Mesenchymal iron deposition is associated with adverse long‐term outcome in non‐alcoholic fatty liver disease

Eder, Sarah; Feldman, Alexandra; Strebinger, Georg; Kemnitz, Jana; Zandanell, Stephan; Niederseer, David; Straßer, Michael; Haufe, Heike; Sotlar, Karl; Stickel, Felix; Paulweber, Bernhard; Datz, Christian; Aigner, Elmar

doi:10.1111/liv.14503

Cited by 18 publications

(16 citation statements)

References 37 publications

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“…Hence, the use of potentially steatogenic medication was not allowed as summarized by Roeb et al [15] and Cataldi et al [16], while mild variants of lipodystrophy were not systematically excluded and other manifestations of the insulin resistance syndrome such as polycystic ovary syndrome were not investigated as was the presence of obstructive sleep apnea which may represent an aggravating or causative factors for NAFLD in lean, overweight and obese subjects. All subjects were re-evaluated over a time period of approximately 9 months and the last available time point or the time of the respective endpoint that was determined was used for calculation [17].…”

Section: Study Cohortsmentioning

confidence: 99%

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects

Feldman

Wernly

Strebinger

et al. 2021

JGLD

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Background and Aims: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects. Methods: 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated. Results: Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01). Conclusion: Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.

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Section: Study Cohortsmentioning

confidence: 99%

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects

Feldman

Wernly

Strebinger

et al. 2021

JGLD

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“…Further investigation, based on large-scale cohort studies, is required to confirm these findings. The percentage of positive iron staining in NAFLD cases was reported as 47% by Eder et al, 48% by Hoki et al, 41% by Keith et al, and 68% by Sumida et al 9,[27][28][29] . These amounts of staining do not represent the severe iron deposition as seen in hemochromatosis but the mild or moderate degrees of hepatic iron accumulation that are common in NAFLD patients 9,22,23 .…”

Section: Discussionmentioning

confidence: 99%

MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model

Sakamoto

Miyanishi

Tanaka

et al. 2021

Sci Rep

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Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh+/+), heterozygous (Mutyh+/−), and MUTYH-null (Mutyh−/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh−/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.

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“…The clinical impact of iron deposition in NAFLD is not yet entirely clear, since all available studies show conflicting results. A recent observational study provided evidence that a mesenchymal pattern of iron deposition may be of particular relevance for the clinical outcome, suggesting that the pattern of iron deposition in liver biopsy may identify patients at risk from vascular or hepatic events, who may need closer monitoring 32 . Therefore, it is good clinical practice to search for iron deposition and to report its eventual presence, pattern and severity in the pathological report.…”

Section: Adjunctive Lesionsmentioning

confidence: 99%

Pathology of non-alcoholic fatty liver disease

Cataldo¹,

Sarcognato²,

Sacchi³

et al. 2021

Pathologica

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Summary Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of different conditions which are characterized by hepatic steatosis in the absence of secondary causes. It is currently the most common chronic liver disease worldwide, and its estimated prevalence is about 1.5-6.5%. The only histological finding of steatosis (“simple” steatosis) represents the uncomplicated form of NAFLD, while non-alcoholic steatohepatitis (NASH) is its inflammatory subtype associated with disease progression to cirrhosis and hepatocellular carcinoma (HCC), and represents the major indication for liver transplantation. NASH is still a diagnostic and therapeutic challenge for clinicians and liver biopsy is currently the only accepted method to reliably distinguish NASH from “simple” steatosis. From the histological perspectives, NAFLD and NASH continue to be an area of active interest for pathologists, with a specific focus on better methods of evaluation, morphologic clues to pathogenesis, and predictors of fibrosis progression. This review focuses on histopathology of NAFLD in adults, with the aim to provide a practical diagnostic approach useful in the clinical routine.

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Mesenchymal iron deposition is associated with adverse long‐term outcome in non‐alcoholic fatty liver disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 18 publications

References 37 publications

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects

MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model

Pathology of non-alcoholic fatty liver disease

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