
==== Front
Saudi J Gastroenterol
Saudi J Gastroenterol
SJG
Saudi J Gastroenterol
Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association
1319-3767
1998-4049
Wolters Kluwer - Medknow India

38726916
SJG-30-252
10.4103/sjg.sjg_428_23
Original Article
The combined pioglitazone and topiramate therapy for management of pediatric patients with severe MASLD
Conroy Callen 1
Radulescu Aurelia 2
Attia Suzanna L. 3
Shelman Nathan 4
Lee James T. 5
Monticelli Roberto Galuppo 6
Hall Sara 7
Kohli Rohit 8
Softic Samir 39
1 University of Kentucky College of Medicine, Lexington, KY, USA
2 Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children’s Hospital, Lexington, KY, USA
3 Department of Pediatrics, Division of Pediatric Gastroenterology, University of Kentucky College of Medicine and Kentucky Children’s Hospital, Lexington, Kentucky, USA
4 Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
5 Abdominal and Emergency Radiology Divisions, Department of Radiology, University of Kentucky, Lexington, KY, USA
6 Department of Radiology-Division of Vascular and Interventional Radiology, University of Kentucky, Lexington, KY, USA
7 Department of Anesthesiology, University of Kentucky HealthCare, Lexington, KY, USA
8 Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California, USA
9 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
Address for correspondence: Dr. Samir Softic, Assistant Professor of Pediatrics, University of Kentucky, 900 South Limestone, Lexington, KY 40536, USA. E-mail: samir.softic@uky.edu
Jul-Aug 2024
10 5 2024
30 4 252259
23 12 2023
14 3 2024
14 3 2024
Copyright: © 2024 Saudi Journal of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults.

Methods:

Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy.

Results:

Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment.

Conclusion:

In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies.

Fatty liver
liver fibrosis
MASLD
obesity
pediatric
pioglitazone
topamax
==== Body
pmcINTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic hepatitis worldwide and is estimated to affect one in four individuals.[1] It can progress to metabolic dysfunction associated with steatohepatitis (MASH), a more severe form of the disease characterized by the development of liver inflammation and fibrosis. MASH, and to a lesser extent MASLD, are risk factors for the development of liver cirrhosis and hepatocellular carcinoma. Thus, MASH is an important cause of liver failure and all-cause mortality.[2] In adult patients, MASH is the number one reason for liver transplant in women and the second most common cause in men.[3]

MASLD does not spare even the youngest members of our society and it is the most common cause of chronic hepatitis in children.[4] While most children with MASLD have mild disease, pediatric patients with severe MASH have increased liver-related and all-cause mortality despite their young age.[5] Moreover, some children with severe MASH develop liver failure, necessitating liver transplantation.[6] This advanced form of pediatric MASH appears to be a more aggressive form of liver disease than that observed in adults; since it develops early in life, children have more liver fibrosis than BMI-matched adults[78], and their liver disease can progress relatively quickly.[7910] While advanced MASH is still a rare cause of liver transplant in pediatric patients, it is the fastest-growing indication for liver transplant in young adults 18-40 years of age.[11] Therefore, it is imperative to successfully treat adolescent patients with severe MASH to change the negative outcomes of this fast-expanding liver disease.

Several clinical trials have tested the efficacy of pharmacotherapy including vitamin E or metformin[12]; vitamin E and hydroxytyrosol[13]; docosahexaenoic acid, choline, and vitamin E[14]; vitamin E and vitamin C[15]; docosahexanoic acid and vitamin D[16]; vitamin D,[17] cysteamine bitartrate,[18] and losartan[19] to improve liver histology in children. While none of the therapies improved hepatic fibrosis, liver biopsies performed for these studies provide valuable information for future drug development and confirmed the severe phenotype of pediatric MASH.[20] Pioglitazone, an insulin sensitizer in thiazolidinedione drug class, is a peroxisome proliferator-activated receptor gamma agonist and has been shown to improve serum markers of liver injury and liver histology[2122] in adult patients with MASH. Some studies suggest that pioglitazone may even improve hepatic fibrosis.[2324] In spite of its perceived efficacy, pioglitazone is not widely used for management of adult patients with MASLD, likely due to its side effect profile. Pioglitazone has been linked with increased risk of weight gain, pedal edema, bone loss, bladder cancer, and precipitation of congestive heart failure.[25] Except for weight gain, these side effects are largely not pertinent to a pediatric patient. Indeed, pioglitazone has been tested in adolescents for the treatment of various conditions including polycystic ovarian syndrome,[26] autism,[27] and type 1 diabetes,[28] without encountering serious side effects. Moreover, pioglitazone has been successfully used in children as young as 5-12 years of age[29], and a case report documents its efficacious use in an infant.[30] Similar to pioglitazone, rosiglitazone, a drug in the same class, was found to be well-tolerated and an effective adjuvant to metformin therapy in children with type 2 diabetes.[31]

In light of these studies, we thought to use pioglitazone as a clinical intervention for the treatment of adolescents with advanced fatty liver disease, as defined by the presence of at least F2 liver fibrosis on liver biopsy. Topiramate was added to mitigate the known side effects, of weight gain, associated with pioglitazone use. In this report, we retrospectively reviewed the outcomes of seven patients who were started on this treatment regimen. We considered the response to the combined pioglitazone and topiramate therapy in terms of serum ALT and BMI percentiles as primary and secondary endpoints.

PATIENTS AND METHODS

This is a retrospective study reporting on a series of seven adolescents cared for at the Kentucky Children’s Hospital Pediatric Fatty Liver Clinic, a regional referral clinic serving a pediatric population with MASLD.[32] Children 10-18 years of age with obesity (BMI ≥95th % for age and sex) and severe MASLD, characterized by F2 or greater liver fibrosis, were studied. The subjects had stepwise escalating evaluation first with MR elastography (MRE) performed on Siemens 1.5T Aera and used Resoundant 2D GRE MR elastography scanner, SIMENS Healthineers, Cary, NC to assess liver fibrosis. The subjects with MRE of ≥2.7 kPa were considered to have significant ≥F2 liver fibrosis[33] and were offered a liver biopsy. Liver biopsy was graded by a single clinical pathologist who assigned NAFLD activity score (NAS) and quantified liver fibrosis based on a publication by Kleiner.[34] If a liver biopsy confirmed severe MASLD with ≥F2 liver fibrosis, the patients were considered to have met the inclusion criteria. The exclusion criteria included chronic hepatitis from other causes such as autoimmune hepatitis, vital hepatitis B and C, hemochromatosis, Wilson’s disease, or alpha 1 antitrypsin deficiency, which were screened for at the time of the first visit. The eligible patients were offered the combined pioglitazone and topiramate therapy based on the best clinical judgment. Pioglitazone was started at a dose of 15 mg taken by mouth once per day, and increased to 30 mg once daily after two weeks. Topiramate was initiated at 25 mg once daily and increased by 25 mg every two weeks until the target dose of 50 mg twice daily was reached. The subjects and their caregivers were instructed on potential side effects of pioglitazone and topiramate. The children started on topiramate had complete metabolic profile (CMP) performed at every visit, and urine pregnancy test was offered to female patients before starting the medication. The participants were instructed to drink 6-8 bottles of water per day while taking topiramate to mitigate the risk of kidney stones. The patients were projected to stay on the therapy for two years.

The patients were followed up every 2-3 months. At every visit, the patients were evaluated by a pediatric gastroenterologist, an obesity specialist certified by the American Board of Obesity Medicine, and a registered dietician. All patients received lifestyle interventions. Anthropometric data including body weight, height, BMI percentiles, waist circumference, mid-upper arm circumference, and InBody™ 570 Body Composition Analyzer, Cerritos, CA, were performed at each visit. Laboratory monitoring including CMP, gamma-glutamyl transferase (GGT), hemoglobin A1c and lipid profile was obtained when clinically indicated during the study.

Data collection was approved by the Institutional Review Board from the University of Kentucky College of Medicine. Approval date was 4/3/2022. Study data were collected and managed using Research Electronic Data Capture, REDCap™, Nashville, TN, hosted at the University of Kentucky. Statistical analysis was performed using Prism, GraphPad Software, Boston, MA. Significance was determined using a two-tailed, paired t-test with P < 0.05, considered statistically significant.

RESULTS

Anthropometric and laboratory measurements at the initial visit

We evaluated the effectiveness of the combined pioglitazone and topiramate therapy to improve liver enzymes in children with severe obesity and advanced MASLD. Seven subjects were started on the therapy. All subjects were of Caucasian ethnicity, and there were five boys and two girls [Supplemental Table 1]. Mean age of the participants was 12.4 ± 2.0 years, ranging from 10 to 15 years of age [Table 1]. All children had severe class II or class III obesity based on their BMI percentage of the 95th percentile, ranging from 124 to 213 percent. Mean weight of the participants was 105.7 ± 36.1 kg, waist circumference was 124.0 ± 16.9 cm and mid-upper arm circumference was 37.6 ± 7.3 cm, consistent with severe obesity in these children. Impedance InBody™ composition analyzer revealed mean percent body fat of 47.5 ± 5.2 and mean muscle mass of 68.0 ± 27.5 pounds.

Supplemental Table 1 Demographics

	Number	Percentage	
Gender			
 Female	2	28.6	
 Male	5	71.4	
Ethnicity			
 Caucasian	7	100	
 Black	0	0	
 Asian	0	0	
 Hispanic	0	0	

Table 1 Initial anthropometric data in children before treatment with pioglitazone and topiramate

Initial Anthropometric Data	
	
	Age	BMI % >95th	Weight	Waist Circ (cm)	Mid Arm Circ (cm)	Body Fat %	Muscle Mass (lb)	
Subject 1	10	139	72.6	104.0	29.0	48.8	42.6	
Subject 2	14	151	151.0	129.0	42.3	38.9	116.2	
Subject 3	10	146	73.9	112.5	34.5	47.5	46.3	
Subject 4	15	213	157.0	152.5	49.5	53.5	91.7	
Subject 5	14	155	113.0	128.4	37.4	52.7	66.4	
Subject 6	12	124	96.4	117.3	33	42.8	67.7	
Subject 7	12	130	75.9	NA	NA	48.4	44.8	
Mean	12.4	151	105.7	124.0	37.6	47.5	68.0	
St dev	2.0	29	36.1	16.9	7.3	5.2	27.5	
Age is reported in years. BMI% >95th represent body mass index (BMI) as a percentage of the 95th percentile according to sex- and age-specific growth charts published by the Centers for Disease Control and Prevention (CDC). Waist circumference (Waist Circ) was measured in centimeters (cm). Middle upper arm circumference (Mid Arm Circ) was measured in centimeters (cm). Body fat % as measured by InBodyTM. Muscle mass in pounds (lbs) was measured by InBodyTM

Next, we quantified serum markers of metabolic dysfunction. Mean serum ALT was 165 ± 80 U/L), and all children except one had ALT of over 100 U/L [Table 2]. Mean GGT was 49 ± 25 U/L in agreement with elevated ALT. Assessment of glucose metabolism revealed mean hemoglobin A1c of 6.0 ± 2.0%. Two children had A1c in the diabetic range, 7.3% and 9.0%, respectively. Mean blood glucose concentration was 109 ± 41 mg/dL. Serum lipid profile showed mean total cholesterol of 158 ± 56 mg/dL, triglycerides (TG) 147 ± 77 mg/dL, high-density lipoprotein (HDL) 34 ± 8 mg/dL, and low-density lipoprotein (LDL) 100 ± 47 mg/dL, documenting dyslipidemia in these children. In summary, our cohort consists of children with severe obesity and metabolic dysfunction characterized by elevated liver enzymes, mean Hgb A1c in prediabetic range and serum dyslipidemia characterized by high TGs and low HDL.

Table 2 Biochemical markers at first visit in seven children before treatment with pioglitazone and topiramate

Serum metabolic labs at first visit	
	
	ALT	GGT	HbA1c	Glucose	T Chol	TG	HDL	LDL	
Subject 1	198	28	5.6	76	149	129	43	100	
Subject 2	295	92	7.3	96	280	307	28	201	
Subject 3	101	68	5.3	86	107	110	23	62	
Subject 4	52	25	5.2	128	130	81	38	76	
Subject 5	211	59	9.0	195	135	183	33	65	
Subject 6	169	42	5.0	87	155	108	29	104	
Subject 7	126	28	4.9	96	152	110	45	92	
Mean	165	49	6.0	109	158	147	34	100	
St dev	80	25	2.0	41	56	77	8	47	
Alanine aminotransferase (ALT) is reported in units per liter (U/L). Gamma-glutamyltransferase (GGT) is measured in units per liter. HbA1c shows percent of glycosylated hemoglobin. Total cholesterol (T chol), triglycerides (TG), high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL) reported in milligrams per deciliter

Assessment of liver disease

All subjects had MRE as a non-invasive test for liver fibrosis. Mean elastography was 3.2 ± 0.4 kPa, ranging from 2.70 to 3.88 kPa [Table 3]. Liver biopsy showed mean steatosis of 2.9 ± 0.4, inflammation of 1.4 ± 0.5, and balloon degeneration of 1.3 ± 0.5. Combined, these three histological variables resulted in a composite NAS score of 5.6 ± 0.8, consistent with severe liver disease. Liver fibrosis was scored separately and ranged from F2 to F3 with mean score of 2.3 ± 0.5. Taken together, our subjects had severe MASLD characterized by mean ALT >100 U/L, elastography consistent with ≥F2 fibrosis and liver biopsy documenting mean NAS over 5.

Table 3 Quantitative assessment of disease based on liver biopsy

Assessment of liver disease	
	
ID	MR Elastography	Liver biopsy	
	
Steatosis	Inflammation	Ballooning	MAS	Fibrosis	
Subject 1	3.10	3	1	1	5	2	
Subject 2	3.10	3	1	1	5	2	
Subject 3	3.04	3	1	1	5	3	
Subject 4	3.00	3	2	1	6	2	
Subject 5	3.36	3	2	2	7	2	
Subject 6	3.88	2	1	2	5	3	
Subject 7	2.70	3	2	1	6	2	
Mean	3.2	2.9	1.4	1.3	5.6	2.3	
St dev	0.4	0.4	0.5	0.5	0.8	0.5	
Magnetic resonance elastography (MR elastography) is measured in kilopascals (kPa). Liver biopsies were graded by a single clinical pathologist. Steatosis was graded on a scale of 0-3, inflammation was graded on a scale of 0-3, ballooning was graded on a scale of 0-2. The MASLD Activity Score (MAS) is calculated using the sum of the steatosis, inflammation, and ballooning scores. Fibrosis staging was determined separately on a scale of F0-F4: F0 represents no fibrosis, F1 represents perisinusoidal or periportal fibrosis, F2 represents perisinusoidal and portal/periportal fibrosis, F3 represents bridging fibrosis, and F4 represents cirrhosis

Response to the combined pioglitazone and topiramate therapy

Following the diagnosis of severe MASLD, the children were treated with combined pioglitazone and topiramate therapy. Five children completed 12 months of treatment, and one child was on the medications for 24 months and another one for 6 months at the time of data collection. Compared to the mean pre-treatment ALT of 165 ± 80 U/L, mean post-treatment ALT decreased significantly to 89 ± 62 U/L [Figure 1a]. Over time, ALT improved in all children after 6 months of therapy [Figure 1b], except for subject number 6. Subjects 2, 4, and 6 were found to be non-compliant as their serum topiramate level was <1 ug/ml. All children were included in the study per intention to treat analysis.

Figure 1 ALT and BMI response to the combined therapy. (a) Serum ALT for all of the subjects at the beginning of the treatment as compared to the ALT value of all the subjects at the end of treatment. Bar graphs represent mean ± SD. Each symbol represents one patient. (b) The ALT values of each subject were collected and graphed at the beginning of therapy, 3 months, 6 months, 12 months, and 24 months into the therapy. (c) The weight of the subjects at the beginning of the treatment, compared to the weight at the end of the treatment. Bar graphs represent mean ± SD. Each symbol represents one patient. (d) The BMI % above the 95th percentile was calculated, according to sex and age-specific growth charts, and graphed at the beginning of therapy, 3 months, 6 months, 12 months, and 24 months into the therapy

Pioglitazone usually results in weight gain, so we assessed if the combined pioglitazone and topiramate therapy increased body weight. Indeed, all children had higher post-treatment (118 ± 29 kg) compared to pre-treatment (106 ± 36 kg) body weight [Figure 1c]. However, children are expected to grow and get taller, so when we compared the BMI percentage of the 95th percentile, it remained stable over the treatment period [Figure 1d]. Indeed, mean pre-treatment BMI % (151 ± 29%) of the 95th percentile was not different from post-treatment BMI % (152 ± 28%, P = 0.8) [Figure 2a]. Furthermore, there was no difference in waist circumference, mid upper arm circumference, percent body fat, or muscle mass before and after treatment [Figure 2b]. There was a trend (P = 0.13) toward reduced hemoglobin A1c after treatment compared to pre-treatment [Figure 2c], but this did not reach statistical significance, likely due to the small sample size. Similarly, there was no difference in lipid levels pre- and post-treatment [Figure 2d].

Figure 2 Treatment effects on anthropometric measures and serum markers of metabolic dysfunction. (a) The BMI % above the 95th percentile as calculated according to sex and age-specific growth parameters before and after the treatment. (b) Measurement of waist and mid upper arm circumference in centimeters, as well as InBody™ quantification of percent body fat and muscle mass in pounds before and after the treatment. (c) Hemoglobin A1c measured before and after the treatment (d) Serum lipid profile consisting of total cholesterol, LDL, HDL and TGs at the beginning and end of the treatment period. All bar graphs represent mean ± SD. Each symbol represents one patient

Subject number 3, completed the whole 24 months of therapy. His pre-treatment ALT was 105 U/L, and post-treatment ALT decreased to 14 U/L. Moreover, his pre-treatment FibroScan assessment of liver stiffness was 8.9 kPa, in agreement with MR elastography and liver biopsy showing F3 fibrosis. After 24 months of treatment, his FibroScan assessed liver stiffness as having decreased to 5.6 kPa [Supplemental Figure], but we did not perform a repeat liver biopsy. Given these marked improvements, we discontinued further pioglitazone and topiramate therapy.

DISCUSSION

In the present study, we have retrospectively evaluated the impact of the combined pioglitazone and topiramate treatment in seven pediatric patients with severe obesity and advanced MASLD. The combined therapy improved serum ALT over time, documenting a statistically significant decrease post-treatment compared to pre-treatment. One subject who completed 24 months of therapy showed improvement in hepatic fibrosis, as assessed by FibroScan™ elastography. The subjects did not experience any major adverse events during the therapy. The most common side effect reported was transient tingling of the arms, which was attributed to topiramate use. Importantly, the subjects did not experience an increase in BMI percentiles even though pioglitazone monotherapy is strongly associated with weight gain. Similarly, there was no change in waist circumference, mid-upper arm circumference, percent body fat, and muscle mass pre- and post-treatment. This study supports further evaluation of the combined pioglitazone and topiramate treatment for management of pediatric patients with severe fatty liver disease.

Our study suggests that the combined pioglitazone and topiramate therapy can effectively lower serum ALT without increasing BMI percentiles. The improvement in ALT is likely driven by pioglitazone arm of the therapy, as established in adult studies.[21222324] One subject who completed two years of combined therapy showed a decrease in liver elastography, consistent with an improvement in hepatic fibrosis. Interestingly, while the combined therapy reduced serum ALT, there was no statistically significant reduction in glycosylated hemoglobin A1c. This is likely due to limited sample size. No serious side effects were encountered with pioglitazone use, and the therapy was well-tolerated. Pediatric patients have different comorbidity profiles compared to adults. Thus, the worrisome side effect profile observed in adult studies may not be entirely pertinent to a pediatric patient. In agreement with our experience, clinical trials that have evaluated the efficacy of pioglitazone in children have not reported concerning side effects.[26272829] While pioglitazone has been studied in pediatric patients, there are no clinical trials that have evaluated its efficacy for the management of MASLD in children. Our study provides a proof of concept framework for future prospective, randomized, blinded studies to evaluate the combined pioglitazone and topiramate therapy for the management of severe MASLD in adolescents.

In adults, the age of the patient and type 2 diabetes are strong predictors of poor liver-related outcomes and increased mortality. In pediatrics, the severity of obesity appears to be a more important driver of MASLD development.[3536] Thus, any therapy designed to treat pediatric MASLD should be, at the minimum, weight neutral. In our case series, the combined pioglitazone and topiramate therapy did not increase BMI percentiles. Moreover, there was no difference in serum lipid levels before and after the treatment, which was in line with the no change in BMI percentiles. Lastly, there was no difference in waist circumference, mid-upper arm circumference, percent body fat and muscle mass pre- compared to post-treatment. This is likely due to topiramate arm of the therapy. Indeed, topiramate has been shown to decrease weight in adolescents with severe obesity[37] and in adult patients with type 2 diabetes,[38] by reducing food intake.[39] Moreover, topiramate combined with phentermine is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. Thus, combined therapy may provide the beneficial effects of pioglitazone to improve insulin sensitivity and the satiety effects of topiramate to maintain weight neutrality. However, any combination therapy has to consider drug-to-drug interactions. Fortuitously, the concomitant administration of pioglitazone and topiramate has been studied.[40] While no safety concerns were reported, the combined therapy may reduce antiepileptic properties of topiramate. This finding is of limited applicability for our intended use since none of our patients had epilepsy. Moreover, while topiramate may abrogate weight gain associated with pioglitazone, it comes with its own side effect profile. The possible side effects of topiramate include cognitive slowing, decreased sweating, renal tubular acidosis, kidney stones, paresthesia, and its teratogenic effects necessitate documenting negative pregnancy test in female patients. Besides transient paresthesia, our subjects have not reported any other side effects. However, twice daily dosing for topiramate may be too cumbersome for our patients. Indeed, three out of seven patients in our study had non-detectable topiramate levels, consistent with poor compliance. ALT improved in most patients in spite of non-compliance, since all patients received dietary and lifestyle counseling. The limitations of our study include a small sample size, a lack of a placebo control group, poor compliance, and the retrospective nature of the study. Most of these limitations can be overcome by conducting a larger, prospective, placebo-controlled trial.

While our combined therapy did not increase the markers of adiposity, it also did not result in weight loss. A new class of drugs called glucagon-like peptide 1 (GLP-1) agonist was recently FDA-approved for the management of pediatric obesity based on a meaningful reduction in body weight after 68 weeks of therapy.[41] Moreover, GLP-1 agonist was shown to improve NASH in adult patients.[42] However, GLP-1 agonists have not been shown to improve liver fibrosis, and may increase the risk of developing neoplasms.[42] Despite these limitations, GLP-1 agonists or a combination of GLP-1, gastric inhibitory polypeptide (GIP), and glucagon receptor agonists are likely to play a significant role in MASLD management in the future. Unfortunately, due to their high costs, these agents are not covered by most insurance policies and are out of reach for many of our patients. Thus, exploring the efficacy of readily available and inexpensive medications should be encouraged to manage this highly prevalent disease.

In summary, the combined pioglitazone and topiramate therapy may effectively reduce serum ALT without increasing BMI percentiles. Future prospective, placebo-controlled, randomized studies in pediatric patients with severe MASLD are needed to test if the combined therapy can successfully improve MASLD without aggravating weight gain.

Financial support and sponsorship

This work was supported, in part, by the COCVD Pilot and Feasibility Grant (GM127211) awarded to SS for his basic science work.[43]

Conflicts of interest

There are no conflicts of interest.

Supplemental Figure Fibroscan elastography before and after the treatment.

Acknowledgments

We are thankful to Mary Rinella, MD, for initial discussions regarding the use of pioglitazone in patients with NAFLD.
==== Refs
REFERENCES

1 Younossi ZM Koenig AB Abdelatif D Fazel Y Henry L Wymer M Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes Hepatology 2016 64 73 84 26707365
2 Ekstedt M Hagstrom H Nasr P Fredrikson M Stal P Kechagias S Hultcrantz R Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up Hepatology 2015 61 1547 54 25125077
3 Noureddin M Vipani A Bresee C Todo T Kim IK Alkhouri N NASH leading cause of liver transplant in women: Updated analysis of indications for liver transplant and ethnic and gender variances Am J Gastroenterol 2018 113 1649 59 29880964
4 Lavine JE Schwimmer JB Nonalcoholic fatty liver disease in the pediatric population Clin Liver Dis 2004 8 549 58 viii-ix 15331063
5 Feldstein AE Charatcharoenwitthaya P Treeprasertsuk S Benson JT Enders FB Angulo P The natural history of non-alcoholic fatty liver disease in children: A follow-up study for up to 20 years Gut 2009 58 1538 44 19625277
6 Alkhouri N Hanouneh IA Zein NN Lopez R Kelly D Eghtesad B Liver transplantation for nonalcoholic steatohepatitis in young patients Transpl Int 2016 29 418 24 26402655
7 Xanthakos SA Lavine JE Yates KP Schwimmer JB Molleston JP Rosenthal P Progression of fatty liver disease in children receiving standard of care lifestyle advice Gastroenterology 2020 159 1731 51.e10 32712103
8 Holterman AX Guzman G Fantuzzi G Wang H Aigner K Browne A Nonalcoholic fatty liver disease in severely obese adolescent and adult patients Obesity (Silver Spring) 2013 21 591 7 23592668
9 Kohli R Boyd T Lake K Dietrich K Nicholas L Balistreri WF Rapid progression of NASH in childhood J Pediatr Gastroenterol Nutr 2010 50 453 56 20179647
10 Molleston JP White F Teckman J Fitzgerald JF Obese children with steatohepatitis can develop cirrhosis in childhood Am J Gastroenterol 2002 97 2460 2 12358273
11 Doycheva I Issa D Watt KD Lopez R Rifai G Alkhouri N Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States J Clin Gastroenterol 2018 52 339 46 28961576
12 Lavine JE Schwimmer JB Van Natta ML Molleston JP Murray KF Rosenthal P Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: The TONIC randomized controlled trial JAMA 2011 305 1659 68 21521847
13 Nobili V Alisi A Mosca A Crudele A Zaffina S Denaro M The antioxidant effects of hydroxytyrosol and vitamin E on pediatric nonalcoholic fatty liver disease, in a clinical trial: A new treatment? Antioxid Redox Signal 2019 31 127 33 30588836
14 Zohrer E Alisi A Jahnel J Mosca A Della Corte C Crudele A Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: A randomized controlled clinical trial Appl Physiol Nutr Metab 2017 42 948 54 28511023
15 Nobili V Manco M Devito R Di Ciommo V Comparcola D Sartorelli MR Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: A randomized, controlled trial Hepatology 2008 48 119 28 18537181
16 Della Corte C Carpino G De Vito R De Stefanis C Alisi A Cianfarani S Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: Results from a single centre trial PLoS One 2016 11 e0168216 doi:10.1371/journal.pone.0168216 27977757
17 El Amrousy D Abdelhai D Shawky D Vitamin D and nonalcoholic fatty liver disease in children: A randomized controlled clinical trial Eur J Pediatr 2022 181 579 86 34459959
18 Schwimmer JB Lavine JE Wilson LA Neuschwander-Tetri BA Xanthakos SA Kohli R In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores Gastroenterology 2016 151 1141 54 e1149 27569726
19 Vos MB Van Natta ML Blondet NM Dasarathy S Fishbein M Hertel P Randomized placebo-controlled trial of losartan for pediatric nonalcoholic fatty liver disease Hepatology 2022 76 429 44 35133671
20 Softic S Kohli R Pediatric NASH therapies: A speedbump on the road to success Hepatology 2022 76 292 4 35000211
21 Belfort R Harrison SA Brown K Darland C Finch J Hardies J A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis N Engl J Med 2006 355 2297 307 17135584
22 Sanyal AJ Chalasani N Kowdley KV McCullough A Diehl AM Bass NM Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis N Engl J Med 2010 362 1675 85 20427778
23 Aithal GP Thomas JA Kaye PV Lawson A Ryder SD Spendlove I Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis Gastroenterology 2008 135 1176 84 18718471
24 Cusi K Orsak B Bril F Lomonaco R Hecht J Ortiz-Lopez C Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial Ann Intern Med 2016 165 305 15 27322798
25 Shah P Mudaliar S Pioglitazone: Side effect and safety profile Expert Opin Drug Saf 2010 9 347 54 20175701
26 Stabile G Borrielli I Artenisio AC Bruno LM Benvenga S Giunta L Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome J Pediatr Adolesc Gynecol 2014 27 177 82 24814528
27 Boris M Kaiser CC Goldblatt A Elice MW Edelson SM Adams JB Effect of pioglitazone treatment on behavioral symptoms in autistic children J Neuroinflammation 2007 4 3 17207275
28 Zdravkovic V Hamilton JK Daneman D Cummings EA Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes J Pediatr 2006 149 845 9 17137905
29 Capano L Dupuis A Brian J Mankad D Genore L Hastie Adams R A pilot dose finding study of pioglitazone in autistic children Mol Autism 2018 9 59 30498564
30 Migliavacca M Assanelli A Ferrua F Cicalese MP Biffi A Frittoli M Pioglitazone as a novel therapeutic approach in chronic granulomatous disease J Allergy Clin Immunol 2016 137 1913 5 e1912 27056268
31 Group TS Zeitler P Hirst K Pyle L Linder B Copeland K A clinical trial to maintain glycemic control in youth with type 2 diabetes N Engl J Med 2012 366 2247 56 22540912
32 Radulescu A Killian M Kang Q Yuan Q Softic S Dietary counseling aimed at reducing sugar intake yields the greatest improvement in management of weight and metabolic dysfunction in children with obesity Nutrients 2022 14 1500 doi:10.3390/nu14071500 35406113
33 Xanthakos SA Podberesky DJ Serai SD Miles L King EC Balistreri WF Use of magnetic resonance elastography to assess hepatic fibrosis in children with chronic liver disease J Pediatr 2014 164 186 8 24064151
34 Kleiner DE Brunt EM Van Natta M Behling C Contos MJ Cummings OW Design and validation of a histological scoring system for nonalcoholic fatty liver disease Hepatology 2005 41 1313 21 15915461
35 Radulescu A Dugan AJ Killian M Attia SL Mouzaki M Fuchs GJ Stratification by obesity class, rather than age, can identify a higher percent of children at risk for non-alcoholic fatty liver disease and metabolic dysfunction Pediatr Obes 2021 17 e12862 doi:10.1111/ijpo.12862 34662928
36 Huang SC Yang YJ Serum retinol-binding protein 4 is independently associated with pediatric NAFLD and fasting triglyceride level J Pediatr Gastroenterol Nutr 2013 56 145 50 22983378
37 Fox CK Marlatt KL Rudser KD Kelly AS Topiramate for weight reduction in adolescents with severe obesity Clin Pediatr (Phila) 2015 54 19 24 25027265
38 Moradi S Kerman SR Mollabashi M The effect of topiramate on weight loss in patients with type 2 diabetes J Res Med Sci 2013 18 297 302 24124426
39 Tremblay A Chaput JP Berube-Parent S Prud’homme D Leblanc C Almeras N The effect of topiramate on energy balance in obese men: A 6-month double-blind randomized placebo-controlled study with a 6-month open-label extension Eur J Clin Pharmacol 2007 63 123 34 17200837
40 Manitpisitkul P Curtin CR Shalayda K Wang SS Ford L Heald D Pharmacokinetic interactions between topiramate and pioglitazone and metformin Epilepsy Res 2014 108 1519 32 25219351
41 Weghuber D Barrett T Barrientos-Perez M Gies I Hesse D Jeppesen OK Kelly AS Mastrandrea LD Sorrig R Arslanian S Investigators ST: Once-Weekly Semaglutide in Adolescents with Obesity N Engl J Med 2022 387 2245 2257 36322838
42 Newsome PN Buchholtz K Cusi K Linder M Okanoue T Ratziu V Sanyal AJ Sejling AS Harrison SA Investigators NN: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis N Engl J Med 2021 384 1113 1124 33185364
43 Helsley RN Park SH Vekaria HJ Sullivan PG Conroy LR Sun RC Romero MDM Herrero L Bons J King CD Rose J Meyer JG Schilling B Kahn CR Softic S: Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation J Hepatol 2023 79 25 42 36822479
