (p0.01), severe fibrosis (p0.03) with bridging septa (p0.02) and established cirrhosis (p0.04) in the initial liver biopsy. Ninety-five of the 97 children (98%) are currently alive; two died after LT.The advent of liver transplantation has significantly improved the prognosis of liver disease associated with PiZZ alpha1ATD. Duration of jaundice, severity of histological features and biochemical abnormalities predict outcome at an early stage of the disease.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)- alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up- regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation

Two patients undergoing liver transplantation for classical end-stage primary biliary cirrhosis (PBC) are described, who went on to develop de novo autoimmune hepatitis (AIH) in the transplanted liver. The presentation, in both instances, was with malaise and lethargy. Markedly elevated serum transaminases were found, together with a raised serum IgG and/or globulin fraction and histological features on liver biopsy typical of AIH. Both cases had had changes in their immunosuppressive therapy before the onset of AIH episodes, and both rapidly responded to reinstitution of steroid therapy. The finding, in each case, of a coincidental multiple HLA class I allele match between the recipient and their liver donor suggests that HLA class I-restricted mechanisms may play an important role in the pathogenesis of AIH.

Background: The accuracy of histological assessment of frozen section (FS) of the pancreatic resection margin (PRM) at pancreatico-duodenectomy can be improved by concurrent FS examination of a sample of the suspected pancreatic lesion. Methods: A prospective trial was conducted using archived material. FS of all the PRM and suspected pancreatic lesion of 12 patients randomly selected from a historical group who underwent pancreatico-duodenectomy for suspected malignancy were examined by five histopathologists. They were asked to examine the PRM alone and alongside the suspected lesion. The diagnosis of the PRM was ‘benign’, ‘malignant’ or ‘defer to paraffin section’. All the histopathologists were blinded to the paraffin section diagnosis. Results: The main outcome measures were sensitivity, specificity and the incidence of deferring to paraffin section. In this respect examination of the PRM alone had a sensitivity of 70% and a specificity of 87.5%. Concurrent FS examination of PRM with the pancreatic lesion increased the sensitivity to 90% and the specificity to 92.5%. The incidence of deferring to paraffin section was reduced from 17 to 7% (P = 0.03). Conclusion: This policy is recommended because it improves the diagnostic accuracy of FS evaluation of the PRM resulting in a reduction of residual pancreatic cancer at the pancreatic transection line.

In cirrhosis, as in other conditions of protein catabolism, there is a state of acquired GH resistance, as defined by high circulating GH levels with low insulin-like growth factor I levels. However, patients with end-stage liver failure respond to supraphysiological doses of GH with an increase in circulating insulin-like growth factor I levels. The present study represents a detailed analysis of GH receptor (GHR) expression in cirrhotic liver from 17 patients with end-stage liver disease. Specific binding of labeled GH was identified in all cirrhotic livers studied. The binding affinity for the GHR was similar in cirrhotic and normal livers, but the number of binding sites per mg protein of liver membrane was variable in both normal and cirrhotic liver, although it were generally lower in cirrhotic liver. GHR expression was identified in cirrhotic liver by Northern blotting, RT-PCR, and ribonuclease protection assay. On Northern blotting, a single transcript of 4.8 kb was identified in normal and cirrhotic tissues. RT-PCR identified expression of both full-length GHR and a truncated form of the GHR; this was confirmed by ribonuclease protection assay. In situ hybridization and immunohistochemistry confirmed the expression of GHR in regenerating hepatocytes and isolated cells in fibrous tissue. In conclusion, 1) the low level of GHR in cirrhotic liver may contribute to the acquired GH resistance found in cirrhotic patients; 2) the reduced expression of both full-length and truncated GHR is compatible with the low level of GH-binding protein found in cirrhosis, as this truncated receptor has previously been reported to generate large amounts of GH-binding protein; and 3) the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to supraphysiological doses of GH.

Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-alpha) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-alpha (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-treated patients (21%; P=.05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P=.43) or the ribavirin (P=.96) group. Posttreatment viremia levels were significantly reduced in IFN-alpha-treated (P=.05) but not in ribavirin-treated (P=.88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to < 10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P=.02 and P=.004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-alpha retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.

Background/Aims: Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60–80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options. Methods: CD20/CF45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in situ hybridisation for Epstein-Barr virus genome detection; κ/λ immunostaining and gene rearrangement analysis for clonality. Results: There were six females and four males (age range 24–56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver ( n =4), lymph nodes ( n =5), bone marrow ( n =2), lungs ( n =2), kidneys ( n =2), brain, ovaries, : and pancreas ( n = 1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months. Conclusions: Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.