Nash Comorbidities

NAFLD AND NASH: A MULTI-SYSTEM DISEASE​

NASH is “the liver manifestation of the metabolic syndrome (MetS)”. However, the consequences of NASH can extend well beyond just liver disease, especially impacting the cardiovascular (CV) system. In fact, NAFLD and NASH are part of a multi-system disease covering a wide spectrum of liver diseases that increase risk of T2DM, CVD, CKD and certain cancers.

The aetiology of increased risk of CVD is complex but atherogenic dyslipidaemia is an important factor. Genotypes can increase severity of liver disease and diabetes, while attenuating risk of CVD.

RELATED Comorbidities VIDEOS

RELATED Comorbidities ARTICLES

Comorbidities in NAFLD/NASH and their complex interplay

NAFLD is often described as the hepatic manifestation of the metabolic syndrome. However, NAFLD represents a complex disease process with both metabolic and liver complications, and can be observed in patients with no clinical manifestations of the metabolic syndrome. Common comorbidities in NAFLD patients include obesity, insulin resistance and/or type-2 diabetes, dyslipidaemia, hypertriglyceridaemia, hypertension and cardiovascular disease.

Estimated prevalence of common comorbidities in NAFLD and NASH

Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis and urolithiasis.

The most common cause of mortality in NAFLD is cardiovascular disease (CVD), independent of known CV risk factors such as abdominal obesity, hypertension, atherogenic dyslipidaemia and insulin resistance/dysglycaemia. A 2021 meta-analysis of longitudinal studies showed that NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1.45, 95% CI 1.31-1.61). This risk markedly increased as NAFLD increased in severity, especially the stage of fibrosis (pooled random-effects HR 2.50, 95% CI 1.68-3.72). Accordingly, it is recommended that clinicians should screen their patients with NAFLD for CV disease and initiate treatment if necessary.

The impact of NAFLD /NASH

NAFLD /NASH is also a leading cause of liver diseases, representing an increasing comorbidity burden, with related healthcare resource utilization (HRU) and costs. Comorbidity burden is high and increasing as patients progress through liver disease severity stages. An evaluation by Loomba et al. of the impact of disease severity, demographics and comorbidities on risk of mortality and time to progression in a large, real-world cohort of diagnosed NAFLD patients revealed that among patients with NAFLD, 71% had NAFLD/NASH alone and 29% had NAFLD cirrhosis. Overall, 86% of patients had hypertension, 84% dyslipidaemia, 69% had cardiovascular disease and 56% diabetes. The cumulative risk of progression of NAFLD to cirrhosis, and compensated cirrhosis to decompensated cirrhosis was 39% and 45%, respectively, over 8 years of follow-up. The independent predictors of progression included cardiovascular disease, renal impairment, dyslipidaemia and diabetes. The cumulative risk of mortality for NAFLD, NAFLD cirrhosis, decompensated cirrhosis and hepatocellular carcinoma was 13%, 31%, 51% and 76%, respectively. This highlights the need for early identification and effective management of NAFLD/NASH patients to minimize comorbidity burden, HRU, and costs.

  1. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care. 2017;40:419-30
  2. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015 Apr;62(1 Suppl):S47-64
  3. Gordon SC, Fraysse J, Li S, Ozbay AB, Wong RJ. Disease severity is associated with higher healthcare utilization in nonalcoholic steatohepatitis medicare patients. Am J Gastroenterol. 2020 Apr;115(4):562-574.
  4. Itier R, Guillaume M, Ricci JE,et al. Non-alcoholic fatty liver disease and heart failure with preserved ejection fraction: from pathophysiology to practical issues. ESC Heart Fail. 2021 Apr;8(2):789-798.
  5. Janssen A, Grobbee D and Dendale P. Non-alcoholic fatty liver disease, a new and growing risk indicator for cardiovascular disease. Eur J Prev Cardiol 2020 Jul; 27(10):1059-1063.
  6. Kaps L, Labenz C, Galle PR, Weinmann-Menke J, Kostev K, Schattenberg JM. Non-alcoholic fatty liver disease increases the risk of incident chronic kidney disease. United European Gastroenterol J. 2020 Oct;8(8):942-948.
  7. Li L, Liu DW, Yan HY, Wang ZY, Zhao SH, Wang B. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev. 2016;17:510-9.
  8. Loomba R, Wong R, Fraysse J, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020 Jun;51(11):1149-1159.
  9. Mantovani A, Csermely A, Petracca G, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(11):903-13.
  10. Nabi O, Boursier J, Lacombe K, et al. Comorbidities are associated with fibrosis in NAFLD subjects: a nationwide study (NASH-CO Study). Dig Dis Sci. 2021 May 24 [Epub ahead of print].
  11. Rosato V, Masarone M, Dallio M, Federico A, Aglitti A, Persico M. NAFLD and extra-hepatic comorbidities: current evidence on a multi-organ metabolic syndrome. Int J Environ Res Public Health. 2019 Sep 14;16(18):3415.
  12. Schattenberg JM, Lazarus JV, Newsome PN, et al. Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis. Liver Int. 2021 Jun;41(6):1227-1242.
  13. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020 Sep;69(9):1691-1705.
  14. Targher G, Corey KE, Byrne CD. NAFLD, and cardiovascular and cardiac diseases: factors influencing risk, prediction and treatment. Diabetes Metab. 2021 Mar;47(2):101215.
  15. Wong RJ, Kachru N, Martinez DJ, Moynihan M, Ozbay AB, Gordon SC. Real-world comorbidity burden, health care utilization, and costs of nonalcoholic steatohepatitis patients with advanced liver diseases. J Clin Gastroenterol. 2020 Aug 18 [Epub ahead of print].
  16. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.
  17. Younossi Z, Tacke F, Arrese M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019 Jun;69(6):2672-2682.
  18. Younossi ZM, Tampi RP, Racila A, et al. Economic and clinical burden of nonalcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Diabetes Care. 2020 Feb;43(2):283-289
  19. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.
  20. Schattenberg JM, Lazarus JV, Newsome PN, et al. Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis. Liver Int. 2021 Jun;41(6):1227-1242.