If you are an adult, there’s a high probability you already have liver disease. Even if you are of average weight and teetotal. Non-alcoholic fatty liver disease (NAFLD) now affects more than 30% of the world's population, a number that has risen rapidly over the last 20 years. Cytokines are key modulators of liver disease and understanding their role may be key to improved therapies.
NAFLD is the hepatic manifestation of metabolic syndrome and ranges from mild steatosis (fatty liver) to the more serious non-alcoholic steatohepatitis (NASH). Liver disease is governed by pro-inflammatory changes in the organ. Chronic inflammation and subsequent repair can ultimately lead to severe damage manifested as fibrosis. This can progress to cirrhosis and potentially even to hepatocellular carcinoma (the third leading cause of cancer-related deaths worldwide).
Individuals with NAFLD have an increased risk of overall mortality compared with the general population particularly cardiovascular disease, malignancy, and liver-related complications. Globally, prevalence ranges from 30% in Southeast Asia, and Central and South America to 24% in Europe and the US and 14% in Africa. In 2016, the USA's economic burden of chronic liver diseases was $32.5 billion, with over 65% of this spending being on inpatient or emergency care. In the UK, it is estimated that 2 out of every 3 adults have early stages of NAFLD with 20% harbouring NASH. Mortality rates for liver disease have increased and in people aged 65 years and below, they have risen by almost 500% since the 1970s.
Liver disease causes significant mortality. For example, in 2020, liver disease accounted for 2.5% of all deaths in England with 50% of these individuals being between 15-64 years old.
Liver disease is a hidden health crisis: Most of the estimated 14.1 million individuals with NAFLD in the UK remain undiagnosed and the prevalence of advanced fibrosis and cirrhosis is projected to double to 1 million individuals by 2030. Furthermore, insulin resistance is a common feature of NAFLD that contributes to its pathogenesis.
Cytokine involvement in NAFLD
Under normal conditions, there is very little production of cytokines in the liver. This changes with a pathological condition such as the large accumulation of lipid molecules, triggering the production of inflammatory molecules by liver cells. Many of these molecules are pro-inflammatory cytokines generated by two known pathways. One is mediated by the inflammasome's formation and the other is independent of it.
In the pathological state, the NLRP3 inflammasome complex triggers pathways resulting in the production and activation of pro-inflammatory cytokines. It activates the caspase-1 enzyme which cleaves the inactive or ‘pro’ cytokine form of IL-1b and IL-18 converting them to their active forms. IL-1 b promotes liver steatosis, inflammation and fibrosis through the IL-1 receptor pathway. This stimulates triglycerides and cholesterol accumulation and inflammatory signalling which attracts neutrophils. This has a knock-on effect of inducing IL-6 production which further activates local immune cells and other white blood cells leading to a chronic inflammatory state. Although its role has not been fully elucidated, IL-18 production is also associated with liver inflammation and injury. This pathway plays an important role in the induction of NAFLD, especially in patients with obesity.
The inflammasome-independent pathway is mediated by neutrophil serine proteases. These enzymes activate a number of pro-inflammatory cytokines by cleaving their inactive forms. These also include IL-1b and IL-18 as well as IL-1a, TNF and IL-33. IL-33 is involved in the later stages of fibrosis leading to the production of pro-fibrotic cytokines.
Further studies involving liver transcriptomics highlighted interleukin-32 as a novel NAFLD-related cytokine. IL-32 was first reported in IL-2-activated T lymphocytes without a known function. It has since been found in a number of human tissues exhibiting many properties associated with a pro-inflammatory response. Studies are now showing it may be broadly involved in inflammation as it is also markedly upregulated in Chronic Obstructive Pulmonary Disorder, Crohn’s disease and psoriasis.
Current treatments and opportunities
Currently, there is no specific drug treatment licensed or in development for NAFLD. Management of the condition is mainly around lifestyle modifications to reduce the risk of progression of NAFLD and the related risks of cardiac and liver-related morbidity and mortality. NICE and EASL guidelines state PPARγ ligands e.g. pioglitazone may be used off-label (in the absence of type 2 diabetes mellitus) for NASH. However, their use is limited by side effects, such as weight gain, fluid retention, osteopenia and increased fracture risk, especially in older women.
Early evidence from clinical trials suggests that features of NASH are receptive to pharmacological intervention, though trials focused on regulating apoptosis pathways in inflammation and fibrosis for NASH have not demonstrated efficacy. Furthermore, less than 40% of patients in trials benefit from a single therapy, suggesting a combination approach is needed.
Increasingly, NAFLD is being identified in non-obese individuals with around 40% of the global NAFLD population classified as non-obese and 20% as lean. It is also not clear which individuals affected with NAFLD will progress to advanced liver fibrosis and/or hepatocellular carcinoma. Therefore, an increased understanding of the mechanisms of NAFLD and its progression will be vital to finding new therapeutic approaches.
IMAGE Alcoholic liver cirrhosis
Credit Centers for Disease Control and Prevention/ Dr. Edwin P. Ewing, Jr.