Why Liver Health Belongs in the Cardiometabolic Conversation

By Andres Quintero, MD, MPH, MBA, U.S. Medical Affairs Director for Cardiovascular and Liver Health Portfolio at Novo Nordisk

Cardiometabolic diseases—including obesity, type 2 diabetes, hypertension and dyslipidemia—are well-recognized drivers of cardiovascular and renal disease. Increasingly, evidence suggests that the liver needs to be considered a vital component of cardiometabolic health.^1-3

Steatotic liver disease (SLD), formerly known as fatty liver disease, is now recognized as one of the most common chronic liver diseases worldwide. Rather than representing an isolated liver disorder, SLD often develops because of common conditions that clinicians manage daily, including obesity, type 2 diabetes, hypertension and dyslipidemia.^1-3

SLD As The Hepatic Manifestation of Metabolic Syndrome

The most common subtype of SLD is metabolic dysfunction-associated steatotic liver disease (MASLD), which occurs in individuals with at least one cardiometabolic risk factor and without significant alcohol intake or other chronic liver diseases. International consensus criteria recognize obesity, type 2 diabetes, hypertension, dyslipidemia and insulin resistance as key contributors to disease development.¹ MASLD is estimated to affect more than one-third of adults globally, and it is becoming increasingly prevalent in its more advanced stages of fibrosis.² As these conditions become increasingly prevalent, the burden on healthcare systems will also rise.²

The relationship between liver health and metabolic disease is not one-directional. Metabolic dysfunction promotes fat accumulation in the liver, while hepatic steatosis worsens insulin resistance, impairs glucose metabolism and dysregulates lipid metabolism. This reciprocal relationship is why MASLD is described as the hepatic manifestation of metabolic syndrome.³ In addition, studies suggest that MASLD is independently associated with an increased risk of cardiovascular events, underscoring the importance of recognizing MASLD as a broader indicator of cardiometabolic disease.⁹

Alcohol Intake Contributes to SLD

Although metabolic dysfunction is responsible for the majority of SLD cases, alcohol intake remains an important contributor to liver disease and is the strongest determinant of disease progression.

Historically, clinicians viewed metabolic liver disease and alcohol-related liver disease (ALD) as mutually exclusive entities. We now recognize that among patients with MASLD, many drink alcohol. Moreover, among patients with ALD, an estimated 95% of patients have at least one cardiometabolic risk factor.⁴ In effect, these co-occurring risk factors for hepatic injury place patients at greater risk of morbidity and mortality than if they existed in isolation.

Patients with metabolic dysfunction who consume 20–50 g/day of alcohol (women) or 30–60 g/day (men) on average are classified as having metabolic dysfunction and alcohol-associated liver disease (MetALD). Above these thresholds—more than 50 g/day for women and more than 60 g/day for men, on average—patients are classified as having ALD, regardless of whether cardiometabolic risk factors are also present.

Recognizing whether a patient’s SLD is attributed to MASLD, MetALD or ALD is important because the therapeutic goals and management strategy may vary as a function of these etiologies.^{1, 5}

SLD Develops Silently

Among the greatest challenges with SLD is that it frequently develops silently. Most patients remain asymptomatic for years, and despite having clinically significant disease, routine liver enzyme levels often remain within normal limits. Consequently, opportunities for early intervention are often missed, and many patients are not identified until they develop advanced fibrosis, cirrhosis or liver-related complications.^6,7

To mitigate the risk of these outcomes, professional societies advocate for routine screening in the asymptomatic population with overweight or obesity, type 2 diabetes, hypertension, dyslipidemia or unhealthy alcohol use.^4-6 Screening aims to identify advanced liver fibrosis, the strongest predictor of liver-related outcomes and mortality in this population. Through earlier detection, clinicians can identify patients, initiate treatment or specialist referrals when appropriate, and monitor for disease progression or improvement.⁸

The Landscape Is Changing

Advances in non-invasive fibrosis assessment now allow clinicians to assess the risk of liver-related morbidity and mortality without relying exclusively on liver biopsy. To identify higher-risk patients most likely to benefit from specialist evaluation, treatment and ongoing monitoring, clinicians can incorporate simple blood-based algorithms, such as the Fibrosis-4 (FIB-4) index, followed by second-line tests when the FIB-4 is elevated.^10,11 While several second-line tests exist, the most common is the vibration-controlled transient elastography (FibroScan^®), which directly estimates liver stiffness as a surrogate marker of hepatic fibrosis.

The goals of managing SLD include reducing weight, improving glycemic control, optimizing blood pressure and lipids, and reducing alcohol intake or achieving abstinence through lifestyle modification and with pharmacotherapy when indicated. Moreover, the FDA has recently approved two therapies demonstrating safety and efficacy for addressing liver fibrosis and steatohepatitis, the latter being an important feature of SLD attributed to MASH.^10,11 (MASH is the biopsy-confirmed equivalent of MASLD.) There are currently no FDA-approved drugs for ALD or MetALD.

An Integrated Approach to Managing SLD

As healthcare continues to embrace integrated management of chronic disease, liver health can no longer remain on the periphery of cardiometabolic care. Primary care clinicians, endocrinologists, cardiologists, obesity medicine specialists, addiction medicine specialists, gastroenterologists and hepatologists each have a key role in identifying individuals at risk of SLD and coordinating longitudinal management.

Recognizing that the liver is a critical component of cardiometabolic health can help clinicians improve patient outcomes through earlier risk stratification, detection and multidisciplinary management.

This blog is brought to you by Novo Nordisk, and the views expressed are solely those of the sponsor.

References

1. Rinella ME, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023.
2. Younossi ZM, et al. Global epidemiology of NAFLD/MASLD and NASH/MASH. Hepatology. 2023;77:1335–1347.
3. Godoy-Matos AF, et al. The role of the liver in the pathophysiology of metabolic syndrome. Diabetology & Metabolic Syndrome. 2020;12:60.
4. Jophlin LL, et al. ACG Clinical Guideline: Alcohol-Associated Liver Disease. American Journal of Gastroenterology. 2024;119:30–54.
5. Rinella ME, et al. AASLD practice guidance on the clinical assessment and management of steatotic liver disease. Hepatology. 2023;77:1797–1835.
6. Cusi K, et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of NAFLD. Endocrine Practice. 2022;28:528–562.
7. Dulai PS, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–1565.
8. Mantovani A, et al. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. The Lancet Gastroenterology & Hepatology. 2021;6:903–913.
9. Kanwal F, et al. Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021;161:1657–1669.
10. Cusi K, et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of NAFLD. Endocrine Practice. 2022;28:528–562.

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