Florid Duct Lesions Research Articles

Comparative histologic features among liver biopsies with biliary-pattern injury and confirmed clinical diagnoses

Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.

S2969 Distinction Between Mitochondrial Antibody Positive and Negative Primary Biliary Cholangitis: Case Report and Literature Review

Introduction: Anti-mitochondrial antibody-positive primary biliary cholangitis (AMA-pos PBC) is an autoimmune disorder in which monoclonal antibodies are produced against epitopes with in the mitochondrial membranes of biliary epithelial cells, resulting in progressive non-suppurative biliary cholangitis. Up to 5 % of PBC patients lack these auto antibodies, termed as anti-mitochondrial antibody negative (AMA-neg) PBC. This is a somewhat new entity and a variant of AMA-pos PBC but not an overlap syndrome. There have not been good studies describing this phenomenon or associated terminology in the literature. Case Description/Methods: An 87-year-old woman was referred to our clinic after her medical oncologist found elevated isolated levels of serum alkaline phosphatase (714 units/L). She reported fatigue but denied any other symptoms. The physical examination was benign, except for bilateral lower extremity swelling secondary to lymphedema. Her serum alkaline phosphatase level decreased to 413 units/L after an initial dose of prednisone 40 mg daily, and she was maintained on 10 mg daily. Her antinuclear antibody titer was greater than 1:2560 in a centromere pattern. Anti- mitochondrial antibody was not detected. Total IgG level was 871 mg/dL (normal, < 1600 mg/dL), serum anti-smooth muscle antibody was negative, and the hepatitis panel was normal. Computed tomography of the abdomen and pelvis without contrast showed normal liver parenchyma and no acute intra-abdominal pathology. Histopathological examination indicated florid duct lesions. Background parenchyma showed no significant steatosis, and the inflammatory changes were limited primarily to the portal areas. Periodic acid-Schiff staining highlighted the intact hepatic parenchyma and architecture. The patient was diagnosed with AMA-neg PBC and responded well to Urosdeoxycholic acid therapy. (Figure) (Table). Discussion: This case highlights the importance of recognizing AMA-neg PBC as a variant of AMA-pos PBC and being able to differentiate them. Autoimmune cholangitis is a vague and imprecise term that cannot be used in this context. All AMA-negative PBC patients should be tested for other PBC-specific autoantibodies. Although prognosis and bile duct damage and loss are worse in AMA-neg PBC for unknown reasons, treatment remains the same for both.Figure 1.: A: The position of AMA-neg PBC in the spectrum of autoimmune hepatobiliary cholangiopathy PBC, primary biliary cholangitis; ANA, antimitochondrial antibody; IgM, immunoglobulin M; UDCA, ursodeoxycholic acid; AMA-neg, antimitochondrial antibody negative; ANA, antinuclear antibodies; IgG, Immunoglobulin G; ASMA, anti-smooth muscle antibody; anti-LKM-1, anti-liver kidney microsomal antibodies; Anti-LC-1, anti-liver cytosol antibodies; anti-SLA/LP antibodies, anti-soluble liver antigen/liver pancreas antibodies; MRCP, magnetic resonance cholangiogram; ERCP, endoscopic retrograde cholangio-pancreatogram. B and C:Two photomicrographs showing histologic features typical of the florid duct lesion seen in primary biliary cholangitis.. The portal areas show granulomatous inflammation and lymphocytic cholangitis of the bile ducts (pointed yellow arrows) (hematoxylin and eosin stain, 200X original magnification). Table 1. - Diagnostic criteria of AMA-Pos PBC The diagnosis of AMA-pos PBC can be established when two of the criteria listed in Table 1 are met[5] Evidence Criteria 1) Biochemical evidence of cholestasis Elevated alkaline phosphatase levels 2) Serological:AMA-Pos PBCAMA-Neg PBC Mitochondrial antibody positiveMitochondrial antibody negative/Presence of other PBC specific autoantibodies i.e., sp100 or gp210 3) Histopathological Nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.

S1037 Portal-Based Lymphocytic Infiltration Is Associated With Disease Activity in Patients With Primary Biliary Cholangitis

INTRODUCTION: Primary biliary cholangitis (PBC) is a cholestatic liver disease that results in inflammation of the intrahepatic bile duct and the portal tract. While the liver biopsy is the gold standard in relation to disease activity and fibrosis, histological findings have not been compared to serum alkaline phosphatase (ALP) changes with therapy. This is important as ALP is a well-established serum marker in the assessment of PBC. METHODS: Patients with biopsy-confirmed PBC, received a retrospective medical record review. The histological features were stratified by a GI pathologist into the following categories: 1) lymphocytic infiltration of the portal tract, 2) neutrophilic infiltration of the portal tract, 3) eosinophilic infiltration of the portal tract, 4) plasma cell infiltration of the portal tract, 4) florid duct lesions and bile duct loss, 5) bile flow obstruction, 6) inflammation of the hepatic parenchyma, and 7) hepatic necrosis. The primary endpoint was the non-reduction in ALP over the 1-year period. RESULTS: Of the 217 patients in the study, 173 (79.7%) did not have a reduction in their ALP levels over a 1 year period even though 148 of the 173 patients (85.5%) were undergoing therapy. Of the histological features analyzed in the study, lymphocytic infiltration of the portal tract was associated with the non-reduction in ALP levels (P = 0.02, OR 2.18 95%CI 1.11–4.30). However, other features including neutrophilic infiltration (P = 0.97, OR 0.98 95%CI 0.37–2.59), eosinophilic infiltration (P = 0.27, OR 1.87 95%CI 0.68–5.10), plasma cell infiltration (P = 0.27, OR 1.94 95%CI 0.71–5.28), bile duct damage (P = 0.52, OR 1.24 95%CI 0.64–2.41), hepatic inflammation (P = 0.13, OR 0.58 95%CI 0.28–1.18), and hepatic necrosis (P = 0.17, OR 1.65 95%CI 0.81–3.38) were not significantly associated with disease exacerbation that is demonstrated by the maintenance or elevation in ALP levels. In a multivariate model, the association between lymphocytic infiltration and the non-reduction in ALP remained significant (P = 0.26, aOR 2.31 95%CI 1.11–4.84), despite controlling for age (P = 0.34), gender (P = 0.49), race (P = 0.78), weight (P = 0.80), diabetes (P = 0.03), alcohol use (P = 0.998), and ursodiol therapy (P = 0.88). CONCLUSION: A lack of reduction in serum ALP correlates with disease activity and lymphocytic infiltration of the portal tract in patients with PBC. Hence, patients with these characteristics in biochemical and histological analysis would likely benefit from escalation of therapy and close surveillance.Figure 1.: Multivariate model: lymphocytic infiltration of the portal tract is an independent predictor of PBC disease activity as demonstrated by the non-reduction in the level of alkaline phosphatase.

S2550 Liver Transplantation in a Patient With Refractory Pruritus From Follicular Cholangitis

INTRODUCTION: Follicular cholangitis is rare and can present as a mimicker of cholangiocarcinoma. Surgical intervention is considered on follicular cholangitis patients for suspicion of rapidly progressive cholangiocarcinoma. Here we present the case of a 43-year-old female who initially underwent a Whipple procedure due to concern for a cholangiocarcinoma. Pathology showed follicular cholangitis. She continued with intractable pruritus and a liver transplant was pursued for that indication. CASE DESCRIPTION/METHODS: A 43-year-old previously healthy female presented with progressive fatigue and pruritus. Laboratory evaluation was significant for elevated liver chemistries, filamentous-actin of 121 and a positive antinuclear antibody. A liver biopsy showed dense portal inflammation, mostly lymphocytes, rare plasma cells, mild interface hepatitis, paucity of bile ducts, but no florid duct lesion or fibrosis. Initially, she was started on immunosuppression with no improvement in labs. A magnetic resonance cholangiopancreatography (MRCP) was obtained to rule out bile duct obstruction. MRCP was significant for common bile duct (CBD) stones. Endoscopic retrograde cholangio-pancreatography (ERCP) showed CBD stricture with cytology concerning for cholangiocarcinoma. At this time, she underwent a Whipple procedure. Surgical pathology was suggestive of follicular cholangitis and no malignant cells were identified. Post operatively, she continued to have pruritus and fatigue. Immunosuppression was resumed with no change in symptoms. Repeat MRCP showed right hepatic lobe strictures, but subsequent ERCP was unsuccessful due to post-whipple anatomy. Percutaneous cholangiogram was pursued and did not show any obvious lesion. She was then trialed on multiple pruritus medications including naltrexone, rifampin and sertraline without any improvement in symptoms as well as numerous side effects. She was ultimately maintained on ursodiol with minimal improvement. Liver transplant was considered due to quality of life concerns from pruritus. At that time her MELD was 6. She recently received a liver transplant, and is now pruritus free for months, maintained on standard immunosuppression. DISCUSSION: Clinicians should consider follicular cholangitis in the differential for obstructive jaundice. Review of the literature showed 11 cases of follicular cholangitis and one liver transplant due to cirrhosis. This is the first reported liver transplant case for refractory pruritus due to follicular cholangitis.

Autoimmune liver diseases

Autoimmune liver diseases comprise aspectrum of progredient idiopathic inflammatory diseases. Typical histological features of autoimmune hepatitis (AIH) include the pattern of chronic hepatitis with predominant plasma cell-rich interface activity, rosetting of hepatocytes, and emperipolesis. Florid bile duct lesions are the key feature of primary biliary cholangitis (PBC); onion-like periductal fibrosis characterizes the primary sclerosing cholangitis (PSC). Variants of AIH, or overlap syndromes, show intersecting histomorphologic findings with PBC or PSC. The diagnosis of the different autoimmune inflammatory liver diseases is based on clinical presentation, a hepatitic or cholestatic pattern of liver enzymes, immuno-serological findings, image analysis in PSC, and liver biopsy as afacultative or obligatory adjunct. Liver biopsy plays amajor role in the diagnosis of AIH, small-duct PSC, AMA-negative PBC, IgG4-related diseases, overlap syndrome, and in the recognition of concurrent liver diseases, especially drug-induced liver diseases. Herewith pathologists can help clinicians find adequate therapy for different autoimmune inflammatory liver diseases.

Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

A Clinical Review of Primary Biliary Cholangitis.

Primary biliary cholangitis is a slowly progressive immune-mediated cholestatic disease that causes a destruction of the intrahepatic bile ducts and may lead to cirrhosis of the liver, end-stage liver disease, and the need for liver transplantation. The disease is among the most common reasons why adults require liver transplantation. The primary signs of the disease include the presence of antimitochondrial and antinuclear antibodies, elevated alkaline phosphatase, hyperbilirubinemia, hypercholesterolemia, and histologic features, such as intense inflammation with a florid duct lesion and hepatic fibrosis. The patient's quality of life is impacted by fatigue, pruritus, malabsorption syndrome, sicca syndrome, osteoporosis, and challenges coping with chronic illness. Advanced practice registered nurses need to understand the pathophysiology, clinical presentation, diagnostic approaches, disease and symptom management, and priority nursing assessment and care in patients with this rare disease to differentiate it from primary sclerosing cholangitis, autoimmune hepatitis, obstructed bile duct lesions, drug-induced cholestasis, cholestasis in pregnancy, cholangiocarcinoma, hepatic malignancy, and peptic ulcer disease.

Hepatic Langerhans Cell Histiocytosis (LCH) Mimicking Antimitochondrial Antibody (AMA)–Negative Primary Biliary Cholangitis (PBC), Presenting as a Harbinger of Multisystem LCH

Abstract Objectives LCH is a rare systemic disorder characterized by an infiltration of CD1a+/Langerin+ histiocytes. LCH commonly involves bone, skin, and lymph nodes in children. Hepatic involvement is rarely observed in multisystem LCH. We describe an exceptional case of hepatic LCH in an adult, mimicking AMA-negative PBC, preceding the diagnosis of multisystem LCH. Methods A 65-year-old man presented with intermittent pruritus, weakness, dyspnea, fever, and chills that have been progressive for 4 years. Physical examination was unremarkable. Laboratory work revealed elevated alkaline phosphatase (471 U/L; ref 40-120 U/L), GGT (271 U/L; ref 0-41 U/L), total bilirubin (2.0 mg/dL; ref 0.0-1.2 mg/dL), and direct bilirubin (1.1 mg/dL; ref 0.0-0.3 mg/dL). Indirect bilirubin, AST, and ALT were within normal limits. Liver biopsy was performed. Results Liver biopsy showed lobular and portal nonnecrotizing granulomas with one “florid duct lesion” with duct injury, suggestive of PBC. Tests for autoimmune diseases including AMA were negative. ERCP was negative for biliary obstruction. One month after the liver biopsy, he developed flaking, red, and burning rash on the right scalp, forehead, and epigastric skin. A skin biopsy at an outside institution revealed dermal and epidermal infiltration of CD1a-positive histiocytes with indented nuclei and pale eosinophilic cytoplasm, consistent with LCH. Subsequent reexamination of the liver biopsy showed that the histiocytes within the florid duct lesion were positive for CD1a and S-100, while the remaining granulomas were negative. The following day, a small focus of LCH was noted in his gastric biopsy performed for gastritis symptoms. Conclusion Hepatic LCH may mimic AMA-negative PBC histologically and clinically, and may present as a harbinger of multisystem LCH. While rendering the diagnosis would be challenging without prior history of LCH and with focal involvement, awareness of such presentation and communication with clinical colleagues may be helpful.

A Rare Case of Cholestasis

This is the case of 49-year-old woman with no past medical history who was found to have a rare case of cholangitis. A 49-year-old woman with no significant past medical history presented with a 1-month history of dull abdominal pain, early satiety, fatigue, pruritus, and weight loss. She had no history of drug, alcohol, or tobacco use, and no family history of hepatobiliary disease or autoimmunity. Her vital signs were within normal limits. Physical exam revealed mild jaundice without abdominal tenderness or ascites. Initial lab testing showed elevated liver enzymes in a cholestatic pattern, with AST/ALT 147/34 U/L, alkaline phosphatase 493U/L, and total bilirubin 6.8 mg/dl (direct 4.0 mg/dl). Imaging, including CT, ultrasound, and MRCP, was suggestive of mild inflammation of the pancreas and mild splenomegaly, as well as mild fatty infiltration of the liver without gallstones, ductal obstruction, or focal hepatic or gallbladder abnormalities. Infectious studies were negative for viral hepatitis and HIV. ESR and CRP were elevated concerning for autoimmune etiology. Anti-nuclear antibody (ANA, titer 1:1280) and anti-actin antibody were positive. Anti-mitochondrial antibody (AMA) titer was negative. Liver biopsy was performed and showed biliary pattern cirrhosis and florid biliary duct destruction consistent with autoimmune cholangitis. The patient was started on prednisone and ursodeoxycholic acid with resolution of symptoms 1 month later. AST was 45U/L, alkaline phosphatase 130U/L, and total bilirubin decreased to 1.2 mg/L. Autoimmune cholangitis (AIC) is a rare cause of cholestasis not commonly encountered in clinical practice. Maintaining it as a differential diagnosis will aid in prompt diagnosis and treatment. The patient met diagnostic criteria for AIC, which is characterized by the clinical, biochemical, and histologic features of primary biliary cirrhosis (PBC) but with negative AMA and positive ANA and/or anti-actin antibody. Like PBC, AIC has a female preponderance, a cholestatic liver enzyme pattern, and florid bile duct lesions on histology; both slowly progress to fibrosis and cirrhosis if left untreated. AIC is probably a heterogeneous syndrome that includes patients with AMA-negative PBC, small duct primary sclerosing cholangitis, autoimmune hepatitis with bile duct damage, and various transition states. Therapy consists of ursodeoxycholic acid and corticosteroids; liver transplantation is the treatment of choice for end-stage disease.

Positive antimitochondrial antibody but normal serum alkaline phosphatase levels: Could it be primary biliary cholangitis?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease, typically diagnosed by elevated cholestatic liver enzymes and a positive antimitochondrial antibody (AMA) test. The clinical significance of AMA positivity in patients with normal cholestatic liver enzymes is uncertain. Charts of patients with normal cholestatic liver enzymes and AMA positivity who underwent liver biopsy between 2012 and 2015 were retrospectively analyzed. Six AMA-positive patients with normal cholestatic liver enzymes who underwent a liver biopsy were identified. Four (67%) showed florid bile duct lesion compatible with early-stage PBC, whereas the other two showed mild and non-specific histological findings. The patients with histological findings compatible with PBC had higher enzyme-linked immunosorbent assay-determined AMA titers and significantly elevated immunoglobulin M (IgM) level. Patients with non-specific histological findings (33%) had low-titer AMA and a borderline elevated IgM level. Antimitochondrial antibody-positive patients with normal cholestatic liver enzymes should be meticulously evaluated for PBC including a liver biopsy, mainly in patients with high-titer seropositivity for AMA and a significantly elevated IgM level. More studies are required to clarify the role of liver biopsy in these patients and further follow-up may elucidate the relationship of these patients to those with more classical forms of PBC.

The diagnosis of antimitochondrial antibody-negative primary biliary cholangitis

Autoimmune liver diseases are heterogenous disorders that share largely non-specific clinical, serological and pathological features. The correct diagnosis requires discriminative features which are highly specific, for example high-titer antimitochondrial antibodies (AMA) and florid duct lesion in primary biliary cholangitis (PBC). However, the imperfect sensitivities of these characteristic features and abuse of scoring systems led to many artificial diagnoses such as overlap syndromes and outliers for example "autoimmune cholangitis" which is now called as "AMA-negative PBC". Patients lacking detectable AMA (up to 20% in indirect immunofluorescence -IF), but otherwise presenting signs and symptoms of PBC should be regarded as affected by "AMA-negative PBC" because they seem to follow a natural history similar to that of their AMA positive counterparts. The complementary use of IF, ELISA and immunoblotting have disclosed that the majority of patients initially considered AMA-negative are in fact AMA positive. Moreover, the use of PBC-specific ANA's like Gp210 and sp100 have diminished the AMA-negative cases (if truly exists!) to less than 5%. The histological spectrum of PBC includes typical florid duct lesions and/or compatible features such as non-specific hepatitic and biliary findings. In the absence of florid duct lesion and AMA positivity, histology alone cannot differentiate PBC from other biliary disorders. However, the analysis of compatible histological features with the clinical, serological and imaging findings usually points to a specific diagnosis. In this review, we present serological, clinical and pathological pitfalls regarding AMA-negative PBC including illustrative cases and a diagnostic algorithm.

Co-occurrence of Idiopathic Granulomatous Hepatitis and Primary Biliary Cirrhosis

Purpose: Purpose: To report a possible association between idiopathic granulomatous hepatitis and primary biliary cirrhosis (PBC). Methods: Review of two cases Case 1: A 42 year old asymptomatic woman had an elevated alkaline phosphatase, 343 IU (normal <130), a positive antimitochondrial antibody, titer 1:64, and 20% eosinophils. Liver biopsy demonstrated florid bile duct lesions with minimal fibrosis, consistent with Stage II PBC. She was treated with methotrexate 15 mg weekly (ursodiol was unavailable at the time). Six months later her alkaline phosphatase was normal, 75 IU. 15 years after the diagnosis of PBC the patient presented with one week of fevers, chills, and night sweats. Her alkaline phosphatase was elevated, 313 IU. Liver biopsy showed numerous granulomas with giant cells throughout the liver lobule with some areas of palisading necrosis and intense inflammation, consistent with a diagnosis of idiopathic granulomatous hepatitis. The methotrexate dose was increased to 22.5 mg per week. Her symptoms remitted, alkaline phosphatase returned to normal, and liver biopsy was essentially normal. Case 2: A 42 year old female with fatigue was referred for evaluation of abnormal liver function tests. Her alkaline phosphatase level was slightly elevated, 149 IU (normal <125). Antimitochondrial antibody was negative. Liver biopsy showed a granulomatous type inflammation of the portal tracts consistent with idiopathic granulomatous hepatitis. She was treated with oral methotrexate; two and seven years later liver biopsies and alkaline phosphatase levels were essentially normal. 12 years after diagnosis of idiopathic granulomatous hepatitis, alkaline phosphatase was 284 IU, antimitochondrial antibody was strongly positive (113.2 units by ELISA; normal <20), and liver biopsy showed bile duct inflammation and occasional fibrous bridging, consistent with a diagnosis of Stage II-III PBC. Ursodiol therapy was initiated. Alkaline phosphatase has since ranged from 115 - 149 IL (normal <130). Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, and granulomas in portal and lobular regions of the liver. We describe the first reported case of idiopathic granulomatous hepatitis occurring in a patient with PBC, as well as the first known diagnosis of PBC in a patient with idiopathic granulomatous hepatitis. Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. The cause of both diseases is unknown.

S1870 Clinical Significance of Cd38-Positive Plasma Cells Surrounding Interlobular Bile Ducts in Primary Biliary Cirrhosis (PBC)

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 ageand 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, CD4and 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.

S1873 The use of Liver Biopsy Evaluation in Determination of Autoimmune Hepatitis vs. Drug-Induced Liver Injury

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 ageand 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, CD4and 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.

S1871 The Association of Low Level of Both Vitamin a and Retinol Binding Protein With the Liver Complications in Patients With Primary Sclerosing Cholangitis

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 ageand 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, CD4and 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

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 ageand 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, CD4and 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.

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

EASL Clinical Practice Guidelines: Management of cholestatic liver diseases

EASL Clinical Practice Guidelines (CPG) on the management of cholestatic liver diseases define the use of diagnostic, therapeutic and preventive modalities, including non-invasive and invasive procedures, in the management of patients with cholestatic liver diseases. They are intended to assist physicians and other healthcare providers as well as patients and interested individuals in the clinical decision-making process by describing a range of generally accepted approaches for the diagnosis, treatment and prevention of specific cholestatic liver diseases. The clinical care for patients with cholestatic liver diseases has advanced considerably during recent decades thanks to growing insight into pathophysiological mechanisms and remarkable methodological and technical developments in diagnostic procedures as well as therapeutic and preventive approaches. Still, various aspects in the care of patients with cholestatic disorders remain incompletely resolved. The EASL CPG on the management of cholestatic liver diseases aim to provide current recommendations on the following issues:

AMA Negative Primary Biliary Cirrhosis (PBC) and Small Duct Primary Sclerosing Cholangitis (PSC) Overlap Syndrome

Purpose: Overlap syndromes of two autoimmune liver diseases are not uncommon and usually involve autoimmune hepatitis with either PBC or PSC. We describe a case of AMA negative PBC and small duct PSC overlap syndrome, an extremely rare cause of autoimmune liver disease. Case Report: A 58 year old male was referred for evaluation of elevated liver enzymes: total bilirubin 2.4 mg/dL, alkaline phosphatase 630 IU/L, AST 262 IU/L, and ALT 447 IU/L. These were associated with fever, night sweats, dark urine, and pruritis. Serologies revealed an elevated pANCA (1:1280) but negative ANA, AMA, and ASMA. Complete serologic evaluation, including viral and metabolic serologies, was otherwise negative. Abdominal ultrasound revealed a normal liver and gallbladder. MRCP revealed normal intrahepatic ducts, common hepatic duct, and common bile duct. No strictures or irregularities of the biliary tree were identified. Liver biopsy revealed features of both PBC and PSC: portal hepatitis, a florid duct lesion, granulomas, and loss of small bile ducts. There was also concentric periductal fibrosis (“onion skinning”), affecting multiple small bile ducts. Trichrome and reticulin stains noted periportal fibrosis. A repeat AMA was performed using the more specific mitochondrial M2 test; this was also negative. The patient was assigned the diagnosis of AMA negative PBC and small duct PSC overlap syndrome. He was started on ursodeoxycholic acid 1200 mg daily in divided doses. Liver enzymes returned to normal within 6 months of therapy and he has had no further symptoms. The patient had undergone a screening colonoscopy 1 year prior to the elevated liver enzymes. This had revealed a hyperplastic colon polyp with normal appearing colon mucosa. Discussion: Overlap syndromes are noted in approximately 18% of patients with autoimmune liver disease and usually involve autoimmune hepatitis and either PBC or PSC. The very rare variant of PBC and PSC overlap syndrome has been reported in 4 cases in the literature. Our patient with features of both AMA negative PBC and small duct PSC represents an additional case of this extremely rare overlap syndrome.

Case Report: Histologic Features of Steatohepatitis in Patients with a Clinical Diagnosis of Autoimmune Cholestasis

Nonalcoholic steatohepatitis (NASH) is a disease included in the spectrum of nonalcoholic fatty liver disease, which is able to continue progression toward cirrhosis (1). The definition of NASH relies on the common exclusion of significant alcohol use (<20 g/day) and the characteristic histological lesions include some degree of steatosis in addition to mixed lobular inflammation and hepatocyte damage (ballooning degeneration with or without Mallory’s hyaline) (2). NASH has been found in patients suffering from chronic hepatitis C (3) and also in other forms of liver diseases, such as chronic hepatitis B, autoimmune hepatitis, drug-induced liver disease, and α-1 antitrypsin deficiency (4). Primary biliary cirrhosis (PBC) should be considered when patients show a biochemical and histological cholestatic pattern along with positive serum antimitochondrial antibodies (AMA), including immunoblot studies, or PBC-specific antinuclear antibodies (ANA), mainly anti-SP100 and anti-GP210 (5), while patients showing a cholestatic pattern together with negative AMA and positive ANA (different from rim-like or multiple nuclear dots) need to be classified as having autoimmune cholangitis (AIC) (5, 6). Differences found between both groups according to biochemical or histological features are minimal. Indeed, histopathologic features of both entities consist of characteristic interlobular and septal bile ducts lesions (florid duct lesion), cholestasis, ductular proliferation, portal and periportal hepatitis, usually mild