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S1875 Hyperferritinemia and Iron Overload in Type 1 Gaucher Disease
and AIH (n=28) cases were evaluated in a blinded fashion by 4 experienced hepatopathologists. DILI was subclassified into hepatocellular injury (HC, n=19) and cholestatic/mixed injury (CS, n=16) based on the International Consensus Criteria. The following were recorded: Ishak scores for interface hepatitis, confluent necrosis, focal necrosis, portal inflammation, and fibrosis; predominant inflammatory cell types in portal and intra-acinar areas; presence or absence of emperipolesis, rosette formation and cholestasis. Multiple logistic regression models with ROC curves were used to assess the performance of histologic features in the diagnosis of AIH vs. DILI(HC) and AIH vs. DILI(CS). Results.In 46% of cases, there was 100% agreement of the 4 pathologists and no case of AIH was diagnosed as DILI by the pathologists. 22 cases (35%) were diagnosed as indeterminate or different diagnosis: 2 (12.5%) DILI(CS) and 3 (15.8%) DILI(HC) cases were histologically diagnosed as AIH. In AIH vs. DILI(HC), interface hepatitis, focal necrosis and portal inflammation were present in all cases with AIH and DILI(HC) but were more severe in AIH (ps<0.05). Portal plasma cells (86% vs. 32%; p=0.0002), intra-acinar plasma cells (68% vs. 21%; 0.002), rosette formation (75% vs. 38%; p=0.014), and emperiopolesis (75% vs. 31%; p=0.009) were features that favored AIH. A model of the combination of focal necrosis, portal inflammation, fibrosis, emperiopolesis, portal plasma cells, and intra-acinar lymphocytes yielded an area under the ROC curve (AUC) of 0.90 in predicting DILI(HC) vs. AIH. In AIH vs. DILI(CS), all Ishak scores were more severe in AIH (ps≤0.05). Rosette formation (75% vs. 31%; p= 0.005), emperiopolesis (75% vs. 38%; p=0.014), portal plasma cells (86% vs.25%; p= 0.0001), and intra-acinal plasma cell (68% vs. 19%; p=0.002) were more prevalent in AIH; portal neutrophils (3.6% vs. 31%; p=0.01) and intracellular cholestasis (7% vs. 38%; p= 0.012) were more prevalent in DILI(CS). The combination of interface hepatitis, portal plasma cells, portal neutrophils, and intracellular cholestasis yielded an AUC of 0.90 in predicting DILI(CS) vs. AIH Conclusions.While overlap of histologic findings exists for AIH and DILI, pathologists can utilize combinations of lesions to suggest the correct diagnosis.
Clinical Significance of Cd38-Positive Plasma Cells Surrounding Interlobular Bile Ducts in Primary Biliary Cirrhosis (PBC) Toru Takahashi, Tomofumi Miura, Junichiro Nakamura, Satoshi Yamada, Tsutomu Miura, Masahiko Yanagi, Hiroyuki Usuda, Iwao Emura, Merrill E. Gershwin Background/Aims: There has been increased interest in the potential role of B cells and antimitochondrial antibodies in PBC. Indeed a new paradigm in PBC includes the potential of B cells to act as both regulatory elements and as components of the inflammasone induced by apoptosis of biliary cells. We submit that a rigorous dissection of the inflammatory infiltrate in PBC will provide further insight on these issues. Materials and Methods: We took advantage of well-characterized Mabs to CD3, CD4, CD8, CD20, CD38, CD56, CD68, and pan-keratin antigens, and immunohistochemistry (IHC), to study the distribution of liver infiltrating CD38-positive plasma cells in 26 consecutive patients with PBC (AMA positive in 20 and negative in 6), all of whom had detailed staged clinical data. All data was “blindly” evaluated. We simultaneously studied 10 age- and gender-matched patients with chronic hepatitis C as a control. Results: Noteworthy within the IHC data was the presence of an intense coronal arrangement (CR) of CD38-positive cells around interlobular bile ducts, generally in specimens with chronic non-suppurative destractive cholangitis (CNSDC). In contrast, CD20-positive B lymphocytes (precursor cells of plasma cells) were found scattered and/or aggregated within the lymphoplasmocytic infiltration. Such CD20positive B cells also occasionally formed follicle-like aggregations but importantly were not observed in the proximity of CNSDC. PBC patients with CR demonstrated significantly higher titers of AMA (119.5±16.1 vs. 59.7±17.1, p=0.018) and lower levels of total cholesterol (TC) (195.1±9.0 vs. 223.6±9.6, p=0.04) than those without CR. Interestingly the CR correlated with titer of AMA (r=0.46), IgM (r=0.32), the presence of CNSDC (r=0.32) and inversely with age (r=-0.37), γ-GTP (r=-0.38) and TC (r=-0.41). In contrast, CD4- and CD8-positive T lymphocyte infiltration was noted either in proximity of, or within the degenerated cholangioepithelium, suggesting the participation of these cells in the destructive processes of interlobular bile ducts. No CR was found in control subjects. Conclusion: The presence of CD38+ plasma cells surrounding biliary epithelium has clinical and serologic significance; further it correlates with disease progression exemplified by TC decrease and the development of florid duct lesions. These data further highlight the functional significance of B cells/ plasma cells; it also reflects a multilineage loss of tolerance in PBC. We submit that study of B cells in PBC should go beyond simple measurement of AMA titer and include rigorous phenotypical and functional dissection of the liver specific B cell lineage populations.
S1874 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis Einar Bjornsson, Jayant A. Talwalkar, Sombat Treeprasertsuk, Patrick S. Kamath, Naoki Takahashi, Keith D. Lindor Background: Drug-induced autoimmune hepatitis (DIAIH) has been reported to be caused by several drugs. It is not known how common this condition is among patients with well characterized autoimmune hepatitis (AIH). There is also a lack of data comparing these patients with other patients with AIH. We aimed to compare clinical features, histology, treatment responses and the prognosis in patients with DIAIH vs. patients with AIH not induced by drugs. Method: A search was performed using computerized diagnoses database in a single institution for AIH patients and DIAIH patients identified over ten years. Individuals with overlap syndromes and decompensated liver disease were excluded. Results: Overall 261 patients (204 females, median age 52) were identified, and 24 (9.2%) were considered to be DIAIH cases with a median age of 53 years (IQR 24-61). Two drugs, nitrofurantoin (n=11) and minocycline (n=11) were the main causes. A similar proportion of DIAIH patients had positive antinuclear antibodies (83% vs. 70%) and smooth muscle antibodies (50% vs. 45%) as compared to AIH patients. IgG levels (normal <1500 g/L) were 1905 (1600-2455) vs. 2020 (1618-2702) (p=NS) in DIAIH and AIH patients, respectively. Histological grade and stage were similar in patients with DIAIH vs. AIH but none of the DIAIH patients had cirrhosis at baseline; this was present in 13% of the other AIH cases. Liver imaging was normal in all minocycline cases. 8/11 (73%) of nitrofurantoin patients had abnormalities on hepatic imaging (mainly liver atrophy) a finding seen in only 8/33 (24%) of a random sample of the rest of the AIH group (p=0.0089). Corticosteroid responsiveness was similar in DIAIH and the AIH patients. Discontinuation of immunosuppression was tried in only 14/24 (58%) but successful in all these 14 DIAIH cases, with no relapses (0%). However, 65% of the AIH patients had a relapse after discontinuation of immunosuppression (p<0.0001). Conclusion: A significant proportion of patients with AIH had drug-induced AIH, mainly due to nitrofurantoin and minocycline induced AIH. These two groups had similar clinical and histological patterns. However, DIAIH patients do not seem to require long-term immunosuppressive therapy.
S1871 The Association of Low Level of Both Vitamin a and Retinol Binding Protein With the Liver Complications in Patients With Primary Sclerosing Cholangitis Sombat Treeprasertsuk, Peter L. Jansen, Kris V. Kowdley, Velimir A. Luketic, M. Edwyn Harrison, Timothy M. McCashland, Alex Befeler, Denise M. Harnois, Roberta A. Jorgensen, Jill C. Keach, Jeff Schmoll, Tanya Hoskin, Prabin Thapa, Felicity Enders, Keith D. Lindor Background: A recent study showed that vitamin A deficiency in mice may contribute to increased intraluminal pressure in the cholangioles resulting in liver damage. We aimed to determine the association of vitamin A and retinol binding protein (RBP) levels and the outcome of liver complications in patients with PSC. Methods: We used prospectively collected data from a multicenter randomized trial of high dose UDCA for PSC versus placebo. The outcomes of liver complications were the presence of liver-related death, transplant, development of varices, cholangiocarcinoma or progression to cirrhosis. Serum samples were analyzed from all 76 of the 150 patients with PSC (50.7%)who had serum available. Vitamin A level was measured by standard high-pressure liquid chromatography and serum RBP levels was measured by nephelometryin the Academic Medical Center, Amsterdam. Those performing the assays were blinded to the results of primary outcome. Results: The median age (range) was 44 years (17.9, 75.6) with 51.3% male. Low vitamin A and low RBP levels were found in 26.3% and 44.7% of patients, respectively. Eighteen patients (23.7%) had low level of both vitamin A and RBP. Of the 76 patients, 68 had available results of both vitamin A and RBP level. Twenty-two patients (32.4%) developed liver complications during follow-up. By linear regression, vitamin A level had a significant relationship with RBP level (P <0.0001, R-square=0.4), total bilirubin level (P = 0.0001, Rsquare=0.2), and platelet counts (P = 0.0002, R-square=0.2). In univariate logistic regression model, patients with liver complications had significantly higher Mayo risk score, had advanced liver fibrosis and varices at baseline more often, higher total bilirubin, higher ALP, and higher AST/ALT ratio at baseline, lower albumin, lower level of both vitamin A and RBP at baseline than those without liver complications (P<0.05). By a multivariable logistic analysis, presence of low level of both vitamin A and RBP and higher ALP level were significantly associated with the presence of liver complications (OR= 6.3, 95%CI=1.6-25.5 and 1.0, 95%CI=1.0-1.004, respectively). Conclusions: One-fourth of patients with PSC had low level of both vitamin A and RBP. Presence of low level of both vitamin A and RBP and higher ALP level at baseline were associated with the increasing risk of liver complications. It is unknown if there is a causal connection between low vitamin A and RBP levels and the liver complications.
S1875 Hyperferritinemia and Iron Overload in Type 1 Gaucher Disease Philip B. Stein, Dhanpat Jain, Pramod K. Mistry AIM: To describe the clinical spectrum of hyperferritinemia in Gaucher disease and its association with HFE mutations, iron overload and indicators of disease severity METHODS: In 114 patients with type 1 Gaucher disease, we determined serum ferritin, transferrin saturation and HFE genotype. The results were correlated with the extent of hepatosplenomegaly, overall Gaucher disease severity score index, and response to enzyme replacement therapy. In a subset of patients with radiological and/or laboratory evidence of systemic iron overload, liver biopsy was performed. RESULTS: There was a mean 3.7-fold elevation of serum ferritin over the upper limit of normal (ULN). Prior splenectomy was associated with most severe hyperferritinemia compared to patients with intact spleen (6.53 xULN vs. 2.69 xULN, P=0.003). HFE genotyping revealed two patients homozygous for H63D mutation and 30% of patients heterozygote carriers of H63D mutation; no patients harbored C282Y mutation. Ferritin level correlated weakly but significantly with liver volume (Pearson correlation coefficient = 0.254, p=0.035) and it was negatively correlated with hemoglobin (r = 0.315, p=0.004); there was no relationship with other indicators of Gaucher disease activity. Enzyme replacement therapy(ERT) resulted in amelioration of hyperferritinemia: 707±898 ng/ml vs. 301±310 ng/ml (p=0.001), transferrin saturation remained normal. Three patients were suspected of clinical iron overload, confirmed on liver biopsy. Iron accumulation was variably noted in hepatocytes and Kupffer cells. CONCLUSION: There is a high prevalence of hyperferritinemia in type 1 Gaucher disease that is associated with indicators of disease severity and it is reversed by ERT. The incidence of iron overload in type 1 Gaucher disease is increased and it is not related to HFE mutations.
S1873 The use of Liver Biopsy Evaluation in Determination of Autoimmune Hepatitis vs. Drug-Induced Liver Injury Ayako Suzuki, Thomas C. Smyrk, Rosa Miquel, David E. Kleiner, Elizabeth M. Brunt, Raul J. Andrade, M. Isabel Lucena, Agustin Castiella, Keith D. Lindor, Einar Bjornsson Background.Distinguishing drug-induced liver injury (DILI) from autoimmune hepatitis (AIH) can be challenging because certain features of AIH may occur in DILI. We aimed to characterize the histologic findings of these conditions to test the role of biopsy in this differential diagnosis. Methods. Liver biopsies of clinically well-characterized DILI (n=35)
S-807
AASLD Abstracts
AASLD Abstracts
S1870
Clinical Significance of Cd38-Positive Plasma Cells Surrounding Interlobular Bile Ducts in Primary Biliary Cirrhosis (PBC) Toru Takahashi, Tomofumi Miura, Junichiro Nakamura, Satoshi Yamada, Tsutomu Miura, Masahiko Yanagi, Hiroyuki Usuda, Iwao Emura, Merrill E. Gershwin Background/Aims: There has been increased interest in the potential role of B cells and antimitochondrial antibodies in PBC. Indeed a new paradigm in PBC includes the potential of B cells to act as both regulatory elements and as components of the inflammasone induced by apoptosis of biliary cells. We submit that a rigorous dissection of the inflammatory infiltrate in PBC will provide further insight on these issues. Materials and Methods: We took advantage of well-characterized Mabs to CD3, CD4, CD8, CD20, CD38, CD56, CD68, and pan-keratin antigens, and immunohistochemistry (IHC), to study the distribution of liver infiltrating CD38-positive plasma cells in 26 consecutive patients with PBC (AMA positive in 20 and negative in 6), all of whom had detailed staged clinical data. All data was “blindly” evaluated. We simultaneously studied 10 age- and gender-matched patients with chronic hepatitis C as a control. Results: Noteworthy within the IHC data was the presence of an intense coronal arrangement (CR) of CD38-positive cells around interlobular bile ducts, generally in specimens with chronic non-suppurative destractive cholangitis (CNSDC). In contrast, CD20-positive B lymphocytes (precursor cells of plasma cells) were found scattered and/or aggregated within the lymphoplasmocytic infiltration. Such CD20positive B cells also occasionally formed follicle-like aggregations but importantly were not observed in the proximity of CNSDC. PBC patients with CR demonstrated significantly higher titers of AMA (119.5±16.1 vs. 59.7±17.1, p=0.018) and lower levels of total cholesterol (TC) (195.1±9.0 vs. 223.6±9.6, p=0.04) than those without CR. Interestingly the CR correlated with titer of AMA (r=0.46), IgM (r=0.32), the presence of CNSDC (r=0.32) and inversely with age (r=-0.37), γ-GTP (r=-0.38) and TC (r=-0.41). In contrast, CD4- and CD8-positive T lymphocyte infiltration was noted either in proximity of, or within the degenerated cholangioepithelium, suggesting the participation of these cells in the destructive processes of interlobular bile ducts. No CR was found in control subjects. Conclusion: The presence of CD38+ plasma cells surrounding biliary epithelium has clinical and serologic significance; further it correlates with disease progression exemplified by TC decrease and the development of florid duct lesions. These data further highlight the functional significance of B cells/ plasma cells; it also reflects a multilineage loss of tolerance in PBC. We submit that study of B cells in PBC should go beyond simple measurement of AMA titer and include rigorous phenotypical and functional dissection of the liver specific B cell lineage populations.
S1874 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis Einar Bjornsson, Jayant A. Talwalkar, Sombat Treeprasertsuk, Patrick S. Kamath, Naoki Takahashi, Keith D. Lindor Background: Drug-induced autoimmune hepatitis (DIAIH) has been reported to be caused by several drugs. It is not known how common this condition is among patients with well characterized autoimmune hepatitis (AIH). There is also a lack of data comparing these patients with other patients with AIH. We aimed to compare clinical features, histology, treatment responses and the prognosis in patients with DIAIH vs. patients with AIH not induced by drugs. Method: A search was performed using computerized diagnoses database in a single institution for AIH patients and DIAIH patients identified over ten years. Individuals with overlap syndromes and decompensated liver disease were excluded. Results: Overall 261 patients (204 females, median age 52) were identified, and 24 (9.2%) were considered to be DIAIH cases with a median age of 53 years (IQR 24-61). Two drugs, nitrofurantoin (n=11) and minocycline (n=11) were the main causes. A similar proportion of DIAIH patients had positive antinuclear antibodies (83% vs. 70%) and smooth muscle antibodies (50% vs. 45%) as compared to AIH patients. IgG levels (normal <1500 g/L) were 1905 (1600-2455) vs. 2020 (1618-2702) (p=NS) in DIAIH and AIH patients, respectively. Histological grade and stage were similar in patients with DIAIH vs. AIH but none of the DIAIH patients had cirrhosis at baseline; this was present in 13% of the other AIH cases. Liver imaging was normal in all minocycline cases. 8/11 (73%) of nitrofurantoin patients had abnormalities on hepatic imaging (mainly liver atrophy) a finding seen in only 8/33 (24%) of a random sample of the rest of the AIH group (p=0.0089). Corticosteroid responsiveness was similar in DIAIH and the AIH patients. Discontinuation of immunosuppression was tried in only 14/24 (58%) but successful in all these 14 DIAIH cases, with no relapses (0%). However, 65% of the AIH patients had a relapse after discontinuation of immunosuppression (p<0.0001). Conclusion: A significant proportion of patients with AIH had drug-induced AIH, mainly due to nitrofurantoin and minocycline induced AIH. These two groups had similar clinical and histological patterns. However, DIAIH patients do not seem to require long-term immunosuppressive therapy.
S1871 The Association of Low Level of Both Vitamin a and Retinol Binding Protein With the Liver Complications in Patients With Primary Sclerosing Cholangitis Sombat Treeprasertsuk, Peter L. Jansen, Kris V. Kowdley, Velimir A. Luketic, M. Edwyn Harrison, Timothy M. McCashland, Alex Befeler, Denise M. Harnois, Roberta A. Jorgensen, Jill C. Keach, Jeff Schmoll, Tanya Hoskin, Prabin Thapa, Felicity Enders, Keith D. Lindor Background: A recent study showed that vitamin A deficiency in mice may contribute to increased intraluminal pressure in the cholangioles resulting in liver damage. We aimed to determine the association of vitamin A and retinol binding protein (RBP) levels and the outcome of liver complications in patients with PSC. Methods: We used prospectively collected data from a multicenter randomized trial of high dose UDCA for PSC versus placebo. The outcomes of liver complications were the presence of liver-related death, transplant, development of varices, cholangiocarcinoma or progression to cirrhosis. Serum samples were analyzed from all 76 of the 150 patients with PSC (50.7%)who had serum available. Vitamin A level was measured by standard high-pressure liquid chromatography and serum RBP levels was measured by nephelometryin the Academic Medical Center, Amsterdam. Those performing the assays were blinded to the results of primary outcome. Results: The median age (range) was 44 years (17.9, 75.6) with 51.3% male. Low vitamin A and low RBP levels were found in 26.3% and 44.7% of patients, respectively. Eighteen patients (23.7%) had low level of both vitamin A and RBP. Of the 76 patients, 68 had available results of both vitamin A and RBP level. Twenty-two patients (32.4%) developed liver complications during follow-up. By linear regression, vitamin A level had a significant relationship with RBP level (P <0.0001, R-square=0.4), total bilirubin level (P = 0.0001, Rsquare=0.2), and platelet counts (P = 0.0002, R-square=0.2). In univariate logistic regression model, patients with liver complications had significantly higher Mayo risk score, had advanced liver fibrosis and varices at baseline more often, higher total bilirubin, higher ALP, and higher AST/ALT ratio at baseline, lower albumin, lower level of both vitamin A and RBP at baseline than those without liver complications (P<0.05). By a multivariable logistic analysis, presence of low level of both vitamin A and RBP and higher ALP level were significantly associated with the presence of liver complications (OR= 6.3, 95%CI=1.6-25.5 and 1.0, 95%CI=1.0-1.004, respectively). Conclusions: One-fourth of patients with PSC had low level of both vitamin A and RBP. Presence of low level of both vitamin A and RBP and higher ALP level at baseline were associated with the increasing risk of liver complications. It is unknown if there is a causal connection between low vitamin A and RBP levels and the liver complications.
S1875 Hyperferritinemia and Iron Overload in Type 1 Gaucher Disease Philip B. Stein, Dhanpat Jain, Pramod K. Mistry AIM: To describe the clinical spectrum of hyperferritinemia in Gaucher disease and its association with HFE mutations, iron overload and indicators of disease severity METHODS: In 114 patients with type 1 Gaucher disease, we determined serum ferritin, transferrin saturation and HFE genotype. The results were correlated with the extent of hepatosplenomegaly, overall Gaucher disease severity score index, and response to enzyme replacement therapy. In a subset of patients with radiological and/or laboratory evidence of systemic iron overload, liver biopsy was performed. RESULTS: There was a mean 3.7-fold elevation of serum ferritin over the upper limit of normal (ULN). Prior splenectomy was associated with most severe hyperferritinemia compared to patients with intact spleen (6.53 xULN vs. 2.69 xULN, P=0.003). HFE genotyping revealed two patients homozygous for H63D mutation and 30% of patients heterozygote carriers of H63D mutation; no patients harbored C282Y mutation. Ferritin level correlated weakly but significantly with liver volume (Pearson correlation coefficient = 0.254, p=0.035) and it was negatively correlated with hemoglobin (r = 0.315, p=0.004); there was no relationship with other indicators of Gaucher disease activity. Enzyme replacement therapy(ERT) resulted in amelioration of hyperferritinemia: 707±898 ng/ml vs. 301±310 ng/ml (p=0.001), transferrin saturation remained normal. Three patients were suspected of clinical iron overload, confirmed on liver biopsy. Iron accumulation was variably noted in hepatocytes and Kupffer cells. CONCLUSION: There is a high prevalence of hyperferritinemia in type 1 Gaucher disease that is associated with indicators of disease severity and it is reversed by ERT. The incidence of iron overload in type 1 Gaucher disease is increased and it is not related to HFE mutations.
S1873 The use of Liver Biopsy Evaluation in Determination of Autoimmune Hepatitis vs. Drug-Induced Liver Injury Ayako Suzuki, Thomas C. Smyrk, Rosa Miquel, David E. Kleiner, Elizabeth M. Brunt, Raul J. Andrade, M. Isabel Lucena, Agustin Castiella, Keith D. Lindor, Einar Bjornsson Background.Distinguishing drug-induced liver injury (DILI) from autoimmune hepatitis (AIH) can be challenging because certain features of AIH may occur in DILI. We aimed to characterize the histologic findings of these conditions to test the role of biopsy in this differential diagnosis. Methods. Liver biopsies of clinically well-characterized DILI (n=35)
S-807
AASLD Abstracts
AASLD Abstracts
S1870