HPHS Journal Watch: May/June 2020


Clinicopathological features and outcomes of parenchymal rejection in liver transplant biopsies.

Fels Elliott DR, Tavakol M, Calixto‐Hope L, et al. Histopathology May; 76(6): 822-831.


The authors performed a retrospective analysis of liver transplant biopsies with parenchymal rejection (PR), and compare PR with portal-based acute cellular rejection (ACR). Biopsies from 173 patients were evaluated (retrospective database search 1990-2017), including 49 isolated PR, 35 PR with portal ACR (PR/ACR), 34 mild ACR and 52 moderate ACR cases. The rise and fall of serum liver enzymes was calculated as a measure of acute liver injury and response to immunotherapy, respectively. Isolated PR was associated with delayed-onset acute rejection (P < 0.001), as well as younger age (P = 0.004), and showed a similar rise in liver enzymes to mild ACR. PR/ACR and moderate ACR showed the highest elevations in transaminases (P < 0.05). Isolated PR on an initial biopsy was associated with recurrent episodes of PR (P = 0.01), chronic ductopenic rejection (P = 0.002) and chronic vascular rejection (P = 0.017). Immunohistochemistry for C4d was performed, and strong C4d staining of venules was only detected in one severe isolated PR case (one of three, 33%) and one moderate ACR case (one of 20, 5%). The authors conclude that isolated PR represents a form of late acute rejection with distinct clinical and histological features. There is value in reporting PR in liver transplant biopsies to identify patients at higher risk of developing recurrent PR and chronic rejection. Standardization of terminology and histological criteria of PR can help in uniform reporting and ensure appropriate management.

Biliary intraductal tubule‐forming neoplasm: a whole exome sequencing study of MUC5AC‐positive and ‐negative cases.

Akita M, Hong SM, Sung YN, et al. Histopathology Jun; 76(7): 1005-1012.


Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear. The authors aimed to elucidate genetic features of biliary intraductal tubular neoplasms. Six resected cases of biliary intraductal neoplasm with >70% tubular configuration were characterized by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n = 2) and -positive cases (n = 4). The intraductal tumors consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n = 2), perihilar (n = 1) and distal bile ducts (n = 1). MUC5AC-negative cases harbored mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas. The authors conclude that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.


Quantifying and monitoring fibrosis in non-alcoholic fatty liver disease using dual-photon microscopy.

Wang Y, Wong GL, He FP, et al. Gut Jun; 69(6): 1116-1126.


It is well accepted that fibrosis is a key prognostic factor in metabolic associated fatty liver disease and is increasingly being used as the endpoint for clinical trials. This can be challenging, as the changes in fibrosis scores over the relatively short length of such trials is small (and subjective). Even the use of Sirius Red staining and automated image analysis has not resolved this problem. Dual-photon microscopy, which can be applied to unstained sections, allows automated quantification of fibrosis-related parameters (q-FPs), and has already been applied to several different liver diseases including HBV. This paper describes the application of this techniques to 428 liver biopsies taken from 344 patients.  The technique generates information about many fibrosis related measurements including the perimeter of collagen fibres and the number of long collagen fibres both of which had high sensitivities and specificities for fibrosis stage in the validation cohort. At a median follow-up of 5.6 years, baseline q-FPs predicted liver-related events. These results are interesting and potentially significant, but this technique is unlikely to be used, anytime soon, other than as a research tool or in clinical trials.

American Journal of Clinical Pathology

Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies.

Ju JY, Dibbern ME, Mahadevan MS, et al. Am J Clin Pathol May; 153: 598-604.


Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. The authors analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining, and submitted all results with MMR loss for MSI testing.  The authors found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001).  No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. 

Smooth Muscle Distribution Patterns of Choledochal Cysts and Their Implications for Pathogenesis and Postoperative Complications.

Hwang HS, Mee-Jeong K, Seung-Soo L, et al. Am J Clin Pathol June; 153: 760-771.


This study suggests that histopathologic characteristics of choledochal cysts based on smooth muscle distribution are predictive of postoperative complications.  Briefly, smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated.  Mean patient age was 23.3 ± 19.8 years, with male:female ratio of 0.3.  Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%).  Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P < .001) compared to cysts with thick muscle bundles. Severe chronic cholangitis (P = .049), pyloric metaplasia (P = .019), mucosal smooth muscle aggregates (P < .001), biliary intraepithelial neoplasia (P = .021), and associated bile duct (P = .021) and gallbladder carcinomas (P = .03) were more common in adults (age >20 years vs ≤20 years).

Journal of Hepatology

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma.

Müller M, Bird TG, Nault JC. J Hepatol. May; 72(5): 990-1002.


Chronic liver disease and primary liver cancer are immense worldwide concerns with reported increasing prevalence.  HCC, the most prevalent form of primary liver cancer, occurs following years of chronic liver disease.  This review article addresses the landscape of progressive gene mutations, using recent technological advances in genomic sequencing, that fuel carcinogenesis in chronic liver disease mainly during its end stages.  The authors sought to define key driver mutations and contributory passenger mutations that can be used to track tumor evolution. 

Update on NAFLD genetics: From new variants to the clinic.

Trépo E, Valenti L. J Hepatol. June; 72(6): 1196-1209.


This review article provides compelling new insights into the biology of NAFLD using genome-wide association studies demonstrating reproducible associations between variation in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13 and the natural history of NAFLD.  NAFLD is highly prevalent in high-income countries with increasing burden at an alarming rate. The risk of developing NAFLD and related complications is highly variable among individuals and is determined by environmental and genetic factors.  Novel genome-wide association studies have uncovered robust and reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13 and the natural history of NAFLD.

Human Pathology

Regenerative hepatic pseudotumor: a new pseudotumor of the liver.

Torbenson M, Yasir S, Anders R, et al. Hum Pathol May; 99: 43-52.


This study describes a new pseudotumor of the liver: a reactive, hyperplastic mass-like lesion that forms in association with localized vascular thrombi. This lesion can closely mimic other benign or malignant hepatic tumors on imaging and histology.

DNA flow cytometric analysis of paraffin-embedded tissue for the diagnosis of malignancy in bile duct biopsies.

Lee H, Rabinovitch P, Mattis A, et al. Hum Pathol May; 99: 80-87.


Differentiation of reactive versus neoplastic epithelial changes can be challenging in bile duct biopsies. Aneuploidy assessment by DNA flow cytometry was performed on formalin-fixed paraffin-embedded (FFPE) tissue from 63 bile duct biopsies: 10 with a malignant diagnosis; 3 with an atypical diagnosis; 28 likely reactive biopsies; and 22 benign. Aneuploidy was detected in 10 of the 13 biopsies with definite neoplasia or atypia, and none of the 50 benign biopsies. The estimated sensitivity of aneuploidy as a diagnostic marker of malignancy (adenocarcinoma and HGD) was 70%, with the specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. Although the sample size is small, the results indicate that this assay can be potentially useful in challenging atypical cases.


The May issue of Gastroenterology aims to provide an up-to-date resource for clinicians and researchers on the risk factors, natural history, diagnosis and treatment of NAFLD. It highlights a selection of scientific topics pertinent to the development and progression of NAFLD: adipose tissue-liver interactions, the gut microbiome, and factors that lead to hepatic fibrogenesis given its importance to patient outcome. It also showcases some newer concepts pertinent to NAFLD: the importance of circadian rhythms in disease development and treatment, and the notion that the liver plays a central role in the extrahepatic complications of fatty liver disease, including cardiovascular and central nervous system disease. From a scientific and clinical perspective, this issue aims to provide a map of the complex interactions within and outside the liver in defining the disease course and outcomes in NAFLD. The links are below:

Nonalcoholic Fatty Liver Disease in 2020

Maher JJ, Schattenberg JM. Gastroenterology May; 158(7): 1849-1850.  https://pubmed.ncbi.nlm.nih.gov/32302525/

Nonalcoholic Fatty Liver Disease 2020: The State of the Disease

Cotter TG, Rinella M. Gastroenterology May; 158(7): 1851-1864. 


Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond

Krawczyk M, Liebe R, Lammert F. Gastroenterology May; 158(7): 1865-1880. 


Nonalcoholic Fatty Liver Disease: Modulating Gut Microbiota to Improve Severity?

Aron-Wisnewsky J. Gastroenterology May; 158(7): 1881-1898. 


Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease

Azzu V. Gastroenterology May; 158(7): 1899-1912. 


Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis

Schwabe RF, Tabas I, Pajvani UB. Gastroenterology May; 158(7): 1913-1928. 


Metabolic Inflammation—A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?

Saran AR, et al. Gastroenterology May; 158(7): 1929-1947. 


Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease

Saran AR, et al. Gastroenterology May; 158(7): 1948-1966. 


Nonalcoholic Fatty Liver Disease in Children: Unique Considerations and Challenges

Goldner D, Lavine JE. Gastroenterology May; 158(7): 1967-1983. 


Therapeutic Landscape for NAFLD in 2020

Brent NA. Gastroenterology May; 158(7): 1984-1998.


MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

Eslam M, et al. Gastroenterology May; 158(7): 1999-2014.


American Journal of Surgical Pathology

Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency

Crotty R, Taylor MS, Farmer J, et al. Am J Surg Pathol 2020; 44: 617-625.


This study focuses on a cohort of hepatic CVID biopsies, to define the spectrum of histologic and biochemical alterations. The authors reviewed 26 liver biopsies from 24 patients with CVID (from 4 institutions, 2010-2019). They also included a control cohort of 21 patients with nodular regenerative hyperplasia (NRH) without CVID. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were noted in 2 patients (florid duct lesions, prominent bile duct injury and positive antimitochondrial antibodies). Mild to moderate portal and lobular inflammation were present in 18/24 and 17/24 biopsies, respectively. NRH-like changes were seen in 22/24 cases. Plasma cells were absent. Giant cells, granulomas, steatosis and periportal copper deposition were incidentally found. The authors also described a distinct pattern of delicate pericellular fibrosis present in 23/26 biopsies, as opposed to coarser pericellular fibrosis seen in NASH and hepatic outflow obstruction. Fibrosis ranged from focal centrizonal fibrosis to bridging fibrosis, and was accompanied by increased intrasinusoidal lymphocytes in 13/24 biopsies. In summary, hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. The authors also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

Archives of Pathology and Laboratory Medicine

Clinicopathologic and Prognostic Significance of Gallbladder and Cystic Duct Invasion in Distal Bile Duct Carcinoma

Jun Sy, An S, Sung YN, et al. Arch Pathol Lab Med 2020; 144: 755-763.


This study investigated the patterns of gallbladder and cystic duct (CD) invasion and evaluated their clinicopathologic and prognostic significance in patients with distal bile duct carcinomas (DBDC). Gallbladder invasion was rare in DBDCs and found as neck invasion with intraductal cancerization. CD invasion, seen in 12% of DBDCs, occurred by stromal infiltration and intraductal cancerization, whereas all pancreatic and duodenal invasion noted had stromal infiltration pattern. Gallbladder and/or CD invasion did not affect survival rates of patients with DBDC, as opposed to pancreatic and duodenal invasion. The authors proposed that differences in survival rates may originate from the different invasive patterns observed in DBDCs.


Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea

Gao E, Cheema H, Waheed N, et al. Hepatol 2020; 71: 1879-1882.


This is a case report that describes clinicopathologic findings of the first human case of OSTα deficiency in a child with unexplained elevated liver transaminases, cholestasis, and congenital diarrhea. Solute carrier family 51 alpha subunit (SLC51A ) encodes the alpha subunit of the heteromeric organic solute transporter alpha–beta (OSTα–OSTβ), an important contributor to intestinal bile acid (BA) reabsorption in enterohepatic circulation. Histologically, there was distorted architecture with expanded portal areas and mild bile ductular proliferation. Portal/periportal fibrosis with many thin fibrous septa were noted as well as nodularity suggestive of early cirrhosis. Bile ducts were missing in three of the portal tracts without evidence of bile duct paucity. In addition, mild lymphocytic inflammation, no interface and rare foci of subtle cholestasis were observed.

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Strauss K, Ahlfors C, Soltys K, et al. Hepatol 2020; 71: 1923-1939.


This article describes the pathophysiology, treatment, and outcome of Crigler‐Najjar type 1 syndrome (CN1) in 28 UGT1A1  c.222C>A homozygotes followed for 520 aggregate patient‐years.  In 12/28 cases (43%) numerous small pigmented stones of cholelithiasis were noted in cholecystectomy specimens. Liver tissues was available in 15/27 (56%) and showed intrahepatic cholestasis and fibrosis ranging from mild to severe.  Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

Liquid Biopsies for Hepatocellular Cancer and Their Potential in Clinical Practice

Jeffrey GP, Gordon LG, Hill MM, et al. Hepatol 2020, 71: 2160-2163.


This article discusses the use of liquid biopsies in the diagnosis of hepatocellular carcinoma.

Somatic Mutations in Liver Disease: Adaptation Without Carcinogenesis?

Bhan I, Ting DT. Hepatol 2020, 71: 2162-2163


Studies of somatic mutations have focused on those occurring during carcinogenesis, but recent research suggests that functional mutations can accumulate in the absence of cancer. This study highlights the mutational landscape in chronic liver disease, identifying recurrent mutations that may promote clonal expansion of hepatocytes without inducing carcinogenesis and the opportunity for future studies to explore the functional role of these mutations in pharmacological interventions to promote pro-regenerative and anti-neoplastic pathways as part of a chemopreventive strategy.

Journal of Pathology

Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes.

Aoki Y, Mizuma M, Hata T, et al. J Pathol 2020, 251: 38-48


Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently, a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands and the type 2 IPNBs consist of complex branching glands, with seldom foci of solid‐tubular components. The authors described thirty‐six IPNBs studied retrospectively. Clinicopathological features as well as molecular alterations of 31 genes were evaluated by means of targeted next‐generation sequencing and immunohistochemical examination of expression of mucin and cancer‐associated molecules. The type 1 IPNBs (N:22) were associated with a non‐invasive phenotype, intestinal and oncocytic subtypes, development in the intrahepatic bile duct, overt mucin production, and a relatively good prognosis. The type 2 IPNBs (N:14) were associated with an invasive phenotype, the pancreatobiliary subtype, development within the extrahepatic bile duct, and worse prognosis compared with the type 1 IPNBs. Mutations in KRAS and GNAS were enriched in the type 1 IPNBs, whereas mutations in TP53 , SMAD4 , and KMT2C  were enriched in the type 2 IPNBs. These results indicate that IPNBs consist of two distinct types of neoplasms specifically associated with clinicopathological features and molecular phenotypes.

Modern pathology

Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.

Tian S, Xiong Y, Liu H, et al. Mod Path June 33(6): 1007–1014.


This paper includes a description of liver changes due to COVID-19.

Journal of Gastroenterology and Hepatology

Hallmarks of postoperative liver regeneration: An updated insight on the regulatory mechanisms.

Shi JH, Line PD. J Gastroenterol Hepatol. June; 35(6): 960-966.


This article is a basic science review paper on liver regeneration for those who are interested.

Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. 

Sawada K, Hayashi H, Nakajima S, et al. J Gastroenterol Hepatol. June; 35(6): 1042-1048.


In this study, non‐alcoholic fatty liver disease (NAFLD) was a risk factor for PD‐1 inhibitor‐associated drug-induced liver injury (DILI).

Clinical Gastroenterology and Hepatology

Clinical Features of COVID-19-Related Liver Functional Abnormality.

Fan Z, Chen L, Li J, et al.  Clin Gastroenterol Hepatol. June; 18(7): 1561-1566.


The authors performed a retrospective, single-center study of 148 consecutive patients with confirmed COVID-19 in Shanghai and determined that more than one third of patients admitted to the hospital with SARS-CoV-2 infection had abnormal liver function.  This was associated with longer hospital stay. In addition, a significantly higher proportion of those with abnormal liver function had received treatment with lopinavir/ritonavir after admission.

Health Care Costs of Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease Are Nearly Twice Those of Matched Controls.

Hagström H, Nasr P, Ekstedt M, et al. Clin Gastroenterol Hepatol. June; 18(7): 1592-1599.


In this study, the authors preformed a retrospective analysis of 646 patients with biopsy-proven NAFLD and determined that healthcare costs approach twice as much for patients with NAFLD when compared to controls. The more advanced fibrosis in the liver, the higher the healthcare costs, which reached a mean of $4397 per year in those with stage 3-4/4 fibrosis.

Hepatology Communications

Multispectral Imaging Enables Characterization of Intrahepatic Macrophages in Patients With Chronic Liver Disease.

Saldarriaga OA, Freiberg B, Krishnan S, et al. Hepatol Commun. May; 4(5): 708-723.


The authors optimized a multi-spectral imaging platform to analyze intrahepatic macrophages in liver biopsies from patients with different types of chronic liver disease including viral hepatitis C, fatty liver disease (NASH), and autoimmune hepatitis. Patients with advanced fibrosis had increased systemic and pro-fibrotic macrophages in their livers when compared to those with minimal fibrosis.

Nonalcoholic Fatty Liver Disease and Alcoholic Liver Disease are Major Drivers of Liver Mortality in the United States.

Paik JM, Golabi P, Biswas R, et al.  Hepatol Commun. June; 4(6): 890-903.


In the United States, chronic viral hepatitis B and C (CHB and CHC), non‐alcoholic fatty liver disease (NAFLD) and alcohol‐related liver disease (ALD) are the main causes of liver deaths attributable to hepatocellular carcinoma (HCC) and cirrhosis.  The rising burden of HCC and cirrhosis are primarily driven by NAFLD and ALD.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group

Daniela Allende MD; 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
Heather Stevenson-Lerner MD PhD; University of Texas

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