Therapeutic management of metabolic dysfunction associated steatotic liver disease

Abstract

The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) have been steadily increasing worldwide, with a huge societal and economic burden. Recently, NAFLD and non-alcoholic steatohepatitis have been renamed and redefined as metabolic dysfunction associated steatotic liver disease (MASLD) and steatohepatitis (Metabolic Dysfunction Associated Steatohepatitis (MASH)), which result from an imbalance between metabolic and inflammatory stress (mainly as a consequence of adipose tissue dysfunction and insulin resistance) and the defence and repair mechanisms of the steatotic liver. Once MASLD progresses to end-stage of liver disease, treatment efficacy becomes limited and may require liver transplantation. Early detection and intervention are crucial. Lifestyle modification is consequently the cornerstone of its management. Timely consideration of bariatric surgeries should be given to patients meeting specific criteria. A multidisciplinary approach is warranted, starting from the concept that MASLD/MASH is at the centre of the cardiovascular-liver-metabolic syndrome. In some cases, pharmacological treatment can complement lifestyle modification. Several drugs used to treat the cardiometabolic co-morbidities have some potential efficacy in slowing Down disease progression, and some have demonstrated efficacy on histological endpoints that are likely to translate into long-term clinical benefits. Optimising the use of these drugs within their licenced indications is thus paramount for patients with MASLD. Several MASH-specific drugs are on the horizon and are likely to enrich our therapeutic armamentarium in the near future, particularly in non-cirrhotic stages of the disease. Much work still needs to be done to understand the specific features of MASH cirrhosis and develop efficacious treatments for this disease stage.

Keywords: MASH; MASLD; NAFLD; NASH; management; metabolic dysfunction associated steatotic liver disease; metabolic syndrome lifestyle; therapy.

FIGURE 1

Metabolic dysfunction associated steatotic liver disease is a heterogeneous disease. Disease severity increases with more severe metabolic pressure, depending on the body's capacity to cope with an obesogenic environment. The armamentarium of the liver to deal with damage and inflammation adds to the inter‐individual variability. The contribution of all these factors explains the variability of liver disease severity in relation to metabolic risk factors.

FIGURE 2

Schematic concept of progression of disease in Metabolic Dysfunction Associated Steatotic Liver Disease. Disease progression depends intrahepatically on the balance between pro‐fibrogenic mechanisms and defence/repair mechanisms. Fibrosis is driven by upstream processes of damage and inflammation, which result from a metabolic pressure. An efficacious management of Metabolic Dysfunction Associated Steatohepatitis most likely needs to tackle these upstream drivers of disease to be successful. Adapted from.

FIGURE 3

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) as an important driving force of multisystemic disorders and its management. MASLD covers a spectrum from simple steatosis to Metabolic Dysfunction Associated Steatohepatitis (MASH), and then cirrhosis and hepatocellular carcinoma. It is well‐known that MASLD not only leads to end‐stage liver disease but also has clinical implications on extrahepatic tissues with reduced quality of life, including increasing the risk of type 2 diabetes, chronic kidney disease, and non‐hepatic malignancy. Given its pathophysiology, the management of the underlying metabolic drivers of the disease by lifestyle modification and weight loss is the cornerstone of the treatment of MASLD/MASH. For MASLD patients with overweight/obesity, a weight loss of 3%–5% can reduce steatosis, while a 7% weight loss can lead to MASH regression, and a 10% weight loss may result in fibrosis regression. Some drugs already on the marked for the treatment of co‐morbidities have shown some efficacy. Liver transplantation and bariatric surgery should be performed in some patients with good indications. Combination therapies targeting multiple pathways and the integration of digital health interventions hold potential for enhancing the efficacy and safety of MASLD treatments.

FIGURE 4

The complex pathophysiology of Metabolic Dysfunction Associated Steatohepatitis (MASH). MASH is driven by the complex interplay of metabolic, inflammatory and fibrogenic processes. Within the liver, hepatocytes (and its intracellular organelles, most notably mitochondria), play an important role, alongside the stellate cells and several resident and infiltrating immune cells of different populations. The liver is at the centre of an important crosstalk between the liver, the adipose tissue, the gut the pancreas and the cardiovascular system,, with MASH being an important driver of complex vicious circles involving many organs. Drugs/pathways that have been tested in MASH or that are under development, mentioned and/or referenced in the text are depicted anchoring point in the complex pathophysiology of MASH. DNL, de novo lipogenesis; FGF21, fibroblast growth factor 21; FXR, farnesoid receptor X; GIP, glucose‐dependent insulinotropic polypeptide; GLP‐1, glucagon‐like peptide 1; HSD17B13, Hydroxysteroid 17β dehydrogenase; IFNγ, interferon gamma; IL1‐β, interleukin 1 beta; IL‐6, interleukin 6; IL‐17, interleukin 17; LD, lipid droplets; MCP‐1, monocyte chemoattractant protein 1; NEFA, non‐esterified fatty acids; NKT cell, natural killer T cell; PNPLA3, patatin‐like phospholipase domain‐containing protein 3; RA, receptor agonist; ROS, reactive oxygen species; siRNA, small interfering RNA; Th17, T helper 17 cell; TGFβ, tumour growth factor beta; TNFα, tumour necrosis factor alpha; VLDL, very low density lipoproteins. Source: Figure adapted from (courtesy J. Haas) and Ref.