HPHS Journal Watch: July/August 2019


Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials.

Brunt EM, Kleiner DE, Wilson LA, et al. Hepatology. 2019 Aug;70(2):522-531.

This is a retrospective study focusing on outcomes from Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) and analyzing baseline and final biopsies. This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. In PIVENS 221/240 subjects had baseline and 96-week biopsies, and in FLINT 200/283 subjects had baseline and 72-week biopsies. Fibrosis improvement was seen in a greater total number of PIVENS (38%) treated subjects (pioglitazone 44%, vitamin E 41%) compared to FLINT total (29%) treated subjects and less likely in placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improved fibrosis was associated with improved steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.
Phenobarbital-Induced Liver Injury With Nodal Angiomatosis.

Cheng LT, Yeh MM, Lu CC. Hepatology. 2019 Jul;70(1):437-439.

This is a case report on an 18 year old presenting with fever, atypical lymphocytosis, and lymphadenopathy due to phenobarbital induced injury. The authors found approximately 90 and 41 cases of phenobarbital-induced liver injury reported in LiverTox and VigiBase, respectively. In their case, RUCAM scores for phenobarbital were 8 corresponding to “probable” status after excluding other etiologies. Histologic findings in the liver included interface hepatitis with inflammatory infiltrates in the portal area extending into the hepatic lobule. Foci of hepatocytic lytic necrosis, hepatocytic swelling, cholestasis, and acidophil bodies were observed. Although similar, autoimmune hepatitis was excluded based on clinical presentation and resolution of liver enzymes without steroids. Bone marrow revealed normal cellularity without abnormal blasts or malignant cells. Histological examination of the axillary lymph nodes showed a proliferation of small blood vessels in the sinus lined by hyperplastic endothelial cells, compatible with nodal angiomatosis. Bacillary angiomatosis and Kaposi sarcoma were reasonably excluded based on the absence of bacteria, neutrophils, Warthin-Starry staining, and malignant cells from nodal biopsy and negative serum tests.

American Journal of Surgical Pathology

Macrotrabecular Hepatocellular Carcinoma: An Aggressive Subtype of Hepatocellular Carcinoma.

Jeon Y, Benedict M, Taddei T, Jain D, Zhang X. Am J Surg Pathol. 2019 Jul;43(7):943-948.

The macrotrabecular (MT) subtype of hepatocellular carcinoma (MT-HCC) has recently been shown to have specific molecular alterations and a worse prognosis. Previous studies have defined MT-HCC as neoplasms with trabeculae >6 cells thick that comprise >50% of the tumor. The purpose of this study was to determine the significance of lesser proportions of a MT component. This retrospective study compared 41 HCCs with a MT component to 105 conventional HCCs (CV-HCC). HCCs with 10-29% MT component showed similar clinicopathologic features to CV-HCC. Meanwhile, HCCs with ³30% MT component more commonly showed the following characteristics compared to CV-HCC: tended to be larger; seen in non-cirrhotic livers; present in patients with chronic viral hepatitis B; contained anaplastic tumor cells; displayed microvascular invasion; had higher pathologic stage; were of higher histologic grade; associated with higher AFP levels. Patients that had HCCs with ³30% MT component had a decreased overall and recurrence-free survival. This study confirms prognostic findings from previous studies and the authors propose a lower cutoff for MT pattern requirement (³30% rather than >50% MT component) for diagnosis of MT-HCC.
Clinical Gastroenterology and Hepatology
Primary Gastrointestinal Stromal Tumor of the Liver

Hu HJ, Fu YY, Li FY. Clin Gastroenterol Hepatol. 2019 August;17(9):e106.

A 79-year-old woman presented with epigastric discomfort.  A mass was excised from the liver and additional studies including immunohistochemical stains (GIST1 and CD34) confirmed the presence of a gastrointestinal stromal tumor (GIST).  A primary from another site was not identified and the tumor was diagnosed as a primary hepatic GIST.

Modern pathology

Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.

Akazawa Y, Nakashima R, Matsuda K, et al. Modern Pathology. 2019 Jul;32(7):997-1007.

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients.  The authors investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease tissues by immunofluorescence microscopy in 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls. They showed that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease compared to controls, both in nonalcoholic fatty liver and nonalcoholic steatohepatitis patients (p < 0.01). Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Journal of Gastroenterology and Hepatology 

Screening for non‐alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography.

Lai LL, Wan Yusoff WN, Vethakkan SR, et al. Gastroenterol Hepatol. 2019 Aug;34(8):1396-1403.

This paper studies the prevalence of NALFD and advanced fibrosis among T2DM patients. The study includes 557 patients (mean age 61.4 ± 10.8 years, male 40.6%). Of the 171 patients with liver stiffness measurement ≥ 8 kPa, 71 patients underwent liver biopsy. The majority had non-alcoholic steatohepatitis (83.1%) and ≥ F1 fibrosis (87.3%) while advanced fibrosis was seen in 36.6%. The prevalence of NAFLD and advanced fibrosis based on transient elastography was 72.4% and 21.0%, respectively. On multivariate analysis, independent factors associated with NAFLD were central obesity (OR 4.856, 95% confidence interval [CI] 2.749-8.577, P = 0.006), serum triglyceride (OR 1.585, 95% CI 1.056-2.381, P = 0.026), and alanine aminotransferase levels (OR 1.047, 95% CI 1.025-1.070, P < 0.001) while advanced fibrosis was associated with serum high-density lipoprotein cholesterol (OR 0.355, 95% CI 0.126-0.997, P = 0.049), alanine aminotransferase (OR 1.023, 95% CI 1.009-1.037, P = 0.001), γ-glutamyltransferase (OR 1.005, 95% CI 1.001-1.008, P = 0.017), and platelet levels (OR 0.995, 95% CI 0.992-0.999, P = 0.010). Seventy-one patients underwent liver biopsy.

Journal of Hepatology

Wilson’s disease: Fatal when overlooked, curable when diagnosed.

Ferenci P, Ott P. J Hepatol. 2019 Jul;71(1):222-224.

A snapshot summary of the highlights of Wilson’s disease (WD) could be found in the July issue. Briefly, WD is an autosomal recessive disorder caused by mutations in the ATP7B gene. Hepatic ATP7B protein regulates the whole body content of copper by mediating its excretion into bile or irreversible incorporation into ceruloplasmin. Liver histology is non-specific and may include the whole spectrum of liver pathology. Steatosis is a common finding in non-cirrhotic patients where it may resemble non-alcoholic steatohepatitis. Most often a range of tests including measurements related to copper metabolism (serum copper, ceruloplasmin, urinary copper excretion, hepatic copper content) and molecular genetic testing are needed to diagnose or exclude WD. Life-long treatment with copper-chelators (D-penicillamine triethylenetetramine, tetrathiomolybdate) or zinc is needed.

Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.

Chen DP, Ning WR, Jiang ZZ, et al. J. Hepatol. 2019. Aug;71(2), 333–343.

Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been described to carry a key role in checkpoint blockade therapy.  Understanding of mechanisms that control the manifestation of PD-L1 on tumor-infiltrating monocytes/macrophages will usher development of new PD-L1 blockade schemes with high specificity and efficiency. The current study shows a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, recognizing possible targets for upcoming immune-based anticancer therapies.
PD-L1 expression on antigen-presenting cells (APCs) is vital for T cell impairment, and PD-L1-expressing dendritic cells and macrophages may therapeutically predict the clinical efficacy of PD-L1/PD-1 blockade. The authors state that the current study provides proof that cellular glycolysis arbitrates the stimulation of monocytes by tumor microenvironmental signals, which lead to the induction of PD-L1 expression on these cells and consequent autologous CD8+ T cell suppression in peritumoral tissues of human HCC. Notably, a key glycolytic enzyme, PFKFB3, has been identified as an important mediator regulating PD-L1 expression on peritumoral monocytes by activation of the NF-jB signaling pathway.

American Journal of Clinical Pathology 

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites.

Nasir A, Lehrke HD, Mounajjed T, et al. Am J Clin Pathol. 2019 Jul 5;152(2):190-199.

The authors evaluated 221 tumors for albumin mRNA. Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Carcinomas of lung (20%), gallbladder (39%), and breast (18%) origin showed expression. Yolk sac tumor (25%) and acinar cell carcinoma (29%) also showed expression. The authors discuss the potential diagnostic pitfalls of albumin ISH.


British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.

Chapman MH, Thorburn D, Hirschfield GM, et al. Gut. 2019 Aug;68(8):1356-1378.

When assessing the role of liver biopsy, the authors (quoting Am J Gastroenterol 2003;98:1155) are consistent with other recent guidelines (including, e.g., AASLD) that the newer imaging techniques have reduced the need for a liver biopsy. They suggest that there is a role when there is a clinical suspicion of IgG4-SC, PSC overlap/variant syndromes and for diagnosis of small duct PSC, and that biopsy may also help in otherwise unexplained cholestasis.
They provide a useful review of the range of pathological changes seen in PSC (Gut 1980; 21:870) but point out that onion skin fibrosis is rarely seen in a liver biopsy and that the biopsy usually only shows the generic features of chronic cholestasis. The way in which PSC can be staged histologically is also described (Hepatology 1981;1:632), although this is rarely done in practice. Overall, they recommend that liver biopsy is normally reserved for possible small duct PSC, assessment of suspected possible overlap variants, or instances where the diagnosis is unclear. They assess this as strong recommendation supported by moderate quality evidence.
Also included is a useful review of IgG4-related sclerosing cholangitis which emphasizes the role of biopsy and the diagnostic criteria. They point out that while FNA cytology is useful to exclude malignancy it cannot be relied upon to make the diagnosis of IgG4-RD. On the other hand, the safety and ease whereby biopsies of the major papilla can be taken makes this a useful site to obtain tissue from.

American Journal of Gastroenterology

Gastrointestinal Manifestations of Rheumatological Diseases.

Krӧner PT, Tolaymat OA, Bowman AW, et al. Am J of Gastroenterology. 2019 Sep;114(9):1441-54.

This is a useful review which, understandably, focuses on the gut involvement in these diseases, but hepato-biliary involvement is also covered.

Human Pathology

Evaluation of histologic changes in the livers of patients with early and late hepatic artery thrombosis.
Lee M, Agostini-Vulaj D, Gonzalez RS. Hum Pathol. 2019 Aug;90:8-13.
Hepatic artery thrombosis (HAT) following orthotopic liver transplant (OLT) is a common vascular postoperative complication that can occur early (<30 days since OLT) or late (>30 days since OLT). This study investigated the histopathologic features in biopsy and resection specimens of early and late HAT. 94 cases (25 biopsies and 69 explanted hepatectomies) from 69 patients were studied.  Common histologic findings in HAT included lobular necrosis, portal inflammation, ductular reaction, lobular cholestasis, and bile-tinged macrophages. Lobular necrosis was more common in early HAT and ductular reaction and bile in veins were more common in late HAT.  This study reports on the spectrum of findings and highlights potential diagnostic pitfalls.


Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.

Adachi M, Kai K, Yamaji K, Ide T, Noshiro, Kawaguchi, Aishima S. Histopathology. 2019 Jul;75(1):63-73.


The aim of this study is to clarify the role of iron regulatory protein in the progression of hepatocellular carcinoma (HCC) and patient outcome. The authors investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2 in 210 cases of HCC. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and also compared the clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome. The authors conclude that an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.
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
Eric Yee MD; University of Arkansas

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