reversible. It starts with steatosis; hepatic triglyceride accumulation initiates the disease continuum. Patients with liver steatosis who have at least one cardiometabolic risk factor (type 2 diabetes, obesity, hypertension, high triglycerides) can be diagnosed with MASLD once other etiologies are excluded. 3 Steatosis leads to fibrosis. The disease progression reflects a complex interaction between metabolic stress, inflammation, and fibrogenesis. MASH is an advanced stage of MASLD that indicates liver cell injury and necrosis that has developed within the broader context of metabolic dysfunction. It reflects the progression from isolated fat accumulation within hepatocytes to the development of inflammation and hepatocyte necrosis (ballooning). There may be minimal to no fibrosis in its earliest stage. 4 Liver disease is increasingly understood as a manifestation of systemic metabolic dysfunction driven by ectopic fat deposition, insulin resistance, and chronic inflammation. Accumulation of toxic lipid species within hepatocytes promotes lipotoxicity, leading to cellular injury through mitochondrial dysfunction and endoplasmic reticulum stress. This sustained metabolic stress triggers inflammatory signaling and hepatocellular damage, with ballooned hepatocytes representing dead and dying cells. Although hepatocytes retain the capacity to regenerate, repeated injury results in maladaptive
the risk of liver failure, liver cancer, and death.” After screening, the rate of fibrosis determines treatment. “The threshold at which to act is when we reach clinically significant fibrosis, or stage F2,” says Cusi, adding that, at this point, if you continue to have metabolic risk factors without intervention, the condition will progress to end-stage liver disease. “But the liver has incredible plasticity,” Cusi says. “So, if you catch a patient when there is moderate scarring, you may be able to reverse it, or freeze it, so it doesn’t advance. MASH with fibrosis staging of F2 or greater is considered to be at-risk MASH.” 6 Prevalence of MASLD & MASH MASLD and MASH are highly prevalent in the U.S.: About 30 percent of adults and 70 percent of adults with type 2 diabetes have MASLD, and around half of those with type 2 diabetes have MASH—and one in five have advanced fibrosis. 3,6 Because this condition is not routinely screened for (and not treated), it represents a growing public health burden and is often identified at more advanced stages of disease. “A common complaint of liver specialists,” says Cusi, “is that by the time a patient is referred to them, they already have cirrhosis.” Importantly, there are opportunities for earlier identification and intervention across the disease continuum. New research has resulted in better
The threshold at which to act is when we reach clinically significant fibrosis, or stage F2. At that point, if you continue to have the typical metabolic risk factors, unless you do something, the condition will progress on a path to end-stage liver disease. —Kenneth Cusi, MD, FACP, FACE
repair with deposition of scar tissue and progressive fibrosis. These processes collectively drive the transition from isolated steatosis to steatohepatitis and advancing hepatic fibrosis. 4,5 Fibrosis progression remains the key determinant of outcomes of MASLD/MASH. Staging (F0–F4) reflects degrees of scarring, synonymous with fibrosis, from no scarring to cirrhosis (F4). As fibrosis advances, so does the risk of liver failure, hepatocellular carcinoma (HCC), and mortality. 6,7 Says Isaacs: “The higher the fibrosis stage, the higher
screening tools (see pp. 12–15) to help identify patients at risk for fibrosis, allowing them to catch it in earlier, and more treatable, stages. As understanding of liver biology evolves, management approaches increasingly address both systemic metabolic drivers, as well as liver-specific disease processes. New therapeutics, in conjunction with more targeted lifestyle interventions, are expanding management options for patients who, if treated earlier, can stop the progression—and sometimes even reverse the disease.
SCAN FOR MASLD, MASH CLINICAL GUIDANCE
Healthful Living Rx 5
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