Publications by authors named "Matthew M Yeh"

161 Publications

Comparing the Clinicopathological Characteristics of Combined Hepatocellular-Cholangiocarcinoma with Other Primary Liver Cancers Using the Updated WHO Classification.

Histopathology 2021 Apr 10. Epub 2021 Apr 10.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 WHO classification modified the definition and discarded the subtypes harboring stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of the study is to investigate the characteristics of cHCC-CCA in comparisons with other primary liver cancers utilizing the updated WHO classification.

Methods And Results: We retrospectively analyzed 64 cHCC-CCA and 55 HCCscf patients from Dec2007 to May2018. A propensity score matching was conducted to compare with HCC and iCCA patients. Clinicopathological characteristics, event-free (EFS) and overall survival (OS) were evaluated with multivariate Cox proportional hazard regression. In a median follow-up of 55.9 months, patients with cHCC-CCA had a significantly poor survival as compared with HCCscf and an intermediate survival outcome between HCC and iCCA. HBV infection and high tumor infiltrating lymphocytes (TILs) were associated with a favorable survival in cHCC-CCA. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low TILs were significant negative prognostic factors in cHCC-CCA. After pooling with other primary liver cancers, tumor type of cHCC-CCA and iCCA predicted the worse survival results.

Conclusion: cHCC-CCA have an intermediate survival between HCC and iCCA and HBV infection and high TILs predict the favorable survival. Our study provides clinical correlations for the new 2019 WHO classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14384DOI Listing
April 2021

S100P as a marker for poor survival and advanced stage in gallbladder carcinoma.

Ann Diagn Pathol 2021 Mar 22;52:151736. Epub 2021 Mar 22.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States. Electronic address:

Aims: Gallbladder carcinomas usually present in advanced stages and has a dismal prognosis despite modern imaging techniques and aggressive surgical intervention. Identification of biologic markers for early diagnosis and improved therapeutic strategies is thus of paramount importance. S100P has been identified in a variety of malignant neoplasms of the gastrointestinal and pancreaticobiliary systems, but it is not yet known if S100P expression is associated with clinically-relevant characteristics of gall bladder carcinoma. The aims of the present study were: 1) to investigate the relationship between S100P expression and histological type, grade, tumor-node-metastasis stage, presence of vascular invasion, perineural invasion and necrosis; and 2) to evaluate for any S100P-defined difference in the risk for tumor recurrence or death.

Method: Immunostains for S100P were performed on 4 tissue microarray blocks containing 91 cases of gall bladder carcinoma.

Result: The intensity of S100P staining was significantly associated with pathological T stage 4 (p = 0. 0238). Staining intensity ≥3 in ≥25% tumor cells was associated with pathological T stage 4 (p = 0.0005). A higher S100P immunoreactivity score (IRS) was significantly associated with higher TNM stage (p = 0.0341). Age (p = 0.0485), presence of vascular invasion (p = 0.0359), pathological T stage (p = 0.0291) and TNM stage (p = 0.0153) were significantly associated with tumor recurrence. Intense S100P reactivity was associated with decreased overall survival [hazard ratio = 9.614; 95% confidence interval (CI), 1.873-49.338; p = 0.0067].

Conclusion: Our findings indicate that S100P over-expression is a potential prognostic marker for gall bladder carcinoma and is significantly associated with advanced tumor stage and poorer survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2021.151736DOI Listing
March 2021

Hepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver.

Hum Pathol 2021 Feb 24;108:93-99. Epub 2020 Nov 24.

University of Washington, Department of Laboratory Medicine and Pathology, Seattle, WA 98195, United States; University of Washington, Department of Medicine, Seattle, WA 98195, United States. Electronic address:

Hepatocellular neoplasms can develop in multiple genetic metabolic disorders. While there have been rare case reports, clinical and pathological characterizations have not been systematically performed. We conducted a retrospective study in 9 patients with these rare genetic metabolic disorders, including glycogen storage disease type 1, ornithine carbamyl transferase deficiency, hereditary tyrosinemia type 1, and Navajo neurohepatopathy, who developed hepatocellular neoplasms. Our results show that steatosis is a common finding in both tumor (6/9 cases, 67%) and background liver parenchyma (8/9 cases, 89%), underlying a possible role for steatosis in tumorigenesis in these genetic metabolic disorders. Our findings also raise a consideration of underlying genetic metabolic disorder when young patients with hepatocellular neoplasm show steatosis in both the tumor and background liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2020.11.012DOI Listing
February 2021

Interobserver agreement in pathologic evaluation of bile duct biopsies.

Hum Pathol 2021 Jan 29;107:29-38. Epub 2020 Oct 29.

Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA. Electronic address:

Intraductal biopsy is commonly used for preoperative evaluation of the etiology of biliary strictures. Interpretation of intraductal biopsies is frequently challenging. The diagnosis often suffers from interobserver disagreement, which has not been studied in the literature. We sought to assess interobserver concordance in the interpretation of intraductal biopsies. Eighty-five biopsies were retrieved, falling into five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eight gastrointestinal pathologists blindly reviewed all the slides. Agreement among pathologists was analyzed using Fleiss κ and weighted concordance coefficient S∗. A face-to-face consensus/training session was held to discuss the classification criteria, followed by a second round review. The overall interobserver agreement was fair in the first round review (κ = 0.39; S∗ = 0.56) and improved to moderate in the second round review (κ = 0.48; S∗ = 0.69). The agreement before and after consensus meeting was substantial to nearly perfect for CA (κ = 0.65, S∗ = 0.83; and κ = 0.80, S∗ = 0.91), fair for HGD (κ = 0.28, S∗ = 0.69; and κ = 0.40, S∗ = 0.63), and moderate for NED (κ = 0.47, S∗ = 0.50; and κ = 0.47, S∗ = 0.53). Agreement improved from fair to moderate for LGD (κ = 0.36, S∗ = 0.61; and κ = 0.49, S∗ = 0.71) and slight to fair for IND (κ = 0.16, S∗ = 0.51; and κ = 0.33, S∗ = 0.50). Compared with Hollande's fixed specimens, the agreement was higher in almost all diagnostic categories in formalin-fixed biopsies. Overall, interobserver concordance was improved after a consensus/training session. Interobserver reproducibility was high at the end of the diagnostic spectrum (CA) but fair to moderate for other diagnostic categories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2020.10.003DOI Listing
January 2021

Duodenal intraepithelial lymphocytosis in Helicobacter pylori gastritis: comparison before and after treatment.

Virchows Arch 2021 Apr 6;478(4):805-809. Epub 2020 Oct 6.

Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, 1959 NE Pacific Street, NE140D, Box 356100, Seattle, WA, 98195-6100, USA.

Our aims were to assess performance of duodenal intraepithelial lymphocyte counting for diagnosis of Helicobacter pylori (H. pylori) gastritis, and effects of eradication therapy on intraepithelial lymphocytosis. Paired duodenal and gastric biopsies from subjects with a pathologic diagnosis of H. pylori gastritis were reviewed. Higher duodenal intraepithelial lymphocyte counts were observed in 40 subjects with H. pylori gastritis (26 ± 5 per villus) than 52 subjects negative for H. pylori (12 ± 2 per villus). After successful eradication therapy, duodenal lymphocytes were indistinguishable from H. pylori-negative subjects, whereas they remained elevated after failed eradication therapy. This study confirms previous reports of increased duodenal intraepithelial lymphocytes in patients with concurrent Helicobacter pylori gastritis. Intraepithelial lymphocyte counts of > 15 per villus or > 10 per 100 enterocytes were predictive of infection. Duodenal lymphocytosis decreases significantly after successful eradication therapy but remains elevated when treatment fails.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-020-02941-2DOI Listing
April 2021

Non-alcoholic fatty liver disease: A review with clinical and pathological correlation.

J Formos Med Assoc 2021 Jan 9;120(1 Pt 1):68-77. Epub 2020 Jul 9.

Department of Pathology, University of Washington School of Medicine, Seattle, United States; Department of Medicine, University of Washington School of Medicine, Seattle, United States. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in North America and Europe, with increasing prevalence in other regions of the world. Its spectrum encompass steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. It is considered as the manifestation of metabolic syndrome in liver, and its development and progression is influenced by complex interaction of environmental and genetic factors. In this review we discuss the histopathological features, differential diagnoses, and the commonly used grading and staging systems of NAFLD. NAFLD associated with other diseases, histological changes after therapeutic intervention and recurrence or occurrence of NAFLD after liver transplantation are also addressed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2020.07.006DOI Listing
January 2021

Steatohepatitis-Like Changes in Hepatocellular Adenoma.

Am J Clin Pathol 2020 09;154(4):525-532

Department of Pathology, University of Washington School of Medicine, Seattle.

Objectives: Our aim was to investigate the frequency of steatohepatitic morphology in hepatocellular adenoma (HCA) and correlate with its clinical parameters and risk factors underlying nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

Methods: We examined a series of 41 liver resection specimens diagnosed with HCA for steatohepatitic changes. Background nonneoplastic liver was also evaluated. Clinical records were reviewed for risk factors of NAFLD/NASH.

Results: Six steatohepatitic HCAs (SH-HCAs) were identified, with an overall prevalence of six (14.6%) of 41, of which three were HNF1α inactivated and three were inflammatory, but none were β-catenin mutated. Five of the six patients with SH-HCA had at least one known risk factor for NAFLD/NASH, including obesity (n = 4; 66.7%), diabetes (n = 5; 83.3%), hypertension (n = 3; 50%), and dyslipidemia (n = 1; 16.7%). Compared with the patients without SH-HCA, the patients with SH-HCA had a higher frequency of type 2 diabetes, obesity, and hypertension. Of the six SH-HCAs, background nonneoplastic liver showed significant steatosis in three (50%) cases and steatohepatitic changes in one (16.7%) case.

Conclusions: Approximately 15% of HCAs in our series demonstrated steatohepatitic changes. Lack of such morphology in β-catenin-mutated subtype suggests reassurance in this morphologic variant of HCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqaa075DOI Listing
September 2020

Serology Is More Sensitive Than Urea Breath Test or Stool Antigen for the Initial Diagnosis of Helicobacter pylori Gastritis When Compared With Histopathology.

Am J Clin Pathol 2020 07;154(2):255-265

Department of Laboratory Medicine, University of Washington, Seattle.

Objectives: To assess the concordance and performance characteristics of Helicobacter pylori laboratory tests compared with histopathology and to propose algorithms for the diagnosis of H pylori that minimize diagnostic error.

Methods: H pylori diagnostics were reviewed from a 12-year period within a health system (2,560 cases). Analyses were performed to adjust diagnostic performance based on treatment and consensus histopathologic diagnoses among pathologists. Markers of access to care, including test cancellation frequency and turnaround time, were assessed. Costs and performance of candidate noninvasive testing algorithms were modeled as a function of disease prevalence.

Results: Serum H pylori IgG demonstrated a higher sensitivity (0.94) than urea breath and stool antigen tests (0.64 and 0.61, respectively). Evidence of an advantage in access to care for serology included a lower cancellation rate. Interobserver variability was higher (κ = 0.34) among pathologists for cases with a discordant laboratory test than concordant cases (κ = 0.56). A model testing algorithm utilizing serology for first-time diagnoses minimizes diagnostic error.

Conclusions: Although H pylori serology has modestly lower specificity than other noninvasive tests, the superior sensitivity and negative predictive value in our population support its use as a noninvasive test to rule out H pylori infection. Reflexive testing with positive serology followed by either stool antigen or urea breath test may optimize diagnostic accuracy in low-prevalence populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqaa043DOI Listing
July 2020

Exercise retards hepatocarcinogenesis in obese mice independently of weight control.

J Hepatol 2020 07 14;73(1):140-148. Epub 2020 Apr 14.

Liver Research Group, ANU Medical School, Australian National University at The Canberra Hospital, Garran, ACT, Australia. Electronic address:

Background & Aims: Obesity and type 2 diabetes increase hepatocellular carcinoma (HCC) incidence in humans and accelerate diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. We investigated whether exercise reduces HCC development in obese/diabetic Alms1 mutant (foz/foz) mice and studied protective mechanisms.

Methods: We measured HCC development in DEN-injected male foz/foz and wild-type (WT) littermates housed with or without an exercise wheel from week 4 until 12 or 24 weeks, and in foz/foz mice pair-fed to WT littermates. We also studied HCC development in DEN-injected Jnk1.foz/foz mice generated by cross breeding, as well as their genetic controls. Dysplastic hepatocytes were identified by glutathione-S-transferase pi form (GST-pi) immunohistochemistry, liver nodules were counted, and HCC was analysed by histopathology.

Results: Exercising foz/foz mice maintained similar weight as WT mice up to 10 weeks, but then gained weight and were obese by 24 weeks; a similar body weight profile was obtained by pair-feeding foz/foz mice to WT. At 12 weeks, livers of exercising foz/foz mice exhibited fewer GST-pi positive hepatocytes than sedentary counterparts; by 24 weeks, fewer exercising foz/foz mice developed HCC (15% vs. 64%, p <0.05). Conversely, pair-feeding foz/foz mice failed to reduce HCC incidence. In these insulin-resistant foz/foz mice, exercise failed to activate hepatic AMPK or Akt/mTORC1. Instead, it improved insulin sensitivity, ameliorated steatosis and liver injury, activated p53 to increase p27 expression, and prevented JNK activation. This was associated with suppression of hepatocellular proliferation. DEN-injected Jnk1.foz/foz mice failed to develop liver tumours or HCC at 24 weeks.

Conclusions: Direct effects of exercise dampen proliferation of dysplastic hepatocytes to reduce 3-month dysplastic foci and 6-month incidence of DEN-induced HCC in obese, insulin-resistant mice. The effects of exercise that potentially slow hepatocarcinogenesis include p53-mediated induction of p27 and prevention of JNK activation.

Lay Summary: Fatty liver disease commonly occurs alongside obesity and diabetes, contributing to rapidly increasing rates of liver cancer throughout the world. Herein, we show that exercise reduces the incidence and progression of hepatocellular carcinoma in mouse models. The effect of exercise on cancer risk was shown to be independent of changes in weight. Exercise could be a protective mechanism against liver cancer in at-risk individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.02.006DOI Listing
July 2020

A Review on the Update of Combined Hepatocellular Cholangiocarcinoma.

Semin Liver Dis 2020 May 30;40(2):124-130. Epub 2019 Dec 30.

Department of Pathology, University of Washington School of Medicine, Seattle.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a primary liver tumor with neoplastic components of both hepatocytic and cholangiocytic differentiation. This unique neoplasm is gaining increasing recognition due to the intriguing pathology, tumor biology, and clinical behavior. It also poses challenges in diagnosis, treatment, and research, largely because of its histological and phenotypic diversity that lead to confusion in terminology and classification. There have been efforts attempting to unify the terminology of this neoplasm recently. Advances in investigation in various aspects have also been made. This review aims to update the terminology, classification, and clinical and pathological characteristics of cHCC-CCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-3402515DOI Listing
May 2020

Loss of nectin-3 expression as a marker of tumor aggressiveness in pancreatic neuroendocrine tumor.

Pathol Int 2020 Feb 19;70(2):84-91. Epub 2019 Dec 19.

Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.

Pancreatic neuroendocrine tumors (PanNETs) are rare, and prediction of aggressive characteristics, such as recurrence and metastasis and prognosis of PanNETs remain difficult. Nectins are cell adhesion molecules that regulate the formation of adherens and tight junctions. In this study, we investigated the clinicopathological significance of nectin-3 expression in patients with PanNETs. Immunohistochemical analysis of nectin-3 expression was performed on 78 cases of PanNET. Low nectin-3 expression in the membrane (positive ratio ≤25%) was observed in 62 cases (79.5%) and was significantly correlated with larger tumor size (>20 mm; P = 0.003), G2/G3 tumors (P = 0.025), higher Ki67 labeling index (≥3%; P = 0.009), lymphatic involvement (P = 0.047), advanced pT-factor (T2-T4; P = 0.003), lymph node metastasis (P = 0.006), advanced Union for International Cancer Control/American Joint Committee on Cancer-stage (Stage II-IV; P = 0.001), advanced ENETS stage (Stage IIa-IV; P = 0.001), nonfunctioning tumors (P = 0.002), and a shorter disease-free survival (P = 0.019). However, there was no significant correlation between nectin-3 expression in the membrane and/or cytoplasm and the clinicopathological parameters. The present results suggest that decreased nectin-3 expression in the membrane is associated with increased tumor aggressiveness of PanNETs. Clinically, immunohistochemical analysis of nectin-3 may help predict tumor aggressiveness for PanNETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pin.12881DOI Listing
February 2020

Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.

Histopathology 2020 Feb 1;76(3):470-480. Epub 2019 Dec 1.

Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.

Aims: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab.

Methods And Results: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8 /CD4 cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis.

Conclusions: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8 lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14000DOI Listing
February 2020

Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases.

World J Gastroenterol 2019 Aug;25(30):4074-4091

Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States.

Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3748/wjg.v25.i30.4074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700705PMC
August 2019

Prevalence, risk factors, and surveillance patterns for gastric intestinal metaplasia among patients undergoing upper endoscopy with biopsy.

Gastrointest Endosc 2020 01 16;91(1):70-77.e1. Epub 2019 Aug 16.

Division of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA.

Background And Aims: Gastric intestinal metaplasia (GIM) is an important precursor lesion to gastric cancer (GC), the second leading cause of cancer death worldwide. There exist few data regarding the prevalence of, risk factors for, and clinical practice patterns regarding GIM in the United States. Furthermore, there are currently no U.S. guidelines regarding screening/surveillance for GIM.

Methods: All consecutive upper endoscopic procedures from 2 academic medical centers in Seattle between 1999 and 2014 were reviewed. Demographic, clinical, and endoscopic covariates were recorded at time of endoscopy. Procedures with gastric biopsy were matched to final the histologic diagnoses, including the presence of Helicobacter pylori. Cases of GIM and dysplasia were recorded and compared with non-GIM controls using univariate and multivariable regression. Surveillance patterns for cases of GIM were recorded.

Results: Data from 36,799 upper endoscopies, 17,710 gastric biopsies, 2073 cases of GIM, 43 cases of dysplasia, and 78 cases of GC were captured. The point prevalence of GIM was 11.7% in patients who underwent gastric biopsy. Non-white race (P < .001), increasing age (P < .001), and presence of H pylori (P < .001) were associated with GIM. If GIM was present, increasing age (P < .001) and male gender (P < .001) were associated with progression, and the presence of H pylori (P < .001) was inversely associated with progression to dysplasia/GC. Few cases of GIM/dysplasia/GC were identified during procedures for GIM screening/surveillance. Only 16% of patients with a diagnosis of GIM received a recommendation for surveillance.

Conclusions: There is a high prevalence of GIM among non-white and Hispanic Americans. Risk factors for development of GIM may be distinct from the risk factors for progression to GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gie.2019.07.038DOI Listing
January 2020

Diagnosis and Management of Gastric Intestinal Metaplasia: Current Status and Future Directions.

Gut Liver 2019 11;13(6):596-603

Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.

Gastric intestinal metaplasia (GIM) is a known premalignant condition of the human stomach along the pathway to gastric cancer (GC). Histologically, GIM represents the replacement of normal gastric mucosa by mucin-secreting intestinal mucosa. infection is the most common etiologic agent of GIM development worldwide. The prevalence of GIM is heterogeneous among different regions of the world and correlates with the population endemicity of carriage, among other environmental factors. GC remains the third leading cause of cancer-related mortality globally. GIM is usually diagnosed by upper endoscopy with biopsy, and histologic scoring systems have been developed to risk-stratify patients at highest risk for progression to GC. Several recent endoscopic imaging modalities may improve the optical detection of GIM and early GC. Appropriate surveillance of GIM may be cost effective and represents an opportunity for the early diagnosis and therapy of GC. Certain East Asian nations have established population-level programs for the screening and surveillance of GIM; guidelines regarding GIM surveillance have also recently been published in Europe. By contrast, few data exist regarding the appropriateness of surveillance of GIM in the United States. In this review, we discuss the pathogenesis, epidemiology, diagnosis, and management of GIM with an emphasis on the role of appropriate endoscopic surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5009/gnl19181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860040PMC
November 2019

Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy.

Semin Diagn Pathol 2019 Nov 24;36(6):434-440. Epub 2019 Jul 24.

Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States; Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States. Electronic address:

Liver injury triggered by immune checkpoint inhibitors has been increasingly seen in clinical practice, and the incidence is likely to rise further in the next several years because of expanded indications for cancer immunotherapy. Tissue damage driven by disrupted immune tolerance against self-antigens is called an immune-related adverse event (irAE). irAEs in the liver histologically presents panlobular hepatitis (∼70%), isolated central zonal necrosis (∼20%), primarily granulomatous hepatitis (∼5%), and other minor forms of tissue injury (∼5%). Infiltrating cells are mainly lymphocytes and occasional eosinophils. Unlike classic autoimmune hepatitis (AIH), plasma cell infiltration is not conspicuous. Immunostaining reveals a large number of CD8+ T lymphocytes and a markedly smaller number of CD4+ cells or CD20+ B lymphocytes. The unique CD3+/CD20+ and CD4+/CD8+ ratios shifted in favor of CD8+ cytotoxic T lymphocytes are helpful to discriminate irAEs from other conditions (e.g., AIH, idiosyncratic drug-induced liver injury). Another hepatobiliary manifestation of irAEs is sclerosing cholangitis clinically characterized by elevations of biliary enzymes, diffuse duct wall thickening, and duct dilatation. Lymphocytic infiltration can be observed by endoscopic biopsies from the thick extrahepatic bile ducts, and liver needle biopsies may also show severe lymphocytic cholangitis resembling primary biliary cholangitis. An important differential diagnosis of irAEs is previously asymptomatic or subclinical liver disease unmasked by cancer immunotherapy, which is often challenging and requires close clinicopathological correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.semdp.2019.07.009DOI Listing
November 2019

Block of NF-kB signaling accelerates MYC-driven hepatocellular carcinogenesis and modifies the tumor phenotype towards combined hepatocellular cholangiocarcinoma.

Cancer Lett 2019 08 22;458:113-122. Epub 2019 May 22.

Institute of Physiological Chemistry, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. Electronic address:

Primary liver cancer ranks among the leading causes of cancer death worldwide. Risk factors are closely linked to inflammation, such as viral hepatitis and alcoholic as well as non-alcoholic steatohepatitis. Among the pathways involved in the pathogenesis of malignant liver tumors, dysregulation of NF-κB signaling plays a prominent role. It provides a link between inflammation and cancer. To examine the role of NF-κB in a MYC-induced model of hepatocellular carcinoma we deleted NEMO (IKKγ) specifically from hepatocytes. NEMO deletion accelerated tumor development and shortened survival, suggesting a tumor-suppressive function of NF-κB signaling. We observed increased proliferation, inflammation and fibrosis, as well as activation of MAPK and STAT signaling. Importantly, deletion of NEMO modified the tumor phenotype from hepatocellular carcinoma to combined hepatocellular cholangiocarcinoma. The intrahepatic cholangiocarcinoma tumor component showed increased expression of progenitor markers such as Sox9 and reduced expression of mature hepatic markers such as CPS1. In both cases tumorigenesis was reversible by turning off MYC expression. To our knowledge this is the first mouse model of combined hepatocellular cholangiocarcinoma and may provide insights into the development of this rare malignant tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2019.05.023DOI Listing
August 2019

Validation of a Congestive Hepatic Fibrosis Scoring System.

Am J Surg Pathol 2019 06;43(6):766-772

Departments of Pathology.

Congestive hepatopathy is a complication of right heart failure and chronically elevated right heart pressure. Histologic findings include sinusoidal dilatation, centrilobular hepatocellular plate atrophy, and fibrosis. We performed a validation study of a recently proposed scoring system (0 to 4 scale) for congestive hepatic fibrosis on 38 liver biopsies. Glutamine synthetase immunohistochemistry was also performed, and loss of centrizonal immunoreactivity correlated with increasing fibrosis score (P<0.01). Interobserver concordance for congestive hepatic fibrosis score based on Masson trichrome stain was initially fair (Fleiss κ=0.28, weighted concordance coefficient=0.60) and significantly improved (κ=0.40, weighted concordance coefficient=0.66) following a multiheaded microscope training session and inclusion of glutamine synthetase immunohistochemistry. Average congestive hepatic fibrosis score correlated with significantly higher right atrial pressure, severity of right atrial dilation, presence of right ventricular dilation, elevated serum alanine aminotransferase, platelet counts, prothrombin time, and model for end-stage liver disease score. In conclusion, the congestive hepatic fibrosis scoring system is reproducible among pathologists and correlates with clinical and laboratory markers of congestive hepatopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001250DOI Listing
June 2019

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis.

J Leukoc Biol 2019 05 5;105(5):1015-1026. Epub 2019 Mar 5.

Organ Care Research and Liver Care Network, Seattle, Washington, USA.

We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid-derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow-derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL-1β, IL-6, and TNF-α; it also increased protein levels of CD68, TNF-α, IL-1β, and IL-6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL-4 led to the down-regulation of M2 markers: arginase-1, Mgl-1, and M2-specific transcriptional regulator, KLF4. Iron loading of macrophages with IL-4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL-6, IL-1β, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage-driven inflammation and fibrogenesis in NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.3A0318-108RDOI Listing
May 2019

Phenobarbital-Induced Liver Injury With Nodal Angiomatosis.

Hepatology 2019 07 10;70(1):437-439. Epub 2019 Apr 10.

Department of Pathology, University of Washington School of Medicine, Seattle, WA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30579DOI Listing
July 2019

Knowledge gaps in the appendix: a multi-institutional study from seven academic centers.

Mod Pathol 2019 07 14;32(7):988-996. Epub 2019 Feb 14.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Appendix pathology represents uncommonly encountered specimens with unique diagnostic challenges. To delineate common knowledge gaps, extramural consults submitted to seven institutions between 2016-2017 were reviewed. All appendix consults were resections (100%, n = 43), and the majority were directed for consultation by the originating pathologist (95%, n = 41) with no additional studies performed by the consultant (65%, n = 28). This study was dominated by inquiries related to low grade appendiceal mucinous neoplasms (44%, n = 19) and goblet cell carcinoid related neoplasms (19%, n = 8). Of the 43 appendiceal consults, 19 were submitted by the contributing pathologist as low grade appendiceal mucinous neoplasm, but only half of these were diagnosed by the consultant as such (n = 9). Low grade appendiceal mucinous neoplasm-related consultation themes included diverticular disease, criteria for invasion, high grade atypia, extra-appendiceal mucin, and staging. Examples of major disagreements that were downgraded included consults submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as serrated polyp (n = 3), appendicitis (n = 1), and benign appendix (n = 1). Examples of major disagreements-upgraded included cases submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as low grade appendiceal mucinous neoplasm with high-risk features (n = 2) and mucinous adenocarcinoma (n = 2). One case contained both a major disagreement-upgrade (low grade appendiceal mucinous neoplasm changed to high grade appendiceal mucinous neoplasm) and a major disagreement-downgrade (pT3 changed to Tis). Of the 15 cases diagnosed by the consultants as low grade appendiceal mucinous neoplasm, submitted diagnoses included low grade appendiceal mucinous neoplasm (n = 9), adenocarcinoma (n = 5), and one case was submitted without a diagnosis. For goblet cell carcinoid-related consults, the usual inquiry related to distinguishing goblet cell carcinoid from goblet cell carcinoid with adenocarcinoma (adenocarcinoma ex-goblet cell carcinoid). Of the 38 overall consults with a submitted diagnosis, 53% (n = 20) were disagreements, and most of these were major disagreements-downgraded (n = 13).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0216-xDOI Listing
July 2019

Update on the pathology of liver neoplasms.

Ann Diagn Pathol 2019 Feb 12;38:126-137. Epub 2018 Oct 12.

Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America. Electronic address:

Many advances have developed in the pathology of liver tumors in the recent decade. Examples of these advances include the use of glutamine synthetase in the diagnosis of focal nodular hyperplasia, subtyping of hepatocellular adenomas using molecular and immunohistochemical methods, the unraveling of the fusion transcript between the DNAJB1 gene and the PRKACA gene in fibrolamellar carcinoma, and the more unified classification and terminology in intrahepatic bile duct tumors and their precursor lesions. Nevertheless, challenges still remain, e.g., the differential diagnosis between well-differentiated hepatocellular carcinoma and hepatocellular adenoma; distinction among poorly differentiated hepatocellular carcinoma, cholangiocarcinoma and metastatic neoplasm; terminology of the combined hepatocellular carcinoma-cholangiocarcinoma, etc. This review aims to address updates in the pathologic diagnosis and clinical relevance of tumors of the liver and intrahepatic bile ducts in adults and their differential diagnosis and diagnostic pitfalls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2018.10.005DOI Listing
February 2019

Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis.

Hepatology 2019 05;69(5):2241-2257

Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany.

Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30333DOI Listing
May 2019

Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling.

Nat Commun 2018 10 26;9(1):4490. Epub 2018 Oct 26.

Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.

The underlining mechanisms of dietary cholesterol and nonalcoholic steatohepatitis (NASH) in contributing to hepatocellular carcinoma (HCC) remain undefined. Here we demonstrated that high-fat-non-cholesterol-fed mice developed simple steatosis, whilst high-fat-high-cholesterol-fed mice developed NASH. Moreover, dietary cholesterol induced larger and more numerous NASH-HCCs than non-cholesterol-induced steatosis-HCCs in diethylnitrosamine-treated mice. NASH-HCCs displayed significantly more aberrant gene expression-enriched signaling pathways and more non-synonymous somatic mutations than steatosis-HCCs (335 ± 84/sample vs 43 ± 13/sample). Integrated genetic and expressional alterations in NASH-HCCs affected distinct genes pertinent to five pathways: calcium, insulin, cell adhesion, axon guidance and metabolism. Some of the novel aberrant gene expression, mutations and core oncogenic pathways identified in cholesterol-associated NASH-HCCs in mice were confirmed in human NASH-HCCs, which included metabolism-related genes (ALDH18A1, CAD, CHKA, POLD4, PSPH and SQLE) and recurrently mutated genes (RYR1, MTOR, SDK1, CACNA1H and RYR2). These findings add insights into the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203711PMC
October 2018

Nonalcoholic fatty liver disease (NAFLD): Diagnosis, pitfalls, and staging.

Ann Diagn Pathol 2018 Dec 27;37:83-90. Epub 2018 Sep 27.

Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with obesity, diabetes and the metabolic syndrome, not only in the Western societies, but also in most regions of the world in the 21st century. The spectrum of its histopathology ranges from steatosis to nonalcoholic steatohepatitis (NASH), with risk for progressive fibrosis that may lead to cirrhosis and hepatocellular carcinoma (HCC). Benign and malignant liver tumors have also been more frequently reported with the increasing prevalence of obesity and diabetes. This review addresses the pathology of NAFLD and NASH, and their diagnostic features, diagnostic pitfalls, grading and staging, and clinical correlation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2018.09.009DOI Listing
December 2018

Gallbladder carcinoma and epithelial dysplasia: Appropriate sampling for histopathology.

Ann Diagn Pathol 2018 Dec 5;37:7-11. Epub 2018 Sep 5.

Department of Pathology, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195, United States of America. Electronic address:

Gallbladder carcinoma (GC) is an uncommon malignancy with an overall 5-year survival of <5%. Due to overlap of clinical presentation with the more common cholecystitis, an estimated 50-65% of all GCs are found incidentally. Epithelial dysplasia is identified in ~50% of specimens with invasive carcinoma. Recent expert panel guidelines have recommended histologic examination of the entire gallbladder in cases where initial sampling reveals dysplasia. 89 cases of GC, 34 high grade dysplasia (HGD), and 60 low grade dysplasia (LGD) were identified in cholecystectomy specimens assessed at our institution over the last 15 years. Pre-operative imaging (either ultrasound or CT) only identified 52% of mass lesions in GC cases. Among gallbladder specimens with epithelial dysplasia only at initial sampling, additional sectioning was performed in 59% of HGD and 55% of LGD. Additional sectioning of gallbladder specimens with HGD had a higher yield (10%) for identifying invasive carcinoma than those with LGD (0 of 28). The diagnostic yield of additional sectioning is significantly higher in the setting of high grade as compared to low grade dysplasia, suggesting that sampling at the discretion of the pathologist may be sufficient for the latter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2018.08.003DOI Listing
December 2018

Endoscopic resection of gastric adenocarcinoma by use of a full-thickness resection device.

VideoGIE 2018 Aug 12;3(8):244-246. Epub 2018 Jun 12.

Department of Gastroenterology, University of Washington, Seattle, Washington, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vgie.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095660PMC
August 2018

Frequent GNAQ and GNA14 Mutations in Hepatic Small Vessel Neoplasm.

Am J Surg Pathol 2018 09;42(9):1201-1207

Department of Pathology, University of California, San Francisco, San Francisco, CA.

Hepatic small vessel neoplasm (HSVN) is a recently described infiltrative vascular neoplasm of the liver, composed of small vessels. Although the infiltrative nature can mimic angiosarcoma, HSVN are thought to be benign or low-grade neoplasms because they lack cytologic atypia and increased proliferation. To characterize the molecular pathogenesis of HSVN, we performed both targeted panel sequencing and exome sequencing on 18 benign or low-grade vascular neoplasms in the liver including 8 HSVN, 6 classic cavernous hemangioma (CH), and 4 variant lesions (VL) with overlapping features between HSVN and CH. All 18 lesions had simple genomes without copy number alterations. In total, 75% (6/8) of HSVN demonstrated known activating hotspot mutations in GNAQ (2/8, p.Q209H) or GNA14 (4/8, p.Q205L), and the remaining 2 had the same missense mutation in GNAQ, p.G48L, which has not been previously described. 25% (1/4) of VL had a hotspot GNAQ p.Q209H mutation and another VL had a GNAQ p.G48L mutation. Known pathogenic mutations were not identified in any of the 6 CH. These data suggest that HSVN share a similar molecular biology to several other vascular lesions (congenital hemangioma, tufted angioma, anastomosing hemangioma, lobular capillary hemangioma, and kaposiform hemangioendothelioma) recently reported to have GNAQ, GNA11, or GNA14 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001110DOI Listing
September 2018

Data set for the reporting of intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Histopathology 2018 Sep 30;73(3):369-385. Epub 2018 May 30.

Clinpath Laboratories, Kent Town, South Australia, Australia.

Optimal patient management benefits from comprehensive and accurate pathology reports that contribute to cancer staging and prognostication. Proforma reports are used in many countries, but these vary in their structure and implementation. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer the European Society of Pathology and the American Society of Clinical Pathology (ASCP), with the aim of developing an evidence-based reporting data set for each cancer site. It is argued that this should reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of the main malignant liver tumours: intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set incorporates definitions and classifications in the most recent World Health Organisation (WHO) publication on hepatic malignancies (4th edition) and the recently published tumour-node-metastasis (TNM)8 staging system. Widespread adoption and implementation of this data set will enable consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and ultimately result in better patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.13520DOI Listing
September 2018

Mouse models of non-alcoholic steatohepatitis: A reflection on recent literature.

J Gastroenterol Hepatol 2018 Jul 24;33(7):1312-1320. Epub 2018 Mar 24.

Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.

Non-alcoholic steatohepatitis (NASH) is strongly associated with overnutrition, insulin resistance, and predisposition to type 2 diabetes. To critically analyze the translational significance of currently used animal models of NASH, we reviewed articles published during the last 3 years that studied NASH pathogenesis using mouse models. Among 146 articles, 34 (23%) used models in which overnutrition was reported, and 36 (25%) demonstrated insulin resistance, with or without glucose intolerance. Half the articles contained no information on whether mice exhibited overnutrition or insulin resistance. While 75 papers (52%) reported > 2-fold increase of serum/plasma alanine aminotransferase (ALT) compared with controls, ALT levels were near normal or not reported in 48%. Liver pathology was assessed by a pathologist with an interest in liver pathology in 53% of articles published in gastroenterology/hepatology journals, versus 43-44% in other journals. While there appears to be a trend to use models that are potentially relevant to the pathogenesis of human NASH, journals currently publish data on mouse models in which overnutrition and insulin resistance do not occur, without ALT increase or appropriate analysis of NASH pathology. We recommend that investigators, reviewers, and journal editors carefully consider the validity of NASH models in current use and that moves are made to reach a consensus on what the minimal criteria should be.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.14122DOI Listing
July 2018