Risk of complications in adulthood following childhood metabolic dysfunction-associated steatohepatitis based on Korean national health insurance data

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which can be complicated by metabolic dysfunction-associated steatohepatitis (MASH), is increasing worldwide. This study aimed to determine the risk of complications occurring in adulthood due to childhood MASH. This matched cohort study enrolled 12,894 children and adolescents aged between 7 and 18 years registered with the Korean National Health Insurance Service Database for the period 2002–2021. MASH was defined by the diagnostic code K75.8 before 19 years of age. The control group enrolled patients without MASH. The MASH and non-MASH population were matched 1:5. Among 12,894 MASH patients and 921,141 non-MASH patients, we analyzed the frequency of complications for 1–10 years, starting from 19 years of age, and medical costs, The MASH group had a higher hazard ratio of complications than the non-MASH group in adulthood, including liver fibrosis and cirrhosis, hypertensive disease, hyperlipidemia, diabetes, cancer, and mental illness. In addition, patients in the MASH group had higher medical costs than patients in the non-MASH group for other diseases, including for cerebrovascular and liver fibrosis. Children with MASH are at an increased risk of various complications in adulthood, inflicting a significant medical burden, necessitating more active management and intervention.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-97229-3.

Introduction

Recently, the prevalence of patients with metabolic dysfunction-associated fatty liver disease (MASLD) is increasing worldwide¹. Although MASLD was thought to be a major disease in adults, the number of children and adolescents with MASLD is also increasing². Furthermore, according to the Korean National Nutrition Survey, about 8% of pediatric patients and up to 34% of obese patients are expected to have MASLD^3–5. MASLD encompasses a broad range of liver pathologies, from simple fat accumulation in the liver to metabolic dysfunction-associated steatohepatitis (MASH) and liver cirrhosis^6,7. As MASLD does not remain asymptomatic, even cirrhosis can occur. Moreover, MASLD is closely related to other metabolic diseases; hence, efforts to identify and manage it are ongoing^8,9. MASLD can cause many complications such as diabetes mellitus, hyperlipidemia, and hypertension; therefore, it is important to identify and manage it as soon as possible^10–12. Moreover, MASLD is known to cause social problems, rather than just personal problems, as medical costs increase^13,14.

Complications from MASLD result in high medical costs, causing an inability to lead a proper social life as an adult due to complications that occurred in childhood^15,16. If MASLD occurs at a young age, it becomes difficult to live a normal social life as an adult due to the various complications that accompany it¹⁷. When MASLD occurs in women, it can cause polycystic ovary syndrome and affect reproductive health, causing gestational diabetes mellitus during pregnancy, which can lead to problems in the next generation. Additionally, MASLD continues even after menopause, and the longer a person has MASLD, the more complications may occur¹⁸. Men can also suffer from sexual dysfunction and infertility; hence, MASLD does not self-resolve but also causes problems in the next generation. Therefore, it is better to prevent complications before they occur rather than treat them after; however, this is not easy in many situations¹⁹.

For example, the intrauterine environment is an important cause of MASLD. Both small-for-gestational-age and large-for-gestation-age infants have a high probability of developing MASLD in childhood and adolescence²⁰. A child’s microbiome and breastfeeding status are also known to affect the development of MASLD²¹. MASLD can also occur due to genetic aberrations and a high intake of fructose or ultra-processed foods²². One prior study found that the number of patients with MASLD has increased worldwide due to coronavirus disease (COVID)-19²³. Although COVID-19 may have directly affected the liver, it may also have occurred due to the decrease in physical activity during the pandemic²⁴. Some studies have shown that the number of patients with MASLD increases with increased use of mobile devices, increased intake of westernized diets, and decreased activity levels²⁵. Consequently, due to this milieu, the number of children with MASLD and its accompanying complications is increasing.

MASH is associated with many risks and complications; however, it has received insufficient attention. When patients develop diseases such as diabetes, hypertension, cancer, and mental illness, which are commonly known, most people are afraid and worry about their future. However, regarding MASH, most parents indicate that the condition arises because children like to eat food or because they do not like to exercise²⁶. Furthermore, many parents think liver enzyme levels are a little high, showing a lack of awareness. This is because the diagnosis of MASH has only recently become known; hence, there is insufficient research to strongly counsel parents. Several studies have shown the importance of managing patients with MASLD and predicting complications; however, most studies distinguish between children and adults. Consequently, longitudinal observational studies of MASLD from childhood to adulthood are scarce. Moreover, patients with simple steatosis and normal liver enzymes in MASLD are rarely identified using disease codes. Hence, this study aimed to determine the risk of complications occurring in adulthood due to childhood MASH compared with a population without MASH.

Methods

Data source

In the present study, we extracted data from the National Health Insurance Service (NHIS) database of South Korea for analysis. The Korean NHIS database comprises information on a unique anonymous identification number for each patient, age, gender, diagnosic code according to the 10th revision of the International Classification of Diseases (ICD-10), and medical costs. Researchers can request access to a customized database for academic research purposes. Detailed information about the database can be accessed through the Health Insurance Data Service homepage (http://nhiss.nhis.or.kr). This retrospective study was approved by the Institutional Review Board of Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, South Korea (Approval No. CR322341), which waived the requirement for informed consent. All methods were conducted in accordance with the relevant guidelines and regulations.

Study population

We conducted a matched-cohort study using the Korean NHIS database among children aged under 19 years old between January 1, 2002, and December 31, 2016. Patients with MASH were defined as those with the diagnostic code “K75.8” once, and a total of 53,017 patients were identified. MASH patients who had the diagnostic code before age 7, born after 2002, or who died before the age of 19, were excluded. Additionally, to minimize the influence of congenital liver or bile duct diseases, we excluded all patients in both the MASH and control groups who had rare disease codes, as these conditions are systematically registered and managed under a designated coding system in Korea. As a result of these criteria, 40,123 cases were excluded, and 12,894 cases were finally analyzed.

The control group included individuals who were never diagnosed with MASH before turning 19 years old. To ensure comparability, we applied the same exclusion criteria as in the MASH group. Specifically, we excluded individuals who received a MASH diagnosis before the age of 7, were born after 2002, or died before turning 19. Additionally, to reduce the potential impact of congenital liver or bile duct diseases, we excluded individuals in both groups who had rare disease codes, as these conditions are systematically recorded and monitored under Korea’s designated coding system. After applying these criteria, the final control group included 921,141 individuals, matched 1:5 with the MASH group based on age and sex. While these individuals did not have MASH, they may have had other common medical conditions that were not systematically excluded. Our aim was to compare outcomes between those with and without MASH, rather than to establish a control group of entirely healthy individuals.

The complications were analyzed only from the age of 19 years or more, up to 10 years, due to the possibility of bias. Hence, the analysis was conducted from a minimum of 1 year to a maximum of 10 years, starting from the age of 19 years or older. The cases with complications that developed under the age of 19 years were excluded from both groups, and the final ratio of the MASH to non-MASH group was 1:5 (Table 1). To enhance clarity, we analyzed two subgroups of MASH patients: those with a single visit and those with two or more visits. This distinction aimed to differentiate between transient diagnoses and more persistent cases, as multiple visits suggest higher diagnostic certainty.

Table 1.

Basic characteristics of the enrolled population.

Variable	MASH with 1 visit	MASH with 2 visits	Non-MASH
	(n = 12,894)	(n = 5,729)	(n = 921,141)
Age at diagnosis of MASH, mean (SD), year	14.7 (2.8)	14.8 (2.7)
Sex, n (%) of patients
Male	8,304 (64.4)	3,924 (68.5)	577,341 (62.7)
Female	4,590 (35.6)	1,805 (31.5)	343,800 (37.3)

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation.

Outcomes

Each complication was compared only if it occurred at 19 years of age or more. Circulatory system disease was defined as the presence of either: ischemic heart disease (code I20-I25); cerebrovascular disease (I60-I69); disease of arteries, arterioles, and capillaries (I70-I79); or hypertensive disease (I10–I15). Metabolic disease was defined as either diabetes (E11-E14) or hyperlipidemia (E78.0-E78.5). Cancer was defined by the disease codes (C00–C97). Mental and behavioral disorders were defined as those with disease codes (F00–F99). Liver fibrosis and cirrhosis were defined as disease code (K74) (Fig. 1). An identical analysis was performed for the patients who visited the hospital more than twice for additional analysis. Moreover, the total medical costs were analyzed for the amounts incurred from the age of 19 years or more.

Fig. 1.

Flow chart of the study design. MASH metabolic dysfunction-associated steatohepatitis.

Covariates

Covariates included demographic characteristics, including age and sex. Data for children were limited; therefore, no additional covariates were used for analysis.

Statistical analysis

Categorical data are presented as numbers with corresponding percentages and subjected to comparison using either Pearson’s chi-squared tests or Fisher’s exact tests. For continuous data, represented as the mean (standard deviation), independent t-tests were used, depending on their distribution. Additionally, matching and analysis between MASH patients and a non-MASH population at a ratio of 1:5 based on age and sex was done. During this matching process, individuals with specific disease codes were excluded from the analysis. Cox proportional hazard regression analysis was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for each variable. All reported p-values were two-sided, and p-values < 0.05 were considered statistically significant. SAS system for Windows, version 9.4 (SAS Institute Inc., Cary, NC, USA), and R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses.

Results

Basic characteristics of the enrolled population

Table 1 describes the characteristics of the enrolled MASH and non-MASH populations. Patients with MASH (defined as those with a diagnostic code K75.8 once and without complications of the disease of interest) between the age of 7 and 18 years were assigned to the MASH with 1 visit group (n = 12,894), while an age- and sex-matched non-MASH (without MASH or complications of the disease of interest before the age of 19 years) group was selected as the control. Patients with MASH (with a diagnostic code K75.8 twice or more and without complications of the disease of interest) were assigned to the MASH with 2 visits group (n = 5,729). Further details regarding MASH patients with two visits are provided in Supplementary Tables S1–S5.

Risk of circulatory system disease

Table 2 describes the results of the analysis of 11,028 patients diagnosed with MASH and their subsequent risk of developing circulatory system disease at 19 years of age or more. The prevalence of hypertensive disease in patients with MASH was 6.9% (n = 791) compared with 2.7% (n = 1,506) in the non-MASH group (p < 0.0001). The risk of ischemic heart disease was 4.2% (n = 466), cerebrovascular disease was 2.1% (n = 233), and disease of vessels was 5.9% (n = 649), which were more common in the MASH group than in the non-MASH group (p < 0.0001). The highest medical cost was observed in patients with MASH complicated with cerebrovascular disease, at 40,759,320 KRW, compared with the non-MASH group at 9,942,587 KRW (p < 0.0001).

Table 2.

Risk of circulatory system disease in MASH patients with one visit.

Variable	MASH with one visit		p-value
	MASH	Non-MASH
	(n = 11,028)	(n = 55,140)
Age at diagnosis of MASH, mean (SD), year	14.7 (2.8)
Sex, n (%) of patients			1.000
Male	7,068 (64.1)	35,340 (64.1)
Female	3,960 (35.9)	19,800 (35.9)
Hypertensive disease, n (%) of patients	761 (6.9)	1,506 (2.7)	< 0.0001
Follow-up duration, mean (SD), days	1,265.2 (977.5)	1,428.8 (1052.4)	0.0004
Age at diagnosis, mean (SD), year	21.97 (2.7)	22.39 (2.9)	0.0008
Sex, n (%) of male patients	612 (80.4)	1178 (78.2)	0.2490
Total medical costs, mean (SD), KRW	13,797,332 (22,716,441)	9,578,355 (27,579,082)	< 0.0001
Ischemic Heart Disease, n (%) of patients	466 (4.2)	1428 (2.6)	< 0.0001
Follow-up duration, mean (SD), days	1,620.7 (1006.9)	1,535.6 (1007.9)	0.7811
Age at diagnosis, mean (SD), year	22.62 (2.7)	22.66 (2.7)	0.7500
Sex, n (%) of male patients	300 (64.4)	868 (60.8)	0.1659
Total medical costs, mean (SD), KRW	13,725,945 (24,500,677)	8,038,169 (10,970,546)	< 0.0001
Cerebrovascular disease, n (%) of patients	233 (2.1)	732 (1.3)	< 0.0001
Follow-up duration, mean (SD), days	1,543.8 (986.5)	1,585.5 (978.5)	0.8645
Age at diagnosis, mean (SD), year	22.7 (2.7)	22.82 (2.7)	0.5543
Sex, n (%) of male patients	136 (58.4)	456 (62.3)	0.2838
Total medical costs, mean (SD), KRW	40,759,320 (37,507,000)	9,942,578 (15,152,701)	< 0.0001
Diseases of arteries, arterioles and capillaries, n (%) of patients	649 (5.9)	2290 (4.2)	< 0.0001
Follow-up duration, mean (SD), days	1,429.2 (959.1)	1,556.3 (970.2)	0.0031
Age at diagnosis, mean (SD), year	22.39 (2.6)	22.74 (2.6)	0.0023
Sex, n (%) of male patients	357 (55.0)	1268 (55.4)	0.8694
Total medical costs, mean (SD), KRW	11,778,720 (18,917,795)	6,727,500 (8,617,834)	< 0.0001

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation, KRW Korean won.

Supplementary Table S1 presents an identical analysis for patients with two or more visits for MASH diagnosis. The risk of hypertensive disease increased to 9.1% (n = 428) and that of ischemic heart disease increased to 4.6% (n = 214) (p < 0.0001). The risks of cerebrovascular disease and diseases of the arteries, arterioles, and capillaries were 2.2% (n = 102) and 6.1% (n = 287), respectively (p < 0.0001).

Risk of diabetes mellitus and hyperlipidemia

The risk of diabetes and hyperlipidemia occurring at 19 years of age or more was compared and analyzed in the MASH (n = 6,046) and non-MASH (n = 30,230) groups (Table 3). The results revealed that diabetes mellitus occurred in 11.4% (n = 691) of patients with MASH compared with only 6.0% (n = 1, 808) of patients without MASH. Hyperlipidemia was confirmed in 27.6% (n = 1,670) of patients in the MASH group, compared with only 17.4% (n = 5,258) in the non-MASH group. The highest medical cost was 11,410,962 KRW in patients with MASH complicated by hyperlipidemia, compared with 7,461,632 KRW in the non-MASH group (p < 0.0001).

Table 3.

Risk of metabolic disease in MASH patients with one visit.

Variable	MASH with one visit		p-value
	MASH	Non-MASH
	(n = 6,046)	(n = 30,230)
Age at diagnosis of MASH, mean (SD), year	14.6 (2.9)
Sex, n (%) of patients			1.000
Male	3,810 (63.0)	19,050 (63.0)
Female	2,236 (37.0)	11,180 (37.0)
Diabetes, n (%) of patients	691 (11.4)	1,808 (6.0)	< 0.0001
Follow-up duration, mean (SD), days	1,544 (1034.8)	1,715.8 (1015.8)	0.0002
Age at diagnosis, mean (SD), year	22.71 (2.8)	23.19 (2.8)	0.0001
Sex, n (%) of male patients	428 (61.9)	1045 (57.8)	0.0598
Total medical costs, mean (SD), KRW	2,309,563 (22,413,106)	8,684,892 (19,615,597)	0.0002
Hyperlipidemia, n (%) of patients	1,670 (27.6)	5,258 (17.4)	< 0.0001
Follow-up duration, mean (SD), days	1,396.2 (1006.4)	1,606.7 (1004.2)	< 0.0001
Age at diagnosis, mean (SD), year	22.33 (2.7)	22.9 (2.7)	< 0.0001
Sex, n (%) of male patients	1,011 (60.5)	2,982 (56.7)	0.0059
Total medical costs, mean (SD), KRW	11,410,962 (22,066,592)	7,461,632 (15,205,626)	< 0.0001

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation, KRW Korean won.

Supplementary Table S2 presents an identical analysis for patients with diabetes and hyperlipidemia with two or more visits with a MASH diagnosis. The risk of diabetes increased to 14.6% (n = 319), while that of hyperlipidemia increased to 31.6% (n = 692), which was confirmed to have increased significantly compared with that for the one-visit cases (p < 0.0001). The total medical costs also increased to 12,605,741 KRW for hyperlipidemia in patients with MASH.

Risk of cancer

The risk of cancer at 19 years of age or more was compared between the MASH (n = 12,354) and non-MASH (n = 61,770) groups. In the MASH group, cancer developed in 3.4% (n = 418) of patients, whereas in the non-MASH group, it developed in 1.8% (n = 1,108). The total medical cost incurred was 21,590,656 KRW in patients with MASH compared with 11,566,836 KRW in the non-MASH population (p < 0.0001) (Table 4).

Table 4.

Risk of cancer in MASH patients with one visit.

Variable	MASH with one visit		p-value
	MASH	Non-MASH
	(n = 12,354)	(n = 61,770)
Age at diagnosis of MASH, mean (SD), year	14.7 (2.8)
Sex, n (%) of patients			1.000
Male	7,960 (64.4)	39,800 (64.4)
Female	4,394 (35.6)	21,970 (35.6)
Cancer, n (%) of patients	418 (3.4)	1,108 (1.8)	< 0.0001
Follow-up duration, mean (SD), days	1,430.2 (982.6)	1,663 (1,018.4)	0.0001
Age at diagnosis, mean (SD), year	22.43 (2.7)	23.03 (2.8)	< 0.0001
Sex, n (%) of male patients	219 (52.4)	434 (39.2)	< 0.0001
Total medical costs, mean (SD), KRW	21,590,656 (45,234,993)	11,566,836 (19,339,188)	< 0.0001

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation, KRW Korean won.

Supplementary Table 3 presents an identical analysis of cancer in patients with two or more visits with a MASH diagnosis. Cancer risk increased by 4.1% (n = 219). The total medical cost incurred when a patient with MASH developed cancer increased to 24,086,998 KRW compared with 11,097,681 KRW in the non-MASH group (p < 0.0001).

Risk of mental and behavioral disorders

The MASH and non-MASH groups were compared to determine the effect of MASH in children on mental and behavioral disorders when children were 19 years or older. Table 5 shows the risk of mental and behavioral disorders in the MASH (n = 8,256) and non-MASH (n = 41,280) groups. In the MASH group, 23.4% (n = 1,934) cases were confirmed to have mental and behavioral disorders, while in the non-MASH group, only 17.7% (n = 7,298) cases were confirmed. The total medical costs for complications of mental and behavioral disorders were 10,463,902 KRW in patients with MASH compared with 6,312,775 KRW in the non-MASH population (p < 0.0001).

Table 5.

Risk of mental and behavioral disease in MASH patients with one visit.

Variable	MASH with one visit		p-value
	MASH	Non-MASH
	(n = 8,256)	(n = 41,280)
Age at diagnosis of MASH, mean (SD), year	14.6 (2.8)
Sex, n (%) of patients			1.000
Male	5,402 (65.4)	27,010 (65.4)
Female	2,854 (34.6)	14,270 (34.6)
Mental and Behavioral Disorders, n (%) of patients	1,934 (23.4)	7,298 (17.7)	< 0.0001
Follow-up duration, mean (SD), days	1,298.5 (935.3)	1,354.6 (943.9)	0.0199
Age at diagnosis, mean (SD), year	22.06 (2.5)	22.21 (2.6)	0.0239
Sex, n (%) of male patients	1,099 (56.8)	4,129 (56.6)	0.8448
Total medical costs, mean (SD), KRW	10,463,902 (20,426,649)	6,312,775 (10,654,797)	< 0.0001

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation, KRW Korean won.

Supplementary Table S4 presents an identical analysis of mental and behavioral disorders in patients with two or more visits with a MASH diagnosis. The risk of mental and behavioral disorders was 22.5% (n = 790) in patients with MASH compared with 16.9% (n = 2,966) in the non-MASH group (p < 0.0001). Furthermore, the total medical costs increased to 12,391,754 KRW for mental and behavioral disorders in patients with MASH compared with 6,285,960 KRW in the non-MASH group (p < 0.0001).

Risk of liver fibrosis and cirrhosis with MASH

The risk of liver fibrosis and cirrhosis occurring at 19 years of age or more was compared and analyzed in the MASH (n = 12,780) and non-MASH (n = 63,900) groups (Table 6.). In the MASH group, 0.7% were confirmed to have liver disease, whereas in the non-MASH group, 0.15% were confirmed to have liver disease. The total medical costs for the complications of liver fibrosis and cirrhosis were 33,112,011 KRW in patients with MASH and 17,367,077 KRW in the non-MASH population.

Table 6.

Risk of liver fibrosis and cirrhosis in MASH patients with one visit.

Variable	MASH with one visit		p-value
	MASH	Non-MASH
	(n = 12,780)	(n = 63,900)
Age at diagnosis of MASH, mean (SD), year	14.7 (2.8)
Sex, n (%) of patients			1.000
Male	8,222 (64.3)	41,110 (64.3)
Female	4,558 (35.7)	22,790 (35.7)
Liver fibrosis and cirrhosis, n (%) of patients	90 (0.7)	95 (0.2)	< 0.0001
Follow-up duration, mean (SD), days	1,414.9 (1012.4)	1,489.7 (1029.3)	0.6191
Age at diagnosis, mean (SD), year	22.36 (2.7)	22.53 (2.8)	0.6759
Sex, n (%) of male patients	63 (70.0)	59 (62.1)	0.2574
Total medical costs, mean (SD), KRW	33,112,011 (67,614,469)	17,367,077 (37,136,771)	0.0496

MASH metabolic dysfunction-associated steatohepatitis, SD standard deviation, KRW Korean won.

Supplementary Table S5 presents an identical analysis for liver fibrosis and cirrhosis in patients with two or more visits with a diagnosis of MASH. The risk of liver fibrosis and cirrhosis was 1.12%. Furthermore, the total medical costs increased to 40,435,828 KRW for liver fibrosis and cirrhosis in patients with MASH compared with 15,267,357 KRW in those without (p < 0.0001).

Risk of various complications with MASH

Figure 2 shows the HRs for each disease in the MASH and non-MASH groups at 19 years of age or more. For all complications, the MASH group had a higher HR than the non-MASH group. Liver fibrosis and cirrhosis had the highest HR of 4.76 (95% CI: 3.57–6.36), hypertensive disease had an HR of 2.59 (95% CI: 2.38–2.83), hyperlipidemia had a HR of 1.73 (95% CI: 1.64–1.83), diabetes had an HR of 1.98 (95% CI: 1.81–2.16), cancer had an HR of 1.91 (95% CI: 1.71–2.14), and mental and behavioral disease had an HR of 1.40 (95% CI: 1.33–1.47).

Fig. 2.

Hazard ratio of complications in MASH and non-MASH population after 19 years old. (a). MASH with one visit, (b.) MASH with two visits. MASH, MASH metabolic dysfunction-associated steatohepatitis, CI confidential interval.

Furthermore, we found that the HR for all complications was higher in patients who visited twice rather than once with the diagnosis of MASH, with an HR of 5.93 (95% CI: 4.16–8.44) for liver fibrosis and cirrhosis, 3.17 (95% CI: 2.82–3.55) for hypertensive disease, 1.98 (95% CI: 1.83–2.15) for hyperlipidemia, 2.59 (95% CI: 2.29–2.93) for diabetes, and 2.19 (95% CI: 1.89–2.55) for cancer.

Figure 3 shows that the MASH with one-visit group had a higher risk of complications than the non-MASH group over the age of 19 years. Moreover, Fig. 4 shows that the difference between the two groups was steeper than that shown in Fig. 3 (p < 0.0001).

Fig. 3.

Kaplan–Meier curves for developing complications of MASH with one visit vs. the non-MASH population aged 19 years or older. (a). hypertensive disease; (b). ischemic heart disease; (c). cerebrovascular disease; (d.) diseases of arteries, arterioles and capillaries; (e.) diabetes; (f). hyperlipidemia; (g). cancer; (h). mental and behavior disorder; i. liver fibrosis and cirrhosis. MASH, metabolic dysfunction-associated steatohepatitis.

Fig. 4.

Kaplan–Meier curves for developing complications of MASH with two visits vs. the non-MASH population aged 19 years or older. (a). hypertensive disease; (b). ischemic heart disease; (c). cerebrovascular disease; (d). diseases of arteries, arterioles and capillaries; (e). diabetes; (f). hyperlipidemia; (g). cancer; (h). mental and behavior disorder; i. liver fibrosis and cirrhosis. MASH, metabolic dysfunction-associated steatohepatitis.

Discussion

As various factors, such as the environment and food intake, have changed over the years, the number of patients with MASH has also increased, resulting in an increase in MASH complications requiring management²⁷ With time, an increasing number of children are being diagnosed with MASH, consequently resulting in an increase in the incidence of complications. Zhang et al. found that the incidence of MASLD and MASH among children, adolescents, and young adults has increased to 29.49 million globally². A similar MASLD prevalence was reported among Korean children and adolescents between 2010 and 2015³.

Cardiovascular disease, type 2 diabetes mellitus, sleep disorders, and osteoporosis have all been suggested as complications arising in children with MASLD^28,29. Teng et al. previously reported that the global prevalence of adult MASLD is 32%.³⁰ The resulting complications include chronic kidney disease, cancer, psychological dysfunction, gastroesophageal reflux, and obstructive sleep apnea syndrome³¹.

Simon et al. reported that biopsy-proven MASLD in 718 children and young adults was associated with increased long-term mortality compared with healthy controls, with an HR of 5.88³². Similarly, in the present study, we found an increased HR of cancer and cardiovascular disease when MASH occurred at a young age.

Several studies have described the longitudinal disease course in children³³. Hassan et al. reviewed 18 cases of children with MASLD for 2.3 years, and Kuntz et al. showed the disease course of 58 children for 1.8 years^34,35. However, despite this high and increasing prevalence and its dangerous complications, there have been no large-scale studies describing the disease course of childhood MASH in adults.

Although this study did not attempt to determine the exact incidence, the number of children and adolescents diagnosed with MASH is increasing. These patients have not only increased in number, but have also developed various complications in those aged 19 years and above. In this study, we found that MASH in childhood has an HR of 2.59 for hypertension and an HR of 1.98 for diabetes mellitus. Moreover, we also found that cancer and mental and behavioral disorders have high HRs of 1.91 and 1.40, respectively. Although the number of patients was small, those diagnosed with liver fibrosis or cirrhosis had a high HR of 4.76. Additional analysis by defining patients with MASH as those with two MASH disease codes showed that the HR for hypertension increased to 3.17, for diabetes mellitus to 2.59, for cancer to 2.19, and for liver fibrosis and cirrhosis to 5.93.

Multiple MASH disease codes could mean that the MASH diagnosis was more certain or that patients visited the hospital due to a lack of MASH control. Depending on the doctor’s treatment approach, some cases may be diagnosed after only one visit; however, in most cases, patients require two or more visits, and need treatment until MASH improves. Considering this situation, our results showed that patients with definite childhood MASH are at a high risk of complications at over the age of 19 years. In addition, not only complications, but also medical costs incurred due to MASH are higher than those in patients without MASH. Moreover, for patients who visited more than twice, medical expenses nearly doubled compared to that of patients who visited the facility once. In some cases, such as those in this study, patients may have MASH without complications until adulthood. However, we found that even in such cases, many complications may occur when the patient becomes an adult. Therefore, patients and caregivers should actively manage MASH even if patients do not have other complications at a young age. We found that MASH not only results in more disease complications, but also increases medical costs, thus raising the burden on patients and the government.

This study has several limitations that should be mentioned. First, MASH diagnosis was based on ICD coding alone, which may result in misclassification. Owing to database constraints, histopathological confirmation via liver biopsy or FibroScan was not available. In the International Classification of Diseases 10th Revision, “K75.8” is classified as another specified inflammatory liver disease and MASH; hence, there is a possibility that other diagnoses such as hepatitis may be used instead of MASH. Moreover, in some cases, the diagnosis is included owing to insurance issues; therefore, caution may be needed while interpreting the results. Additionally, disease incidence may have been underestimated because of poor evaluation, which could have led to more severe complications than currently predicted. Second, because the HR for complications increases more when the MASH diagnostic code is set at two visits compared with one, the HR may be higher if there are more visits. Consequently, the HR may even be higher than currently presented; hence, the HR may have been underestimated. Third, there is no guarantee that the biopsy was proven directly in the patient, and because MASH was confirmed and complications were identified based only on the diagnosis, the risk mentioned may not be accurate. Fourth, the number of patients with liver fibrosis and cirrhosis was small. This may have occurred because, rather than filling in the diagnostic code for fibrosis and cirrhosis, additional complications were often included due to insurance issues. Fifth, diabetes and hypertension are diseases that can be more easily diagnosed if patients visit hospitals frequently. Therefore, the HR may be higher than that of ischemic heart disease or cerebrovascular disease. Sixth, another limitation is the predominance of male patients in our dataset. While this may reflect real-world epidemiological trends, potential selection bias cannot be ruled out. To overcome these limitations, future studies should not rely solely on ICD codes for MASH diagnosis and complication identification. Instead, incorporating clinical and imaging data, such as liver biopsy, FibroScan, and MRI-based liver fat quantification, is necessary to enhance diagnostic accuracy and ensure more precise risk assessments. However, despite these limitations, this is a highly valuable study because, to the best of our knowledge, it is the first to longitudinally observe children with MASH using large-scale data to determine the complications and medical costs that occur in adulthood.

Conclusions

In children with MASH, the risk of developing various complications is higher when they turn 19 years of age or older, compared with the non-MASH population. This suggests the need for more active management of MASH in children. Hence, the government and society may need to implement policies to increase awareness of the risks of childhood MASH and to intervene and manage it more actively.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

Yunkoo Kang and Hong Koh conceptualized the study and drafted the manuscript. Yeonjae Park performed the data analysis. All authors reviewed and approved the manuscript.

Data availability

The datasets generated and analyzed during the current study are not publicly available because they are only accessible through designated computers for analysis using specific statistical programs. However, the results derived from the analysis are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.