The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999–2004

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Abstract

Background: There is evidence that vitamin B12 and associated metabolite levels are changed in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, their association has been in dispute. Methods: We included 8397 individuals without previous liver condition or excess alcohol intake from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. NAFLD was diagnosed with Fatty Liver Index (FLI) ≥ 60 or USFLI ≥ 30, and participants with advanced fibrosis risks were identified with elevated non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 index (FIB-4), or aspartate aminotransferase (AST)/platelet ratio index (APRI). Step-wide logistic regression adjusting for confounders was used to detect the association between NAFLD or advanced fibrosis with serum vitamin B12, folate, red blood cell folate (RBC folate), homocysteine (HCY), and methylmalonic acid (MMA). Results: The weighted prevalence of NAFLD was 44.2%. Compared with non-NAFLD participants, patients with NAFLD showed significantly increased RBC folate level and RBC counts, decreased serum vitamin B12 and folate, and similar HCY and MMA levels. NAFLD with advanced fibrosis risk had higher MMA and HCY, reduced serum vitamin B12, and similar serum folate and RBC folate levels than NAFLD with low fibrosis risk. Only RBC folate was independently associated with an increased risk of NAFLD (OR (95% CI): 2.24 (1.58, 3.18)). In all participants, MMA (OR: 1.41 (1.10, 1.80)) and HCY (OR: 2.76 (1.49, 5.11)) were independently associated with increased risk for advanced fibrosis. In participants with NAFLD, this independent association still existed (OR: 1.39 (1.04, 1.85) for MMA and 1.95 (1.09, 3.46) for HCY). In all participants, the area under the receiver operating characteristic curve (ROC AUC) on fibrosis was 0.6829 (0.6828, 0.6831) for MMA and 0.7319 (0.7318, 0.7320) for HCY; in participants with NAFLD, the corresponding ROC AUC was 0.6819 (0.6817, 0.6821) for MMA and 0.6926 (0.6925, 0.6928) for HCY. Conclusion: Among vitamin B12-associated biomarkers, RBC folate was independently associated with elevated NAFLD risk, whereas MMA and HCY were associated with increased risk for advanced fibrosis in the total population and NAFLD participants. Our study highlighted the clinical diagnostic value of vitamin B12 metabolites and the possibility that vitamin B12 metabolism could be a therapeutic target for NASH. Further studies using recent perspective data with biopsy proven NASH could be conducted to validate our results.

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Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Zobair Younossi, Quentin M Anstee, Milena Marietti … (2018)

NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

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NAFLD: a multisystem disease.

Christopher Byrne, Giovanni Targher (2015)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded.

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The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population

Giorgio Bedogni, Stefano Bellentani, Lucia Miglioli … (2006)

Background Fatty liver (FL) is the most frequent liver disease in Western countries. We used data from the Dionysos Nutrition & Liver Study to develop a simple algorithm for the prediction of FL in the general population. Methods 216 subjects with and 280 without suspected liver disease were studied. FL was diagnosed by ultrasonography and alcohol intake was assessed using a 7-day diary. Bootstrapped stepwise logistic regression was used to identify potential predictors of FL among 13 variables of interest [gender, age, ethanol intake, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase (GGT), body mass index (BMI), waist circumference, sum of 4 skinfolds, glucose, insulin, triglycerides, and cholesterol]. Potential predictors were entered into stepwise logistic regression models with the aim of obtaining the most simple and accurate algorithm for the prediction of FL. Results An algorithm based on BMI, waist circumference, triglycerides and GGT had an accuracy of 0.84 (95%CI 0.81–0.87) in detecting FL. We used this algorithm to develop the "fatty liver index" (FLI), which varies between 0 and 100. A FLI < 30 (negative likelihood ratio = 0.2) rules out and a FLI ≥ 60 (positive likelihood ratio = 4.3) rules in fatty liver. Conclusion FLI is simple to obtain and may help physicians select subjects for liver ultrasonography and intensified lifestyle counseling, and researchers to select patients for epidemiologic studies. Validation of FLI in external populations is needed before it can be employed for these purposes.