Monday, September 24, 2018

HPHS Journal Watch: July/August 2018

Advances in Anatomic Pathology

An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens.
Lenggenhager D,  Weber A. Adv Anat Pathol 2018;25:273–281.

This review paper highlights how to diagnose hepatitis E (HEV) on liver specimens. Once thought to be a self-limiting waterborne infection restricted to developing countries where it had its worst impact on pregnant women, it has become clear for nearly a decade that HEV is more common in industrialized countries than previously known. The seroprevalence is 30% in France and up to 21% in the US. Molecular detection of HEV RNA in the blood is over a short viremic period of about 3 weeks. In stool samples, the virus is detectable for an additional 2 weeks. Molecular detection is more robust than antibody-based serological testing. Acute HEV infection can be in the typical acute hepatitis pattern. The cholestatic pattern can show swollen hepatocytes, rosette formation and bilirubinostasis. Immunocompromised patients may get chronic HEV infection with rapid progression to cirrhosis. Chronic HEV can look similar to those of chronic viral HBV or HCV. Ancillary tools are necessary to help make the diagnosis given the nonspecific and overlapping morphologic histologic features. PCR targeting the ORF2 and 3 gene region of the virus can be done on formalin-fixed paraffin embedded tissues. In situ RNA testing is specific but less sensitive than PCR. Immunohistochemistry using ORF2 antibody can be useful particularly in immunocompromised patients.

Clinical Gastroenterology and Hepatology

Nonalcoholic Fatty Liver Disease Associates With Increased Overall Mortality and Death From Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men.
Hwang YC, Ahn HY, Park SW, Park CY. Clin Gastroenterol Hepatol 2018;16:1131–1137.

Using a large health study database of 318,224 people from Korea, followed for a median of 5.7 years, the causes of mortality were identified in subjects with NAFLD. The prevalence of NAFLD determined by ultrasound was 26%. The cumulative mortality rate was 0.51%, with cancer being the highest cause of death. In men, having NAFLD at baseline was not associated with overall cardiovascular or liver associated death. Women with NAFLD at baseline had higher cancer related and liver related mortality. Having liver fibrosis had an additional risk of death compared to NAFLD alone in women as well. In men, neither obesity nor NAFLD alone was associated with cancer-related mortality. Cardiovascular-related mortality was increased in men who had either obesity or NAFLD alone. In women, having either obesity or NAFLD alone was associated with increased overall and cancer related mortality, although the combination of the 2 conditions did not confer additional predictive power for mortality. In women, cardiovascular and liver related mortality was increased when they had both obesity and NAFLD. The study concludes that the impact of NAFLD appears stronger in women than in men, with NAFLD associating more closely with obesity metabolic syndrome and inflammation in women than in men, which may explain the higher mortality rate.

High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study.
Caballería L, Pera G, Arteaga I, et al. Clin Gastroenterol Hepatol 2018;16:1138–1145.
This population-based, cross-sectional study investigated the prevalence of liver fibrosis as evaluated by transient elastography using Fibroscan with M probe. Three thousand fourteen participants were randomly chosen from a total of 162,950 subjects between 18-75 years. Those with a history of liver disease were excluded. In 92 subjects, a liver biopsy was performed and assessed by 2 liver pathologists blinded to the liver stiffness measurement. Risk factors associated with increased liver stiffness included male gender, abdominal obesity, type 2 diabetes, serum glucose level, triglyceride levels, and increased AST or ALT levels. Comparing biopsy to liver stiffness measurement, patients with F0 to F1 had measurement of 8.4, whereas those with F4 had a measurement of 30.8kPa. Per the table listed in the article, 53% of those with F0 had liver stiffness measurement of greater than 8.0kPa. The authors state that using a cutoff of >6.8kPa, 32% of the the patients had significant liver fibrosis, but using a cutoff of >9.0 kPa, 65% of the patients had significant liver fibrosis (defined by F1-F4). This gave a sensitivity of 93%, specificity of 78%, and predictive accuracy of 83%. They propose a screening algorithm that starts with a detailed medical history identifying risk factors for liver fibrosis, followed by calculating fatty liver index, and then screening with transient elastography for only those with risk factors and a fatty liver index >60. They suggest that transient elastography can be useful for screening for liver fibrosis in the community.


Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease.
Kendall TJ, Dolman GE, Duff CM, et al. Histopathol 2018;73(1):90-100.

Elastin is an extracellular matrix (ECM) protein conferring elastic recoil to tissues. The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus-related chronic liver disease. The authors evaluated elastin contents in liver biopsies by image analysis and correlated it with outcome in patients with advanced (Ishak stage ≥5) chronic hepatitis C virus-related chronic liver disease. Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virological response, the median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with a hepatic elastin content of >3.4% progressed to a clinical outcome, as compared with only six of 15 (40%) with an elastin content of <3.4%. The difference in time to outcome was significant. This study describes a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.

Hepatic angiomyolipoma: mutation analysis and immunohistochemical pitfalls in diagnosis.
Yan Z, Grenert JP, Joseph NM, et al. Histopathol 2018;73(1):101-108.

Hepatic angiomyolipoma (AML) often shows epithelioid morphology with inconspicuous fat and can mimic hepatocellular adenoma (HCA) or carcinoma (HCC). This study examines the expression of commonly used markers for HCA or HCC in hepatic AML and highlights pitfalls in diagnosis. 16 resected cases of AML were stained with reticulin, LFABP, glutamine synthetase (GS), beta catenin, CD68 and CD117.  Sanger sequencing of exon 3 of CTNNB1 and next-generation sequencing (NGS) was also performed. High-risk histological features were often present in tumors with benign outcome: marked atypia (19%), mitoses (20%) and necrosis (33%). GS staining (≥10% of tumor) was seen in epithelioid components in 13 (87%) cases, and was diffuse (>50% of tumor) in six (40%) cases. LFABP staining or nuclear beta catenin staining was not seen in any case. Sanger sequencing and NGS did not reveal CTNNB1 mutation in any tested case. NGS demonstrated TSC2 mutations in all five cases tested. The authors conclude that absence of LFABP and presence of fat can be mistaken for HNF1a-inactivated HCA. Diffuse GS staining can be mistaken for b-catenin-activated HCA or HCC. Diffuse GS expression is not related to CTNNB1 mutation. All tested cases showed TSC2 mutation, supporting this as the driving genetic event for hepatic AML.

Hepatic granulomas: a 17-year single tertiary centre experience.
Gaspar R, Andrade P, Silva M, et al. Histopathol 2018;73(2):240-246.

The reported incidence of granulomas in liver biopsies ranges from 1 to 15%. The authors assess the clinical relevance, presenting features and underlying aetiology in a non-transplant, tertiary referral center. During the 17-year study period (January 1998–December 2014), 9374 biopsies were performed and granulomas were found in 297. Of these, 57 were excluded. Overall, the most common etiology was tuberculosis (35.8%), followed by primary biliary cholangitis (PBC) - 15.0%. In 30 patients (12.5%) granulomas were idiopathic. From 1998 to June 2006 there were 147 granulomas in 5304 biopsies (2.8%), a frequency that did not change significantly compared to the period from July 2006 to December 2014 (93 granulomas in 4070 biopsies, 2.3%, P > 0.05). However, for the majority of cases (61.9%) there was a shift in granuloma etiology during the former time-period that infectious diseases were responsible, whereas in the latter, autoimmune liver diseases (43%) were the main etiology. The authors conclude that hepatic granulomas can result from various infectious and non-infectious diseases. During recent years, an epidemiological shift regarding granuloma etiology was observed, from systemic infectious diseases to non-infectious, mainly immune-mediated primary liver disorders.

Liver transplantation

Morphological characterization of chronic antibody-mediated rejection in ABO-identical or ABO-compatible pediatric liver graft recipients.
Dao M, Habès D, Taupin JL, et al. Liver Transpl 2018;24(7):897-907.

This study aims to define the morphological profile associated with the presence of donor‐specific antibodies (DSAs) and/or C4d immunostaining in ABO‐identical or compatible pediatric liver grafts. The authors study a cohort of 53 cases with a 10‐year protocol biopsy aims to define the morphological changes associated with the presence of DSA and/or C4d immunostaining in liver grafts, in order to refine the diagnosis criteria of cAMR. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 ± 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients. LAFSc, perivenular fibrosis and portal inflammation were significantly higher in the double‐DSA and C4d‐positive group versus the double‐negative group. The authors defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody‐mediated rejection (cAMR; 11/53 versus 13/53). Their study confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR.

American Journal of Surgical Pathology

A Point-based Histologic Scoring System for Hepatocellular Carcinoma Can Stratify Risk of Posttransplant Tumor Recurrence.
Roberts DE, Kakar S, Mehta N, et al. Am J Surg Pathol 2018;42(7):855-865.

Eligibility for liver transplant in patients with HCC relies on tumor size and number that is based on radiographic assessment. However, the pre-operative radiographic impression and pathologic assessment of explanted livers for HCC has been shown to be discordant in up to 30% of cases. The goal of this study was to determine whether certain histologic features were associated with tumor recurrence after transplant. Evaluation of 109 explanted livers showed that scirrhous and solid growth patterns, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, and cytoplasmic amphophilia were found to be high-risk histologic features. Assigning points based on these parameters, the total score was called the Recurrence Risk Assessment Score (RRAS). The authors then validated the RRAS performance in a separate cohort of 81 explants in predicting tumor recurrence. When compared against conventional tumor grade by WHO histologic criteria, the RRAS was superior in predicting HCC recurrence. This study provides further support that histologic evaluation may provide another useful, if not better, method of predicting HCC recurrence as compared to radiographic studies alone.

Archives of Pathology and Laboratory Medicine

Factors Impacting the Performance Characteristics of Bile Duct Brushings: A Clinico-Cytopathologic Analysis of 253 Patients.
Hacihasanoglu E, Memis B, Pehlivanoglu B, et al. Arch Pathol Lab Med 2018;142(7):863-870.

The goal of this study was to determine the performance of bile duct brushings (BDBs) in detecting malignancies over a span of 15 years at a major academic medical center. 253 cases with at least 18 months of histopathologic or clinical follow-up were reviewed. Overall, the authors found BDBs to have a sensitivity of 35%, specificity of 100%, positive predictive value of 100%, negative predictive value of 58%, and accuracy of 66% in detecting malignancy. In addition, a number of detailed analyses and statistics were generated, including various grouping of diagnostic categories (from benign, atypical, suspicious, and malignant), comparison of conventional smears to ThinPrep, accounting for stent effects, categorizing the type of carcinoma, and evaluating test performance over time. In brief, the finding that sensitivity nearly doubled and accuracy increased while specificity and positive predictive value only minimally decreased when atypical, suspicious, and malignant categories were combined suggests that further refinement in atypical and suspicious categories may be helpful. Also, in cases where patients had a history of stenting, the statistics generated suggest that cases were only diagnosed as malignant when cytologic features were unequivocal.

Human Pathology

Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.
Zhang H, Jenkins SM, Lee CT, et al. Hum Pathol. 2018;78:97-105.

Bim protein is an important cell apoptosis initiator that can be altered in tumorigenesis.  The authors analyzed the correlation of Bim expression by immunohistochemistry with various clinicopathological features and survival in a cohort of 56 patients with intrahepatic cholangiocarcinoma.  Nineteen of 56 (34%) tumors had high Bim expression (>10%).  Patients who had tumors with high Bim expression had significantly longer overall survival than those with low or no staining.  Additionally, high Bim expression correlated with low Ki-67 index and lack of lymph node metastasis at the time of surgery.  The study findings suggests Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.

Mucinous intrahepatic cholangiocarcinoma: a distinct variant.
Chi Z, Bhalla A, Saeed O, et al. Hum Pathol 2018;78:131-137.

In this retrospective study from a tertiary medical center with a large volume of hepatectomies, mucinous variant of intrahepatic cholangiocarcinomas (n=7) were compared to conventional intrahepatic cholangiocarcinomas (n=79).  This study describes demographic, histopathologic, immunohistochemical, and molecular findings specific to mucinous intrahepatic cholangiocarcinomas.  This variant presents at advanced stage upon diagnosis with shorter survival time compared with conventional type cholangiocarcinomas.

Resection of the largest reported hepatic small vessel neoplasm.
Walcott-Sapp S, Tang E, Kakar S, et al. Hum Pathol 2018;78:159-162.

A case report describing a large hepatic small vessel neoplasm with characteristic morphologic and staining features, which underscores consideration for his entity regardless of lesion size.


Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study. Costentin CE, Layese R, Bourcier V, et al. Gastroenterol 2018;155(2):431-442.

This multi-center study aimed to determine how compliance with hepatocellular carcinoma semi-surveillance guidelines affects survival times of patients with HCV and HBV-associated compensated cirrhosis who developed HCC.  216 patients with detected HCC with biopsy-proven viral cirrhosis were included.  After lead-time adjustment, overall survival time was longer in patients compliant with surveillance guidelines (53.2 months) than noncompliant patients (25.4 months).  This study offers the most robust evidence available of a survival benefit with six-month HCC surveillance and strongly supports the implementation of interventions aiming at improving patients’ compliance.

Incidence of Hepatocellular carcinoma in Patients with HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents.
Calvaruso V. Gastroenterol 2018;155(2):411-421.

Studies have produced conflicting results of the incidence of hepatocellular carcinoma (HCC) in patients with in hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antivirals (DAAs).  This was a large prospective study of 2, 249 consecutive patients with HCV-associated cirrhosis treated with DAAs were followed.  At 1 year after exposure to DAAs, HCC developed in 2.1% of patients with Child-Pugh class A with an SVR and 6.6% of patients with no SVR; and in 7.8% of patients with Child-Pugh class B with an SVR and 12.4% of patients with Child-Pugh class B.  This study demonstrated that the SVR to DAA treatment decreased the incidence of HCC over a mean follow-up of 14 months.


Macrotrabecular-Massive Hepatocellular Carcinoma: A Distinctive Histological Subtype with Clinical Relevance.
Ziol M, Pote N, Amaddeo G, et al. Hepatology 2018; 68(1): 103-112.

The authors report a series of “macrotrabecular-massive” hepatocellular carcinoma (MTM-HCC), defined as the presence of >50% macrotrabecular architecture (more than six cells thick). They retrospectively reviewed 237 HCC resections and 284 HCC biopsies, and identified MTM-HCC in 12% of the whole cohort. It was associated with poor prognostic factors, including tumor size, AFP level, satellite nodules, and vascular invasion. It was an independent factor of early and overall recurrence. There is an editorial on the paper by Dr. David Kleiner in the same issue.

cHCC-CCA: Consensus Terminology for Primary Liver Carcinomas With Both Hepatocytic and Cholangiocytic Differentiation.
Brunt E, Aishima S, Clavien PA, et al. Hepatol 2018; 68(1): 113-126.

This article is a consensus paper from an international group of pathologists, radiologists, and clinicians and gives recommendations for working terminology surrounding combined hepatocellular-cholangiocarcinoma (cHCC-CCA). They recommend the diagnosis be based on H&E, with immunostains being supportive of the diagnosis. Other recommendations include morphologically typical HCC with positive CK19 or other markers of “stemness” should NOT be called cHCC-CCA, and morphologically typical CCA with only immunohistochemical expression of hepatocytic or stem-cell markers should NOT be called cHCC-CCA. They also recommend “there should no longer be formal diagnostic subtypes based on the identification of stem/progenitor cells, but rather if stem/progenitor cell features are observed, they are noted in a comment as ‘stem/progenitor cell features present.’” The paper is essential reading for anyone who routinely diagnoses primary liver carcinomas.

Polycystic Liver Disease: Hepatic Venous Outflow Obstruction Lesions of the Noncystic Parenchyma Have Major Consequences.
Barbier L, Ronot M, Aussilhou B, et al. Hepatol 2018; 68(2): 652-662.

The authors retrospectively reviewed 125 cases (resection or transplantation) of polycystic liver disease and evaluated for features of hepatic venous outflow obstruction (HVOO), seen in 92% of the cases, and correlated the findings with clinical parameters.

Modern Pathology

Progression and regression of fibrosis in viral hepatitis in the treatment era: the Beijing classification.
Theise ND, Jia J, Sun Y, et al. Mod Pathol 2018; 31:1191–1200.

New staging system, the Beijing Classification, for assessment of liver biopsies from patients with treated chronic viral (B and C) hepatitis. The Beijing Classification includes extent (stage) of fibrosis, and adds quality of fibrosis to the staging in order to clarify presence of regressive vs progressive fibrosis.

Journal of Gastroenterology and Hepatology
Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas.
Kawashita H, Morine Y, Saito Y, et al. J Gastroenterol Hepato 2018;33(7):1407-1412.

Clinical significance and biological effect of Heat shock factor 1 (HSF1) expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. Specimen from forty‐nine patients with intrahepatic cholangiocarcinoma (IHCC) who underwent hepatic resection was stained with HSF1 immunostain. HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival.

American Journal of Clinical Pathology

Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. 
Lin F, Shi J, Wang HL, et al.  Am J Clin Pathol, 150: 58–64.

Ever wonder what the data is regarding the detection of albumin expression by ribonucleic acid (RNA) in situ hybridization in HCC, ICCs, and carcinomas from various organs using manual and automated staining?  This original article addresses the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) employing 482 cases on tissue microarray sections and on 22 cases of ICCs.  This study concludes that RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs.  Further, rare non-HCC and non-ICC, can also have aberrant expression of albumin. 

Journal of Hepatology

European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. 
Thursz M, Gual A, Lackner C, et al. J Hepatol. 2018 Jul;69(1):154-181.

The July publication of J. of Hepat contains the current clinical practice guidelines for alcohol-related liver disease.  While many clinical aspects are addressed, the article merits a closer read by pathologists specifically regarding the importance of our role in diagnosis, identification of co-morbidities, and in provision of prognostic pathological features. 

Hepatology Snapshot: Drug-induced chronic liver injury.
Dakhoul L, Ghabril M, Chalasani N.  J Hepatol. 2018 Jul;69(1):248-250.

Visit this extremely helpful, easy to use, and guaranteed to make your signouts more efficient tabular illustration of drug induced liver injury by causative agents detailing distinguishing histopathological findings and helpful clinicopathological features. 

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan

Wednesday, September 19, 2018

Save the Date: HPHS Reception at USCAP 2019

Dear Members,

You are cordially invited to join the Hans Popper Hepatopathology Society reception at the USCAP national meeting.  Please save the date:

     Date: Saturday March 16, 2019 6:00-8:00 PM
     Location: National Harbor, Maryland

We look forward to seeing you!

Monday, July 30, 2018

HPHS Journal Watch: May/June 2018

Clinical Gastroenterology and Hepatology

Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple
Steatosis: A Systematic Review and Meta-analysis.

Verhaegh P, Bavalia R, Winkens B, et al. Clin Gastroenterol Hepatol. 2018;16(6):837-861.

This systematic review and meta-analysis studied whether noninvasive tests can differentiate nonalcoholic steatohepatis (NASH) from simple steatosis (SS). There were 122 studies evaluating 219 different blood markers and 22 other tests. Alanine aminotransferase had a pooled sensitivity of 63.5% and specificity of 74.4% to diagnose NASH. Ferritin had pooled sensitivity of 79.1%, specificity of 71.9%, and adinopectin had pooled sensitivity of 72.0% and specificity of 75.7%. The cleaved CK18-M30 as an assay had a pooled sensitivity of 68.4% and specificity of 74.2%. Of –omics approaches, the GlycoNASH test data had a pooled sensitivity of 67.1% and specificity of 63.8%. Scoring systems that combined blood markers, such as NASHTest (combining 10 markers with age, gender, weight, height, and SteatoTest positivity) showed specificity of 95.3% but sensitivity of 22.9% in differentially NASH from borderline NASH and SS. In summary, none of the pooled markers showed both sensitivity and specificity over 80%. More standardized study designs are needed as the majority of the studies contained only limited numbers of patients with significant fibrosis or did not provide the stages of fibrosis.

Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women.
Rubin JB, Hameed B, Gottfried M, et al; Acute Liver Failure Study Group. Clin Gastroenterol Hepatol. 2018;16(6):936-946.

Acetaminophen overdose is the leading cause of acute liver failure (ALF) and acute liver injury (ALI), accounting for approximately 50% of all ALF cases. Previous data regarding drug-induced liver injury have shown that women are noted to be at increased risk for progressing to ALF and require subsequent transplant. From a national registry of 32 academic medical centers, 1162 patients with acetaminophen induced ALI (22%) or ALF (78%) were identified. Their presentation, clinical course, and overall survival between genders were studied. Sixty-eight percent (170) of acetaminophen induced ALI and 76% (864) of ALF patients were women. About half of patients with ALF had unintentional acetaminophen overdose and 40% were suicide attempts. More women than men co-ingested acetaminophen with sedating agents such as opioids or benzodiazepines (70% vs. 52%). On presentation, men had higher ALT, bilirubin, albumin, and MELD scores than women, but otherwise, weight-adjusted ALT was similar.  More women had severe clinical courses, including severe hepatic encephalopathy (68% women vs. 58% men), and need for critical care needs. However, transplant-free survival were similar between male and females.

Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study.
Mehta N, Guy J, Frenette CT, Dodge JL, et al. Clin Gastroenterol Hepatol. 2018;16(6):955-964.

This was a multi-center study using a standardized down-staging protocol (within Milan criteria) to assess outcomes of liver transplantation in such patients. The type of local regional therapy (LRT) was not standardized. Most received TACE alone or in combination with radio-frequency ablation.16% of patients were not down-staged to within Milan criteria. A factor predicting inability to achieve tumor down-staging was pre-treatment AFP≥1000. The number, size of tumors, MELD score, number of LRT sessions were not significant predictors of inability to be down-staged. Successful down-staging to Milan criteria was achieved in 83.4% (median 2.7 months). Majority were down-staged after a single LRT. Of those who were down-staged, 17% (28 of 156) had subsequent tumor progression and were dropped out of the waitlist. 58% of patients received liver transplant. Following transplant, the explanted liver showed tumor staging within Milan criteria in 45.9% of cases (T1/T2); 19.3% of cases turned out to be understaged by imaging and beyond Milan criteria (T3/T4). Median post-LT follow up was 4.3 years with a survival of 95% at 1 year and 80% at 5 years. HCC recurrence developed in 10% of patients at a median of 19.1 months from transplant. Predictors of recurrence included an AFP >500 and vascular invasion. Down-staging resulted in excellent overall 5-year post-LT survival of 80% and recurrence free probability of 87%. Only 7% had micro- or macro-vascular invasion. Treatment failure predictors included a pretreatment AFP of >1000 and Child’s B/C cirrhosis, suggesting that these patients should not be subjected to the risks of LRT.

Journal of Hepatology

Development of the liver: Insights into organ and tissue morphogenesis
Ober EA, Lemaigre FP.  J Hepatol 2018; 68 (5):1049-1062.

Employing the burgeoning modality of three dimensional imaging and distinct model organisms, this study illustrates the growing understanding of morphogenetic processes in the adult liver.  Stages from endodermal budding giving rise to an asymmetric liver, mechanisms leading to liver and lobe development, morphogenesis of the intra and extrahepatic bile ducts, its reaction to injury, and vascular development are discussed. 

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors
De Martin E, Michot JM, Papouin B, et al. J Hepatol 2018; 68 (6): 1181-1190.   

The goal of this large scale and well organized study was to accurately evaluate the incidence of  hepatic immune related adverse events (IRAEs) in patients with metastatic cancer treated with anti-cancer anti-PD-1, anti-PDL1, and anti-CTLA-4 immunotherapy.  Using data gathered in 1,425 patients from August 2015 to August 2017 by the REISAMIC pharmacovigilance register, individuals who developed grade ≥3 hepatitis were identified according to the Common Toxicity Criteria for Adverse Events (CTCAE).  The severity of liver injury was classified according to the Drug-Induced Liver Injury Network (DILIN) 5-point scale.  Acute hepatitis due to cancer immunotherapy was reported in only 3.5% of treated patients.  Two distinct types of immune mediated hepatitis were described:  granulomatous hepatitis with fibrin depositis associated with anti-CTLA-4 mABs; and lobular, non-granulomatous hepatitis associated with anti-PD-1/anti-PDL1 mABs.  The authors concluded that liver biopsies have a key role in detailing the severity of injury and in providing guidance in treatment choices.

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. 
Wardell CP, Fujita M, Yamada T, et al. J Hepatol 2018; 68 (5): 959-969.

Biliary tract carcinomas (BTCs) are a heterogenous group frequently exhibiting poor response to treatment.  This study is a large-scale genome sequencing analyses of somatic and germline driver events and genomic landscape mapping to enhance comprehension of carcinogenesis, better classify, and improve treatment strategies of BTCs.  412 BTC samples were analyzed by whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing using subtypes of intrahepatic cholangiocarcinomas (ICCs), distal cholangiocarcinomas (DCCs), peri-hilar type cholangiocarcinomas (PHCs), and gallbladder or cystic duct cancers (GBCs/CDCs). 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some negatively affecting prognosis, were identified. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.  Learn more and read about BTCs and their distinct genetic features including somatic events and germline predispositions.

Modern Pathology

Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury.
Zen Y, Yeh MM. Mod Pathol 2018; 31: 965–973.

The authors reviewed adverse effects of immune checkpoint inhibitors in liver and compared clinicopathologic features between checkpoint inhibitor-induced liver injury and acute autoimmune hepatitis or idiosyncratic drug-induced liver injury. They have seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2). They also performed IHC for B and T cell markers and found large numbers of CD3+ and CD8+ lymphocytes in immune checkpoint inhibitor treated livers. CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. They conclude that liver injury caused by cancer immunotherapy shares some features with autoimmune hepatitis; however, there are obvious differences between the two conditions.

Journal of Gastroenterology and Hepatology

Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk
Yang Y, Gao J, Tan YT, et al. J Gastroenterol Hepatol 2018 ;33(5):1131-1137. 

Hepatitis B surface antigen (HBsAg) and viral load are both hallmarks of hepatitis B virus (HBV) infection. The authors carried out a nested case–control study including 211 liver cancer cases and 221 controls who were seropositive for HBsAg within two populationbased cohorts. They found that elevated levels of HBVDNA and HBsAg are associated with increased risks of liver cancer. Compared with subjects with HBVDNA < 2000 IU/ml, the adjusted ORs increased from 2.11 (95%CI: 0.99–4.50) to 10.47 (95%CI: 5.06–21.68) for those with HBVDNA level at 2000–19 999 to ≥ 20 000 IU/ml. Compared with subjects at a low level of HBsAg (0.05–99 IU/ml), the adjusted ORs increased from 1.82 (95%CI: 0.90–3.68) to 2.21 (95%CI: 1.10–4.43) for those with HBsAg level at 100–999 to ≥ 1000 IU/ml.


Histological assessment of the liver explant in transplanted hepatitis C virus patients achieving sustained virological response with direct-acting antiviral agents. 
Putra J., Schiano TD., Fiel MI. Histopathol 2018;72(6):990-996.

Direct-acting antiviral agents (DAAs) have transformed the management of patients with chronic hepatitis C virus, and treatments are now associated with sustained virological response (SVR) rates of > 95 %.  With the success of DAAs, histologic examination for hepatitis C has, at least anecdotally, become less commonplace.  This study evaluated the histologic findings of both inflammation and fibrosis, of HCV patients who achieved SVR after receiving DAA treatment and compared them to the histologic findings of a control group of HCV patients who did not achieve SVR and did not receive DAA treatment.  The authors report a lack of demonstrable association between histologic findings and SVR status and persistent inflammation in HCV patients with SVR despite receiving DAAs.

Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. 
Sasami M, Kuo FY, Huang CC, et al. Histopathol 2018;72(7):1164-1171.

Cellular senescence plays a role in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies.  This study investigated the role of cellular senescence, through established senescence markers p16, p21, and NCAM, in patients with biliary atresia, the most common form of pediatric obliterative cholangiopathy.  The study examined expression of these markers in bile ducts and bile ductules at early (Kasai procedure) and late (transplant) stages of biliary atresia and compared them to a normal control group.  Study findings indicate that increased expression of senescence regulators may be involved in the progression of biliary atresia in a manner similar to that observed in adult cholangiopathies.

American Journal of Pathology

Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine.
Gilgenkrantz H, Collin de l’Hortet A. Am J Pathol 2018; 188(6): 1316-1327.

This review article summarizes the published data in the past five years in liver regeneration, discussing the mechanisms leading to regeneration disruption in chronic liver diseases.

Human Pathology

DJ-1 is a useful biomarker for invasive extrahepatic cholangiocarcinoma. 
Tabata Y., Nakanishi Y., Hatanaka Y., et al.  Hum Pathol. 2018;76:28-36.

Through a liquid -chromatography mass spectrometry-based proteomics approach, the authors previously reported that DJ-1 protein is up-regulated in cholangiocarcinoma compared with non-neoplastic bile duct epithelium.  Building on those findings, the authors evaluated expression of DJ-1 in patients with invasive extrahepatic cholangiocarcinoma (EHCC) by evaluating immunohistochemical (IHC) staining for anti–DJ-1 antibody and the impact of IHC staining score on postoperative survival.  Additionally, serum levels of DJ-1 in invasive EHCC patients with and without metastasis were compared.  Although limited by the number of patients studied, DJ-1 protein in IHC staining and serum examinations may offer a biomarker for prognosis in patients with invasive EHCC.

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.
Pu XH., Ye Q., Yang J., et al. Hum Pathol. 2018; 76:100-109.

Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several tumor types, including intrahepatic cholangiocarcinoma (ICC).  Multiple clinical trials are under way for repurposing the drugs that target the FGF signaling pathway as an innovative ICC treatment.  In Western countries, the   frequency of FGFR2 fusions in ICC ranges from a reported 7%-45%.  This study assess the incidence of FGFR2 aberrations, including translocations and amplification, in Chinese patients.  122 ICCs were evaluated for translocations and amplifications of FGFR2 by fluorescence in situ hybridization as well as protein expression by immunohistochemistry.  The relationship between genetic aberrations and protein expression were then compared to clinicopathologic characteristics and prognostic outcomes.  Molecular aberrations were identified in 23/122 (19%) of tumors.  Low-level amplification of FGFR2 was twice as common as FGFR2 translocation; and these tumors were generally of lower stage and associated with better overall survival.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Cynthia Guy MD; Duke University
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan

Friday, July 13, 2018

Interesting Case: July 2018

Case contributed by:
 Iván González, M.D., resident, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
Deyali Chatterjee, M.D., Assistant Professor, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO

Clinical History
A 71-year-old man with a history of orthotopic liver transplant in 2013 secondary to idiopathic hepatic artery dissection (without previous episodes of acute cellular rejection) presented five years later with transaminitis and hyperbilirubinemia (AST 596 U/L, ALT 743 U/L, alkaline phosphatase 203 U/L), preceded by a viral-like illness. An extensive infectious work-up was negative, other than a CMV viremia of 6447 IU/mL by PCR, for which he was treated with valganciclovir. Liver biopsy showed a mixed portal infiltrate, bile duct injury without ductular reaction, lobular neutrophilic microabscesses, and zone 3 injury with dropout and hemorrhage. He was treated with prednisone without improvement. Over the next 5 months, he developed worsening liver failure (AST 107 U/L, ALT 201 U/L, alkaline phosphatase 88 U/L, total bilirubin 36.6 mg/dl, direct bilirubin 35 mg/dl) and renal failure, and underwent a second liver transplant (explant images shown here).

Imaging Findings
Computed tomography demonstrated an aneurysmal dilatation of the celiac artery with marked short segment narrowing of the origin of the common hepatic artery.  ERCP did not reveal any biliary strictures.



The explant showed submassive hepatocellular necrosis with marked cholestasis, and markedly dystrophic changes in bile duct epithelium in the portal tracts, but there was no ductopenia. Ductular reaction was conspicuously absent. The portal tracts showed mild chronic inflammatory infiltrate, associated with mild focal endothelialitis, and reduced number of small arterial branches. Medium-sized bile ducts showed periductal fibrosis along with dystrophic epithelial changes. Large bile ducts showed foci of intraepithelial lymphocytes, and focal reactive changes. There was central perivenulitis, with foci of lobular microabscesses. There was no foam cell arterial lesion, fibro-muscular intimal thickening, or inflammatory infiltration of muscular arteries. Trichrome stain highlighted fine perisinusoidal fibrosis, extending to portal tracts, but there is no bridging fibrosis. Reticulin showed a largely preserved architecture. A cytomegalovirus immunostain was negative.

Histologic features of chronic rejection and ischemia.

We present an intriguing and unusual presentation of chronic rejection (CR).This challenging case was reviewed by several prominent pathologists within and outside our institution.

CR is an immune-mediated irreversible injury to the bile ducts, arteries and veins, that usually has an insidious onset and is often preceded by prior episodes of acute cellular rejection (ACR), that get progressively resistant to treatment. Nowadays less common with improved immunosuppression, another clinical setting includes a more acute presentation, with rapid progression of graft failure within a few weeks after transplantation. There can also be a late CR with insidious onset and indolent clinical course, without preceding ACR. The clinical course observed in our case, an accelerated clinical course although presenting late after transplantation (> 5 years), is therefore very unusual.

The histologic diagnostic features for CR include presence of dystrophic bile duct epithelium, bile duct loss, and foam cell obliterative arteriopathy. Some cases of late CR have also been reported to show chronic hepatitis-like changes.  As has been described with acute presentations of chronic rejection, this case showed prominent inflammatory infiltrate, including endothelialitis and perivenulitis, which initially raised the histologic concern for acute rejection. The patient however remained unresponsive in spite of marked immunosuppressive therapy, and over time in the course of a few months, the inflammation reduced (reflected by the decrease in liver enzymes) whereas the bile duct dystrophy became more conspicuous, characteristically with no ductular reaction. With these clinical and histologic features, this was deemed as an unusual course of CR.
With the abnormal imaging and operative finding of the small caliber of proximal hepatic artery, and due to histologic overlap with CR, a component of ischemic cholangiopathy could not be entirely excluded. 

Although rare, acute presentation of chronic rejection can occur at any time interval after transplantation. Although cases of chronic rejection presenting acutely can show histologic overlap with acute cellular rejection especially early in the clinical course, dystrophic biliary epithelial changes, absence of ductular reaction, and unresponsiveness to immune suppressive therapy should indicate development of chronic rejection. Ductopenia or foam cell arteriopathy may not be seen in these cases which have an accelerated clinical course.

1-     Burt A, Ferrell L, Hubscher S. MacSween’s Pathology of the Liver. 7th edition. Churchill Livingston Elsevier; 2018. Chapter 14, Transplantation Pathology. 
2-     Demetris A, Adams D, Bellamy C, et al. Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000; 31(3): 792-799.
3-     Blakomer K, Jain A, Ruppert K, et al. Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathologic staging. Transplantation 2000; 69(11): 2330-2336.
4-     Mourad M, Algarni A, Liossis C, Bramhall S. Aetiology and risk factors of ischaemic cholangiopathy after liver transplantation. World J Gastroenterol 2014; 20(20): 6159-6169.

Sunday, July 1, 2018

President's Message July 2018

Dear Friends and Fellow Hepatophiles, 

In recent years, the Society has broadened its activities that would benefit the members. I would like to take the opportunity to highlight some of these activities in this message.

The Journal Watch effort started in 2015 and presents a concise summary of important advances in liver diseases. In addition to pathology journals, relevant articles published in clinical journals are included in the review. The Journal Watch effort is spearheaded by the Education committee chaired by Daniela Allende and includes 6 additional members. If there is an important article that you would like to share with the membership, please send it to the Education committee.

Another regular activity of the Society is the quarterly newsletter apprising the membership of important events and endeavors of the Society. The newsletter is put together by the Newsletter/Publications committee led by Stephen Ward along with 4 other members. The newsletter also includes interesting cases, an activity that dates back to 2009. It has become a more regular feature in recent years and many of the write-ups reach the standards of published case reports in journals.

If you would like to join any of the committees, you can indicate your interest while renewing your membership or contacting us at any time. You can also contribute a case in the newsletter. Case write-ups are an excellent opportunity for residents/fellows interested in liver pathology to start contributing to the Society early in their career. Your feedback and participation is the key for the ongoing success of the Society. Best wishes to all for a wonderful summer.


Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society

Saturday, May 26, 2018

HPHS Journal Watch: March/April 2018

American Journal of Surgical Pathology
MDM2 is an independent oncogene and also a negative regulator of p53. A recent whole-exome sequencing study identified MDM2 amplification in 5% of cholangiocarcinomas. The investigators sought to determine the frequency of MDM2-amplified intrahepatic cholangiocarciomas (iCCAs) and evaluate their clinicopathologic features. The study cohort consisted of surgical resections from Korean and Japanese patients. Tissue microarrays (TMAs) were constructed and tested for MDM2 amplification by in situ hybridization. Tumors that showed MDM2 amplification on TMA had whole tissue sections made and were re-tested to assess for heterogeneity in MDM2 amplification. In addition, all MDM2-amplified and 25 MDM2-nonamplified iCCAs were sequenced for KRAS and IDH1/2 mutations. All cases were tested for SMAD4 expression by immunohistochemistry.
MDM2-amplification was found only in iCCAs with large-duct type morphology and comprised 6% of cases; amplification was diffuse in 77% of iCCAs. KRAS and IDH1 mutations were only detected in MDM2-nonamplified iCCAs. Loss of SMAD4 expression was more frequent in MDM2-amplified iCCAs. Patients with MDM2-amplified iCCAs had a worse survival than those without MDM2-amplification (median survival 16 vs. 28 mo., median follow-up 39 mo.); however, when comparing only patients with large-duct type morphology iCCAs, MDM2-amplified and MDM2-nonamplified patients showed no statistically significant difference in survival. In summary, this study identified that MDM2-amplification is present in a subset of iCCAs and MDM2 inhibitor therapy may play a role in the future.

Liver Transplantation
This review summaries the use of radiation therapy for hepatocellular carcinoma, makes comparisons with other local ablative therapies, and addresses potential novel strategies for optimizing future utility.
Currently, normothermic machine perfusion (NMP) of donor livers using packed red blood cells and fresh frozen plasma is being used in clinical trials, and some suggest it will revolutionize organ transplantation. This paper discusses using NMP with a new synthetic solution created from a polymerized bovine hemoglobin-based oxygen carrier and a gelatin-based colloid suspension as an alternative to using scare and expensive human blood products. Included is a brief discussion, with photomicrographs, of NMP-related histopathologic ischemia-reperfusion injury changes.

This is a nice and fairly comprehensive review of the interplay between the gut microbiota and the liver in health and disease. 

Clinical Gastroenterology and Hepatology
Classically, in adults, the histologic findings of NASH include zone 3 steatosis, inflammation, and ballooned hepatocytes. In children, on the other hand, fatty liver disease may have fewer ballooned hepatocytes, more portal based inflammation, and can have zone 1 steatosis. The purpose of this study was to determine clinically relevant associations between zone 1 vs. zone 3 steatosis in children. Liver biopsies of 776 pediatric patients were scored for degree and location of steatosis, inflammation (lobular & portal), ballooned hepatocytes, and fibrosis.
19% had zone 1 steatosis, 31% had zone 3, and the remaining were panacinar (42%) or azonal (8%). Compared with children with zone 3 steatosis, those with zone 1 steatosis were younger, more likely to be Hispanic, have higher fasting triglyceride levels, male, and have higher AST. Children with zone 3 steatosis had higher waist circumference and blood pressure.
Biopsies with zone 3 steatosis had more ballooned hepatocytes than those with zone 1, higher NAFLD activity score, and NASH. Those with zone 1 steatosis had more portal inflammation and more fibrosis, with 2.34 times the odds of having advanced fibrosis compared to zone 3 steatosis patients.
In conclusion, zone 1 vs. zone 3 steatosis in pediatric NAFLD have informative risk differences in fibrosis and steatohepatitis, with zone 1 patients being more likely to be younger, Hispanic, and male; importantly they are more likely to have fibrosis.

The authors report a case of a 50-year-old woman presenting with concurrent erythema multiforme and autoimmune hepatitis. Despite the presence of several confounding factors, the authors do a convincing job of establishing the diagnosis. There is a brief discussion regarding the challenge of distinguishing lupus-related hepatitis from autoimmune hepatitis, and the clinical significance of doing so.

The authors report an unusual case of hepatocellular carcinoma (HCC) presenting as a lateral eyebrow skin metastasis in an 83-year-old man who was subsequently found to have alcoholic cirrhosis. There is a brief discussion on the limited literature on HCC cutaneous metastases.

American Journal of Pathology
This study evaluated the differences in progenitor cell niche activation between primary sclerosing cholangitis (PSC) (n=20), primary biliary cholangitis (PBC) (n=20), and healthy livers (n=5). Ductular reaction, progenitor cell phenotype, and signaling pathways were investigated by IHC and immunofluorescence. Ductular reaction was found to be more expansive and more proliferative in PBC than PSC. Ductular reaction correlated with fibrosis and clinical prognostic risk scores both in PSC and PBC. The ductular phenotype was predominantly biliary in PBC, as compared to signs of hepatocyte commitment in PSC.

Small-RNA sequencing was used to profile miRNA expression in cirrhotic nodules (CNs), dysplastic nodules, early HCCs, and small progressed HCCs in 17 patients having chronic liver disease of various etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. The authors suggest that identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early HCC diagnosis.

Modern Pathology
These authors shed much needed light on the difficult subject of diagnosing liver graft versus host disease by creating a three-tiered scoring system and histopathological algorithm. Their results show a high sensitivity, specificity and accuracy when compared to controls, including drug-induced liver injury cases. This is an exciting and “must read” paper.  

The aim of this study was to identify the relationship of xanthogranulomatous cholecystitis (XGC) with IgG4-related cholecystitis.  The histological features of 57 XGC cases were compared with those of 104 conventional chronic cholecystitis (CC) cases.  XGC cases showed increased gallbladder wall thickening and histiocytic infiltration as compared with CC cases.  XGC cases also more commonly showed dense lymphoplasmacytic infiltration, storiform fibrosis, and extensive IgG4+ plasma cell infiltration.  XGC demonstrated an increased mean number of IgG4+ plasma cells (35/hpf) as compared with CC (5/hpf) [p <0.001].  The XGC cases were further classified based on a cut-off of 50 IgG4+ plasma cells because this threshold was proposed for IgG4-related disease in the liver, pancreas, and bile duct.  IgG4-high XGC cases (n=16) had a mean number of 78 IgG4+ plasma cells compared to IgG4-low XGC cases (n =41) that had a mean number of 11 IgG4+ plasma cells.  Nine IgG4-high XGC cases (16%) had denser lymphoplasmacytic infiltration, fibrosis, and a higher IgG4/IgG ratio, suggesting that a subset of XGC cases share histological features with IgG4-related cholecystitis.  XGC cases with histological features suggestive of IgG4-related cholecystitis were also found to show clinical features such as extracholecystic involvement and mass-forming inflammation.  Of the nine IgG4-high XGC cases that had histologic features suggestive of an IgG4-related disease, only one case also had IgG4-related disease at another site.  The study findings suggest that XGC and IgG4-related cholecystitis have overlapping histologic features but are at best weakly associated with other typical organ manifestations of IgG4-related disease.

This is a prospective, biopsy-controlled, study conducted to compare 10 liver fibrosis markers in 289 patients [Enhanced Liver Fibrosis test (ELF), FibroTest, transient elastography, 2-D shear-wave elastography, and 6 indirect marker tests] in detection of advanced liver fibrosis (defined as Kleiner stage > F3).  The liver biopsy fibrosis stage was used as the reference standard.  The aim of the study was 1) to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease in primary and secondary health centers using a literature-established cutoff value of 10.5 as seen in the setting of NAFLD; and 2) to assess the diagnostic accuracy for significant fibrosis or cirrhosis and to determine whether combinations of fibrosis markers increases diagnostic yield.  The prevalence of advanced fibrosis by liver biopsy was 23% (66/289); 6% (8/128) in primary care and 36% (58/161) in secondary care. Both ELF and FibroTest identified advanced fibrosis with comparable high accuracy (AUROC of 0.92 and 0.90, respectively) in both primary and secondary care settings. ELF >10.5 correctly diagnosed advanced fibrosis in 79% of patients and absence of advanced fibrosis in 91%.  In the primary care setting, for an ELF score < 10.5, the negative predictive value to rule out advanced fibrosis was 98%, but the positive predictive value to affirm a diagnosis of advanced fibrosis was lower at 60%.  ELF better identified patients with advanced liver fibrosis than indirect markers.  However, combining ELF and FibroTest did not increase diagnostic yield of detecting advanced liver fibrosis and did not differ from transient elastography. The study suggests that ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference).

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis) and pancreas (autoimmune pancreatitis). The sera of patients with IAC/AIP was compared control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies for reactivity against human H69 cholangiocyte lysates on immunoblot. The choice of PSC sera as one of the controls is interesting as it is recognized that in a subset of patients there is an overlap with IgG4-RD. Annexin A11 was identified as the main target antigen. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD and not in controls.  Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. This suggests that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Cynthia Guy MD; Duke University
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan