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Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis

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Date added: 08/22/2017
Date modified: 08/22/2017
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OBJECTIVES: Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD.

METHODS: Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36–45 (n=96), 46–55 (n=197), 56–64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3–F4) for each group was assessed using liver biopsy as the standard.

RESULTS: Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77–0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%).

CONCLUSIONS: The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and... Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and...

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Date added: 05/27/2018
Date modified: 05/27/2018
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"Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study"

Aims/hypothesis
Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR.

Methods
We identified healthy individuals in two population-based cohorts (FINRISK 2007 [n = 5024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; n = 2849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA-IR cut-off for NAFLD (liver fat ≥5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories.

Results
The upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (n = 1167) and FIN-D2D (n = 459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements.

Conclusions/interpretation
The upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR.

PNPLA3 and obesity: a synergistic relationship in NAFLD PNPLA3 and obesity: a synergistic relationship in NAFLD

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Date added: 05/27/2018
Date modified: 05/27/2018
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NAFLD, the hepatic manifestation of the metabolic syndrome, is a multifactorial condition — environmental factors influence an inherited genetic risk. Stender et al. now describe the additive effect of obesity and NAFLD-associated genetic polymorphisms on steatosis, elevated serum alanine aminotransferase levels and cirrhosis, remarkably illustrating the principle of gene–environment interactions.

Refers to Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842–847 (2017)

Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers.. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers..

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Date added: 06/02/2018
Date modified: 06/02/2018
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"Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD"

Background:
Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2^EK/KK) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common ‘obese/metabolic’ NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids.

Methods:
Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs.

Results:
The TM6SF2^EK/KK and TM6SF2^EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2^EK/KK than the TM6SF2^EE group (p <0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p <0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p <0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs.

Conclusions:
Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.

Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1 Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1

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Date added: 05/27/2018
Date modified: 05/27/2018
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Purpose of review
Glucagon and GLP-1 share the same origin (i.e., proglucagon); primarily GLP-1 is generated from intestinal L-cells and glucagon from pancreatic α-cell, but intestinal glucagon and pancreatic GLP-1 secretion is likely. Glucose kinetics are tightly regulated by pancreatic hormones insulin and glucagon, but other hormones, including glucagon-like peptide-1 (GLP-1), also play an important role. The purpose of this review is to describe the recent findings on the mechanisms by which these two hormones regulate glucose kinetics.

Recent findings
Recent findings showed new important mechanisms of action of glucagon and GLP-1 in the regulation of glucose metabolism. Knock out of glucagon receptors protects against hyperglycemia without causing hypoglycemia. GLP-1 not only stimulates insulin secretion, but it has also an independent effect on the liver and inhibits glucose production. Moreover, when coinfused with glucagon, GLP-1 limits the hyperglycemic effects. Both hormones have also central effects on gastric emptying (delayed), intestinal motility (reduced), and satiety (increased).

Summary
The implications of these findings are very important for the management of type 2 diabetes given that GLP-1 receptor agonist are currently approved for the treatment of hyperglycemia and glucagon receptor antagonists and GLP-1/glucagon dual agonists are under development.

The good and the bad collagens of fibrosis – Their role in signaling and organ function The good and the bad collagens of fibrosis – Their role in signaling and organ function

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Date added: 08/07/2018
Date modified: 08/07/2018
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Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression.

We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively.

We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM.

Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease

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Date added: 08/03/2018
Date modified: 08/03/2018
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"Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity"

Objective:
Non-alcoholic fatty liver disease (NAFLD) is a frequent complication of morbid obesity, but its severity varies greatly and thus there is a strong need to better define its natural history in these patients.

Design:
Liver biopsies were systematically performed in 798 consecutive patients with severe obesity undergoing bariatric surgery. Histology was compared with clinical, biological, anthropometrical and body composition characteristics.

Results:
Patients with presumably normal liver (n=179, 22%) were significantly younger at bariatric surgery than patients with NAFLD (37.0 vs 44.4 years, p<0.0001). However, both groups showed quite similar obesity duration, since patients with presumably normal liver reported the onset of obesity at a significantly younger age than those with NAFLD (14.8 vs 20.0 year, p<0.0001). The trunk/limb fat mass ratio increased according to liver disease severity (presumably normal liver: 1.00, steatosis: 1.21, non-alcoholic steatohepatitis (NASH): 1.34, p<0.0001), although the total body fat mass decreased ( presumably normal liver: 50%, steatosis: 49.1%, NASH: 47.4%, p<0.0001). The volume of subcutaneous adipocytes increased according to severity of liver disease but only in female patients (presumably normal liver: 8543 picolitres, steatosis: 9156 picolitres, NASH: 9996 picolitres).

Conclusions:
These results suggest that young adults are more prone to store fat in subcutaneous tissue and reach the threshold of bariatric surgery indication before their liver is damaged. A shift of fat storage from subcutaneous to visceral adipose tissue compartment is associated with liver damages. Liver might also be targeted by subcutaneous hypertrophic adipocytes in females since hypertrophic adipocytes are more exposed to lipolysis and to the production of inflammatory mediators.

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other... Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other...

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Date added: 05/27/2018
Date modified: 05/27/2018
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"Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases"

Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory ‘milieu’ initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (e.g. patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD.

Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD? Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD?

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Date added: 08/07/2018
Date modified: 08/07/2018
Filesize: 256 Bytes
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Whether non-alcoholic fatty liver disease (NAFLD) precedes insulin resistance (IR) or IR preludes/causes NAFLD has been long debated. Recent studies have shown that there are two phenotypes of NAFLD, ‘genetic’ vs ‘metabolic’ NAFLD. The former patients are more at risk of hepatocellular carcinoma and chronic liver disease the latter are more IR and at increased risk of type 2 diabetes (T2D). Even if they are not yet diabetics, from a metabolic point of view having NAFLD is equivalent to T2D with reduced peripheral glucose disposal and impaired suppression of hepatic glucose production, but without fasting hyperglycaemia. T2D develops only when hepatic autoregulation is lost and glucose production exceeds the capacity of muscle glucose disposal.

In NAFLD adipocytes are resistant to the effect of insulin, lipolysis is increased and excess plasma free fatty acids (FFA) are taken up by other organs (mainly liver) where they are stored as lipid droplets or oxidized. Increased adiposity is associated with worsen severity of both ‘genetic’ and ‘metabolic’ NAFLD. FFA oxidative metabolism is increased in NAFLD and not shifted towards glucose during insulin infusion. Although this reduced metabolic flexibility is an early predictor of T2D, it can be seen also as a protective mechanism against excess FFA.

In conclusion, IR precedes and causes ‘metabolic’ NAFLD, but not ‘genetic’ NAFLD. Reduced metabolic flexibility in NAFLD might be seen as a protective mechanism against FFA overflow, but together with IR remains a strong risk factor for T2D that develops with the worsening of hepatic regulation of glucose production.

Inflammation induced IgA+ cells dismantle anti-liver cancer immunity Inflammation induced IgA+ cells dismantle anti-liver cancer immunity

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Date added: 08/07/2018
Date modified: 08/07/2018
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The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.