The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Patients with non-alcoholic steatohepatitis (NASH) have increased plasmatic and hepatic concentrations of bile acids (BA), suggesting that they can be associated with the progression of the disease. Hepatic nuclear receptors are known to modulate genes controlling BA metabolism; thus, in this work we aimed to compare the expression of liver nuclear receptors -farnesoid X (FXR), small heterodimer partner (SHP) and liver X alpha (LXRα) receptors- and BA transporters -sodium+/taurocholate cotransporting polypeptide (NTCP) and bile salt export pump (BSEP)- in liver biopsy samples of patients with simple steatosis (SS) and NASH. MATERIAL AND METHODS: Forty patients with biopsy-proven NALFD were enrolled between 2009 and 2012; liver biopsies were classified as SS (N = 20) or NASH (N = 20) according to the NAFLD activity score. Gene expression of nuclear FXR, LXRα, SHP, NTCP and BSEP was analyzed by real-time reverse transcription polymerase chain reaction and protein level was quantified by western blot. RESULTS: Gene expression of FXR, SHP, NTCP and BSEP was significantly up-regulated in the NASH group in comparison with SS patients (P < 0.05). In contrast, protein level for FXR, SHP and NTCP was decreased in the NASH patients vs. the SS group (P < 0.05). Gene and protein profile of LXRα did not show differences between groups. CONCLUSIONS: The results suggest that liver nuclear receptors (FXR and SHP) and BA transporters (NTCP and BSEP) are associated with the progression of NAFLD.

Colonic cribriform carcinoma, a morphologic pattern associated with low survival.

Colorectal carcinoma is one of the most common cancers in the human body. Colorectal carcinoma is a heterogeneous disease with variegated morphological patterns; some have shown themselves to have prognostic value. The World Health Organization classification recognizes many histological variants associated with adverse prognostic factors, one is the cribriform colonic carcinoma (CCC). In this work, we analyzed 18 cases of CCC compared with 228 conventional adenocarcinomas of colon, with the hypotheses that CCC compared with non-CCC have worse prognosis and decreased overall survival. CCC represent 7.3% of all colonic adenocarcinomas in this series, it presents in a median age of 56.3 years, all cases are in clinical stage III and IV, all invade subserosal adipose tissues or serosa, 90% have >5 positive lymph nodes and 89% have lymphovascular invasion. These known adverse prognostic factors reflect a lower 5-year survival, stage by stage, than conventional intestinal-type adenocarcinoma (56.8% vs 83.3%, P = .035). Cribriform carcinoma is a morphologic pattern that is underrecognized; in this work, we demonstrate its association with low survival, extensive lymphovascular invasion, and extensive lymph node metastasis, strong indicators of aggressive disease. Their proper recognition is mandatory to increase the number of cases and series to support our findings and include it in the current classifications.

Adenomas of the gallbladder. Morphologic features, expression of gastric and intestinal mucins, and incidence of high-grade dysplasia/carcinoma in situ and invasive carcinoma.

We report 201 gallbladder adenomas from 91 patients most of whom were adult females. Fifty-three (58%) patients had gallstones. In 83 (91%) patients the adenomas were single. One gallbladder had 102 adenomas. Histologically, 165 (82%) of 201 adenomas were classified as pyloric, 28 (14%) as intestinal, 5 (2.4%) as foveolar, and 3 (1.4%) as biliary. Two patients had intestinal-type adenomas coexisting with biliary papillomatosis. Twenty-eight percent of pyloric gland adenomas contained squamoid morules. Two pyloric gland adenomas were composed predominantly of columnar oxyphil cells. High-grade dysplasia/carcinoma in situ was identified in 44 (27%) of 165 pyloric gland adenomas and low-grade dysplasia in 25 (15%) of 165. However, only 2 (1%) invasive adenocarcinomas, both of intestinal type, arose in pyloric gland adenomas. Both patients survived more than 5 years. Intestinal-type adenomas were classified as tubular, papillary, and tubulopapillary. High-grade dysplasia/carcinoma in situ was recognized in 13 (46%) of 28 intestinal adenomas. However, only 1 (3.5%) invasive adenocarcinoma with biliary phenotype arose in an intestinal-type adenoma. Foveolar adenomas showed low-grade dysplasia, and biliary adenomas were composed of columnar cells similar to the normal biliary cells of the gallbladder. None of these tumors progressed to adenocarcinoma. MUC5AC and MUC6 labeled 44 (95%) of 46 pyloric gland adenomas, whereas CDX2 was positive in 14 (78%) of 18 intestinal adenomas and MUC2 in 6 (33%) of 18. MUC5AC and MUC6 labeled 2 foveolar adenomas, and 2 biliary adenomas expressed only CK7. The immunophenotype of gallbladder adenomas justifies their classification into pyloric, intestinal, foveolar, and biliary. Our results indicate that adenomas of the gallbladder play a minor role in the pathway of gallbladder carcinogenesis.