Childhood hepatocellular carcinoma: a clinicopathological study of 12 cases with special reference to EpCAM.

AIMS: To elucidate the characteristics of hepatocellular carcinoma (HCC) in children. METHODS AND RESULTS: A retrospective search of our database identified 12 children with HCC (aged 10 months to 11 years; male/female ratio of 5:7). Their pathological features were compared with those of adult HCCs (n = 20), fibrolamellar HCCs (n = 14), and hepatoblastomas (n = 15). All childhood HCCs developed on a background of cirrhosis resulting from tyrosinaemia type 1 (n = 4), bile salt export transporter deficiency (n = 4), biliary atresia (n = 3), and long-standing total parenteral nutrition (n = 1). HCCs in cases of tyrosinaemia type 1 always had clear cell changes, solid architecture, and only mild nuclear atypia, whereas the morphological features of HCCs in the other conditions were basically similar to those of adult HCCs. On immunostaining, all cases of childhood HCC were positive for epithelial cell adhesion molecule (EpCAM); expression was diffuse (>50% of cancer cells) in 11 cases, and particularly strong in six children, all aged <3 years. In contrast, EpCAM was only focally expressed in three cases of adult HCC (15%). EpCAM was also expressed in most fibrolamellar HCCs and hepatoblastomas, but these two neoplasms differed from childhood HCCs in the expression of CK7, ß-catenin, and p53. CONCLUSIONS: The diffuse expression of EpCAM characterizes childhood HCC, and may indicate immaturity of neoplastic cells.

Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis.

BACKGROUND & AIMS: IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition. METHODS: Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. RESULTS: In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. CONCLUSIONS: CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.

Immunoglobulin G4-related sclerosing cholangitis: pathologic features and histologic mimics.

Since immunoglobulin G4 (IgG4)-related sclerosing cholangitis was first described in 2004, this condition has been recognized as a distinct entity characterized by unique pathologic features. Affected bile ducts show diffuse wall thickening, which represents transmural sclerosing inflammation composed of a dense lymphoplasmacytic infiltrate and fibrosis arranged at least focally in a storiform pattern. A diffuse IgG4-positive plasma cell infiltrate is demonstrable by immunohistochemistry. More than 90% of patients with IgG4-related sclerosing cholangitis have type 1 autoimmune pancreatitis, the remaining presenting as isolated cholangitis. The diagnosis requires a multidisciplinary approach, in which pathologic examination has a critical role. Tissue diagnosis on biopsy specimens (ie, bile duct biopsy, liver needle biopsies) is important, particularly for patients with isolated cholangitis, given the fact that radiological findings of IgG4-cholangitis are not reliable enough for establishing the diagnosis. Furthermore, serum IgG4 levels can be, albeit mildly, elevated in other biliary disorders. Histologic mimics of IgG4-related sclerosing cholangitis include primary sclerosing cholangitis, follicular cholangitis, and sclerosing cholangitis with granulocytic epithelial lesion, the latter 2 being recently described entities.

Sclerosing cholangitis with granulocytic epithelial lesion: a benign form of sclerosing cholangiopathy.

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.

Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses.

Fibrinogen A α-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.

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.

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.

Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation.

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.

Intraductal tubulopapillary neoplasm of the bile duct: potential origin from peribiliary cysts.

We report two patients with unique biliary tumors histologically similar to pancreatic intraductal tubulopapillary neoplasm (ITPN). One patient underwent right hepatectomy for a partly cystic mass in the hepatic hilum. The other patient had liver transplantation for cryptogenic cirrhosis and multiple hilar cysts detected in the explanted liver, some obliterated by papillary nodules. Histologically both tumors consisted of intracystic non-invasive and well differentiated adenocarcinoma with a papillary and tubular architecture. Associated cysts were peribiliary cysts partly lined by carcinoma cells that were continuous with the intracystic papillotubular masses. Both tumors shared the same immunophenotype: K7(+)/K20(-)/MUC1(+)/MUC2(-)/MUC5AC(-)/MUC6(+). Genetic analysis of KRAS and BRAF revealed wild type genotypes. These pathological and genetic features are similar to those of pancreatic ITPNs. This report suggested that ITPNs may rarely develop in the bile duct seemingly in association with peribiliary cysts.

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 < 0.001); CDX2, 54% versus 0% (P = 0.003). Less commonly, intestinal-type cholangiocarcinoma showed perineural invasion (P = 0.003). Patients with intestinal-type cholangiocarcinoma had a more favourable cancer-specific prognosis than those with classical-type cholangiocarcinoma (P = 0.043). CONCLUSIONS: Bile ducts in PSC show two distinct dysplasia-carcinoma sequences as evidenced by differences in cell morphology, growth patterns, immunophenotypes and grade of malignancy.

New monoallelic (partial tandem duplication) mutation of HNF1a gene in steatotic hepatocellular adenoma.

Hepatocellular adenomas (HCAs) containing inactivating HNF1a mutations correspond to a homogenous group of tumors with marked steatosis and no cytological abnormalities or inflammatory infiltrates. We report a case of a 60-year-old woman who was referred with a 13-cm mass in the left lobe of the liver with no history of oral contraception use and no family history of note. Histology revealed a severely steatotic HCA. Immunohistochemistry showed no nuclear staining for ß-catenin, limited glutamine synthetase positivity, and slightly attenuated liver-fatty acid binding protein staining. Serum amyloid A2 antibodies produced a coarse granular staining. Mutational screening detected monoallelic partial tandem duplication within exon 4 of TCF1 in tumoral tissue. No mutations in the ß-catenin and IL6ST genes were detected. Quantitative reverse transcription PCR showed lower expression levels of FABP1 and uridine glycosyltransferase 2B7 and higher levels of serum amyloid A2 in tumor than in normal hepatocytes. Clinicopathological and molecular investigation of HCA cases with unique features could result in a better understanding of HCAs pathogenesis.

Intestinal phenotypes in pediatric gallbladder epithelium.

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 <1 year, together with the common expression of cytokeratin 20 (73%), mucin core protein 2 (93%), and caudal-related homeobox protein 2 (53%). In conclusion, intestinal features are physiologically present in gallbladder epithelium of children, particularly those aged <6 years. Intestinal metaplasia, as associated with cholangiopathy or carcinogenesis in adult patients, may represent an immature phenotype of biliary epithelium.

Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation.

We investigated the phenotype of hepatocellular carcinoma (HCC) in livers removed during transplantation after local ablation therapy by transarterial chemoembolization (TACE). This study involved 80 HCC nodules (40 treated with TACE and 40 not treated with local ablation before transplantation) observed in 64 explanted livers and included clinicopathological evaluations as well as single and double immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK19), epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), and CD133. HCCs with complete necrosis post-TACE without viable tumors were excluded from the analysis. Cholangiolar, glandular, or spindle cell areas suggestive of a mixed hepatocholangiocellular phenotype were seen in 14 post-TACE HCCs and in none of the non-TACE HCCs (P < 0.001). According to single-epitope immunohistochemistry of post-TACE HCCs, CD133, CK19, EpCAM, and NCAM were expressed in 14 (35%), 8 (20%), 12 (30%), and 8 (20%), respectively. Only EpCAM was detected in 4 non-TACE HCC cases (10%). RT-PCR experiments using tissues obtained by laser microdissection showed that 4 of 5 investigated post-TACE HCCs expressed at least 1 of the markers, which were coexpressed in 3 of 5 tumors, whereas CD133 and EpCAM were individually expressed in 2 non-TACE HCCs. Double immunostaining showed that CD133(+) cells frequently coexpressed CK19, EpCAM, or NCAM. Interestingly, the recurrence rate for patients with CD133(+) post-TACE HCC was significantly higher than the rate for patients with CD133(-) post-TACE HCC (P = 0.025). In conclusion, HCC with the combined hepatocholangiocellular phenotype appears to be more frequent in post-TACE HCC versus untreated HCC. Further studies are needed to investigate the potential relationships between TACE and HCC subpopulations with a chemoembolization-resistant phenotype and their clinical significance.

Hepatocellular carcinoma in biliary atresia: King's College Hospital experience.

OBJECTIVES: To establish risks for development of hepatocellular carcinoma (HCC) in children with biliary atresia (BA), the most common chronic liver disease of childhood. STUDY DESIGN: In our tertiary referral center database we have identified children with BA who had development of or have been incidentally found to have HCC. Their demographic, clinical, radiologic, and histologic features were analyzed. RESULTS: Between 1990 and 2008, 387 infants were diagnosed with BA at our center. Of these, three (0.8 %) who underwent operation at a median age of 68 (range 66 to 71) days had development of a histologically proven HCC detected at a median age of 2.1 (range 1.8 to 4.9) years. Another two, referred later, were diagnosed with HCC on their liver explants at ages 1.1 and 17.75 years, respectively. Overall, two had elevated serum levels of alpha-fetoprotein. All five children underwent successful liver transplantation at a median age of 2.1 years (range 1.1 to 17.75) and remain well after a median of 2.5 (range 2 to 5.7) years. CONCLUSION: HCC develops in a small percentage of children with BA. Serum alpha-fetoprotein levels and ultrasound screening are helpful but not absolute markers of the malignant change. In the absence of the extrahepatic involvement, liver transplantation represents an effective treatment.

Mucinous cystic neoplasms of the liver: a clinicopathological study and comparison with intraductal papillary neoplasms of the bile duct.

Mucinous cystic neoplasm of the liver has been a controversial entity, in particular, regarding differentiation from intraductal papillary neoplasm of the bile duct. In this study, we compared the characteristics of hepatic mucinous cystic neoplasms with ovarian-like stroma (n=29) to those of cyst-forming intraductal papillary neoplasms of the bile duct (n=12). Radiological or macroscopic appearance, histological grade of malignancy, and postoperative clinical course were recorded. Immunohistochemistry for biliary or gastrointestinal markers was performed to characterize cell phenotypes. The patients with hepatic mucinous cystic neoplasm were all female and ranged in age from 21 to 67 years, which was significantly younger than that in the patients with biliary intraductal papillary neoplasm. Eighteen mucinous cystic neoplasms (76%) were located in the left lobe, with 13 (54%) in segment IV. Mucinous cystic neoplasms were significantly larger than intraductal papillary neoplasms (median diameter: 110 vs 50 mm, P=0.008). In contrast to intraductal papillary neoplasms that were all histologically malignant, 26 mucinous cystic neoplasms (90%) were adenomas, 2 (7%) were borderline malignant, and 1 (3%) was a carcinoma in situ. Benign mucinous cystadenomas had the pure biliary immunophenotype, whereas gastrointestinal markers including cytokeratin 20 and mucin core proteins 2, 5AC, and 6 were more frequently expressed in borderline or malignant mucinous cystic neoplasms and biliary intraductal papillary neoplasms. There was no mortality in the patients with mucinous cystic neoplasm, whereas one patient with intraductal papillary neoplasm died of cancer. In conclusion, hepatic mucinous cystic neoplasms and biliary intraductal papillary neoplasms have different clinicopathological characteristics as evidenced by differences in the age and gender of patients, macroscopic appearance, immunophenotypes, and grades of malignancy.

Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis.

UNLABELLED: 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.

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.

A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency.

UNLABELLED: Alpha(1)-antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by alpha(1)-antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; alpha(1)-antitrypsin King's) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp alpha(1)-antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild-type M alpha(1)-antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp alpha(1)-antitrypsin despite the mutations directing their effects on different parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of alpha(1)-antitrypsin. CONCLUSION: Z and shutter domain mutants of alpha(1)-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure.