Serum Ferritin Is An Independent Predictor of Histologic Severity and Advanced Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

Body iron, serum ferritin, and nonalcoholic fatty liver disease

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

NAFLD Fibrosis Score: Is It Ready for Wider Use in Clinical Practice and for Clinical Trials?

Impact of Type 2 Diabetes on Nonalcoholic Steatohepatitis and Advanced Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Might some of the beneficial effects of the Mediterranean diet on non-alcoholic fatty liver disease be mediated by reduced iron stores?

ObjectiveSeveral single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.DesignPatients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.Results703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.ConclusionIn biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

Purpose: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and elevated liver enzymes. Currently, liver biopsy is required to assess for the presence of non-alcoholic steatohepatitis (NASH) and degree of fibrosis. While predictors of advanced fibrosis include increased age, obesity, AST/ALT ratio >1, insulin resistance and diabetes, there is still a need for a simple clinical predictor to evaluate for the presence of NASH in patients with steatosis. Our aim was to determine if marked elevation of ALT correlates with the presence of NASH or advanced fibrosis in patients with NAFLD. Methods: We conducted a chart review of outpatients, seen by our gastroenterology faculty practice between September 2000 and December 2008, with biopsy-proven NAFLD. Grading and staging of the liver biopsies were based on the Brunt et al. criteria (Am J Gastro 1999). Biochemical parameters were reviewed on all patients. Patients with coexisting liver disease and/or HIV were excluded. The upper limit of normal (ULN) ALT levels were defined as 19 U/L for women and 30 U/L for men (Ann Intern Med 2002). Advanced fibrosis was defined as presence of at least stage 3/4 fibrosis. Linear regression was used to compare ALT elevations (log (pt's level/ULN)) and AST/ALT ratios in patients grouped by biopsy results with and without controlling for age, sex, diabetes, and body mass index. Results: Of 46 patients with NAFLD (mean age 51.9 years; 65% male), 13 (28%) had ALT ≥ 4 × ULN, 33 (72%) had NASH, and 11 (26%) had advanced fibrosis. There was no association between ALT value and presence or absence of NASH or advanced fibrosis (Table 1; p > 0.4 in univariate and multivariate analysis). Advanced fibrosis was present in 6%, 25%, and 54% of patients with AST/ALT < 0.6, 0.6-0.8, or ≥ 0.8, respectively (Table 2; p<0.01).Table 1Table 2Conclusion: We found no relationship between the degree of elevation of ALT and presence of NASH or advanced fibrosis in patients with NAFLD. AST/ALT ratio is increased in patients with advanced fibrosis, as in other studies. Liver biopsy should be considered in patients with AST/ALT ratio >0.8. ALT alone is not predictive of the presence or absence of NASH and cannot guide the decision to biopsy a patient suspected of NAFLD.

High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD. We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into 'high' (n = 89) and 'normal' (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality were obtained from a national, population-based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy. The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (P < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, P < 0.05). There was no difference in mortality between patients with different iron overload patterns. High levels of ferritin are associated with a long-term increased risk of death.

Sensitivity to thyroid hormones is associated with advanced fibrosis in euthyroid patients with non-alcoholic fatty liver disease: A cross-sectional study.

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Referral pathways for NAFLD fibrosis in primary care – No longer a ‘needle in a haystack’

OBJECTIVEApproximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment.RESEARCH DESIGN AND METHODSThis study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI.RESULTSThe mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis.CONCLUSIONSRoutinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists.

Reply to: Correspondence on “EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update”

To evaluate the diagnostic performance of liver surface nodularity (LSN) for the assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We retrospectively analysed patients with pathologically proven NAFLD who underwent liver MRI. Demographic, clinical, and laboratory data (including FIB-4 scores) were gathered. The SAF score was used to assess NAFLD. MRI-proton density fat fraction (PDFF) and LSN were determined on pre-contrast MR sequences. ROC curve analysis was performed to evaluate the diagnostic performance of MRI-LSN for the diagnosis of advanced (F3-F4) liver fibrosis. The final population included 142 patients. Sixty-seven (47%) patients had non-alcoholic steatohepatitis (NASH), and 52 (37%) had advanced fibrosis. The median MRI-PDFF increased with the grades of steatosis: 8.1%, 18.1%, and 31% in S1, S2, and S3 patients, respectively (p < 0.001). The area under the ROC curve (AUC) of MRI-LSN ≥ 2.50 was 0.838 (95%CI 0.767-0.894, sensitivity 67.3%, specificity 88.9%, positive and negative predictive values 77.8% and 82.5%, respectively) for the diagnosis of advanced fibrosis. Combining FIB-4 and MRI-LSN correctly classified 103/142 (73%) patients. This was validated in an external cohort of 75 patients. MRI-LSN has good diagnostic performance in diagnosis of advanced fibrosis in NAFLD patients. A combination of FIB-4 and MRI-LSN derived from pre-contrast MRI could be helpful to detect advanced fibrosis. • MRI-LSN ≥ 2.5 was accurate for the diagnosis of advanced hepatic fibrosis in NAFLD patients. • The combination of FIB-4 and MRI-LSN improved the detection of advanced fibrosis. • MRI-LSN can be easily derived by unenhanced MRI sequences that are routinely acquired.