HPHS Journal Watch: November/December 2021


A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis

Bosch J, Chung C, Carrasco-Zevallos OM, et al. Hepatology. 2021 Dec; 74(6):3146-3160.


This study designed a machine learning (ML) model to predict clinically significant portal hypertension (CSPH) in patients with cirrhosis secondary to NASH as traditional methods of measuring hepatic venous pressure gradient (HVPG) often underestimate portal pressure in this patient population. The ML-predicted HVPG score was derived from image analysis on trichrome-stained liver biopsy slides. Their results showed that the ML-HVPG score was able to discriminate normal and elevated portal pressure from CSPH. Additionally, the ML-HVPG score was found to be superior to evaluation of hepatic collagen by morphometry (AUROCs in test set: 0.76 vs. 0.65). Ultimately, the authors hope that this ML model could eliminate the need for specialized radiology procedures to measure portal pressures, which require expert human interpretation, when a liver biopsy is available.

American Journal of Surgical Pathology

Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants with Cystic Fibrosis and Kasai Portoenterostomy.

Bove K, Bernieh A, Picarsic J, et al. Am J Surg Pathol. 2021 Nov; 45(11):1499-1508.


This series reports four patients with cystic fibrosis (CF) that underwent Kasai procedures because of clinical concern for biliary atresia after prolonged neonatal jaundice. The pre-operative liver biopsy specimens showed brisk pericholangitis and abundant portal PAS-D positive ceroid-laden macrophages rather than periportal duct proliferation and fibrosis typical of BA. Excised gallbladders were remarkable for having abundant inspissated mucin but intact epithelium and muscularis layers and normal ducts. The authors provide detailed clinical history and histology for each of the patients described in order to aid in the rare occurrence of CF with severe and prolonged jaundice.

A Novel NIPBL-NACC1 Gene Fusion is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma

Argani P, Palsgrove DN, Anders RA, et al. Am J Surg Pathol. 2021. Nov;45:1550-1560.


The authors report 3 cases of an intrahepatic tumor with distinctive morphology, immunohistochemical staining pattern, and molecular alterations. Previously described as the cholangioblastic variant of intrahepatic cholangiocarcinoma, these tumors are described as having varied architectural patterns, biphasic cytology (large eosinophilic and small basophilic cells), and diffuse reactivity to both cytokeratin 7 and inhibin A. In the current report, all tumors also demonstrated patchy reactivity to synaptophysin and chromogranin. The authors found that each of the three morphologically distinct tumors harbored a novel NIPBL-NACC1 gene fusion involving exons 8 and 2, respectively. The authors caution against a pitfall of calling this tumor neuroendocrine in nature based on the synaptophysin/chromogranin staining.

Pediatric Hepatocellular Adenomas: The Influence of Age and Syndrome on Subtype

Pacheco MC, Torbenson MS, Wu TT, et al. Am J Surg Pathol. 2021. Dec;45:1641-1647.


Hepatocellular adenomas are rare in the pediatric population. Across five institutions and eleven years, thirty-one (21%) patients diagnosed with hepatocellular adenoma were under the age of 21. Over half of these patients had a known syndromic-association with neoplasia, and the majority of syndromic patients were male. The majority of non-syndromic pediatric adenomas were identified in females. The authors describe the morphology, immunohistochemical staining, and clinical histories associated with these lesions in a younger population.


TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial.
Loomba R, Mohseni R, Lucas KJ, et al. Gastroenterology. 2021 Nov;161(5):1475-1486. https://pubmed.ncbi.nlm.nih.gov/34310978/

The pathophysiology of non-alcoholic steatohepatitis (NASH) involves tissue injury by the elaboration of excess intrahepatic fat and lipotoxins. In the de novo fatty lipogenesis pathway, the metabolites of simple dietary sugars are converted by the enzymes acetyl-CoA-carboxylase and fatty acid synthase into the fatty acid palmitate, which can create both excess fat in the liver and lipotoxins. TVB-2640 is a fatty acid synthase inhibitor that was assessed for safety and efficacy in patients with NASH in this randomized multicenter, placebo-controlled clinical study. The study enrolled 99 patients to receive either placebo or TVB-2640 (25 or 50 mg). Patients on TVB-2640 achieved a significant dose-dependent reduction of liver fat content after 12 weeks of treatment. In the treatment group, 61% of NASH patients achieved a 30% reduction of liver fat by MRI-PDFF and 21% achieved a 50% reduction of liver fat. A small number of patients in the 50-mg cohort did have a reduction in liver fat by MRI. About 30% of the patients in each cohort had abnormal ALT levels at baseline; in this subgroup, 33% of placebo patients normalized ALT post-treatment compared to 60% of the patients treated with 50 mg of TVB-2640. Patients in the treatment group also showed a reduction in serum markers of fibrosis (PRO-C3, TIMP-1 and PIIINP). By contrast, the placebo group had increased liver fat, liver enzymes, CK18 and cholesterol levels over 12 weeks.

Outcomes of SARS-CoV-2 Infection in Patients With Chronic Liver Disease and Cirrhosis: A National COVID Cohort Collaborative Study
Ge J, Pletcher MJ, Lai JC; N3C Consortium. Gastroenterology. 2021 Nov;161(5):1487-1501.

Liver involvement by SARS-CoV-2 infection has been clinically manifested by features ranging from liver function test abnormalities to acute liver failure. The authors of this study used the National COVID Cohort Collaborative (N3C), an electronic health record dataset of 6.4 million that includes data on patients tested for SARS-CoV-2 and those with related symptoms, to investigate SARS-CoV-2 outcomes in patients with chronic liver disease and cirrhosis. Among the study population of 221,000 nationally representative, diverse patients, the authors found that SARS-CoV-2 infection in patients with cirrhosis was associated with 2.38 times mortality hazard.

Downstaging Outcomes for Hepatocellular Carcinoma: Results From the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT)
Mehta N, Frenette C, Tabrizian P, et al. Consortium. Gastroenterology. 2021 Nov;161(5):1502-1512.

Approximately 30% of liver transplantation in the United States is for hepatocellular carcinoma (HCC). The Milan criteria for liver transplant (a single tumor < 5 cm or 2-3 tumors (none exceeding 3 cm) and no vascular invasion and/or extrahepatic spread) have traditionally informed transplant eligibility. However, tumor downstaging, which is defined as the reduction of viable tumor burden by locoregional therapy (ex. chemoembolization, Y-90 radioembolization) to meet acceptable transplant criteria, has gained increasing support in recent years. This prospective multicenter study investigated the outcomes of downstaging from seven centers in four UNOS regions of the United States.  The study demonstrated an 87.7% probability of successful downstaging to Milan criteria with a low likelihood of subsequent tumor progression and found a 2-year post transplant survival of 95%. However, the authors also noted a high rate of tumor understaging, and advocate for downstaging to within Milan criteria as a minimal requirement for liver transplant, as well as further locoregional therapy to achieve complete tumor necrosis before transplant.

Results of Early Transplantation for Alcohol-Related Cirrhosis: Integrated Addiction Treatment With Low Rate of Relapse
Carrique L, Quance J, Tan A, et al. 2021 Dec;161(6):1896-1906.

The “6-month rule” refers to the requirement that patients with alcohol-related liver disease abstain from alcohol for 6-months prior to liver transplant. The rule is intended to both allow for hepatic recovery and increase the likelihood of abstinence after transplant, but enforcement can result in mortality rates of up to 70%. Further, there is limited evidence to indicate that the rule is efficacious with respect to either maintaining abstinence or yielding good patient survival outcomes after transplant. Among the 703 referrals received, 101 patients with alcoholic liver disease met inclusion criteria and were provided relapse prevention therapy and biomarker monitoring while being listed for transplant; during the study period 44 patients received a transplant and these patients underwent continued addition treatment and biomarker monitoring. The study found no significant differences in survival rates between those receiving transplants and those in a control group with more than 6-months of abstinence.


Diversity in cell differentiation, histology, phenotype and vasculature of mass-forming intrahepatic cholangiocarcinomas

Canh HN, Takahashi K, Yamamura M, et al. 2021 Nov;79(5):731-750.


Mass-forming intrahepatic cholangiocarcinomas (MF-iCCAs) remain treated as a single entity. The authors examine the diversity in histology, phenotype and tumor vasculature of MF-iCCAs. Based on morphology and immunophenotype, the MF-iCCAs were classified into small bile duct (SBD), cholangiolocarcinoma (CLC), ductal plate malformation (DPM) and hepatocellular carcinoma (HCC)-like subtypes. Genetic correlations among the histological subtypes were examined by multi-region tumor sequencing. Vasculatures and other clinicopathological features were compared among tumor groups with various proportions of the histological subtypes in 62 MF-iCCAs. Cases of pure SBD, CLC, DPM and HCC-like subtypes numbered 18 (29%), seven (11.3%), none (0%) and two (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, isocitrate dehydrogenase (IDH)1/2, KRAS, TP53, polybromo-1 (PBRM1) and BRCA1-associated protein 1 (BAP1), were shared among SBD, CLC, DPM and hepatoid components within a tumor. Increased CLC component was correlated with longer overall survival time (r = 0.44, P = 0.006). Pure SBD tumors had a lower 5-year overall survival rate compared with MF-iCCA with CLC pattern (30.5 versus 72.4%, P = 0.011). The authors conclude that MF-iCCAs comprise four histological subtypes. Their sharing of some driver gene alterations indicate they can have a common cell origin; however, differ in cell differentiation, histology, phenotype or tumor vasculature.

Aberrant expression of SATB2, CDX2, CDH17 and CK20 in hepatocellular carcinoma: a pathological, clinical and outcome study

Kmeid M, Lukose G, Hodge K, et al. 2021 Nov;79(5):768-778.


The authors evaluate the expression of intestinal markers in hepatocellular carcinoma (HCC).  Tissue sections and/or tissue microarrays (TMAs) from 202 known HCCs were immunostained using CK19, CK20, CDH17, CDX2 and SATB2 antibodies. Associations of staining with clinicopathological features and survival outcomes were evaluated. CK19, CK20, CDH17, CDX2 and SATB2 were positive in 12.8, 5.4, 10.3, 8.6 and 59.9%, respectively. All but SATB2 were strongly associated with higher tumor grade and AFP levels > 400 ng/ml (P < 0.05). CK19-positive HCC were more likely to express CDX2 (P = 0.001), CDH17 (P < 0.001) and/or CK20 (P = 0.012). CK20, CDX2 and CDH17 co-expression was seen in five cases (2.5%). CK19 and SATB2 positivity, tumor size ≥ 5 cm, background cirrhosis, AFP > 400 ng/ml and having no treatment were associated with decreased overall survival by log-rank test and univariable proportional hazards regression. However, in a multivariable model, CK19 and SATB2 positivity were not independent predictors of decreased survival while their association with known poor prognosticators in HCC was evident. HCC can express markers of intestinal differentiation. This phenotypical aberrancy correlates with variable clinicopathological parameters, some of which are independent predictors of poor survival.

Diagnostic challenges of focal nodular hyperplasia: interobserver variability, accuracy, and the utility of glutamine synthetase immunohistochemistry

Rowan DJ, Allende DS, Bellizzi AM, et al. 2021 Nov;79(5):791-800.


The diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. The authors evaluated the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH. Virtual needle biopsies were generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non-lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). Diagnostic accuracy was significantly higher with the addition of a GS stain. A map-like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non-map-like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42). Pathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo-map-like GS staining pattern were associated with increased difficulty. Therefore, although a map-like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map-like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH.


Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance

Sun N, Shen C, Zhang L,  et al.  2021 Nov;70:2183–2195.


This study explores the role of a transcription factor, Krüppel-like factor 16 (KLF16) and its involvement in hepatic lipid catabolism, hepatosteatosis, and insulin resistance. Krüppel-like factor 16 (KLF16) is an abundant transcription factor that is involved in anti-tumorigenicity and endocrine homeostasis. KLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mouse models using hepatocyte-specific KLF16-deficient mice fed on a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. KLF16 expression was decreased in patients with NAFLD. KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor a (PPARa) to accelerate fatty acid oxidation and attenuate mitochondrial and oxidative stress.

American Journal of Clinical Pathology

Thick fibrous septa on liver biopsy specimens predict the development of decompensation in patients with compensated cirrhosis

Jain D, Sreenivasan P, Inayat I, et al. Am J Clin Pathol. 2021 156(5):802-809.


In a prior study by the same group, thick fibrous septa and small nodules in liver biopsy specimens were shown to correlate with the presence of clinically significant portal hypertension (CSPH; hepatic venous pressure gradient (HVPG) >10 mmHg), which in turn is the strongest predictor of decompensation (presence of clinically evident complications, including ascites, variceal hemorrhage, hepatic encephalopathy, and jaundice) and death. In this follow-up study, septal thickness and size of nodules were evaluated as possible histologic predictors of decompensation. 168 total patients with available liver biopsies and compensated cirrhosis were followed (median 50 months), with 43 (26%) patients developing clinical decompensation. To more closely mimic routine clinical practice, septal thickness (thin, intermediate, thick) and nodule size (small, large, mixed) were assessed semi-quantitatively without use of a micrometer or scale. Septal thickness (thick) but not nodule size, was significantly associated with decompensation on univariate analysis and was also found to be an independent predictor of decompensation on multivariate analysis. Thus, the authors propose that histologic substaging/subclassification of cirrhosis (mild, moderate, severe) may be clinically relevant.

Journal of Hepatology

Development and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease

Lackner C, Stauber RE, Davies S, et al. J Hepatol. 2021 5(4):810-819.


Most studies of alcohol-related liver disease (ALD) have used the Clinical Research Network (CRN) grading and staging system that has been designed and validated for non-alcoholic fatty liver disease (NAFLD) due to the lack of a universally accepted system for ALD. In this study, the Study of Alcohol-related Liver disease in Europe (SALVE) Histopathology Group developed a grading and staging system specifically for ALD that includes grading of the degree of steatosis (similar to NAFLD), activity (hepatocellular injury/ballooning or Mallory-Denk bodies, lobular neutrophils), and cholestasis (canalicular and ductular cholestasis). The staging system was based on a scale of 0-4, with cirrhosis further subdivided into stage 4A, 4B, and 4C based on the width of the fibrous septa. The grading/staging system was then validated on a cohort of 445 patients from 4 European centers, with substantial interobserver agreement (kappa statistic >0.6 for each grading and staging parameter). This SALVE grading/staging system may be useful in the histologic assessment of liver biopsies in ALD patients, but will require further confirmation of prognostic value.

Antibody-mediated rejection of the liver allograft: An update and a clinico-pathological perspective

Lee BT, Field MI, Schiano TD. J. Hepatol. 2021 75(5):1203-1216.


This review summarizes recent advances in clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation as well as histopathologic features of acute and chronic antibody-mediated rejection.

Clinical Gastroenterology and Hepatology

An Unusual Extrahepatic Hepatocellular Carcinoma

Jacob R, Kasim Ismail A, Prakoso E. 2021 Dec;19(12):e123-e124.


The authors present an unusual case of metastatic hepatocellular carcinoma (HCC) as a rapidly enlarging exophytic upper palate lesion.  Metastases in the oral cavity are not common and represent only about 1-3% of oral neoplasms.

Advances in Anatomic Pathology

Role of the Surgical Pathologist in Diagnosis of Drug-induced Liver Injury: Recognizing Specific Patterns of Drug Injury

Chopra S, Gawrieh S, Vuppalanchi R, Saxena R. 2021 Nov 1;28(6):383-395.


The authors present a nice review article that describes the role of the surgical pathologist in recognizing specific patterns of drug-induced liver injury DILI.  They show representative histology images from several cases including sinusoidal obstructive syndrome/veno-occlusive disease, “bland” cholestasis caused by anabolic androgenic steroids, cholestatic hepatitis caused by an antimicrobial, amiodarone toxicity resembling alcoholic hepatitis, acetaminophen toxicity, and drug-induced sclerosing cholangitis.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Vishal Chandan, MBBS; University of California Irvine
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Mojgan Hosseini, MD; University of California San Diego
Meredith Pittman, MD; Maimonides Medical Center
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Heather Stevenson-Lerner, MD, PhD; University of Texas

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