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BACKGROUND AND AIM: Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients.METHODS: In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed.RESULTS: Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P CONCLUSION: Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis.

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3 thorn )] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size. NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.

Background Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients. Methods Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed. Results Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls. Conclusion Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

Background and aim: Insulin resistance (IR) plays a central role in the complex pathophysiology of nonalcoholic fatty liver disease (NAFLD). IR is linked to fat infiltration in skeletal muscle (myosteatosis) and loss of skeletal muscle mass and function (sarcopenia). The clinical significance of myosteatosis in NAFLD is not well investigated. In this exploratory study we aimed to investigate the association between myosteatosis and NAFLD related hepatic and systemic variables in a well characterized NAFLD cohort.Methods: We cross-sectionally studied forty-five NAFLD patients. The muscle fat fraction (MFF) was measured with chemical shift gradient echo MRI. In addition, the hepatic fat fraction (MRI), liver stiffness (FibroScan) and appendicular skeletal muscle mass (Dual-energy X-ray absorptiometry) were analyzed.Results: The median hepatic fat fraction was 15.64% (IQR 12.05-25.13) and significant (F2-F3) liver fibrosis (liver stiffness >= 7 kPa) was diagnosed in 18 NAFLD patients (40%). MFF was not correlated with hepatic fat fraction (r = -0.035, P = 0.823) and did not differ between subjects with or without significant fibrosis (P = 0.980). No patient was diagnosed with sarcopenia based on the skeletal muscle mass index. In a linear regression model, anthropometric parameters, including body mass index (BMI) (P = 0.018) and total body fat percentage (P = 0.005), were positively associated with MFF while no association with insulin resistance (HOMA-IR) was observed.Conclusion: Myosteatosis did not correlate with the degree of hepatic steatosis or fibrosis in this well characterized NAFLD cohort, but was positively correlated with total body fat percentage and BMI. (C) 2020 Elsevier Masson SAS. All rights reserved.

We present a p.C282Y homozygous patient with high hepcidin levels and normal iron parameters during systemic inflammation. This suggests that in the absence of a proper functioning HFE, resulting in blockage of the BMP/SMAD pathway, the innate low hepcidin concentration can be upregulated by inflammation, probably via the JAK/STAT3 pathway.

Non-alcoholic fatty liver disease (NAFLD) is a widespread liver disease in Western society, but its multifactorial pathogenesis is not yet fully understood. Ultrastructural analysis of liver sinusoidal endothelial cells (LSECs) in animal models and in vitro studies shows defenestration early in the course of NAFLD, promoting steatosis. LSECs and fenestrae are important in the transport of lipids across the sinusoids. However, human ultrastructural data, especially on LSECs and fenestrae, are scarce. This study aimed to explore the ultrastructural changes in perfusion type fixed liver biopsies of NAFLD patients with and without non-alcoholic steatohepatitis (NASH), with a special focus on LSECs and their fenestration. Liver biopsies from patients with NAFLD were fixed using two perfusion techniques, jet and injection fixation, for needle and wedge biopsies, respectively. Ultrastructural changes were studied using transmission electron microscopy. NASH was diagnosed by bright-field microscopy using the SAF score (steatosis, activity, fibrosis). Thirty-seven patients were included, of which 12 (32.4%) had NASH. Significantly less defenestration was found in NASH compared to noNASH samples (p=0.002). Other features, i.e., giant mitochondria and fenestrae size did not differ between groups. Furthermore, we described new structures, i.e., single cell steatonecrosis and inflammatory fat follicles (IFF) that were observed in both groups. Concluding, defenestration was more common in noNASH compared to NASH in human liver samples. Defenestration was not related to the degree of steatosis or fibrosis. We speculate that defenestration can be a protective mechanism in simple steatosis which is lacking in NASH.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS: We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sens(p)) and specificity (spec(p)) values were determined using the Meta-Analysis Package for R (metafor). RESULTS: In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sens(p), 63.5% and spec(p), 74.4%) within routine biochemical tests, adiponectin (sens(p), 72.0% and spec(p), 75.7%) within inflammatory markers, CK18-M30 (sens(p), 68.4% and spec(p), 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sens(p), 69.0% and spec(p), 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sens(p) and 95.3% spec(p)) and the GlycoNASH test (67.1% sens(p) and 63.8% spec(p)). CONCLUSION: In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (>= 80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with >= 80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis.

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.

Objective Phenotypes of the HFE-related haemochromatosis vary considerably, making it hard to predict the course of iron accumulation. The aim of this retrospective study was to determine if the Iron Avidity Index (IAI) is a good phenotypic predictor of the number of phlebotomies needed per year during maintenance treatment (NPDMT) in patients with homozygous p.C282Y hereditary haemochromatosis (HH). Methods Patients with HH homozygous for p.C282Y, on maintenance treatment for at least 1 year were included. The IAI (ferritin level at diagnosis/age at diagnosis) was calculated. Results Ninety-five patients were included in the analysis. Linear regression analysis showed the confounding effect of sex on the relationship between IAI and NPDMT. A modified IAI, adjusted for sex, was calculated. As proton pump inhibitor (PPI) use was independently associated with NPDMT, the group was split in PPI- and non-PPI-users. A positive correlation between the modified IAI and the NPDMT was shown in both groups (PPI r = 0.367, P = 0.023; non-PPI r = 0.453, P < 0.001). An ROC was computed to measure the accuracy of the modified IAI to predict who needed 0–2 vs. ≥3 maintenance treatments per year. The AUROC in the PPI and non-PPI group were respectively 0.576 (0.368–0.784) and 0.752 (0.606–0.899). Conclusion The modified IAI is a fairly good predictor in non-PPI-using homozygous C282Y HH patients, to differentiate who needs ≥3 maintenance phlebotomies per year. Therefore, this index might help to select patients that benefit from an alternative less frequent therapy, e.g. erythrocytapheresis.

Background and Aims: Hemorrhage from gastroesophageal varices in children with prehepatic portal hypertension is best controlled by various types of portosystemic shunt, but long-term follow up of children who have had splenorenal shunt surgery due to portal hypertension gave evidence for assuming the risk of renal venous hypertension (RVH). The purpose of this study was to investigate the impact of portosystemic shunt surgery on renal blood Methods: The results of 170 portosystemic shunt operations were followed from 2005 to 2014. 12 patients applied side to side splenorenal shunt, 12 children assessed the distal splenorenal shunt (DSRSh), 82 had central splenorenal shunt (CSRSh) with splenectomy. 44 iliacomesenterial anastomosis (IMA) and in 20 cases performed mesocaval anastomosis (MCA). Patients had a standard pre and postoperative work up including gastrointestinal endoscopy, Doppler ultrasonography (US), angiography, multislice computed tomography and MR imaging. Results: On Doppler US at early and late postoperative periods PI and RI of left renal artery remained at high numbers (PI = 1.48±0.17 and RI = 0.72±0.19, p ≤ 0.05 respectively) after the CSRSh with splenectomy. After DSRSh, these signs haven’t been detected. 11 (13.4%) patients after CSRSh on Doppler US revealed signs of impeded venous outflow on the left renal vein (LRV). 8 patients after IMA on US Doppler and CT and MRI angiography revealed dilated left testicular and ovarian veins (Figure 1), with retrograde blood flow in them, which clinically manifested as left flank pain, macroand microhematuria, varicocele and ovaricocele Conclusions: Portosystemic shunt surgery is highly effective treatment for children with prehepatic portal hypertension. But study shows that total shunts such as central splenorenal shunt with splenectomy and iliacomesenterial anastomosis more negatively effect on hemodynamics of left kidney. Shunting the large amounts of blood from a system of high pressure to a low manifests as clinical signs of renal venous hypertension.