Tirzepatide use in adolescents with metabolic dysfunction‐associated steatotic liver disease (MASLD): A case series

Abstract

Pediatric obesity and metabolic dysfunction‐associated steatotic liver disease (MASLD) prevalence has risen markedly over the past decade. Due to transition delays and workforce shortages, pediatric specialists often manage patients into young adulthood, and thus familiarity with adult pharmacotherapies for MASLD is essential. Currently, Semaglutide, a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, is approved for adults with metabolic dysfunction‐associated steatohepatitis (MASH) and F2–F3 fibrosis; however, dual and triple agonists are being evaluated. Tirzepatide, a dual agonist that targets gastric inhibitory peptide (GIP) and the GLP‐1 receptor, has demonstrated superior weight reduction to Semaglutide (−20.2% vs. −13.7%) with a more favorable gastrointestinal adverse effect profile. Adult literature has demonstrated its effectiveness in MASH resolution, and pediatric data suggest it is safe in younger populations. Currently, there are no pediatric/adolescent studies exploring the use of Tirzepatide in MASLD. We present our experience using Tirzepatide in two adolescent patients with obesity and MASLD.

What is Known

• Metabolic dysfunction‐associated steatotic liver disease (MASLD) prevalence is rising, and pediatric providers are managing more patients as they transition into adulthood.

• Tirzepatide, a dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist, has demonstrated superior weight reduction compared with semaglutide, efficacy in achieving metabolic dysfunction‐associated steatohepatitis (MASH) resolution without fibrosis progression in adults, and a favorable safety profile in pediatric populations.

What is New

• This is the first case series describing Tirzepatide use in the management of MASLD in adolescent patients with obesity.

• Patients treated with Tirzepatide had improvement in anthropometric, biochemical, and radiological outcomes in MASLD.

1. INTRODUCTION

Over the past decade, the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) in pediatric patients has risen in parallel with the rise in obesity in the United States and globally. ¹ , ² The highest prevalence is reported in late adolescents and young adults, estimated at 25.5% in late adolescents/early young adults and 30.4% in older young adults. ³ In these groups, the prevalence of metabolic dysfunction‐associated steatohepatitis (MASH)‐related fibrosis is estimated to be 6.2% and 11.8%, respectively. ³ Despite the growing disease burden, there are currently no U.S. Food and Drug Administration (FDA)‐approved pharmacologic treatments for MASLD in pediatric patients. ⁴

Lifestyle intervention remains the foundation of therapy; however, achieving and maintaining effective change is challenging in clinical practice. A 10% weight reduction gives the highest rates of MASH resolution and fibrosis regression, supporting the use of therapeutic adjuncts to help attain these desired outcomes. ⁵ , ⁶ Given the efficacy of medications like the glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in weight reduction and MASH, dual agonists that target the gastric inhibitory peptide (GIP) and GLP‐1 receptor, such as Tirzepatide, have garnered interest given their ability to target additional metabolic pathways that enhance the impact of GLP‐1 receptor agonism. ⁷ , ⁸ GIP acts centrally to influence dietary intake and modulates postprandial lipid and glucose metabolism via effects on white adipose tissue. ⁷ Tirzepatide is FDA‐approved for chronic weight management as an adjunct to lifestyle modification in patients at least 18 years of age with moderate to severe sleep apnea and obesity, with obesity alone, or who are overweight with at least one comorbidity present (trade name Zepbound) or for glycemic control in adults and pediatric patients 10 years of age and older with Type 2 diabetes mellitus (trade name Mounjaro). ⁹ , ¹⁰ Current pediatric and adult literature note that Tirzepatide has demonstrated safety in pediatric patients with Type 2 diabetes, efficacy for MASH resolution in adults, and superior weight loss compared to Semaglutide in adults with obesity. ¹¹ , ¹² , ¹³ Furthermore, Tirzepatide has been associated with a more favorable adverse effect profile, with fewer patients discontinuing treatment because of gastrointestinal (GI) side effects compared with Semaglutide. ¹¹

Currently, there are no pediatric studies exploring the use of Tirzepatide in MASLD. Given limited data on Tirzepatide use for MASLD in younger cohorts, we present a case series of two 18‐year‐old adolescents with obesity and MASLD treated with Tirzepatide.

2. CASE 1

An 18‐year‐old female with a complex past medical history including developmental delay, left‐sided hemifacial microsomia, bilateral sensorineural hearing loss, caudal regression syndrome, PNPLA3 gene positivity, and obesity presented for evaluation of chronically elevated and increasing liver enzymes over 2 years. MASLD was diagnosed based on multiple cardiometabolic risk factors, including obesity (body mass index [BMI] 34.9 kg/m², 115% of 95th percentile), hypertriglyceridemia, and low high‐density lipoprotein (HDL), with hepatic steatosis found on ultrasound and proton density fat fraction (PDFF) of 31.5% (severe steatosis, S3) on magnetic resonance elastography (MRE) with normal hepatic stiffness. Liver biopsy was offered to further characterize disease severity but was declined by the family. Her evaluation was otherwise negative for other chronic liver diseases.

Initial management in our multidisciplinary MASLD clinic (physician, registered dietitian, physical activity specialist) emphasized lifestyle interventions. However, sustained changes were difficult to maintain, with BMI increasing to 35.71 kg/m² and persistent alanine aminotransferase (ALT) elevation (102 U/L). Tirzepatide (Zepbound) was prescribed for the indication of weight management in light or continued weight gain and progressive elevation of aminotransferases. Her initial dose was 2.5 mg subcutaneously weekly and after 2 months was titrated up to 5 mg weekly. She tolerated the medication well without adverse events, and parents reported markedly reduced appetite. Given adequate response, no further titration was required.

Thirteen months after initiation of Tirzepatide in conjunction with lifestyle modification, repeat MRE noted improvement of steatosis with PDFF decrease to 12% (absolute change of −19.5%) and continued normal stiffness (Figure 1). At 15 months, total body weight (TBW) decreased by 14% (−9.8 kg), BMI decreased by 13% (−4.67 kg/m²), and BMI z score improved by 19% (−0.37). Her ALT decreased by 71% (−72 U/L), and gamma‐glutamyl transferase (GGT) improved by 67% (−24 U/L), with normalized triglycerides and HDL. A summary of anthropometric, biochemical, and radiological outcomes is included in Table 1.

Figure 1.

MRE data in Case 1. After 13 months of Tirzepatide therapy, repeat MRE noted improvement of steatosis with PDFF decrease from 31.5% to 12% (absolute change of −19.5%) and continued normal LS. LS, liver stiffness; MRE, magnetic resonance elastography; PDFF, proton density fat fraction.

Table 1.

Anthropometric, biochemical, and radiological outcomes with tirzepatide adjunctive therapy.

	Case 1				Case 2
	Baseline	After 13–15 months	Absolute difference	Percent change	Baseline	After 3 months	Absolute difference	Percent change
Anthropometric outcomes
Weight (kg)	70.9	61.1	−9.8	−14%	97.4	90.3	−7.1	−7%
BMI (kg/m2)	35.71	31.04	−4.67	−13%	34.47	31.88	−2.59	−8%
BMI z score	1.98	1.61	−0.37	−19%	2.02	1.80	−0.22	−11%
BMI percentile	98	95	−3	−3%	97.81	96.38	−1.43	−1%
Biochemical outcomes
ALT (IU/L)	102	30	−72	−71%	135	79	−56	−41%
AST (IU/L)	59	27	−32	−54%	49	37	−12	−24%
GGT (IU/L)	36	12	−24	−67%	39	30	−9	−23%
Fasting serum glucose (mg/dL)	92	84	−8	−9%	107	98	−9	−8%
Hemoglobin A1c (%)	5.2	4.7	−0.5	−10%	5.6	5.2	−0.4	−7%
Triglycerides (mg/dL)	164	97	−67	−41%	67	70	3	4%
Total cholesterol (mg/dL)	172	142	−30	−17%	163	158	−5	−3%
HDL‐cholesterol (mg/dL)	36	40	4	11%	34	42	8	24%
LDL‐cholesterol (mg/dL)	103	83	−20	−19%	116	102	−14	−12%
Imaging outcomes
MR elastography
PDFF (%)	31.50%	12%	−19.50	−62%	—	—	—	—
Stiffness (kPa)	2.3	2.5	0.2	9%	—	—	—	—
VCTE (FibroScan)
CAP (dB/m)	—	—	—	—	274	267	−7	−3%
LSM (kPa)	—	—	—	—	8.8	4.7	−4.1	−47%

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; GGT, gamma‐glutamyl transferase; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; LSM, liver stiffness measurement; MR, magnetic resonance; PDFF, proton density fat fraction; VCTE, vibration controlled transient elastography.

3. CASE 2

An 18‐year‐old male with a past medical history of obesity presented with 6 years of chronically elevated liver enzymes. MASLD diagnosis was based on hepatic steatosis seen on ultrasound and multiple cardiometabolic risk factors, including obesity (BMI 33.63 kg/m², 119% of 95th percentile), insulin resistance, and low HDL.

Lifestyle intervention in a multidisciplinary clinic yielded an initial weight loss over 6 months; however, this was followed by weight regain. MRE and liver biopsy were recommended but declined; therefore, serial vibration‐controlled transient elastography (VCTE), FibroScan® (Echosens), was used. Following weight regain, liver enzymes increased, and VCTE parameters worsened—controlled attenuation parameter (CAP) 274 dB/m and liver stiffness measurement (LSM) 8.8 kPa. Tirzepatide was introduced as an adjunct, started at 2.5 mg weekly, increased to 5 mg after 1 month, and then maintained at 7.5 mg weekly. Clinically, he reported decreased hunger and noted he was eating smaller portion sizes. He reported only mild, self‐limited nausea on injection days.

After 3 months, TBW decreased by 7% (−7.1 kg), BMI decreased by 8% (−2.59 kg/m²), and BMI z score improved by 11% (−0.22). His ALT decreased by 41% (−56 U/L), and GGT improved by 23% (−9 U/L), with normalized HDL and low‐density lipoprotein. VCTE parameters improved with CAP decrease of 3% (−7 dB/m) and LSM decrease of 47% (−4.1 kPa). Both cases are summarized in Table 1.

4. DISCUSSION

Both cases demonstrate utilization of Tirzepatide in adolescent patients with good tolerability and favorable response. Notably, at the time treatment was initiated, Semaglutide had not yet received FDA approval for the treatment of MASH with advanced fibrosis in adults; this approval was granted only in August 2025. ¹⁴ Given ongoing disease progression despite lifestyle intervention, Tirzepatide was selected as an adjunct due to its superior weight reduction compared to Semaglutide, demonstrated efficacy in adults with MASH, and favorable adverse effect profile. ¹¹ , ¹² , ¹³ Both patients were at least 18 years of age and had not been treated with anti‐obesity medication previously.

In these cases, Tirzepatide was associated with improvements in MASLD‐related markers and cardiometabolic parameters. Reductions in ALT and GGT exceeded 40% and 20%, respectively, which are thresholds that have been associated with histological improvement in steatohepatitis in prior studies. ⁴ , ¹⁵ Additionally, our patient in Case 1 had an absolute MRE PDFF improvement of 19.5%, which is clinically significant given that natural variability is approximately within ±6%. ¹⁶ This patient was also PNPLA3‐positive, a genotype associated with more severe disease in pediatric populations and potentially greater responsiveness to weight‐reducing therapies. ¹⁷ This genetic predisposition likely contributed to her baseline status and possibly played a role in her response. In Case 2, improvements were noted in FibroScan parameters, including a substantial LSM reduction; however, this finding should be interpreted with caution. VCTE in adolescents can be variable and influenced by BMI, inflammation, and technique, and such changes may not reflect true histologic improvement.

These cases highlight an important gap in adolescent MASLD management. As noted by the American Association for the Study of Liver Disease (AASLD), pediatric gastroenterologists and hepatologists are caring for adolescents transitioning into adulthood, specifically those who are 18 years of age up to 22 years. ⁴ In the setting of a significant adult hepatology workforce shortage in the United States and barriers to transition of care, pediatric specialists need to bridge care and should be familiar with adult‐based treatment options for MASLD, as there are no FDA‐approved medications for MASLD in pediatrics. ⁴ , ¹⁸ , ¹⁹ In contrast, in adults with MASH and F2–F3 fibrosis, Semaglutide (GLP‐1 RA) and Resmetirom (thyroid hormone receptor‐β agonist) are the only pharmacological options that currently have FDA approval. ¹⁴ , ²⁰ Despite the FDA approval of GLP‐1RAs, approximately 20% of patients do not achieve ≥5% TBW reduction, and almost 50% of patients discontinue the medication by 1 year. ²¹ Given this, Tirzepatide may be considered a potential second‐line agent, particularly given its superior weight loss efficacy, emerging evidence in MASH, and favorable tolerability profile. ¹¹ , ¹² , ¹³ Additionally, it may be a reasonable option in patients with baseline GI symptoms, where tolerability may influence medication adherence. ¹¹

Tirzepatide, a dual GIP/GLP‐1 agonist, has had growing evidence supporting its use in obesity, diabetes, and MASLD. ¹¹ , ¹² , ¹³ In the SURMOUNT‐5 Phase 3b, multicenter, randomized controlled trial, Tirzepatide was superior to Semaglutide in TBW reduction from baseline after 72 weeks in adults with obesity (−20.2% vs. −13.7%). ¹¹ This trial noted that GI‐related treatment discontinuation was half as common in the Tirzepatide group (2.7%) versus 5.6% in the Semaglutide group. Furthermore, those treated with Tirzepatide had less vomiting and reflux. ¹¹ Post hoc analysis of SURMOUNT‐1 also suggests Tirzepatide reduces 10‐year predicted cardiovascular disease and Type 2 diabetes risk in adults with obesity and prediabetes. ²² Tirzepatide has also demonstrated efficacy in MASH: In the SYNERGY‐NASH Phase 2, double‐blind clinical trial of adults (mean age 54.4 years) with biopsy‐confirmed MASH and moderate or severe fibrosis 52 weeks of Tirzepatide let to significantly higher rates of MASH resolution without worsening of fibrosis at all doses (5, 10, and 15 mg: 44%, 56%, and 65%) than placebo (10%; p < 0.001 for all). ¹² Lastly, it has been deemed safe and efficacious in BMI reduction in children and adolescents with Type 2 diabetes in the SURPASS‐PEDS clinical trial. ¹³ Improvement in ALT was noted in this trial; however, patients did not have a confirmed diagnosis of MASLD at the time of treatment. ¹³

Tirzepatide is FDA‐approved for chronic weight management as an adjunct to lifestyle modification in patients at least 18 years of age and for glycemic control in patients at least 10 years of age with Type 2 diabetes mellitus (Zepbound and Mounjaro, respectively). ⁹ , ¹⁰ Recommended dosing starts at 2.5 mg subcutaneously weekly for at least 4 weeks, with 2.5 mg increments after at least 4 weeks on a given dose; maximum 15 mg. Maintenance doses of 5, 10, or 15 mg may be used based on response and tolerability. ⁶ Adverse effects that may be reported include nausea, vomiting, poor appetite, dyspepsia, constipation, diarrhea, and hypoglycemia. ⁵ Contraindications for use include history of medullary thyroid cancer or multiple endocrine neoplasia Type 2, or reactions of anaphylaxis/angioedema to Tirzepatide in the patient or family members. ⁶ From a practical standpoint, medication access may be a barrier for many adolescents as this therapy carries substantial financial burden and often requires prior authorization for insurance coverage.

This report has several limitations. Most notably, the absence of liver biopsy precludes diagnosis of definitive diagnosis of MASH, fibrosis staging, and confirmation of histologic response. Additionally, the small sample size and limited follow‐up duration restrict generalizability. Larger cohorts involving a broader age range and longer‐term outcomes of at least 12 months follow‐up in adolescents and young adults are needed to assess efficacy, safety, and durability or response. Although liver biopsy may be useful to correlate noninvasive markers with histology, feasibility may be difficult due to its invasive nature.

5. CONCLUSION

Given the increasing MASLD burden and persistent gaps in transition‐of‐care, pediatric specialists should be familiar with adult pharmacologic therapies. While lifestyle intervention remains the cornerstone of MASLD management, these cases highlight the potential role of GIP/GLP‐1 dual agonists as adjunctive therapy in adolescents/young adults with MASLD and obesity. Tirzepatide appears to be well tolerated in this population and may offer meaningful clinical benefit. In the setting of limited pediatric data, shared clinical experience can help inform practice and pave the way for larger trials to further explore its use.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The parents and patients in Case 1 and Case 2 provided informed consent for inclusion in this publication.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in the table provided in this article. If further information is needed, it can be provided upon request.