Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are a growing health burden across a significant portion of the global patient population. However, these conditions seem to have disparate rates and outcomes between different ethnic populations. The combination of MASLD/MASH and type 2 diabetes increases the risk of hepatocellular carcinoma (HCC), and Hispanic patients experience the greatest burden, particularly those in South Texas.

To compare outcomes between Hispanic and non-Hispanic patients in the United States, while further focusing on the Hispanic population within Southeast Texas to determine whether the documented disparity in outcomes is a function of geographical circumstance or if there is a more widespread reason that all clinicians must account for in prognostic consideration.

This cohort analysis was conducted with data obtained from TriNetX, LLC (“TriNetX”), a global federated health research network that provides access to deidentified medical records from healthcare organizations worldwide. Two cohort networks were used: University of Texas Medical Branch (UTMB) hospital and the United States national database collective to determine whether disparities were related to geographic regions, like Southeast Texas.

This study findings revealed Hispanics/Latinos have a statistically significant higher occurrence of HCC, type 2 diabetes mellitus, and liver fibrosis/cirrhosis in both the United States and the UTMB Hispanic/Latino groups. All-cause mortality in Hispanics/Latinos was lower within the United States group and not statistically elevated in the UTMB cohort.

This would appear to support that Hispanic patients in Southeast Texas are not uniquely affected compared to the national Hispanic population.

Steatotic, or fatty, liver disease (SLD) has been consistently increasing in incidence worldwide and is projected to become the primary etiology responsible for liver transplantation in the near future[1-3]. In June 2023, the American Association for the Study of Liver Diseases (AASLD) released new nomenclature guidelines outlining the terminology and criteria of these new SLD entities[4,5]. SLD encompasses all conditions that result in abnormal accumulation of lipids within hepatocytes, regardless of etiology. Examples of the various SLD etiologies include metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), alcohol-associated liver disease (ALD), combined MASLD and ALD, monogenic conditions that present with hepatic steatosis, drug-induced liver injury (DILI) steatotic liver disease, and cryptogenic steatosis/liver disease.

Per the previous AASLD guidelines on nomenclature and practice from 2012, MASLD is characterized by hepatic parenchyma with at least 5% steatosis without hepatocellular injury; this is opposed to MASH, which also is characterized by at least 5% steatosis of hepatic parenchyma with hepatocellular injury, frequently with hepatocellular ballooning degeneration[6,7]. Long-term potential outcomes from MASLD/MASH progression are cirrhosis and hepatocellular carcinoma (HCC).

AASLD guidelines published in June 2023 now refer to SLD as an overarching term for conditions that result in abnormal lipid accumulation within hepatocytes, with further division into metabolic dysfunction-associated conditions, such as MASLD and MASH, when the patient also demonstrates at least one of five cardiometabolic criteria, such as: (1) Body mass index greater than 25 kg/m² or waist circumference > 94 cm in males or > 80 cm in females (> 23 kg/m² in South and East Asians), waist circumference > 90 cm in South and East Asian males (no changes for females); (2) Fasting serum glucose ≥ 5.6 mmol/L (100 mg/dL) or hemoglobin A1c ≥ 5.7% or type 2 diabetes mellitus (T2DM) or treatment for T2DM; (3) Blood pressure ≥ 130/85 mmHg or treatment with anti-hypertensive therapeutics; (4) Plasma triglycerides ≥ 1.70 mmol/L (150 mg/dL) or lipid-lowering therapeutics; and (5) Plasma high-density lipoprotein-cholesterol ≤ 1.0 mmol/L (40 mg/dL) in males and ≤ 1.3 mmol/L in females or lipid-lowering therapeutics.

These criteria are meant to differentiate those who are diagnosed with SLD from those who may demonstrate steatotic injury or etiology from ALD, DILI, monogenic metabolic conditions, etc. However, overlap conditions do occur, and patients may benefit from the management of underlying metabolic syndrome/dysfunction with lifestyle modification and endocrinology-based interventions[4].

Non-invasive methods for determining fibrosis in chronic liver disease patients, including those with SLD, generally involve use of elastrography-based methods. Fibroscan is one such example of elastography-based detection for determination of fibrosis stage in MASH patients and is used within the University of Texas Medical Branch (UTMB) healthcare system. Fibroscan and other elastrographic methods use complex algorithms to determine a measure of liver stiffness and extrapolate an appropriate fibrosis stage from this measurement. AASLD and other professional hepatology societies have been moving toward more frequent use of non-invasive methodologies for patient care, to reduce potential complications as well as improving patient experience[4]. Indeed, most healthcare organizations (HCOs) with high volume hepatology centers use elastography for surveillance and staging, rather than relying on liver biopsies.

However, there are limitations to elastography-based methodologies, namely the ability to detect subsinusoidal fibrosis or delicate bridging fibrosis, allowing for greater levels of progression surveillance in such patients. Subsinusoidal fibrosis surrounding areas of ballooning hepatocytes could portend a patient who is likely to progress to cirrhosis[8].

Differentiating MASLD from MASH is critical for prognosis, therapeutic considerations, and surveillance requirements per AASLD guidelines. The confirmation of MASLD vs MASH is ensured via histological examination of liver tissue, often in the form of a trans-cutaneous or transjugular biopsy for evaluation by a trained hepatopathologist or surgical pathologist. MASLD as ≥ 5% of hepatocytes display macrovesicular steatosis with: (1) No alternative explanations for said steatosis, such as medications, alterations in nutritional status, or monogenic disorders; and (2) Abstinence from alcohol or very little imbibement of alcohol. MASH requires these 2 conditions with the addition of: (1) Inflammation; (2) Hepatocellular injury resulting in ballooning hepatocytes; and (3) Some level of fibrosis, ranging from periportal or perivenular fibrosis up to cirrhosis[4]. Those with a fibrosis score between 2-4 (out of a possible total score of 4) are at increased risk of liver-related events or mortality[9,10], while those with bridging fibrosis or cirrhosis (3-4 out of 4) experience a far higher rate of related instances of morbidity and/or mortality[11,12].

When MASLD or MASH biopsies are histologically evaluated, hepatopathologists use a standardized score to grade the degrees of steatosis, inflammation, and hepatocellular injury, called the non-alcoholic fatty liver disease activity score (NAS)[13]. This generates an unweighted score of these 3 parameters for a total NAS score between 0 and 8, with those scoring ≥ 5 largely considered diagnostic for MASH, while NAS scores between 3-4 are considered borderline or positive MASH, and 2 deemed non-diagnostic to MASH. Additionally, the trained hepatopathologist will thoroughly review the patient’s history and laboratory results to inform the histological diagnosis and present a unified explanation of the pathology to the clinical team. This allows the pathologist to ensure there are no alternative explanations for the histological appearance of the hepatic parenchyma[14]. A comparison of the histological appearance of a MASLD (NAS 3/8) biopsy vs a MASH (NAS 6/8) is included in Figure 1.

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Figure 1 Histological appearance of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis at 100 × magnification (hematoxylin and eosin stain). A: A non-alcoholic fatty liver diseases activity score (NAS) 3/8; B: A NAS 6/8 which constitutes a moderate-severe steatohepatitis. Blue triangles denote macrovesicular steatosis. Black stars denote ballooned hepatocytes. Black bars in lower right corner denote scale bar of 50 μm.

Management of MASLD/MASH involves treating liver disease and associated metabolic comorbidities, including diabetes, obesity, and hyperlipidemia. While there are no approved drugs for the treatment of MASLD/MASH, clinical practice guidelines from AASLD recommended that first-line treatment for patients should focus on lifestyle intervention and/or insulin therapy targeting diabetes[15]. Antidiabetic therapy is considered the safest and most effective therapeutic management in patients with chronic liver disease. As such, evidence supports the efficacy of the antidiabetic drug pioglitazone in patients with biopsy-proven MASH[16]. Pioglitazone is a thiazolidinedione, a class of drugs that targets insulin resistance and adipose tissue dysfunction, which in turn reduces the lipid content in the liver by modulating several mediators[17]. Numerous studies, including systemic reviews and meta-analyses of pioglitazone in MASH patients, benefit liver function, reducing liver fat, leading to MASH resolution[15,18-20]. More recently, semaglutide, a long-acting glucagon-like receptor 1 agonist, has been approved for treating type 2 diabetes and obesity and is currently in late-stage clinical trials for MASH. Semaglutide has been shown to improve body weight, glucose, and lipid metabolism and may induce MASH resolution with benefits on inflammation[21]. However, larger trials are needed to characterize better the long-term efficacy, clinical outcomes, and adverse effects of diabetes pharmacotherapy in MASH/MASLD patients.

MASLD and MASH have become tremendous healthcare burdens in most countries worldwide[22,23]. While this was previously seen as a problem for high-income countries, including the United States, where 30% of the population is afflicted with MASLD[24], it has since exploded in incidence worldwide[25]. However, these two entities rarely occur alone; instead, patients often present with concomitant conditions, such as metabolic syndrome, T2DM, obesity, and cardiovascular disease[26]. The combination of these conditions, especially T2DM, complicates the course of MASLD and MASH in many of these patients, especially in Hispanic populations[27]. It is well-established that increased hepatic lipogenesis strongly associates with insulin resistance and increased cardiometabolic risk profiles[28]. Additionally, T2DM increases the risk of different cancers, including HCC in patients with underlying MASLD[29], and Hispanic patients experience the greatest burden, particularly those in South Texas[27]. It is important to note that diabetes and obesity, risk factors for MASLD, are also independently associated with HCC in Hispanics[30]. Studies have shown that the prevalence of MASLD is increased in Hispanics/Latinos compared to African Americans, leading to the highest risk of progression to liver cirrhosis and HCC[31]. The prevalence of obesity in the United States (2005-2014) in Hispanics and African males is similar (38%), while Hispanic females have a low prevalence (47%) compared to African Americans (57%). As such, obesity may contribute to liver cancer deaths in African Americans and Hispanics than in non-Hispanic whites in Texas[32]. Yet, the exact contributions of genetic and environmental factors on these differences in the prevalence rates have not been determined. Given the increased burden of MASLD and HCC, high-risk patients, particularly Hispanics and Latinos with T2DM, should be closely monitored for HCC development. These studies investigate the associations between metabolic conditions and HCC development in Hispanic patients with MASLD and MASH. Our aim in this cohort study was to investigate disparities in outcomes between Hispanic/Latino patients and non-Hispanic/Latino patients with MASH and T2DM, determine if there is a geographical difference in any outcome disparities, and to conduct these analyses on the largest cohort of MASH patients to date.

This study was conducted with data obtained from TriNetX, LLC (“TriNetX”), a global federated health research network that provides access to deidentified medical records from HCOs all over the world. TriNetX data contains diagnoses, procedures, medications, laboratory values, and genomic information for more than 120 million patients from over 100 HCOs. The analyses conducted herein utilized local UTMB (about 2 million) and United States Collaborative Network (56 HCOs, about 92 million) patients to compare outcomes between Hispanic and non-Hispanic patients in the United States as a whole while further focusing on the Hispanic population within Southeast Texas to determine whether the documented disparity in outcomes is a function of geographical circumstance or if there is a more widespread reason that all clinicians must account for in prognostic consideration. It is important to note, that the UTMB network was included within the broader United States Collaborative Network for analyses, with the UTMB network acting as a sub-cohort analysis.

The entire process of data collection, processing, and transmission was carried out in accordance with various Data Protection laws applicable to the contributing HCOs, including the EU Data Protection Law Regulation 2016/679, the General Data Protection Regulation, and the Health Insurance Portability and Accountability Act (HIPAA). It is worth noting that HIPAA is a United States federal law protecting healthcare data’s privacy and security. TriNetX EMEA and Global Collaborative Networks are distributed networks that utilize anonymized or pseudonymized/deidentified (as per HIPAA) data kept at the HCOs, with only aggregated results being sent back to the TriNetX platform. Personal data is not transferred from the HCOs. Additionally, TriNetX is ISO 27001:2013 certified and maintains a robust IT security program that safeguards personal and healthcare data.

In total, 147744 patients were reported from 56 HCOs in the United States dataset. Out of the 146914 that were diagnosed with MASH, 17052 patients from 49 HCOs were identified as Hispanic/Latino (HMUS) and 130692 patients from 56 HCOs identified as non-Hispanic/Latino (NHMUS). After undergoing PSM, 17052 Hispanic/Latino patients were compared with 17050 non-Hispanic/Latino patients and were further divided by sex, resulting in 6888 Hispanic/Latino males and 10161 females, with an additional 6815 non-Hispanic/Latino males and 10235 females (Table 1 and Figure 2).

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Figure 2 Patient demographic flow chart. The chart demonstrates the total number of metabolic dysfunction-associated steatohepatitis patients in both United States and University of Texas Medical Branch cohorts, total number of Hispanic/Latino and non-Hispanic/Latino patients in each cohort, the effects of Propensity Score Matching on cohort size, and the total number of male and female patients in each sub-cohort. MASH: Metabolic dysfunction-associated steatohepatitis; UTMB: University of Texas Medical Branch; HCO: Healthcare organizations.

When narrowed to a stand-in for Southeast Texas, UTMB was used. From this single HCO, 4100 patients were identified as Hispanic/Latino with the required MASH diagnosis (HMUT), while 11160 patients identified as non-Hispanic/Latino (NHMUT) (Table 1). After PSM, this was reduced to a comparison between 4100 Hispanic/Latino patients and 4100 non-Hispanic/Latino patients. Further categorization via sex results in 1670 male patients and 2430 female patients in both the Hispanic/Latino and non-Hispanic/Latino categories (Table 1 and Figure 2).

After PSM all 4 cohorts (2 United States cohorts, 2 UTMB-only cohorts, each divided by Hispanic vs non-Hispanic demographic descriptors), we reviewed outcome data amongst them, including risk ratios for developing HCC, T2DM, cirrhosis/hepatic fibrosis, and all-cause mortality. These were calculated using a 95%CI and undergoing Kaplan-Meier survival analysis. Table 2 and Figure 3 contain the visual representation of the results of each outcome’s risk ratios and the Kaplan-Meier survival analysis curves, respectively.

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Figure 3 Kaplan-Meier survival analysis curves for United States and University of Texas Medical Branch cohorts. Hispanic/Latino patients are represented in red, while non-Hispanic/Latino patients are represented in blue. The four primary outcomes (all-cause mortality, hepatocellular carcinoma, type 2 diabetes mellitus, and fibrosis/cirrhosis of the liver) are represented for both cohorts. MASH: Metabolic dysfunction-associated steatohepatitis; UTMB: University of Texas Medical Branch; HCC: Hepatocellular carcinoma; T2DM: Type 2 diabetes mellitus.

MASLD/MASH and its coexistence with T2DM is increasing rapidly worldwide, reaching epidemic proportions, particularly in Hispanic populations. HCC has become one of the fastest-rising causes of cancer-related mortality, with the rising trend of MASLD, MASH, and T2DM. More recent studies demonstrate that MASLD/MASH in combination with T2DM increases the risk of HCC, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients[26,29,33]. Given the global increase in the burden of MASLD and MASH, high-risk patients should be monitored for HCC development.

In South Texas, Hispanics experience more disparate trends in the incidence and prevalence of HCC compared to other ethnic groups[27]. Although Texas accounts for the second-greatest distribution of Hispanics by state, the incidence of HCC among Hispanics in Texas, particularly South Texas, was significantly higher than elsewhere in the United States[27]. This was also seen in the present study, wherein the UTMB Hispanic/Latino population had a 4-fold increase in rates of HCC compared to non-Hispanic/Latino patients, while the US cohort demonstrated only a 2-fold increase in HCC rates. This trend may be caused by the prevalence of unique regional risk factors, such as obesity, T2DM, MASLD, and MASH[27]. However, this conflicts with a reported negative association between T2DM and hepatitis C virus (HCV) infection in Mexican Americans[34]. These data suggest that Mexican American Hispanics may have a decreased risk of HCV compared with non-Mexican Hispanics[34] and that unique risk factors may be involved in the border community. Another cohort analysis investigated the prevalence of MASLD diagnosis at various stages associated with T2DM using the National Health and Nutrition Examination Survey database (2017-2018) by applying transient elastography (FibroScan^®)[35]. This cohort analysis shows a high prevalence of MASLD with fibrosis (≥ F2) in the general United States population (25.3%), with greater prevalence in participants with T2DM (54.6%%)[35]. Although Hispanics formed the largest ethnic group among participants with MASLD, the greatest prevalence (35.5%) was observed in Mexican Americans in their analysis[35]. Despite the regional variation, the global prevalence of HCV in T2DM is increasing overall and is higher than in the general population[18,36]. Studies demonstrate that MASLD doubles the risk of T2DM, varying with the fat and fibrosis liver scores, and accelerates the development of cardiovascular disease. Conversely, T2DM increases the risk of MASLD, cirrhosis, and HCC[16,18].

With confirmation of previously disclosed trends in outcomes between Hispanic and non-Hispanic patients in the largest cohort study to date, the question remains why the outcomes demonstrate such a chasm in severity. Is this due to internal bias amongst United States physicians? Is this the result of unequal access to care, therapeutics, and inter-ventions? Unfortunately, these analyses do not elucidate the cause of the outcome disparities, only that they do not show a geographic difference between the United States and Southeast Texas.

Medical practitioners should be highly cognizant of the well-established outcome disparity between Hispanic and non-Hispanic patients regarding MASLD/MASH and HCC, especially in settings with concomitant metabolic conditions, such as T2DM, obesity, metabolic syndrome, and cardiovascular disease. In addition, developing and validating accurate predictive models, including age, race/ethnicity, and metabolic syndrome features, may help target MASLD, MASH, and HCC screening to those at the highest risk.