Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using ² H ₂ O and ² H-glycerol) and insulin sensitivity using ³ H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.

Context Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting Tertiary referral center. Patients We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m²]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage ≥F3 fibrosis or nonalcoholic steatohepatitis with ≥F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results The scores with an AUROC ≥0.85 to identify ≥F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out ≥F3 fibrosis in groups with BMIs <30.0, 30.0 to 39.9, and ≥40.0 kg/m². This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose ≥F3 fibrosis. Conclusions In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.

Inhibins are gonadal glycoprotein hormones whose main endocrine function is to inhibit pituitary FSH secretion. In addition to testes and ovaries, other steroid-producing organs are sites of inhibin alpha subunit expression. To study the role of inhibins in human adrenal gland, we screened a panel of 150 adrenals (10 normal adrenals, 25 adrenocortical hyperplasias, 65 adrenocortical adenomas, 30 adrenocortical carcinomas and 20 phaeochromocytomas) for inhibin alpha expression. mRNA levels of inhibin alpha subunit were studied in 57 samples and all tissues were stained immunohistochemically with an inhibin alpha subunit-specific antibody. Inhibin alpha mRNA was detected in all adrenocortical tissues. Virilizing adenomas possessed a 10-fold higher median inhibin alpha mRNA expression than did normal adrenals. Bilaterally and nodularly hyperplastic adrenals and other than virilizing adrenocortical tumours had their median inhibin alpha mRNA levels close to those of normal adrenals. Immunohistochemically, inhibin alpha subunit was detectable in all normal and hyperplastic adrenals, as well as in 73% of the adrenocortical tumours. However, the percentage of inhibin alpha-positive cells varied greatly in different tumour types. The median percentage of positive cells was 10 in non-functional and Conn's adenomas, 30 in Cushing's adenomas and 75 in virilizing adenomas. In malignant adrenocortical tumours the median percentage of inhibin alpha-immunopositive cells was 20 in non-functional carcinomas, 30 in Conn's carcinomas, 65 in Cushing's carcinomas and 75 in virilizing carcinomas. All phaeochromocytomas were negative for inhibin alpha subunit both at the mRNA level and immunohistochemically. Our data show that inhibin alpha subunit is highly expressed in both normal and neoplastic androgen-producing adrenocortical cells, with less expression in cortisol-producing and hardly any in aldosterone-producing cells. This suggests a specific role for inhibins in the regulation of adrenal androgen production. We did not find any significant difference in inhibin alpha expression between benign and malignant adrenocortical tumours. Thus inhibin alpha gene does not seem to have a tumour suppressor role in human adrenal cortex.

Background: Well-differentiated follicular thyroid carcinomas (FTCs) usually act indolently, while aggressively acting tumors are difficult to detect early enough. Estrogen receptors (ERs) have prognostic significance in many cancers. Thyroid diseases, including neoplasms, are associated with the female sex. The prognostic significance of ERs in FTCs has not been reported previously. Methods: We studied the role of ERα and ERβ in 83 cases of follicular thyroid adenoma (FTA) and 43 FTC cases, including seven cases of poorly differentiated FTC, obtained from the Department of Surgery, Helsinki University Central Hospital between 1990 and 2009. Patient follow-up was conducted until March 2011. Expression of ERα, ERβ, and MIB-1/Ki-67 was investigated by immunohistochemistry and correlated with clinicopathological characteristics, including survival. Results: Two major observations were apparent. First, ERβ expression was significantly higher in FTA than in FTC, and it was a stronger differential diagnostic marker than MIB-1/Ki-67. Second, low ERβ expression correlated with poor survival in FTC. All cancer-specific deaths due to FTC were among low ERβ-score patients. Conclusion: ERβ is a differential marker for malignancy and could thus be used as a preoperative tool. FTC patients with a low ERβ score need more thorough follow-up and may benefit from more aggressive treatment.

Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine–cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.