Cryptogenic cirrhosis: Old and new perspectives in the era of molecular and genomic medicine.

Cryptogenic cirrhosis (CC) is defined as cirrhosis of unknown etiology despite extensive clinical, laboratory and pathologic work-up, and constitutes approximately 5-10% of all cirrhosis cases. Histologic examination can provide important clues and help identify the potential etiology of CC. Most CC cases can still be classified into four histologic patterns: hepatitic, steatotic, biliary, and patternless (bland). The use of genetic testing has significantly improved diagnostic ability and treatment, especially in pediatric patients with acute and chronic liver diseases. More recently, whole exome sequencing has been used for identifying genetic alterations that lead to a diagnosis in adults with liver disease of unknown etiology. Recent advances in genomic analysis has allowed the unraveling of the underlying etiology in a subset of CC cases, and also helped identify new disorders. Providing a diagnosis for these patients has several important implications for treatment, possible genetic counseling, and transplant eligibility. However, detailed clinical and histologic characterization of the patients still remains an important part of the CC work-up, since clinicopathologic and genomic correlation is crucial in making a diagnosis, or in some cases, discovery of a new entity. This article summarizes the main histologic findings that can be observed in CC cases, potential causes of CC, and recent advances in the field.

Differentiation of Hepatocellular Carcinoma from Other Hepatic Malignancies in Patients at Risk: Diagnostic Performance of the Liver Imaging Reporting and Data System Version 2014.

Purpose To evaluate the diagnostic performance and interrater reliability of the Liver Imaging Reporting and Data System (LI-RADS) version 2014 in differentiating hepatocellular carcinoma (HCC) from non-HCC malignancy in a population of patients at risk for HCC. Materials and Methods This retrospective HIPAA-compliant institutional review board-approved study was exempt from informed consent. A total of 178 pathology-proven malignant liver masses were identified in 178 patients at risk for HCC but without established extrahepatic malignancy from August 2012 through August 2015. Two readers blinded to pathology findings and clinical follow-up data independently evaluated a liver protocol magnetic resonance or computed tomography study for each lesion and assigned LI-RADS categories, scoring all major and most ancillary features. Statistical analyses included the independent samples t test, x2 test, Fisher exact test, and Cohen k. Results This study included 136 HCCs and 42 non-HCC malignancies. Specificity and positive predictive value of an HCC imaging diagnosis (LR-5 or LR-5V) were 69.0% and 90.5%, respectively, for reader 1 (R1) and 88.3% and 95.5%, respectively, for reader 2 (R2). Tumor in vein was a common finding in patients with non-HCC malignancies (R1, 10 of 42 [23.8%]; R2, five of 42 [11.9%]). Exclusion of the LR-5V pathway improved specificity and positive predictive value for HCC to 83.3% and 92.9%, respectively, for R1 (six fewer false-positive findings) and 92.3% and 96.4%, respectively, for R2 (one fewer false-positive finding). Among masses with arterial phase hyperenhancement, the rim pattern was more common among non-HCC malignancies than among HCCs for both readers (R1: 24 of 36 [66.7%] vs 13 of 124, [10.5%], P < .001; R2: 27 of 35 [77.1%] vs 21 of 123 [17.1%], P < .001) (k = 0.76). Exclusion of rim arterial phase hyperenhancement as a means of satisfying LR-5 criteria also improved specificity and positive predictive value for HCC (R1, two fewer false-positive findings). Conclusion Modification of the algorithmic role of tumor in vein and rim arterial phase hyperenhancement improves the diagnostic performance of LI-RADS version 2014 in differentiating HCC from non-HCC malignancy. © RSNA, 2017 Online supplemental material is available for this article.

The impact of diet-induced hepatic steatosis in a murine model of hepatic ischemia/reperfusion injury.

The prevalence of obesity-associated nonalcoholic fatty liver disease has significantly increased over the past decade, and end-stage liver disease secondary to nonalcoholic steatohepatitis has become 1 of the most common indications for liver transplantation. This both increases the demand for organs and decreases the availability of donor livers deemed suitable for transplantation. Although in the past many steatotic livers were discarded due to concerns over enhanced susceptibility to ischemia/reperfusion injury (IRI) and organ failure, the discrepancy between supply and demand has resulted in increasing use of expanded criteria donor organs including steatotic livers. However, it remains controversial whether steatotic livers can be safely used for transplantation and how best to improve the performance of steatotic grafts. We aimed to evaluate the impact of diet-induced hepatic steatosis in a murine model of IRI. Using a diet of high trans-fat, fructose, and cholesterol (HTF-C) and a diet high in saturated fats, sucrose, and cholesterol (Western diet), we were able to establish models of mixed macrovesicular and microvesicular steatosis (HTF-C) and microvesicular steatosis (Western). We found that the presence of hepatic steatosis, whether it is predominantly macrovesicular or microvesicular, significantly worsens IRI as measured by plasma alanine aminotransferase levels and inflammatory cytokine concentration, and histological evaluation for necrosis. Additionally, we report on a novel finding in which hepatic IRI in the setting of steatosis results in the induction of the necroptosis factors, receptor interacting protein kinase (RIPK) 3, RIPK1, and mixed-lineage kinase domain-like. These data lay the groundwork for additional experimentation to test potential therapeutic approaches to limit IRI in steatotic livers by using a genetically tractable system. Liver Transplantation 24 908-921 2018 AASLD.

Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis.

Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator-activated receptor γ. We sought to determine whether a next-generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator-activated receptor γ (MSDC-0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC-0602. We found that MSDC-0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol. Moreover, mice with liver-specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC-0602 directly reduced hepatic stellate cell activation in vitro, and MSDC-0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. CONCLUSION: Collectively, these data demonstrate the effectiveness of MSDC-0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (Hepatology 2017;65:1543-1556).

Lymphoid Aggregates Remodel Lymphatic Collecting Vessels that Serve Mesenteric Lymph Nodes in Crohn Disease.

Early pathological descriptions of Crohn disease (CD) argued for a potential defect in lymph transport; however, this concept has not been thoroughly investigated. In mice, poor healing in response to infection-induced tissue damage can cause hyperpermeable lymphatic collecting vessels in mesenteric adipose tissue that impair antigen and immune cell access to mesenteric lymph nodes (LNs), which normally sustain appropriate immunity. To investigate whether analogous changes might occur in human intestinal disease, we established a three-dimensional imaging approach to characterize the lymphatic vasculature in mesenteric tissue from controls or patients with CD. In CD specimens, B-cell-rich aggregates resembling tertiary lymphoid organs (TLOs) impinged on lymphatic collecting vessels that enter and exit LNs. In areas of creeping fat, which characterizes inflammation-affected areas of the bowel in CD, we observed B cells and apparent innate lymphoid cells that had invaded the lymphatic vessel wall, suggesting these cells may be mediators of lymphatic remodeling. Although TLOs have been described in many chronic inflammatory states, their anatomical relationship to preestablished LNs has never been revealed. Our data indicate that, at least in the CD-affected mesentery, TLOs are positioned along collecting lymphatic vessels in a manner expected to affect delivery of lymph to LNs.

IgG4-related sclerosing cholangitis in the absence of autoimmune pancreatitis mimicking extrahepatic cholangiocarcinoma.

AIMS: IgG4-related sclerosing cholangitis in extrahepatic bile ducts in the absence of autoimmune pancreatitis (AIP) is rare and is poorly studied. Herein, we present the clinicopathological features of four cases of IgG4-related sclerosing cholangitis. METHODS AND RESULTS: The clinicopathological features of IgG4-related sclerosing cholangitis were compared with those of IgG4-related sclerosing cholangitis with AIP (n = 7), extrahepatic cholangiocarcinoma (n = 29), primary sclerosing cholangitis (n = 40), and secondary sclerosing cholangitis (n = 12). Several histomorphologic features distinguish IgG4-related sclerosing cholangitis, including a marked degree of bile duct injury, a higher percentage of lymphoid follicle formation, a higher percentage of perineuritis, and a more diffuse and dense lymphoplasmacytic infiltrate. All four cases of IgG4-related sclerosing cholangitis occurred exclusively in males. Of these cases, none had IgG4 serology checked preoperatively, and all had a preoperative diagnosis of extrahepatic cholangiocarcinoma. Clinical follow-up was available in 2 patients with a mean time of 11 months. Follow-up confirmed the benign course of the disease as the patients showed no evidence of relapse. IgG4-related conditions, including sclerosing cholecystitis and retroperitoneal fibrosis, were noted in three patients. CONCLUSIONS: IgG4-related sclerosing cholangitis in the absence of AIP presents as a distinct and under-recognized disease that mimics extrahepatic cholangiocarcinoma clinically. Awareness of this entity is essential to avoid erroneously diagnosing malignancy. The current threshold of 10 IgG4-positive plasma cells/high-power field (HPF) in the biopsy is not specific enough to exclude cholangiocarcinoma. Therefore, we suggest the diagnostic cut-off to be 50 IgG4-positive plasma cells/HPF in the biopsy.

Advanced colorectal adenomas in patients under 45 years of age are mostly sporadic.

BACKGROUND: The presence of advanced adenomas in younger individuals is a criterion for Lynch syndrome (LS). However, the utility of screening advanced adenomas for loss of mismatch repair (MMR) protein expression to identify suspected LS remains unclear. AIMS: Determine the prevalence of MMR defects to understand whether these patients harbor a defined genetic risk for CRC. METHODS: The study cohort included adult patients ≤45 years of age with advanced adenomas (villous histology, ≥1 cm in diameter, ≥3 polyps of any size) endoscopically removed between 2001 and 2011. Clinical records were reviewed along with detailed pathological review and immunohistochemical MMR analysis. RESULTS: A total of 76 (40.1 % male, age 40.6 ± 5.4 years) patients met inclusion and exclusion criteria. Indications for colonoscopy were gastrointestinal (GI) bleeding 39 (51.3 %), CRC in a first-degree relative 17 (22.4 %) and somatic GI symptoms 20 (26.3 %). Index colonoscopy revealed a median of 1 adenoma (range 1-4), mean diameter of 12.9 ± 7.1 mm, 40 (52.6 %) with villous histology. The mean follow-up duration was 3.3 ± 2 years. Recurrent adenomas developed in 24 (31.6 %), of which 8 (10.5 %) were advanced adenomas; none of these patients developed CRC. One of 66 (1.5 %) adenomas available for immunohistochemical (IHC) testing revealed loss of MLH1 and PMS2. CONCLUSIONS: IHC screening of advanced adenomas from patients younger than 45 years of age identified potential LS in one of 64 patients. The low yield of IHC screening in this population suggests that universal IHC screening of advanced adenomas from patients younger than 45 years of age for MMR defects is not an efficient strategy for identifying LS subjects.

Clinical and Pathological Correlation in Concomitant Celiac Disease and Eosinophilic Esophagitis Suggests Separate Etiologies.

Introduction. Recently, an increased risk of celiac disease or eosinophilic esophagitis has been postulated among patients with either of these disorders, prompting some to suggest a common underlying mechanism, whereas others maintain that their co-existence is coincidental. Methods. We compared clinical and pathological features of 29 patients meeting criteria for both celiac disease and eosinophilic esophagitis to 26 celiac disease and 26 eosinophilic esophagitis controls to determine whether any distinguished study patients from controls. Results. Eight (28%) study patients presented with symptoms of both celiac disease and eosinophilic esophagitis, whereas 14 (48%) had celiac disease symptoms only and 5 had (17%) esophageal symptoms only. Study patients had similar autoimmune and atopic conditions seen in both control groups. Histological severity of disease, including Marsh II-III duodenal histology (study specimens: 87%; controls: 89%), mean peak esophageal eosinophil counts (study specimens: 55/400x field; controls: 80/400X field, P = .1), and presence of eosinophil microabscesses, scale crust, and subepithelial fibrosis were also similar to controls. Gluten-free diet resolved celiac disease-related symptoms (19 of 20, 95%) and histology (10 of 12, 83%), but not esophageal symptoms or eosinophilia in most study patients. Conclusion. Patients with concomitant celiac disease and eosinophilic esophagitis lack distinguishing features compared to controls with celiac disease or eosinophilic esophagitis alone. The occurrence of both disorders is likely coincidental in most cases.