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.
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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
Combordity
NAFLD
NASH
Obesity
51%
82%
Type 2 diabetes mellitus
23%
44%
Hyperlipidaemia
70%
72%
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.
France
Germany
Italy
Spain
UK
Total
Higher-prevalence scenario
(% adult population)
3.6
4.1
4.4
3.9
4.1
NASH diagnosed as % percent of overall prevalence
5.6
24.2
3.7
1.9
20.3
12.7
F3 – F4 CC diagnosed as % of overall F3 – F4 CC prevalance
22.7
65.8
11.7
1.3
73.8
39.1
NASH diagnosed
0.1
0.7
0.1
0.03
0.4
1.3
F3-F4 CC diagnosed
0.1
0.3
0.1
0.004
0.3
0.8
Lower prevalence scenario
(n, % adult population)
2.2
1.4
1.7
2.2
2.2
NASH diagnosed as % of overall
prevalence
5.7
24.2
3.8
1.9
20.3
11.8
F3 – F4 CC diagnosed as % of overall F3 – F4 CC prevalence
22.7
65.8
11.7
1.3
73.8
37.8
NASH diagnosed
0.1
0.2
0.03
0.02
0.2
0.6
F3-F4 CC diagnosed
0.04
0.1
0.02
0.002
0.2
0.4
Note: Numbers may not sum because of rerounding.
Abbreviations: F3, fibrosis stage 3, F4 CC, fibrosis stage 4 compensated cirrhosis, NASH, non-alcoholic steatohepatisis: UK,
United Kingdon
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