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Cardiovascular and extrahepatic outcomes

TL;DR — The disease is named after the liver and most of its deaths are not hepatic. Pooled mortality rates in NAFLD cohorts diagnosed without biopsy are 12.60 per 1,000 person-years all-cause, 4.20 cardiac, 2.83 extrahepatic cancer and 0.92 liver-specific — cardiac deaths outnumbering liver deaths roughly 4.5:1 (Younossi 2023, PMID 36626630). Meta-analysis of 36 longitudinal studies and 5,802,226 people with 99,668 incident cardiovascular events puts the association at pooled HR 1.45 (95% CI 1.31–1.61), rising to 2.50 (1.68–3.72) with advanced fibrosis, independent of age, sex, adiposity, diabetes and conventional risk factors (Mantovani 2021, PMID 34555346). The Swedish biopsy cohort gives the absolute difference: MACE 24.3 versus 16.0 per 1,000 person-years (adjusted HR 1.63, 1.56–1.70), with a stepwise gradient reaching aHR 2.15 (1.77–2.61) in cirrhosis (Simon 2022, PMID 34489307). Beyond the heart, MASLD raises incident CKD stage ≥3 by ~1.45-fold (HR 1.43, 1.33–1.54) (Mantovani 2022, PMID 33303564) and extrahepatic cancers by 1.5–2-fold for gastrointestinal sites and 1.2–1.5-fold for lung, breast, gynaecological and urinary sites (Mantovani 2022, PMID 33685968). The American Heart Association issued a scientific statement in 2022 stating plainly that atherosclerotic cardiovascular disease is the principal cause of death in NAFLD (Duell 2022, PMID 35418240). Yet diagnosis, staging and treatment pathways are organised around the liver, and no care model has been tested in which cardiovascular risk reduction is the primary managed outcome.

Cardiovascular risk, quantified

Source Design Effect
Mantovani 2021, PMID 34555346 Meta-analysis, 36 longitudinal studies, 5,802,226 people (mean age 53), 99,668 fatal/non-fatal CVD events, median 6.5 years Pooled random-effects HR 1.45 (95% CI 1.31–1.61), I²=86.18%; with advanced fibrosis HR 2.50 (1.68–3.72), I²=73.84%; independent of age, sex, adiposity, diabetes and other cardiometabolic risk factors
Targher 2016, PMID 27212244 Meta-analysis of incident CVD Earlier quantification of the same association
Simon 2022, PMID 34489307 Swedish nationwide histology cohort, 10,422 with biopsy-confirmed NAFLD and no baseline CVD vs 46,517 matched controls, median 13.6 years MACE 24.3 vs 16.0/1,000 PY (difference 8.3; aHR 1.63, 1.56–1.70); IHD aHR 1.64 (1.54–1.75); CHF 1.75 (1.63–1.87); stroke 1.58 (1.46–1.71); CV mortality 1.37 (1.27–1.48). Stepwise increase with severity (p-trend=0.02), highest in cirrhosis (difference 27.2/1,000 PY; aHR 2.15, 1.77–2.61)
Lee 2024, PMID 37907259 Korean national health screening, 9,775,066 adults; 8,808,494 without prior CVD followed median 12.3 years; 272,863 CVD events MASLD/related SLD vs none: HR 1.38 (1.37–1.39). By subtype: MASLD 1.39 (1.38–1.40); MetALD 1.28 (1.26–1.30); MASLD with other combined aetiology 1.30 (1.26–1.34). Prevalence: MASLD 27.5%, MetALD 4.4%, other combined 1.5%

Two things are consistent across these. First, the hazard ratio is modest — 1.4 to 1.6 — but applies to a third of the adult population, so the attributable burden is large. Second, the association scales with fibrosis stage at cohort level. That does not make liver staging tools validated cardiovascular risk calculators: prospective data are not fully consistent across fibrosis strata, and individual cardiovascular discrimination has not been established.

Note also from the Korean data that MetALD carried a lower CVD hazard (1.28) than MASLD (1.39) despite carrying a higher hepatic hazard — see nomenclature and definitions, where the VHA cohort likewise found similar MACE across SLD subtypes while liver outcomes diverged sharply (Ochoa-Allemant 2025, PMID 40522656).

Cause of death, and where the literature conflicts

Population Leading cause of death Source
Unselected NAFLD, non-biopsy cardiac (4.20/1,000 PY) > extrahepatic cancer (2.83) > liver (0.92) Younossi 2023, PMID 36626630
Swedish nationwide biopsy cohort excess mortality dominated by extrahepatic cancer (4.5/1,000 PY, aHR 2.16) and cirrhosis (2.7/1,000 PY, aHR 18.15); CVD 1.4/1,000 PY (aHR 1.35); HCC 1.2/1,000 PY (aHR 11.12) Simon 2021, PMID 33037056
Asian biopsy registry (CLIONE) liver-related death leading; liver-specific mortality 2.34/1,000 PY vs overall 5.34/1,000 PY Fujii 2023, PMID 35051649
MASLD-cACLD, international cohort extrahepatic deaths "a considerable burden" alongside liver-related death Pennisi 2025, PMID 40550340
NASH CRN prospective cohort cardiac events and non-hepatic cancers did not differ across fibrosis stages, while liver events did Sanyal 2021, PMID 34670043

The apparent conflict resolves by stage and by ascertainment. In the general MASLD population cardiovascular death dominates; in biopsy-referred and advanced-fibrosis populations liver-related and cancer death rise to meet or exceed it; and Sanyal's finding that cardiac events are flat across fibrosis stages while liver events rise steeply explains why the ratio inverts as the cohort becomes more advanced. Any statement about "the leading cause of death in MASLD" must specify the population.

Is the association causal, and for which outcome?

The associations above are large and consistent; the causal claim behind them is narrower than usually stated, and the field's most careful synthesis says so explicitly. Reviewing the epidemiology alongside genetic evidence, three separable claims come apart (Driessen 2025, PMID 38147315):

  1. More atherosclerosis, yes. Studies scoring both proxies for atherosclerosis and actual cardiovascular events show increased atherosclerosis in MASLD.
  2. More atherosclerotic cardiovascular mortality, no. The same review states that this evidence does not show increased asCVD mortality — which is the outcome the "patients die of their hearts, not their livers" framing depends on.
  3. The mechanism that survives Mendelian randomisation is lipids. MR studies support MASLD causing atherosclerosis through mixed hyperlipidaemia; equivalent genetic evidence for liver-derived procoagulant factors is lacking.

The confounding structure is the reason: MASLD and atherosclerotic cardiovascular disease share obesity, insulin resistance, type 2 diabetes, smoking, hypertension and sleep apnoea as drivers, so an unadjusted or partially adjusted association is expected whether or not the liver contributes anything. The strongest counter-argument to pure confounding is imaging-based rather than genetic. In 33,616 UK Biobank participants with multiparametric liver MRI and linked outcomes (median follow-up 2.5 years), liver disease activity by iron-corrected T1 mapping, but not liver fat by PDFF, predicted events (Roca-Fernandez 2023, PMID 37348789):

Outcome cT1 hazard ratio
Any major CVD event 1.14 (1.03–1.26), p=0.008
Atrial fibrillation 1.30 (1.12–1.51), p<0.001
Heart failure 1.30 (1.09–1.56), p=0.004
CVD hospitalisation 1.27 (1.18–1.37), p<0.001
All-cause mortality 1.19 (1.02–1.38), p=0.026
CVD hospitalisation, in those without metabolic syndrome 1.26 (1.13–1.40), p<0.001

FIB-4 predicted heart failure only (1.06, 1.01–1.10, p=0.007). Two features make this the most informative single dataset here: the signal persists in participants without metabolic syndrome, which is where confounding by shared drivers should be weakest; and it attaches to inflammation/fibrosis (cT1) rather than to steatosis (PDFF), which is the same dissociation that governs hepatic outcomes (natural history). Follow-up is short (median 2.5 years) and cT1 is a proprietary measurement, so replication with an independent modality is needed.

The heart failure phenotype is specific

Where MASLD contributes to cardiac disease, the phenotype is not primarily ischaemic. In advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction through reduced right-ventricular filling — a mechanism that would also explain the exertional fatigue patients commonly report and that clinical descriptions attribute to nothing in particular (PMID 38147315; see patient experience and advocacy). A dedicated review of the converging mechanisms frames HFpEF and MASLD as organ-specific manifestations of one systemic metabolic dysfunction with bidirectional liver–heart crosstalk, mediated by shared lipotoxicity, meta-inflammation and oxidative stress and by liver-derived hepatokines, metabolites and extracellular vesicles (Capone 2026, PMID 41735546). Evidence also points to an association with cardiac arrhythmias, consistent with the atrial-fibrillation hazard above (PMIDs: 38147315, 37348789).

Chronic kidney disease

Meta-analysis of 13 studies, 1,222,032 individuals (28.1% with NAFLD), 33,840 incident cases of CKD stage ≥3 (eGFR <60 mL/min/1.73 m², with or without overt proteinuria) over a median 9.7 years: HR 1.43 (95% CI 1.33–1.54), I²=60.7%, independent of age, sex, obesity, hypertension, diabetes and conventional CKD risk factors, with no evidence of publication bias (Mantovani 2022, PMID 33303564).

The NASH CRN prospective cohort gives the absolute rates: >40% eGFR decline occurred at 2.98 per 100 person-years in F4 versus 0.97 in F0–F2 (Sanyal 2021, PMID 34670043). The renal component is not incidental to liver outcomes either — creatinine, not bilirubin, was the main driver of MELD increases leading to transplant in NASH cirrhosis (cirrhosis and decompensation) (Lim 2023, PMID 37307997). The MASLD–CKD link is also visible under the new nomenclature specifically (Bilson 2024, PMID 38141808).

Extrahepatic cancer

Meta-analysis of 10 cohort studies, 182,202 middle-aged individuals (24.8% with NAFLD), 8,485 incident extrahepatic cancers over median 5.8 years — no biopsy-proven cohorts were available (Mantovani 2022, PMID 33685968):

Cancer group Approximate risk increase
Gastrointestinal (oesophagus, stomach, pancreas, colorectal) ~1.5–2-fold
Lung, breast, gynaecological, urinary system ~1.2–1.5-fold

All risks were independent of age, sex, smoking, obesity, diabetes and other confounders; heterogeneity was relatively low and funnel plots showed no significant publication bias. A subsequent review adds prostate, thyroid and renal cancers to the list and frames MASLD as a risk factor for both intrahepatic and extrahepatic malignancy (Kalligeros 2024, PMID 39182603). In the Swedish biopsy cohort, extrahepatic cancer was the single largest contributor to excess mortality (aHR 2.16, 2.03–2.30) (PMID 33037056).

That extrahepatic cancer outranks cardiovascular disease as a contributor to excess death in the histology cohort — while cardiovascular disease dominates absolute deaths in unselected populations — is one of the more under-discussed findings in this field.

Sarcopenia and muscle

Finding Source
Muscle mass and grip strength associate with severe NAFLD in 333,295 UK Biobank participants Petermann-Rocha 2022, PMID 35085594
Handgrip strength associates with cardiovascular disease risk in MASLD (UK Biobank prospective) Lim 2025, PMID 40035094
The MASLD–sarcopenia relationship is described as bidirectional (editorial commentary) Ha 2022, PMID 35347595
Skeletal muscle is mechanistically implicated in MASLD Marjot 2025, PMID 40408301

This matters practically because incretin therapy causes lean-mass loss, flagged by AASLD as a monitored risk (GLP-1 and incretin therapy), and because exercise-induced improvement in peripheral insulin sensitivity tracked histological resolution in the one clamp-based trial (lifestyle and weight loss).

The cardiovascular-kidney-metabolic frame

The condition is increasingly described as one organ manifestation of a systemic disorder — a systemic metabolic disorder with cardiovascular and malignant complications (Targher 2024, PMID 38228377), requiring multidisciplinary and holistic management (Targher 2021, PMID 33961787), and best conceived as a multisystem disease (Byrne 2015, PMID 25920090). Under the cardiovascular-kidney-metabolic (CKM) framing, nine CKM-related conditions including MASLD accounted for 50.9% of total disease prevalence and 34.4% of deaths in Asia in 2021 (Duo 2026, PMID 41643809), and CKM syndrome is associated with liver fibrosis progression and liver-related events in MASLD (Zhou 2026, PMID 41400631) and with increased mortality (Chen 2025, PMID 41272273). A roadmap for multiorgan clinical trial design across the MASLD/MASH–CKM spectrum has been proposed (Zannad 2026, PMID 41636667).

The care-model gap

The AHA scientific statement is explicit: NAFLD is typically silent until advanced and potentially irreversible liver impairment occurs, most patients are unaware they have it, and atherosclerotic cardiovascular disease is the principal cause of death (Duell 2022, PMID 35418240). Statin use in MASLD is associated with lower all-cause mortality and liver-related events and slower liver-stiffness progression, though the effect sizes are almost certainly inflated by healthy-user confounding (other pharmacotherapy) (Zhou 2024, PMID 39089860). Resmetirom lowers LDL-C by 13.6–16.3% as a secondary effect (resmetirom and thyromimetics).

What does not exist is a trial of a care model. Query run 2026-09-02: (NASH OR MASH OR NAFLD OR MASLD) AND ("cardiovascular" OR "coronary" OR "atrial fibrillation" OR "heart failure") AND (risk OR cohort OR meta-analysis) — 5,908 records; none tested a service model in which cardiovascular risk reduction, rather than a hepatic endpoint, was the primary managed outcome in a MASLD population.

Open questions

  • Does MASLD cause cardiovascular events, or accompany them? The evidence supports increased atherosclerosis but not increased atherosclerotic-cardiovascular mortality, and the only mechanism surviving Mendelian randomisation is mixed hyperlipidaemia — with no genetic support for liver-derived procoagulant factors (PMID 38147315). Since MASLD and asCVD share every major driver, no observational design can settle this; the decisive test would be whether a liver-directed therapy that does not lower LDL reduces cardiovascular events.
  • Is the cardiac risk in MASLD an HFpEF risk rather than an ischaemic one? Liver disease activity by cT1 predicts atrial fibrillation and heart failure more strongly than composite CVD (HRs 1.30 vs 1.14) (PMID 37348789), and the proposed mechanism is impaired right-ventricular filling in advanced fibrosis (PMIDs: 38147315, 41735546). No MASLD cohort has reported echocardiographic HFpEF diagnoses stratified by fibrosis stage.
  • Why does liver inflammation predict cardiovascular events when liver fat does not? cT1 was associated with every cardiovascular endpoint and PDFF with none, in the same 33,616 participants, and the cT1 association held in people without metabolic syndrome (PMID 37348789). This is the single strongest argument against pure shared-driver confounding, and it has not been replicated with a non-proprietary measure of hepatic inflammation.
  • Who should own cardiovascular risk in MASLD? Cardiovascular disease is the leading cause of death in the general MASLD population (PMIDs: 36626630, 35418240), while diagnosis, staging and follow-up run through hepatology. No randomised comparison of hepatology-led, primary-care-led or integrated cardiometabolic care with cardiovascular endpoints has been retrieved. Re-run this absence before restating it.
  • Should fibrosis stage be used as a cardiovascular risk modifier? Advanced fibrosis raises CVD risk 2.5-fold (PMID 34555346) and the gradient is stepwise in a histology cohort (PMID 34489307), yet no cardiovascular risk calculator incorporates liver fibrosis, and Sanyal's prospective data found cardiac events flat across fibrosis stages (PMID 34670043) — a direct contradiction that has not been reconciled.
  • Why is extrahepatic cancer the largest contributor to excess mortality? aHR 2.16 in the Swedish biopsy cohort (PMID 33037056), and 1.2–2-fold across sites in meta-analysis with no biopsy-proven cohorts available (PMID 33685968). Whether this is shared metabolic aetiology, surveillance bias or a hepatic mechanism is unknown.
  • Does treating MASLD reduce cardiovascular events? Bariatric surgery is associated with lower 10-year MACE (8.5% vs 15.7%, aHR 0.30) in an observational analysis (bariatric and metabolic surgery) (Aminian 2021, PMID 34762106). No MASH drug trial has been powered for MACE.
  • Does incretin-associated lean-mass loss worsen outcomes in a sarcopenic MASLD population? The association between muscle and outcomes is established (PMIDs: 35085594, 40035094); the interaction with therapy is untested.

References

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