HPHS Journal Watch: November / December 2018

Human Pathology 

Genomic structures of dysplastic nodule and concurrent hepatocellular carcinoma.
Lee M, Kim Ku, Kim SY, et al. Hum Pathol 2018 Nov;81:37-46. 
This study used whole-exome sequencing to investigate genomic alterations in high-grade dysplastic nodules (HGDN) and its differences from hepatocellular carcinomas in the hopes of identifying genetic features  that may drive HGDN progression to HCC. Paired HGDNs and HCCs in 6 patients were studied. Although the numbers of mutations, driver mutations, and copy number alterations of HGDNs were not significantly different from those of HCCs, the study discusses some genetic alterations specific to HCCs.
Histologic features of autoimmune hepatitis: a critical appraisal.
Gurung A, Assis D, McCarty TR, et al. Hum Pathol 2018 Dec;82:51-60.
The authors hypothesize that the typical histologic features (lymphoplasmacytic interface hepatitis, emperipolesis, and hepatocyte rosettes) of AIH are related to the severity of hepatitis rather than etiology.  The authors analyzed the histologic features in liver biopsies in AIH patients before treatment and compared them with biopsies from patients with
hepatitis C virus (HCV) infection with similar inflammatory grade and stage of fibrosis.  From the findings, a modified score system excluding emperipolesis and hepatocyte rosette was developed.  The authors showed that this scoring system improved the specificity of AIH diagnosis, but with a decrease in sensitivity.


Risk of Hepatocellular Cancer in Patients with Non-Alcoholic Fatty Liver Disease.

Kanwal F, Kramer JR, Mapakshi S, et al. Gastroenterology 2018 Dec;155(6):1828-1837.
The exact risk of HCC in NAFLD is not fully known. In this large retrospective cohort study, the risk of HCC was 7 fold higher in patients with NAFLD than matched controls. The risk of HCC was the highest in NAFLD patients with cirrhosis. This study is the first to quantify the absolute risk of HCC in a large, geographically and ethnically diverse cohort of NAFLD patients.
Evidence of Chronic Allograft Injury in Liver Biopsies From Long-Term Pediatric Recipients of Liver Transplants.
Feng S, Bucucalas JC, Demetris AJ, et al. Gastroenterology 2018 Dec;155(6):1838-1851.
A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury.  The authors studied nearly 160 long-term pediatric recipients in order to determine whether there are distinct patterns of injury based on histopathologic features (interface activity, periportal or perivenular fibrosis, neither feature) and identified associated immunologic profiles. Systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data was performed. In an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, the authors found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with T-cell mediated rejection.
Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.
Nahon P, Layese R, Bourcier V, et al. ANRS CO12 CirVir Group. Gastroenterology 2018 Nov;155(5):1436-1450.
Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with HCV) associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy versus patients treated with interferon (IFN). Analysis reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.
GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease.
Loomba R, Kayali Z, Noureddin M, et al. Gastroenterology 2018 Nov; 155(5):1463-1473.

In a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver,  decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. Due to the short duration of the trial, liver biopsies were not conducted and patients with cirrhosis were also excluded.

Journal of Hepatology

Hepatology Snapshot: The role of Kupffer cells in hepatic iron and lipid metabolism.
Scott CL, Guilliams M.  J Hepatol 2018; 69 (5):1197–1199. 
Visit the November edition of the Journal of Hepatology and learn more in a snapshot about the role of Kupffer cells in hepatic iron and lipid metabolism.  Briefly, in homeostatic conditions, Kupffer cells express genes involved in uptake, processing and export of iron.  This iron metabolism gene module is controlled by the transcription factors SPI-C and NRF2.   The gene expression profile of Kupffer cells is enriched for genes involved in the uptake, processing and export of excess cholesterol. This lipid metabolism module is likely controlled by the LXR and PPAR family of transcription factors. 
Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort.
Clark VC, Marek G, Liu Ch, et al. J Hepatol 2018; 69 (6): 1357-1364.   
Alpha-1 antitrypsin deficiency (AATD) is an uncommonly documented cause of liver disease in adults.  In this article, authors sought the occurrence and severity of liver fibrosis in an adult AATD population who were not recognized to have cirrhosis, while having risk factors for fibrosis and testing non-invasive markers of disease.  94 adults with definitive genotype ‘PI*ZZ’ AATD were included.   Liver aminotransferases and indicators of synthetic function, transient elastography, and liver biopsy were performed.  The prevalence of clinically substantial liver fibrosis (F ≥ 2) was 35.1%.  Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group.   Individuals identified with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the buildup of abnormal alpha-1 antitrypsin in the liver.  A liver biopsy in ZZ individuals can identify the increase of alpha-1 antitrypsin within the liver and reveal if any associated liver scarring is existent.  Individuals with considerable quantities of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Further, comorbid common medical conditions of diabetes, obesity, high cholesterol, and hypertension (metabolic syndrome) are associated with a greater degree of liver injury.

American Journal of Surgical Pathology

Heterogeneity of Fibrosis in Liver Biopsies of Patients with Heart Failure Undergoing Heart Transplant Evaluation
Dhall D, Kim SA, Mc Phaul C, et al. Am J Surg Pathol. 2018 Dec;42(12):1617-1624.
Heterogeneity in fibrosis on biopsy can pose a challenge for pathologists and clinicians, particularly in patients with congestive hepatopathy (CH). 50 liver biopsies from patients with CH undergoing evaluation for heart transplant were reviewed. 52% showed differences in fibrosis in different areas of the biopsy (termed variable fibrosis/VF); furthermore, half of these cases (26%) showed a 2 stage or more difference (termed heterogenous fibrosis/HF). In comparison to their respective follow-up biopsies and explants (when available), differences in fibrosis stage or areas showing the non-uniform nature of fibrosis were found in some cases. Nodular regenerative hyperplasia was found in 18% of cases and all of these cases showed at least some areas with increased fibrosis. Given these findings, the authors recommend that our reports should specify (1) whether fibrosis is homogeneous or heterogeneous, (2) the range of fibrosis in a given biopsy, and (3) the dominant apparent stage of fibrosis. In conjunction with other laboratory studies, clinical parameters, and imaging, this information on fibrosis stage can better assist treatment planning in CH.
Recurrent Mutations in APC and CTNNB1 and Activated Wnt/B-catenin Signaling in Intraductal Papillary Neoplasms of the Bile Duct.
Fujikura K, Akita M, Ajiki T, et al. Am J Surg Pathol. 2018 Dec;42(12):1674-1685.
This study builds on previous data from these authors who recently proposed classifying intraductal papillary neoplasm of the bile duct (IPNB) into two subtypes: (1) classic IPNB and (2) papillary cholangiocarginomas (PC). A combination of whole exome sequencing and targeted sequencing was performed on 28 cases. Mutations in APC or CTNNB1 were present in 21% of cases and were seen in IPNBs, specifically non-intestinal histologic types, but not in PCs. These findings suggest that activation of the Wnt/B-catenin pathway may play an important role in IPNB pathophysiology.
Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome.
Bove KE, Thrasher AD, Anders R, et al. Am J Surg Pathol. 2018 Dec;42(12):1625-1635.
This study gives new insight into the cause of biliary atresia (BA) and has particular relevance for pathologists who encounter such cases. This study reports the findings in 172 patients who had centrally reviewed and standardized protocol-driven pathologic examination through the ChiLDReN Network. A very detailed histologic evaluation and data analysis was performed to correlate numerous findings with clinical parameters and outcome. Given this data from the largest study to date performed in this manner, the authors believe that extrahepatic BA occurs by a process of active fibroplasia followed by fibrous/fibromyxoid luminal obliteration. Epithelial regression or damage may not be an initial event. The authors further hypothesize that outcome after Kasai portoenterostomy results from an imbalance between active fibroplasia and re-epithelialization of lumens.

Clinical Gastroenterology and Hepatology

Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease.

Caussy C, Chen J, Alquiraish MH, et al. Clin Gastroenterol Hepatol 2018;16:1974–1982
It is unclear what the optimal approach for non-invasively detecting the degree of liver fibrosis is for patients with high BMI and non-alcoholic fatty liver disease. This study attempted to compare whether TE correlates with MRE depending on BMI with the hope that TE would be sufficient and no additional MRE would have to be used. The aim was to assess the association between BMI and discordance between MRE and TE in staging fibrosis. 119 American adults with suspected NAFLD who simultaneously underwent liver biopsy, MRE, and TE were included. Liver biopsy was gold standard. The effectiveness of imaging was judged according to whether it could detect fibrosis stages dichotomized as 0-1 vs. 2-4. Afterwards, independent validation was performed using a separate institution cohort of 75 cases. MRE and TE were considered concordant if they both correctly staged fibrosis according to liver biopsy assessment. Overall, the discordance rate between MRE and TE for both institution cohorts was 43% and 45% respectively. BMI was the significant predictor of whether MRE and TE would be discordant with each other. As BMI increased, the discordance rate between MRE and TE would increase. In addition, the discordance rate between MRE and TE was significantly higher if the BMI>35 kg/m2 compared to patients with BMI <35 kg/m2. Of note, in the main cohort, MRE was discordant from liver biopsy in 21% whereas TE was discordant in 52%.  In summary, this study shows that BMI is a significant factor of discordance between MRE and TE in staging fibrosis. Given the high prevalence of obesity with NAFLD, these results have important ramifications in trying to use either test for detecting liver fibrosis in obese individuals.

Liver transplantation

Lymphocyte-to-Monocyte Ratio Is a Predictor of Survival After Liver Transplantation for Hepatocellular Carcinoma.

Mano Y, Yoshizumi T, Yugawa K, et al. Liver Transpl. 2018 Nov;24(11):1603-1611.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death. Recent studies have shown that systemic inflammation was correlated with poorer prognosis in various cancers. The authors investigated the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients who underwent living donor liver transplantation (LDLT) for HCC. They retrospectively analyzed the records of 216 patients who underwent LDLT for HCC. Patients were divided into high (n = 126) and low (n = 90) LMR groups. Their clinicopathological parameters and survival times were compared. To determine the mechanisms of the change in the LMR, they performed immunohistochemical analyses of CD3 and CD68 expression. The numbers of cells with cytoplasmic or membrane staining in 5 high-power fields (HPFs) were counted. A low LMR was significantly associated with a high Model for End-Stage Liver Disease score; a high Child-Pugh score; elevation of alpha-fetoprotein, des-gamma-carboxyprothrombin, and neutrophil-to-lymphocyte ratio; larger tumor size; more tumors; and poorer prognosis. A low LMR was associated with poor prognosis and represented an independent prognostic factor, particularly among patients beyond the Milan criteria. The ratio of CD3-positive to CD68-positive cells was significantly lower in the low-LMR group. In conclusion, their results show that the LMR was an independent predictor of survival of patients with HCC beyond the Milan criteria who underwent LDLT. The LMR reflected the immune status of the tumor microenvironment.


Idiopathic Portal Hypertension.
Hernandez-Gea V, Baiges A, Turon F, et al. Hepatol 2018; 68(6): 2413-2423.
This review articles nicely summarizes the most recent understanding of idiopathic non-cirrhotic portal hypertension (INCPH), though it continues some of the ambiguity regarding language and terminology (an issue addressed in a recent consensus article by the International Liver Pathology Study Group in the January issue of Histopathology) surrounding this clinicopathologic complex.
Nodular Regenerative Hyperplasia Associated with Immune Checkpoint Blockade.
LoPiccolo J, Brener MI, Oshima K, et al. Hepatol 2018; 68(6): 2431-2433.
The authors report a case of NRH associated with the anti-PD1 agent pembrolizumab. Immune checkpoint inhibitors can lead to a hepatitis as part of a spectrum of immune-related adverse events, but this case suggests NRH can also be part of the histologic spectrum of immune checkpoint inhibitor drug-induced liver injury (DILI).


Liquid biopsy for liver diseases.
Mann J, Reeves HL, Feldstein AE. Gut 2018;67:2204-2212.
There is an increasing literature about the potential role of liquid biopsies in a range of organ systems and disease types. This review focuses on the liver and while not having a direct impact on the way that histopathologists work, is both of general interest and a guide as to the way the way in which diagnostics is going.
A liquid liver biopsy may be defined as “a non-invasive reliable biomarkers that can supplement and eventually replace the invasive liver biopsy for diagnosis, disease stratification and monitoring of response to therapeutic interventions”. In the case of the liver interest has focused on, liver cancer. Circulating extracellular vesicles, nucleic acids (DNA and RNA) and tumour cells have emerged as potential liquid biopsy candidates. This work, however is not limited to cancer.  For example, differences in micro RNAs profiles have been demonstrated between HCV and HBV as well as between alcoholic hepatitis and non-alcoholic steatohepatitis extending the potential range of liquid biopsy beyond malignant liver disease.
Prepared by (in alphabetical order):
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; University of California Irvine
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
Maria Westerhoff MD; University of Michigan
Eric Yee MD; University of Arkansas for Medical Sciences

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