MAFLD: heptaic fibrosis more than NAFLD

 A recent analysis found that those with fatty liver disease but with more metabolic risk factors than NAFLD (nonalcoholic fatty liver disease)), had much higher levels of hepatic fibrosis (see nafld vs mafld prognosis Hepatol2022 in dropbox, or DOI: 10.1002/hep.32131) 

 

Details: 

-- cross-sectional analysis of participants in the Rotterdam study, a large prospective population-based cohort study, assessing the 5445 people who had had liver ultrasound and transient elastography (eg Fibroscan) done between 2009 and 2014 

    -- Rotterdam study: participants >45 years old who lives in a specific suburb of Rotterdam (Ommoord) and were invited “periodically" for assessment. At that time, those consuming >60g of alcohol were excluded, as well as those with viral hepatitis based on HBsAg and anti-hepatitis C testing 

-- those with fatty liver disease (FLD) were categorized into: 

    -- NAFLD (nonalcoholic fatty liver disease): hepatic steatosis, with or without inflammation and fibrosis, and with no secondary causes of hepatic steatosis (including alcoholic liver disease, viral hepatitis, medications such as amiodarone/methotrexate/tamoxifen/steroids/valproate/HIV anti-retrovirals). Alcohol intake had to be <20g/d in females or<30g/d for males 

    -- MAFLD (metabolic dysfunction-associated fatty liver disease): includes coexistence of diabetes, overweight, or evidence of at least two minor criteria of metabolic dysregulation (waist circumference >102 cm in Caucasian men/88 cm in Caucasian women or > 90 cm an Asian men/80 cm in Asian women, blood pressure > 130/85 mmHg or on treatment, plasma triglycerides > 150 or on treatment, HDL < 40 for men or < 50 for women or on treatment, prediabetes, homeostasis model assessment of insulin resistance score at least 2.5, plasma high-sensitivity CRP level >2). MAFLD includes those with high alcohol intake. In this study plasma CRP levels were not evalluated, so data was not available. 

-- mean age 70, 59% female, 

-- 97% of European ancestry 

-- hypertension in 85% with MAFLD/46% NAFLD, prediabetes or diabetes in 20% MAFLD/none MAFLD, metabolic syndrome in 70% MAFLD, none NAFLD 

-- hepatic steatosis was present in 34% (n=1931); Fibroscan done in 73% (n=3957), with 6% (n=239) having fibrosis 

-- Patients were divided into subgroups of: 

    -- no fatty liver disease

    -- both NAFLD and MAFLD 

    -- NAFLD without MAFLD 

    -- MAFLD without NAFLD

 

Results: 

-- NAFLD was diagnosed in 1604 (29.5%) of those without secondary causes of steatosis 

-- MAFLD was diagnosed in 1866 (34.3%) of those with steatosis: 

    -- overweight in 1740 of the 1866 

    -- diabetes in 469, and/or metabolic comorbidity in 1691 

    -- 87% had >1 MAFLD criteria; 22% had all of the criteria 

-- categories evaluated:

    -- neither NAFLD nor MAFLD: 64.7% (3522 of 5445) 

    -- combination of NAFLD and MAFLD: 28.4% (1547 of 5445) 

    -- MAFLD only: 5.4% (319 of 5445) 

         -- not fulfilling NAFLD criteria with 90% having excessive alcohol consumption and/or steatogenic meds in 11% 

    -- NAFLD only: 1.0%  (57 of 5445) 

        -- did not meet MAFLD criteria because no metabolic risk factors 

 

-- Fibrosis assessed by groupings: 

    -- comparing MAFLD-only vs NAFLD-only group, MAFLD had: 

        -- more metabolic syndrome, p<0.001 

        -- more alcohol intake, p<0.001 

        -- higher AST, p=0.004 

        -- higher ALT and GGT, p<0.001 for both 

        --more liver stiffness on Fibroscan, p=0.015, but in total there was 14.9% with MAFLD vs 0.0% with NAFLD (ie none in those with only NAFLD) 

             -- MAFLD diagnosis: sensitivity and specificity to detect fibrosis: 59.4% and 69.9% respectively

    -- comparing MAFLD-only to those with no fatty liver disease: fibrosis higher, with odds ratio of 4.62, after adjusting for age, sex, alcohol consumption, smoking, and education level  [they used a “modified MAFLD” category, which did not include alcohol or viral hepatitis. See below for reasons. But the final analysis with their full MAFLD had similar results to above]

-- percent with fibrosis,  according to number of MAFLD criteria: 

    -- 1 criterion present: 8.3% 

    -- 2 criteria present: 8.9% 

    -- all 3 criteria: 20.5% (comparing 3 vs 1-2 criteria, OR 2.43, p<0.001), even after adjusting for age, sex, education level, smoking and alcohol consumption, with OR 2.42, p<0.001 

    -- overall, the increased risk of fibrosis in MAFLD was independent of alcohol consumption 

 

Commentary: 

-- fatty liver disease affects about 25% of the global population (though <5% are aware of their liver disease); 12 to 14% of those with NAFLD progress to nonalcoholic steatohepatitis, which is one of the most common causes of liver cancer and the second most common indication for liver transplantation 

-- this study reinforces the importance of assessing metabolic dysfunction-associated fatty liver disease (MAFLD), which allows both for assessing the important secondary causes of steatosis (ie the metabolic derangements) as well as including alcohol consumption 

-- this study provides a more specific risk stratification strategy for those with fatty liver disease, a more specific extension of the recent NAFLD guidelines 

    -- for a review of the new guidelines for NAFLD, see http://gmodestmedblogs.blogspot.com/2022/05/nafld-new-guidelines.html, which does comment that type II diabetes as well as features of the metabolic syndrome are major drivers for NAFLD progression to nonalcoholic steatohepatitis 

-- an important perspective here is that hepatic complications for fatty liver disease are relatively uncommon (0.77 deaths per 1000 person-years) versus the cardiovascular mortality (4.79 per 1000 person-years), which further supports the importance of assessing and treating risk factors for heart disease (specifically hypertension, diabetes, and lipid disorders), and this is even true in those with excessive alcohol consumption  

-- I personally like the idea of including high alcohol consumption in the definition of fatty liver disease (vs the NAFLD approach) for several reasons: 

    -- there are somewhat variable definitions of what excessive alcohol consumption is, and I do not believe these definitions are remarkably evidence-based 

    -- patient information on alcohol intake is not particularly reliable in many cases 

    -- there is likely synergy between alcohol intake and other cardio-metabolic risk factors in causing adverse events, so it always seemed important to include alcohol in one’s risk assessment

        -- ie, those with significant alcohol intake should be treated the same as those with lower levels: assessing and treating these metabolic risk factors equally aggressively

        -- and, i think the argument that alcohol is cardioprotective has been sufficiently debunked (see http://gmodestmedblogs.blogspot.com/2015/02/moderate-alcohol-and-cardioprotection_17.html )

-- other studies have confirmed that the vast majority of those with MAFLD have NAFLD (ie, using the MAFLD criteria picks up essentially everyone, and in this Rotterdam study, no one with NAFLD had fibrosis: ie, it is not clear that we really would be missing anyone of significance by just using the MAFLD criteria, since those not developing fibrosis do not seem to be at risk of long-term liver disease)

--in the above comparison between MAFLD and NAFLD, some of the analyses used a “modified” MAFLD assessment (not including alcohol or hepatitis) in order “to allow for a fair comparison between MAFLD and NAFLD”. but the final results were not much different if including alcohol

 

Limitations: 

-- elderly population from one area of one part of the Netherlands: unclear that results are generalizable to other populations and areas 

    -- eg, drinking and other risk factors may not be similar to other areas in the world, limiting generalizability 

-- no real granular data on alcohol consumption in the study, just that 90% with MAFLD-only vs 0% with NAFLD had "excessive alcohol intake"

-- this was a retrospective study and not an RCT, so the results do not confer causality, just association. There may be unmeasured confounders that could explain the associations 

-- the measurements by ultrasound and Fibroscan were not repeated, and it is possible that hepatic fibrosis might have changed over time 

-- several of the groups assessed (specifically the NAFLD-only and MAFLD-only) were very small, limiting the statistical ability to provide significant results 

    -- for example, the results of sensitivity/specificity of NAFLD and MAFLD were the same after excluding those with excessive alcohol and steatogenic drug use, but there were only 57 people with NAFLD-only and 319 with MAFLD-only

-- ultrasound and Fibroscan are not 100% sensitive, both are operator-dependent, areas of fibrosis may be patchy and missed by Fibroscan, and ultrasound can miss mild fibrosis 

-- the study was done before CRP levels were measured; the full definition of MAFLD includes CRP as a measure of inflammation. Missing CRP might have affected the results 

-- the assessment of alcohol intake was not a prespecified datapoint, potentially leading to less accurate quantification 

 

So, as is evident in this study, there was huge overlap in NAFLD and MAFLD, but a few observations: 

-- using NAFLD in this study added nothing in terms of liver fibrosis over using MAFLD (adding the metabolic risk factors in particular).

    -- for example, the MAFLD/NAFLD overlap may be very different in different situations, especially if one's patient population has higher alcohol consumption and would not be considered to have NAFLD 

-- the study confirms that there is a dose-response in the risk of hepatic fibrosis: the more metabolic risk factors the worse (and, though small numbers, those with NAFLD and no metabolic risk factors had no cases of fibrosis) 

-- but, given that these results are from a relatively uniform, older, white population in one suburb in the Netherlands, there should be other studies in other areas of the world with diverse cultures prior to any big changes in our overall approach

    -- though, i would add, that we should be aggressively treating cardiovascular risk factors in those with fatty liver and metabolic syndrome independent of alcohol use (and actually independent of fatty liver...). but with the added target of helping those with alcohol use disorder through counseling, support, and meds

    -- see http://gmodestmedblogs.blogspot.com/2022/06/alcohol-meds-decrease-liver-disease.html , a recent blog documenting significant benefit from alcohol use disorder meds in decreasing alcohol-associated liver disease

geoff

 

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