October is National Liver Awareness Month, a reminder to focus on liver health through education, screenings, and advocacy. Our partners at Ohio Gastro have shared a physician’s guide to two of the most prevalent chronic liver diseases worldwide. 

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Metabolic dysfunction-associated steatotic liver disease (MALSD) and metabolic associated steatohepatitis (MASH) have emerged as the most prevalent chronic liver disease worldwide and represents a major public health challenge contributing significantly to global morbidity and mortality.  There was a nomenclature change in 2023 regarding this disease. MASLD and MASH were previously known as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), respectively. We now have an affirmative name and diagnosis without using stigmatizing language. 

Causes, Risks, and Stages 

MASLD and MASH require early diagnosis, risk stratification, and comprehensive management. MASLD is now defined by the presence of hepatic steatosis in conjunction with one or more cardiometabolic risk factors, excluding harmful alcohol intake.  This reclassification underscores the multisystem nature of MASLD and its close association with obesity, type 2 diabetes (T2DM), dyslipidemia, and hypertension.  In fact, T2DM is the most impactful risk factor for the development of steatotic liver disease (SLD), fibrosis progression, and HCC in this population of patients. However, MASLD can occur in lean individuals, highlighting the importance of metabolic risk factors beyond obesity.  

There are also less common causes of steatotic liver disease including hypobetalipoproteinemia, lysosomal acid lipase deficiency, celiac disease, Wilson’s disease, nutrient deficiency (eg, carnitine, choline, anorexia, bypass patients, short gut) as well as medications (eg, steroids, methotrexate, amiodarone, tamoxifen, 5-FU) 

The disease spectrum ranges from simple steatosis, steatohepatitis, progressive fibrosis, and finally cirrhosis, which then can be complicated by portal hypertension and hepatocellular carcinoma. However, MASLD is a multisystem disorder, conferring increased risk for cardiovascular disease, chronic kidney disease, and extrahepatic malignancies. The economic and healthcare burden is substantial, with impaired quality of life and high resource utilization. 

The pathophysiology of MASLD is multifactorial and arises from a complex interplay of genetic, epigenetic, and environmental factors that disrupt hepatic lipid homeostasis. Insulin resistance is a key driver, leading to increased free fatty acids in the liver, enhanced lipogenesis, and impaired fatty acid oxidation. These processes result in hepatocellular lipid accumulation, mitochondrial dysfunction with resultant oxidative stress further triggering inflammation and fibrosis. However, genetic predisposition, dysregulated nuclear receptor signaling, and gut microbiota alterations further modulate disease progression. Also, as already stated, MASH can occur in individuals with normal body weights, underscoring the heterogeneity of the disease and the importance of metabolic dysfunction beyond obesity alone.  

 The diagnostic criteria for MASLD enables earlier identification and intervention, which is important since MASLD follows a variable course, with most patients remaining asymptomatic until advanced stages. Progression from MASLD to MASH is marked by hepatic inflammation and fibrosis. The presence and severity of fibrosis are the strongest predictors of liver-related outcomes and mortality.  Therefore, early diagnosis is critical for preventing advanced fibrosis and its complications.   

When to screen for SLD 

Providers should screen for MASLD and MASH in all patients with cardiometabolic risk factors. It is important to not solely rely on elevated liver enzymes to initiate screening as liver enzymes can often be normal in patients with SLD.  

Risk factors include diabetes, prediabetes, obesity, or two or more metabolic risks factors such as dyslipidemia, hypertension or increased waist circumference. Patients with persistently elevated aminotransferases for at least 6 months without an etiology or incidental findings of steatosis on radiological imaging should also be screened for MASH.  

Screening for SLD 

The initial screening step to assess disease severity is to calculate a Fibrosis-4 index (FIB-4), which is based on aspartate aminotransferase, alanine aminotransferase, platelets and age. The FIB-4 calculator is readily available online, in medical apps, or can be incorporated into electronic health record smartphrase calculators.  

FIB-4 categorizes patients as low risk (<1.30), indeterminate risk (1.30-2.67), or high risk (>2.67). Patients with high risk should be referred to Hepatology. Those with indeterminate risk require further noninvasive testing (eg, the enhanced liver fibrosis (ELF) test, transient elastography) for fibrosis staging. Those with low risk may be monitored in primary care annually and counseled extensively on lifestyle changes. Patients with MASLD or MASH rarely require liver biopsies now and liver biopsies are typically only reserved for selected cases where diagnosis or staging remain uncertain. 

Managing SLD 

The cornerstone of MASLD management is comprehensive lifestyle modification with diet, weight loss, physical activity, and optimal control of metabolic comorbidities. A diet containing excess calories, particularly excess saturated fats, refined carbohydrates, and sugar-sweetened beverages, is associated with obesity and MASLD. Excessive fructose consumption in particular increases the risk of SLD and advanced fibrosis independent of calorie intake. The Mediterranean diet has evidence for improving hepatic and cardiometabolic outcomes in this population. Coffee consumption (3 or more cups/day), independent of caffeine content, has been associated with less advanced liver disease as well. 

Both aerobic and resistance exercise are beneficial, with effects proportional to engagement and intensity and ideally should be done for at least 30 minutes per day. A goal weight loss of at least 10% of the body weight is ideal and can lead to steatosis, inflammation, and fibrosis improvements. There are also now pharmacologic options for patients with MASH and are indicated for patients with MASH that have significant fibrosis (stage F2-F3). Resmetirom (thyroid hormone receptor beta agonist) is an oral tablet, and the first FDA-approved agent for noncirrhotic MASH with moderate-to-advanced fibrosis (F2 or F3) and has been shown to improve steatohepatitis and fibrosis. This medication is still recommended in conjunction with lifestyle modifications including diet, exercise and weight loss. Semaglutide (GLP-1 receptor agonist ideally 2.4 mg weekly) subcutaneous injection is also approved for noncirrhotic MASH with moderate-to-advanced fibrosis (F2 or F3) and has been shown to improve steatohepatitis and fibrosis.  

This is an exciting time for MASH management since there are multiple other agents currently in clinical trials. Other agents currently under investigation include more GLP-1 receptor agonists, SGLT2 inhibitors, fibroblast growth factor 21 analogs, and PPAR agonists, which target both hepatic and metabolic pathways. These potential future treatment options will allow us to target MASH at different metabolic pathways through potential combination therapy. Bariatric surgery and endoscopic interventions may also be considered in select patients with severe obesity and refractory disease. 

Given the multisystem nature of MASLD and MASH, multidisciplinary care is essential. Cardiovascular disease remains the leading cause of mortality in this population, highlighting the need for integrated management of both hepatic and extrahepatic complications. Statins are safe in patients with SLD including compensated cirrhotics and can be used in decompensated cirrhotics with close monitoring who are at high risk for cardiovascular disease. Therefore, collaboration among hepatologists, gastroenterologists, endocrinologists, dietitians, pharmacists, cardiologists, behavioral health specialists, and primary care providers optimizes management of hepatic and extrahepatic complications. 

Early identification and intervention, particularly in high-risk populations, are essential to prevent progression of disease and improve overall morbidity and mortality in this population. The integration of lifestyle modifications, pharmacologic, and potential surgical therapies, alongside management of metabolic comorbidities, offers the best opportunity to improve outcomes. Continued research into the pathophysiology and therapeutic targets of MASLD and MASH will be critical to addressing the growing global burden of this disease.