In this extensive population-based study, we systematically assessed the prevalence of the most common cancers among patients hospitalized with MASH using the National Inpatient Sample. To date, and to the best of our knowledge, this is the first study to investigate disparities in cancer outcomes among lean and non-lean MASH hospitalized patients. Our findings indicate a notably higher risk of cervical cancer in lean MASH patients, with odds three times greater than those observed in the non-lean cohort. Additionally, the lean group exhibited increased prevalence of non-Hodgkin’s lymphoma, lung, colon, kidney, and liver cancers when compared to their non-lean counterparts. Conversely, among non-lean hospitalizations, a higher incidence of endometrial carcinoma was demonstrated. Notably, the analysis revealed no significant differences in the prevalence of melanoma, multiple myeloma, breast, prostate, thyroid, pancreatic, ovarian, esophageal, brain, gastric, and rectal cancers between the two groups. These findings highlight the complex relationship between body composition, metabolic dysfunction, and cancer risk, highlighting the need for targeted screening and preventive measures based on metabolic health status and body composition in MASH hospitalized patients.
Our study adds to the understanding of increased cancer risk in hospitalized patients with MASLD, including MASH seen in previous studies that revealed increased mortality rate among all stages of steatotic liver disease, including MASH [15,16,17] by stratifying this risk based on BMI using a nationwide population-based study. The most well described in the literature is the progression of from MASLD through MASH, with or without fibrosis to cirrhosis to hepatocellular carcinoma, and the rate of this complication has been increasing over the years [18]. MASH is an independent risk factor for HCC and accounts for about 7% of HCC globally [2]. Interestingly, death in hospitalized patients with MASLD, inclusive of those with MASH have been noted to occur more often from extrahepatic cancers [2].
Our study corroborates existing research linking diabetes and hepatocellular carcinoma (HCC), as well as various extrahepatic solid organ cancers such as prostate, breast, esophagus, colon, lung, pancreas, kidney, and bladder [16]. Notably, while we observed this continued association in cancers like HCC, colon, lung, and kidney, our data also revealed a heightened risk for non-Hodgkin’s lymphoma and cervical cancer within the lean MASH cohort. This expands the conventional understanding that primarily links metabolic dysfunctions such as obesity and diabetes with cancer, suggesting that additional genetic or environmental factors may influence cancer susceptibility in this population.
Previous observational studies have often evaluated cancer risks within the entire spectrum of MASLD but lacked a global perspective. Our findings contribute to this narrative by clarifying that while MASLD is commonly associated with increased risks for hepatocellular and extrahepatic cancers, the specific relationship between MASH, body composition, and cancer risk remains complex. This emphasizes the need for further investigations that are globally representative and stratify patients from initial steatosis through MASH to cirrhosis, thereby enhancing our understanding of how obesity interplays with metabolic liver disease to modulate cancer risk. Additionally, our analysis identified an increased risk of endometrial cancer in the obese MASH cohort, aligning with previous studies that have highlighted the role of hormonal imbalances associated with obesity [19]. This observation reinforces the established link between excess adiposity and hormonal cancers, further emphasizing the importance of managing body weight as part of a comprehensive cancer prevention strategy in patients with MASH. This finding prompts a deeper exploration of hormonal pathways and their modulation by metabolic states in future research, which could unveil new preventive and therapeutic targets. Finally, while our study did not yield statistically significant differences, we observed trends suggesting potentially elevated risks for several cancers, including breast, prostate, thyroid, pancreatic, ovarian, brain, gastric cancers, melanoma, and multiple myeloma. Although these findings did not reach statistical significance, they contribute to the growing body of evidence suggesting a link between excess body fat and the pathogenesis of multiple malignancies. Despite the absence of conclusive significance, these trends emphasize the importance of considering the multifaceted interplay between metabolic dysfunction, adiposity, and cancer susceptibility.
Finally, our sex-stratified analysis revealed striking disparities: lean female MASH patients had 115-fold higher odds of breast cancer but lower odds of liver and kidney cancers compared to non-lean females. While the extreme odds for breast cancer may reflect residual confounding (e.g., undiagnosed genetic risk), the inverse association with hepatocellular and renal cancers aligns with evidence that obesity-driven metabolic dysfunction (e.g., hyperinsulinemia, adipokine imbalance) disproportionately promotes these malignancies in non-lean populations. These contrasts underscore that lean MASH may represent a distinct phenotype where cancer risk is mediated by non-adipose mechanisms, such as estrogen signaling in breast tissue or sarcopenia-related metabolic dysregulation. Future studies should explore whether sex hormones or body composition (e.g., visceral fat vs. muscle mass) modulate these risks independently of BMI.
Clinical implications
The observed disparities in cancer prevalence between hospitalized lean and non-lean MASH patients underscore the critical need for tailored screening protocols that account for metabolic health status and body composition. Clinicians should recognize the heightened cancer risk among hospitalized lean MASH patients and consider incorporating regular cancer screenings into their management plans. Given the threefold higher odds of cervical cancer observed in hospitalized lean MASH patients compared to their non-lean counterparts, routine cervical cancer screenings should be prioritized in this population. Early detection through regular screenings can facilitate timely intervention and improve patient outcomes.
Managing MASH requires a holistic approach that extends beyond liver health to encompass comprehensive care targeting metabolic dysregulation and associated cancer risks. Clinicians should adopt a multifaceted management strategy that addresses both liver-specific concerns and modifiable risk factors implicated in cancer pathogenesis. Obesity and diabetes, known contributors to cancer development, should be actively addressed in the management of MASH patients. Interventions aimed at weight management, lifestyle modifications, and glycemic control are crucial for mitigating cancer risk and improving overall health outcomes.
Public health implications
Moreover, considering the findings highlighted in this analysis among hospitalized MASH patients, particularly among lean individuals, public health initiatives must prioritize raising awareness of these risks. Health promotion campaigns should be tailored to educate the public, with a specific emphasis on lean individuals, about the importance of maintaining a healthy weight and adopting lifestyle modifications to mitigate cancer risk. By disseminating targeted information through various channels, such as social media, community outreach programs, and healthcare facilities, public health campaigns can empower individuals to make informed decisions regarding their health and well-being. Policymakers play a pivotal role in addressing the public health implications of MASH-associated cancer risks. It is imperative for policymakers to integrate cancer screening and prevention strategies into existing healthcare systems, ensuring equitable access to preventive healthcare services for all individuals, including those diagnosed with MASH. This may entail implementing policies that facilitate early detection and intervention, such as reducing barriers to screening programs and promoting the adoption of evidence-based guidelines for cancer prevention and management. By enacting comprehensive policy interventions, policymakers can contribute to reducing the burden of MASH-associated cancers and improving health outcomes on a population level.
Limitations
We acknowledge several limitations in this study. First, the diagnosis of MASH is established using ICD-10 codes from a nationwide database, which may introduce selection bias due to potential misclassification or incorrect coding. Secondly, the lack of longitudinal follow-up in our dataset prevents us from determining if some lean patients were initially non-lean and lost weight due to underlying cancer or other health issues. This limitation is inherent to the use of the NIS, which does not track patients over time. This underscores the need for longitudinal studies to confirm our findings and to better understand the temporal dynamics between body weight changes and cancer development. Thirdly, as this is a cross-sectional study, we cannot measure causality, and only associations can be assumed. Additionally, it is important to note that the unit of analysis in this study is hospitalizations rather than individual patients. As a result, patients who are hospitalized more than once may be counted multiple times, which could impact the interpretation of the data. Despite employing multivariable analysis to control for patient demographics and comorbidities, residual confounding by unmeasured or inadequately measured factors cannot be ruled out. Factors such as lifestyle choices, socioeconomic status, and detailed clinical history were not available in the NIS, which could influence both MASH progression and cancer risk. Furthermore, the use of administrative data restricts the ability to explore deeper clinical nuances that might affect disease classification and outcomes. Clinical subtleties such as the severity of steatohepatitis, patient medication histories, and finer details of metabolic health are beyond the scope of what administrative codes can capture. Moreover, it is crucial to specify that this study is based on hospitalization data from the NIS. While this database could be externally validated to US hospitals, caution should be exercised in generalizing the findings to the broader US population. Moreover, we acknowledge that BMI is frequently underreported in administrative data, which may affect the reliability of our findings. Furthermore, BMI coding (e.g., Z68.2) may overlap lean and non-lean ranges, especially across ethnic groups (e.g., Asians), potentially leading to misclassification. This undercoding could potentially lead to misclassification and bias in our results. Additionally, BMI cutoffs may differ in older adults due to age-related changes in body composition; however, the database did not support age-specific BMI categorization. Therefore, caution should be exercised when interpreting the associations between BMI and cancer risk in this study. Additionally, while our dataset includes hospitalizations from 2016 to 2020, the structure of the NIS only allows analysis at the yearly level making it difficult to differentiate between hospitalizations pre- and post-COVID-19 Pandemic in early 2020. Given the potential impact of the pandemic on cancer detection, screening delays, and healthcare access, this represents an important limitation. However, due to the limited post-pandemic observation period and the lack of monthly-level data, stratifying our analysis by pre- and post-pandemic years could introduce bias. Finally, while this study contributes valuable insights into the role of BMI in cancer pathogenesis among MASH patients, these findings need to be interpreted with caution and verified through additional studies that can address these limitations. This study is among the first to elucidate the potential cancer risk disparities within this patient population, laying the groundwork for more detailed investigations in the future.
Future research
Future research should prioritize validating these findings across diverse datasets and patient populations to ascertain the generalizability and robustness of the observed associations. Studies employing longitudinal databases that track patients over time would be particularly valuable, enabling researchers to observe changes in metabolic status and corresponding shifts in cancer risk profiles. This longitudinal approach would also facilitate a better understanding of the temporal relationship between MASH and cancer development. Prospective studies, ideally with a multi-center design, are crucial to explore not only the cancers examined in this study but also other malignancies that may be associated with MASH. Such studies should incorporate detailed metabolic and genetic profiling to dissect the mechanisms by which metabolic dysfunction influences cancer pathogenesis. Moreover, it would be instructive to explore the impact of interventions targeting metabolic dysfunctions, such as pharmacological treatments, lifestyle modifications, and bariatric surgery, on cancer incidence in MASH patients. This could offer insights into potential preventive strategies that could be implemented in high-risk populations. In addition to clinical studies, bioinformatics approaches involving big data analytics and machine learning could be employed to identify novel biomarkers and potential therapeutic targets for cancers associated with MASH. These computational studies could leverage existing medical datasets to predict cancer risk and outcomes more accurately in patients with various forms of metabolic dysfunction. Ultimately, these efforts should aim to foster a multidisciplinary approach, combining clinical, genetic, and public health strategies to mitigate the elevated cancer risks associated with metabolic dysfunction-associated steatohepatitis.