Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—Rather a Bystander Than a Driver of Mortality (original) (raw)

Journal Article

Georg Semmler ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna

,

Vienna

,

Austria

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Sarah Wernly ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Sebastian Bachmayer ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Isabella Leitner ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Bernhard Wernly ,

Second Department of Medicine, Paracelsus Medical University Salzburg

,

Salzburg

,

Austria

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Matthias Egger ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Lena Schwenoha ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Leonora Datz ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

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Lorenz Balcar ,

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

,

Salzburg

,

Austria

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna

,

Vienna

,

Austria

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Marie Semmler

Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University

Salzburg, Oberndorf

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Salzburg

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Austria

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Editorial decision:

07 May 2021

Corrected and typeset:

02 July 2021

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Georg Semmler, Sarah Wernly, Sebastian Bachmayer, Isabella Leitner, Bernhard Wernly, Matthias Egger, Lena Schwenoha, Leonora Datz, Lorenz Balcar, Marie Semmler, Felix Stickel, David Niederseer, Elmar Aigner, Christian Datz, Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—Rather a Bystander Than a Driver of Mortality, The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 9, September 2021, Pages 2670–2677, https://doi.org/10.1210/clinem/dgab339
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Abstract

Context

Recently, the novel metabolic dysfunction-associated fatty liver disease (MAFLD) definition has been introduced.

Objective

To assess the relevance of MAFLD for mortality.

Methods

Single-center cohort-study using colorectal cancer screening program involving 4718 subjects aged 45 to 80 who were grouped according to their body mass index (BMI) and the presence or absence of MAFLD. Mortality was compared among these groups by performing a systematic read-out of the national health insurance system, fatty liver (FL) was diagnosed using ultrasound.

Results

Overall prevalence of FL was 47.9%: 1200 (25.4%) patients were lean (BMI < 25 kg/m2) and did not have MAFLD, 73 (1.5%) patients were lean and had nonalcoholic fatty liver disease but did not fulfill criteria for MAFLD, and 221 (4.7%) patients were lean and fulfilled criteria for MAFLD. Additionally, 1043 (22.1%) and 925 (19.6%) subjects had MAFLD with overweight (BMI 25-30 kg/m2) and obesity (BMI ≥ 30 kg/m2), respectively, while 1041 (22.1%) and 215 (4.6%) had overweight and obesity, respectively, without FL. During a median follow-up of 7.5 (interquartile range: 4.0-9.6) years, 278 deaths (5.9%) occurred. Of these, 98 (2.1%) were cancer-related, 65 (1.4%) were cardiovascular, and 17 (0.4%) were liver-related. Overall survival was similar between patient strata (after 5 years: 93.9%-98.2%) with lean MAFLD having the numerically worst survival. Although lean and overweight patients with MAFLD had a numerically worse outcome compared to their non-MAFLD counterparts, this association was driven by age and metabolic comorbidities (predominantly diabetes) rather than the presence of MAFLD.

Conclusion

Presence of MAFLD does not increase mortality in a cohort of individuals aged 45 to 80 years.

Recently, the term “nonalcoholic fatty liver disease” (NAFLD) has been revised by a consensus statement proposing the new term “metabolic (dysfunction)-associated fatty liver disease” (MAFLD) (1). Apart from changing the acronym, several new criteria have been proposed for MAFLD. In addition to the presence of fatty liver (FL), either an elevated BMI (≥25 kg/m2 for Caucasians and ≥23kg/m2 for Asians), type 2 diabetes mellitus (T2DM) or at least 2 metabolic risk abnormalities in lean patients (<25 kg/m2 for Caucasians and <23 kg/m2 for Asians) are required to fulfill the definition of MAFLD. However, several authors have raised concerns about this definition since a considerable proportion of patients do not meet these criteria, especially when they are (2-4). Additionally, it is yet unclear whether the new definition provides a better discernibility in terms of hard clinical endpoints (ie, mortality). Although a large body of evidence exists on the association of MAFLD with cardiovascular diseases (CVD) (5), malignancies (6), and liver-related endpoints (7), its impact on mortality is still a matter of debate (8,9).

Methods

Patients and Study Design

In total, 6129 consecutive subjects from a single-center cohort study of patients undergoing screening colonoscopy for colorectal cancer (CRC) in Austria (SAKKOPI) between 2007 and 2020 were screened for inclusion in this cross-sectional study. Patients were excluded if (1) they were <45 years or >80 years old, (2) follow-up was <180 days or unavailable (ie, German citizens without health insurance in Austria), (3) no ultrasound was available for diagnosis of FL, (4) information on alcohol consumption was missing, or (5) patients consumed a significant amount of alcohol (≥20 g/day for females and ≥30 g/day for males). Finally, all patients with known chronic liver disease other than MAFLD (ie, viral hepatitis, autoimmune hepatitis, Wilson disease, hereditary haemochromatosis, alpha-1 antitrypsin deficiency) were excluded. As previously described, participants were examined on 2 consecutive days (10) including abdominal ultrasound, extensive laboratory including oral-glucose tolerance test, and clinical characterization, as well as gastroscopy and colonoscopy.

Follow-up data were obtained from a systematic read-out of the national health insurance system assessing all deaths occurring in Austrian nationals. Data on the reasons for death were obtained from medical documentation and graded according to the primary reason for death: (1) CVD including ischemic stroke, (2) cancer-related (excluding hepatocellular carcinoma [HCC]), (3) liver-related including HCC, (4) respiratory and infectious (excluding infections following trauma or operations), (5) trauma-associated, (6) age-related physical debility, (7) suicide, (8) neurological excluding ischemic stroke or brain tumors, (9) others, and (10) unknown causes of death.

The study was approved by the local ethics committee Salzburg (approval no. 415-E/1262/2), and all patients gave written informed consent to participate.

Definitions and Statistics

See supplementary material (11).

Results

Patient Baseline Characteristics

Overall, 4718 patients were included in this analysis (Fig. 1). Of these, 1200 subjects (25.4%) were lean and did not have FL, 73 (1.5%) patients were lean and had NAFLD but did not fulfill criteria for MAFLD (ie, lean NAFLD), and 221 (4.7%) were lean and fulfilled criteria for MAFLD (Fig. 2). Additionally, 1041 (22.1%) were overweight (BMI 25-30 kg/m2) and did not have FL while 1043 (22.1%) were overweight with MAFLD. Finally, 215 (4.6%) were subjects with obesity (≥30 kg/m2) and did not have FL while 925 (19.6%) also had MAFLD. Overall prevalence of NAFLD and MAFLD combined was therefore 47.9% (n = 2262) and 46.4% (n = 2189), respectively.

Figure 1.

Patient flow chart.

Figure 2.

Prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) across BMI strata in the overall cohort: lean (BMI<25 kg/m2), overweight (BMI 25-29.9 kg/m2) and obese (BMI≥30 kg/m2).

At baseline, significant differences existed between these 7 groups (Table 1). The metabolic syndrome was more frequent in patients with MAFLD (lean without FL vs lean NAFLD vs lean MAFLD: 9.3% vs 0% vs 38.5%; overweight without FL vs overweight MAFLD: 29.4% vs 49.5%; obesity without FL vs obesity with MAFLD: 53.0% vs 78.2%, P < 0.001). Similar differences were seen for T2DM and visceral obesity with lean NAFLD having the lowest prevalence of these metabolic comorbidities (all _P_s < 0.001). In terms of other baseline characteristics, age (_P_ < 0.001), gender (_P_ < 0.001), and history of chronic coronary syndrome (_P_ < 0.001) were significantly different among groups. However, presence of CRC, other active malignancy and history of any malignancy or stroke were comparable. Finally, proportions of subjects with fibrosis-4 score indicating advanced fibrosis (>2.67) and excluding advanced fibrosis (<1.45) was significantly different among these groups with lean MAFLD patients and patients with MAFLD and obesity having the highest prevalence (see Supplementary Table 1 (11)).

Table 1.

Baseline characteristics compared among patients grouped according to the presence or absence of MAFLD

Data are given as n (%) or mean ± standard error of the mean.

Abbreviations: CCS, chronic coronary syndrome; CRC, colorectal cancer; FL, fatty liver; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

Table 1.

Baseline characteristics compared among patients grouped according to the presence or absence of MAFLD

Data are given as n (%) or mean ± standard error of the mean.

Abbreviations: CCS, chronic coronary syndrome; CRC, colorectal cancer; FL, fatty liver; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

Follow-Up

During a median follow-up of 7.5 (IQR: 4.0-9.6) years 278 deaths (5.9%) occurred (Table 2). Of these, 98 (35.3%) were cancer-related, 65 (23.4%) were due to CVD, 22 (7.9%) were due to respiratory diseases or infectious diseases, 17 (6.1%) were liver-related, 12 (4.3%) were trauma-associated, 10 deaths (3.6%) were due to age-related physical debility, 9 (3.2%) were due to neurological diseases, 7 (2.5%) patients committed suicide, and 13 (4.7%) were due to other causes; in 25 (9.0%) subjects, the reason for death remained unknown. Liver-related deaths included 7 deaths following HCC and 10 following hepatic decompensation.

Table 2.

Overview of reasons for death among patients grouped according to the presence or absence of MAFLD

Data are given as n (%) or median (interquartile range).

Abbreviations: CVD, cardiovascular disease; FL, fatty liver; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; n.c., not calculated.

_a_Includes hepatocellular carcinoma.

Table 2.

Overview of reasons for death among patients grouped according to the presence or absence of MAFLD

Data are given as n (%) or median (interquartile range).

Abbreviations: CVD, cardiovascular disease; FL, fatty liver; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; n.c., not calculated.

_a_Includes hepatocellular carcinoma.

Overall survival was comparable among all patient groups (see Supplementary Figure 1 (11)). After 5 years, overall survival was 96.5% in lean patients without FL, 98.2% in lean patients with NAFLD, 93.9% in lean patients with MAFLD, 98.2% in overweight patients without MAFLD, 97.1% in overweight patients with MAFLD, 96.7% in patients with obesity without MALFD, and 96.7% in patients with obesity and MAFLD. When comparing subjects across BMI strata, there were overlapping curves among lean individuals and individuals with obesity while there was a significant difference in overweight subjects (P = 0.005 (11)). After excluding patients with CRC and active malignancy at baseline and censoring trauma-associated deaths, suicide, and deaths from unknown reasons, results were similar with significant lower survival only in overweight subjects (Fig. 3). When further comparing all patients with MAFLD against non-MAFLD patients (including lean NAFLD), a significant difference in survival was seen in Kaplan-Meier analysis (P = 0.021; see Supplementary Figure 2 (11)).

Figure 3.

Overall survival among all patients (A) and comparison among lean, overweight, and obese individuals when only considering patients without colorectal cancer or active malignancy at baseline and excluding deaths from traumatic injury, suicide and unknown origin (B-D).

As a next step, we aimed to investigate whether age and components of the metabolic syndrome/T2DM influences survival. Therefore, we performed multivariable Cox regression analyses adjusting for age and components of the metabolic syndrome (Model A) or T2DM (Model B). Following these analyses, the presence of MAFLD was not associated with mortality in the overall cohort while both age [adjusted hazard ratio (aHR) per year: 1.128 (95% CI): 1.107-1.149), P < 0.001] and components of the metabolic syndrome [aHR per component: 1.115 (95% CI: 1.024-1.299), P = 0.019] or age [aHR per years: 1.124 (95% CI: 1.104-1.145) P < 0.001] and T2DM [aHR: 2.064 [95% CI: 1.533-2.778), P < 0.001] significantly influenced survival (Table 3). Similar results were obtained following subgroup analyses in lean, overweight, and obese subjects (see Supplementary Table 2 (11)).

Table 3.

Cox regression coefficients for survival when only considering patients without colorectal cancer or active malignancy at baseline, and censoring traumatic deaths, suicide, and unknown deaths

Model A was built using age, components of the metabolic syndrome, and MAFLD (vs non-MAFLD) as covariables, and Model B was built using age, T2DM, and MAFLD (vs non-MAFLD) as covariables.

Abbreviations: MAFLD, metabolic dysfunction-associated fatty liver disease; T2DM, type 2 diabetes mellitus.

_a_Lean NAFLD patients were considered as non-MAFLD.

Table 3.

Cox regression coefficients for survival when only considering patients without colorectal cancer or active malignancy at baseline, and censoring traumatic deaths, suicide, and unknown deaths

Model A was built using age, components of the metabolic syndrome, and MAFLD (vs non-MAFLD) as covariables, and Model B was built using age, T2DM, and MAFLD (vs non-MAFLD) as covariables.

Abbreviations: MAFLD, metabolic dysfunction-associated fatty liver disease; T2DM, type 2 diabetes mellitus.

_a_Lean NAFLD patients were considered as non-MAFLD.

Finally, further subdividing MAFLD patients with overweight and obesity according to the presence of ≥2 metabolic risk factors proposed for lean MAFLD did identify 121 overweight MAFLD patients (11.7% of overweight MAFLD) and only 19 MAFLD patients with obesity (2.1% of MAFLD with obesity) who did not have ≥2 of these factors. While survival was different for overweight subjects, the low number of individuals in each obese subgroup did not allow to draw further conclusions (see Supplementary Figure 3 (11)).

Discussion

In this study, we show that the stratification of individuals according to BMI and the presence/absence of MAFLD did not identify patients at higher risk for mortality. In contrast, mortality was driven by age, components of the metabolic syndrome, and especially T2DM, rather than the presence of MAFLD.

While NAFLD has been associated with CVD (5), malignancies (6), and liver-related mortality (7), the role of NAFLD for mortality is controversial with several meta-analyses having achieved inconsistent findings (see Supplementary Table 3 (11)). Specifically, meta-analyses have shown that NAFLD was neither associated with an increase in fatal CVD outcomes when fatal outcomes were analyzed alone (8) nor with overall mortality (9). In other meta-analyses, the significant associations was significantly attenuated when correcting for BMI and T2DM (12) while earlier meta-analyses did not specify which covariables were corrected for (13,14). Indisputably, clear evidence on the association of fibrosis stage in NAFLD with mortality exists (7,15-17). However, the relevance of simple steatosis (ie, NAFLD without steatohepatitis and/or cirrhosis) is unclear (12) although this represents the largest proportion of NAFLD patients (18). In line with our study reporting age and T2DM as the main drivers for mortality, one of the first studies on the natural history of NAFLD also showed that only age, impaired fasting glucose and cirrhosis were associated with mortality in NAFLD patients (19). Importantly, several caveats need to be kept in mind when discussing an increased mortality in NAFLD patients (20): To begin with, fibrosis seems to be the strongest driver of this association (7,17). Thus, studies reporting on selected cohorts undergoing liver biopsy are very likely to overestimate the factor “fibrosis” when analyzing the whole NAFLD cohort together without correcting for fibrosis stage. Also, these patients are likely to suffer from more advanced liver disease since liver biopsy is an invasive procedure with stringent indications, leading to a certain selection bias. Finally, correction for age and sex might not adequately account for metabolic comorbidities among studies comparing selected patients against the “general population.” In several meta-analyses, it remains speculative whether the driver of a higher mortality among NAFLD patients can be attributed to NAFLD rather than unknown metabolic comorbidities (13,14).

In contrast, we obtained a sample of 4718 patients aged 45 to 80 years without specific suspicion of liver disease. We focused on this age group since these patients frequently develop metabolic comorbidities, CVD, and malignancies, and thus individualized healthcare is needed to prevent fatal outcomes. In this specific patient population, we were unable to confirm the relevance of MAFLD across BMI strata showing that age and metabolic alterations including T2DM were the predominant factor influencing the risk of death.

Of note, a recent study by Simon and colleagues (21) comprising all adults in Sweden with biopsy-proved NAFLD showed that NAFLD was associated with an increased overall mortality—even in patients with simple steatosis, which was largely driven by extrahepatic cancers. Interestingly, malignancies were also the most frequent cause of death in our study. Again, differences in cohort design (ie, only included patients undergoing liver biopsy) might explain discrepant outcomes compared to our study. It is high likely that less subjects with advanced liver disease participate in screening colonoscopy, making our cohort substantially healthier. Nevertheless, the high prevalence of FL in our cohort is surprising. Of note, a recent meta-analyses proposed an overall prevalence of FL of ~50% in adults with overweight and obesity (22). However, these studies included all adults (also 18-45 years), which are expected to have a lower prevalence of FL compared to our cohort of subjects aged 45 to 80 years.

For the first time, we investigated whether the novel MAFLD criteria help with risk stratification in lean subjects. Although lean MAFLD patients had a worse survival compared to lean NALFD patients, this association was predominantly driven by age and T2DM. Of note, age is also a central risk factor for metabolic comorbidities, which are required to meet the definition of lean MAFLD. It is therefore not surprising that lean NAFLD patients were significantly younger than lean MAFLD patients. By identifying patients with increased metabolic dysregulation and increased risk of mortality, this stratification partially explains prior inconsistencies regarding a better (23) or similar/worse (24) outcome compared to overweight/obese MAFLD.

Unsurprisingly, patients with MAFLD have a higher risk of liver-related deaths. Since no deaths occurred in non-MALFD patients, this could not be separately assessed in Cox regression analysis.

The main strength of this study is the direct comparison of a rather unselected cohort of MAFLD vs non-MAFLD patients, which underwent extensive metabolic characterization. However, the main limitation of this study is its retrospective design. Since we performed a systematic readout of the national health insurance system, we have detected all deaths. However, the reasons for death are often unclear or insufficiently documented making comparison of specific causes of death difficult. Also, the low number of events could have introduced certain bias. Although an analysis of cardiovascular events or malignancies as another primary outcome would be desirable, such information is difficult to obtain outside of a clinical trial as these events are likely to be missed. Thus, we focused on mortality since these data are fully and reliably documented by the health care system. Moreover, we could only use ultrasound to diagnose MAFLD. Although other methods such as magnetic resonance imaging-derived proton density fat fraction or liver biopsy would increase the accuracy of MAFLD diagnosis, this is not feasible in a larger cohort. Also, this would introduce significant selection bias toward patients undergoing these examinations due to clinical suspicion of a relevant disease justifying these procedures. In this context, also the missing information on the stage of liver disease hampers our conclusions. Although the median follow-up in our study was comparable to other landmark studies on this topic (19), it is comparatively short in contrast to studies with a longer follow-up (15,16,21). It remains to be shown whether longer follow-up would change our results.

In conclusion, we show that the presence of MAFLD compared to patients without FL does not influence survival in a large cohort of subjects aged 45 to 80 years. In contrast, features of the metabolic syndrome, and especially T2DM, seem to be the drivers for mortality in these patients. Nevertheless, novel definition of lean MAFLD identifies patients at a higher risk for mortality if this definition is met compared to lean NAFLD only. However, the clinical utility of these criteria still remains to be validated.

Abbreviations

Abbreviations

• BMI
• CI
• CRC
• IQR
• MAFLD
  metabolic-associated fatty liver disease
• NAFLD
  nonalcoholic fatty liver disease

Acknowledgments

Author contributions: Conception and design: GS and CD; administrative support: GS and CD; provision of study materials or patients: all authors; collection and assembly of data: all authors; data analysis and interpretation: GS and CD; manuscript writing: GS and CD; and final approval of manuscript: all authors.

Additional Information

Disclosures: The authors declare that they have no conflicts of interest regarding the submitted work. However, the following author discloses a conflict of interests outside the submitted work: CD is part of the scientific advisory board of SPAR Österreich AG.

Data Availability

Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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