If you are overweight, then you will suffer a faster pace of aging, more age-related disease, greater lifetime medical costs, and an earlier death. The more excess weight and the longer that weight is held, the worse the outcome. In at least one sense, being overweight literally accelerates aging, increasing the pace at which harmful senescent cells accumulate in the body. These errant cells secrete signals that produce chronic inflammation, but this isn’t the only way in which visceral fat tissue causes unresolved, chronic inflammation, an unwanted overactivation of the immune system that disrupts metabolism and speeds the progression of age-related disease. Fat cells produce signals that mimic those of infected cells, and DNA fragments released from dying fat cells produce a similar outcome.

Whenever one looks at the relationship between mortality and metabolic diseases – such as non-alcoholic fatty liver disease, today’s topic – that are usually the product of being overweight, then one is looking at a proxy measure of the progression of mechanisms by which visceral fat tissue accelerates aging. Today’s research materials note that even mild non-alcoholic fatty liver disease is linked to increased mortality. This is because the most common cause of mild non-alcoholic fatty liver disease is for an individual to be meaningfully overweight, carrying excessive visceral fat tissue that disrupts metabolism and harms future prospects.

Even mild fatty liver disease is linked to increased mortality

Non-alcoholic fatty liver disease, NAFLD, is often caused by obesity and affects nearly one in four adults in Europe and the US. Earlier research has demonstrated an increased risk of death in patients with NAFLD. Now, researchers show that mortality increases with disease severity, but even mild fatty liver disease is linked to higher mortality. The researchers matched 10,568 individuals with biopsy-confirmed NAFLD to general population controls through Sweden’s comprehensive, nationwide registers. They found that all stages of NAFLD were associated with excess mortality risk, even early stages of disease. This risk was driven primarily by deaths from cancer (excluding liver cancer) and cirrhosis, while the risks of cardiovascular mortality or hepatocellular carcinoma (HCC) mortality were relatively modest.

Patients with NAFLD had a 93 percent increased risk of all-cause mortality, but the numbers varied with disease severity. The risk increased progressively from the mildest form of NAFLD (simple steatosis), to non-fibrotic steatohepatitis (NASH), to non-cirrhotic fibrosis, and to severe NAFLD with liver cirrhosis.

Even mild fatty liver disease is linked to increased mortality

This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 2017; n=10,568). NAFLD was categorised as simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs).

Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (aHR=1.93). Compared with controls, significant excess mortality risk was observed with simple steatosis (aHR=1.71), non-fibrotic NASH (aHR=2.14), non-cirrhotic fibrosis (aHR=2.44) and cirrhosis (aHR=3.79). This dose-dependent gradient was similar when simple steatosis was the reference. The excess mortality associated with NAFLD was primarily from extrahepatic cancer (aHR=2.16), followed by cirrhosis (aHR=18.15), cardiovascular disease (aHR=1.35) and hepatocellular carcinoma (HCC) (aHR=11.12).

In conclusion, all NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.