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