Abstract
This cohort study examines the association of sex with liver and nonliver adverse events using data from a US nationwide population-based database of patients with metabolic dysfunction–associated steatotic liver disease.
Introduction
Metabolic dysfunction–associated steatotic liver disease (MASLD) affects approximately 30% of the global population, is increasing, and is a leading cause of liver and nonliver adverse events.1,2 However, data on sex differences, particularly with the updated concept of MASLD,2 are limited. We investigated the association of sex with liver and nonliver adverse events using data from US patients with MASLD.
Methods
This cohort study was approved by the institutional review boards of Stanford University and followed the STROBE reporting guideline. We identified adult patients with MASLD from the 2007 to 2022 Merative MarketScan Research Database and used propensity score matching to balance the baseline characteristics of the male and female groups (eMethods, eFigure, and eTable in Supplement 1). The incidence of liver adverse events (cirrhosis, hepatic decompensation, and hepatocellular carcinoma [HCC]) and nonliver adverse events (cardiovascular diseases [CVD], chronic kidney disease [CKD], and nonliver cancer, specifically non–sex-specific cancers) was estimated and compared by sex. Cox proportional hazards regression and restrict mean survival time (RMST) analysis were used to assess the association between sex and the event of interest.
Results
Of 761 403 patients with MASLD, 344 436 pairs of matched men and women with balanced baseline characteristics were included in the incidence analysis. The mean (SD) age (52.7 [12.4] vs 53.0 [12.3] years), proportions of patients with obesity (16.9% vs 16.8%), diabetes (33.2% vs 33.3%), hypertension (62.6% vs 62.3%), hyperlipidemia (47.7% vs 46.5%), metformin use (10.4% vs 10.4%) or statin use (25.8% vs 25.4%), and mean (SD) Charlson Comorbidity Index (3.91 [2.14] vs 3.91 [1.96]) were all similar between 2 groups.
Women had higher incidence (per 1000 person-years) vs men of any liver adverse event (12.72 vs 11.53) and cirrhosis (12.68 vs 11.55), whereas men had higher incidence of hepatic decompensation (10.40 vs 9.37), HCC (1.88 vs 0.73), CVD (17.89 vs 12.89), CKD (16.61 vs 14.42), and non–sex-specific cancer (6.68 vs 5.06) (Table). The 10-year cumulative incidence rates are shown in the Figure.
Table. Incidence Rate of Study Outcomes by Sex and Association of Sex With Study Outcomes in Patients With Metabolic Dysfunction–Associated Steatotic Liver Disease.
| Outcome | Patients, No. | Person-years, No. | Events, No. | Incidence/1000 person-years | P valuea | HR (95% CI) | P valuea | RMST (95% CI), y | RMST difference (95% CI), y | P valuea |
|---|---|---|---|---|---|---|---|---|---|---|
| Liver adverse events | ||||||||||
| Any liver event | ||||||||||
| Female | 265 337 | 986 542 | 12 548 | 12.72 (12.50 to 12.94) | <.001 | 1 [Reference] | <.001 | 9.41 (9.39 to 9.42) | 0.05 (0.04 to 0.07) | <.001 |
| Male | 256 443 | 943 846 | 10 883 | 11.53 (11.31 to 11.75) | 0.91 (0.88 to 0.92) | 9.46 (9.45 to 9.47) | ||||
| Cirrhosis | ||||||||||
| Female | 265 492 | 987 177 | 12 516 | 12.68 (12.46 to 12.90) | <.001 | 1 [Reference] | <.001 | 9.41 (9.40 to 9.42) | 0.05 (0.04 to 0.07) | <.001 |
| Male | 256 720 | 944 779 | 10 909 | 11.55 (11.33 to 11.77) | 0.91 (0.89 to 0.93) | 9.46 (9.45 to 9.47) | ||||
| Hepatic decompensation | ||||||||||
| Female | 290 663 | 1 085 347 | 10 172 | 9.37 (9.19 to 9.56) | <.001 | 1 [Reference] | <.001 | 9.56 (9.55 to 9.57) | −0.04 (−0.05 to −0.03) | <.001 |
| Male | 286 799 | 1 050 649 | 10 929 | 10.40 (10.21 to 10.60) | 1.11 (1.08 to 1.14) | 9.52 (9.51 to 9.53) | ||||
| Hepatocellular carcinoma | ||||||||||
| Female | 303 667 | 1 138 012 | 828 | 0.73 (0.68 to 0.78) | <.001 | 1 [Reference] | <.001 | 9.96 (9.96 to 9.97) | −0.06 (−0.06 to −0.05) | <.001 |
| Male | 299 809 | 1 098 329 | 2068 | 1.88 (1.80 to 1.97) | 2.59 (2.39 to 2.80) | 9.91 (9.90 to 9.91) | ||||
| Nonliver adverse events | ||||||||||
| Cardiovascular disease | ||||||||||
| Female | 272 124 | 963 729 | 12 420 | 12.89 (12.66 to 13.12) | <.001 | 1 [Reference] | <.001 | 9.34 (9.33 to 9.35) | −0.25 (−0.27 to −0.04) | <.001 |
| Male | 265 196 | 910 389 | 16 286 | 17.89 (17.62 to 18.17) | 1.40 (1.37 to 1.43) | 9.08 (9.07 to 9.10) | ||||
| Chronic kidney disease | ||||||||||
| Female | 272 314 | 955 111 | 13 770 | 14.42 (14.18 to 14.66) | <.001 | 1 [Reference] | <.001 | 9.29 (9.28 to 9.31) | −0.10 (−0.12 to −0.09) | <.001 |
| Male | 266 074 | 908 301 | 15 086 | 16.61 (16.35 to 16.88) | 1.16 (1.13 to 1.18) | 9.19 (9.18 to 9.20) | ||||
| Overall nonliver cancer | ||||||||||
| Female | 277 066 | 1 021 598 | 8925 | 8.74 (8.56 to 8.92) | .98 | 1 [Reference] | .99 | 9.55 (9.54 to 9.56) | 0.01 (0.00 to 0.03) | .04 |
| Male | 275 249 | 1 001 053 | 8743 | 8.73 (8.55 to 8.92) | 1.00 (0.97 to 1.03) | 9.56 (9.55 to 9.57) | ||||
| Non–sex-specific cancerb | ||||||||||
| Female | 272 948 | 1 008 948 | 5107 | 5.06 (4.92 to 5.20) | <.001 | 1 [Reference] | <.001 | 9.73 (9.72 to 9.74) | −0.07 (−0.08 to −0.06) | <.001 |
| Male | 272 957 | 993 822 | 6634 | 6.68 (6.52 to 6.84) | 1.32 (1.27 to 1.37) | 9.66 (9.65 to 9.67) |
Abbreviations: HR, hazard ratio; RMST, restrict mean survival time.
P values were adjusted for multiple testing using the Bonferroni Correction.
Excludes sex-specific cancers, including breast, ovarian, cervical, uterine, prostate, testicular, and penile cancers.
Figure. Cumulative Incidence of Liver and Nonliver Adverse Events in Patients With Metabolic Dysfunction–Associated Steatotic Liver Disease by Sex.
The 10-year cumulative incidences in men and women were 9.9% vs 11.0% for cirrhosis, 8.3% vs 8.0% for hepatic decompensation, 1.7% vs 0.7% for hepatocellular carcinoma (HCC), 20.4% vs 14.9% for cardiovascular disease (CVD), 16.9% vs 14.9% for chronic kidney disease (CKD), and 7.7% vs 6.0% for non–sex-specific cancer. All P < .001, adjusted for multiple testing using the Bonferroni correction.
Women had a 9% higher risk of cirrhosis development vs men, and men had an 11% higher risk of hepatic decompensation and more than double the risk of HCC vs women (hazard ratio [HR], 2.59; 95% CI, 2.39-2.80; P < .001) (Table). Men also had a 40% higher risk of CVD (HR, 1.40; 95% CI, 1.37-1.43; P < .001), a 16% higher risk of CKD (HR, 1.16; 95% CI, 1.13-1.18; P < .001), and a 32% higher risk of non–sex-specific cancers (HR, 1.32; 95% CI, 1.27-1.37; P < .001) than women (Table). The RMST analysis at the 10-year follow-up showed that women had significantly shorter mean time to the development of cirrhosis, whereas men had significantly shorter mean time to hepatic decompensation, HCC, CVD, CKD and non–sex-specific cancers (Table).
Discussion
To our knowledge, this is the first and largest cohort study specifically designed to examine the association of sex with adverse clinical outcomes of MASLD. We found higher incidence and risk of cirrhosis in women, consistent with the observation that MASLD is the primary indication for liver transplantation among women in the US.3 As in prior studies reporting higher HCC risk in men with other chronic liver diseases vs women,4 our study found a significant association between male sex and increased HCC risk among patients with MASLD. In addition, we found higher risks of CVD and non–sex-specific nonliver cancers among male (vs female) patients with MASLD, expanding the existing knowledge of higher CVD and cancer risks for men vs women in the general population.5,6 Our study included only patients with private health insurance in the US, so additional studies are needed to examine the association of sex in patients without insurance or with only government-sponsored insurance and patients in other world regions. Our study provides robust evidence of significant sex differences in the risk of both liver and nonliver adverse events in patients with MASLD to support policies for sex-based preventive, monitoring, and therapeutic management strategies of MASLD.
eMethods.
eReferences
eFigure. Study flowchart
eTable. ICD-9/10-CM diagnosis codes and procedure codes
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods.
eReferences
eFigure. Study flowchart
eTable. ICD-9/10-CM diagnosis codes and procedure codes
Data Sharing Statement
