From the AGA Journals

Meta-Analysis Highlights Litany of MASLD-Associated Complications, Encouraging New Treatment Targets

Publish date: February 7, 2024
By
Will Pass
MDedge News

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Start With the Root Driver — Obesity

In a massive meta-analysis of 129 studies that included over 6 million participants, Chan and colleagues evaluated the associations of MASLD with incident hepatic and extrahepatic outcomes. They report numerous associations for MASLD with metabolic, cardiovascular, and renal events as well as with gastrointestinal, hepatobiliary, and other types of cancers.

Dr. Samer Gawrieh, Division of Gastroenterology and Hepatology at Indiana University School of Medicine, Indianapolis. Director of Hepatology Research and Clinical Fellowship Program Indiana University School of Medicine

Dr. Samer Gawrieh

Some of their findings are congruent with prior research establishing the independent association of MASLD with future development of cardiovascular and renal disease, diabetes, and hepatocellular carcinoma. It is, however, unclear if the additional MASLD associations they report, such as with nonliver malignancies, would persist if adjustment for relevant covariates affecting these outcomes were performed. While the large number of participants from different study populations included in the analysis can be a strength, the resulting considerable heterogeneity calls for caution in interpreting some of the associations and their magnitudes.

The unimpeded pace of the obesity pandemic remains a steady driver of the rise in the burden of metabolic syndrome and its components, including MASLD. Thus, approaches to tackle the rising burden of metabolic diseases including MASLD should start with the root driver, obesity. It is also imperative to consider addressing the cardiometabolic milieu in any approach designed to specifically target MASLD/MASH. Lifestyle modifications that include weight loss, smoking cessation, and avoidance of alcohol use may help reduce risks of cardiovascular disease and cancer, the leading causes of death in patients with MASLD. Anticipated pharmacologic therapies for MASH should not only improve liver endpoints but also have a beneficial or, at minimum, neutral extrahepatic effects on coexisting cardiometabolic conditions.

Samer Gawrieh, MD, is professor of clinical medicine in the Division of Gastroenterology and Hepatology at Indiana University School of Medicine, Indianapolis, where he serves as the Director of Hepatology Research and Clinical Fellowship Program. He receives funding for the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Alcohol Abuse and Alcoholism, and research grant support from Zydus and Viking, and serves on safety committees with TransMedics, Pfizer and Spruce.


 

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with a host of negative clinical outcomes across cardiovascular, metabolic, and oncologic domains, based on a large-scale meta-analysis of longitudinal data.

These findings emphasize the multisystemic nature of MASLD, suggesting that broader treatment targets are needed to reduce systemic events and end organ complications, reported lead author Kai En Chan, MBBS, of the National University of Singapore, and colleagues.

“[D]espite the substantial impact of MASLD, with direct medical costs estimated to reach $103 billion in the United States alone, a comprehensive umbrella meta-analysis of the longitudinal complications associated with MASLD has yet to be conducted,” the investigators wrote in Clinical Gastroenterology and Hepatology, noting that key outcomes associated with sex and disease severity have yet to be elucidated. “A comprehensive understanding of the spectrum of clinical complications associated with MASLD is thus crucial in developing effective disease management strategies and optimizing the allocation of limited healthcare resources.”

To this end, the investigators analyzed data from 129 studies reporting longitudinal risks of clinical outcomes among adults with MASLD. Assessed complications spanned a broad array of organ systems and pathologies. Cardiovascular and oncologic conditions predominated, while chronic kidney disease, liver-related outcomes, gallstone formation, dementia, and reflux esophagitis were also considered.

The analysis revealed significant associations between MASLD and — in ascending level of risk — chronic kidney disease (hazard ratio [HR], 1.38), cardiovascular diseases (HR, 1.43), cancer (HR, 1.54), prediabetes (HR, 1.69), hypertension (HR, 1.75), diabetes (HR, 2.56), and metabolic syndrome (HR, 2.57).

Across cardiovascular diseases, MASLD raised risk of hypertension the most, by 75%. Among cancer types, MASLD increased risk of hepatocellular carcinoma to the greatest degree, by more than fourfold.

No significant sex-specific differences in MASLD-associated risk were detected for cancer, chronic kidney disease, diabetes, or cardiovascular disease, although the investigators urged a cautious interpretation of these findings, since relevant data were scarce.

“It is imperative to understand that MASLD is a complex and multifaceted condition that requires a comprehensive approach to recognition and treatment beyond that of the hepatologist alone,” the investigators wrote.

They also suggested that the link between MASLD and cancer deserves particular attention.

“Although the mechanism by which MASLD gives rise to cardiovascular disease and diabetes has been thoroughly researched, the pathophysiology of MASLD leading to extrahepatic carcinogenesis is less well understood and has been postulated to be linked to chronic inflammation and dysregulation of the gut microbiome in MASLD,” they wrote.

Lastly, considering the multiprong association between MASLD and so many complications, the investigators recommended broader clinical metrics for measuring outcomes in patients with MASLD.

“With the synergistic increases of metabolic diseases globally, treatment targets should in turn act beyond the resolution of fibrosis but also to reduce systemic end organ complications,” they concluded.The investigators disclosed relationships with AbbVie, Echosens, Gilead Sciences, and others.

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