The Endocrine–Gut–Liver Axis in Childhood: Clinical Spectrum, Mechanistic Pathways, and Therapeutic Implications

 Corresponding author: Ashraf T. Soliman Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. The Endocrine–Gut–Liver Axis in Childhood: Clinical Spectrum, Mechanistic Pathways, and Therapeutic Implications Ashraf T. Soliman 1, *, Ashraf Adel 2, Fawzia Alyafei 1, Nada Alaaraj 1, Noor Hamed 1, Shayma Ahmed 1, Mohamed Qusad 1, Manasik Hassan 1, Hibaq Jama 1 and Ahmed Khalil 3 1 Department of Paediatrics, Hamad General Hospital, Doha, Qatar. 2 Department of Paediatrics, Sidra Medicine, Doha, Qatar. 3 Department of Pharmacology, Hamad General Hospital, Doha, Qatar. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 Publication history: Received on 04 October 2025; revised on 11 November 2025; accepted on 14 November 2025 Article DOI: https://doi.org/10.30574/gscarr.2025.25.2.0349 Abstract Background: Gastrointestinal (GI) and hepatic manifestations are increasingly recognized as important clinical components of pediatric endocrine disorders. Because endocrine hormones directly influence gut motility, nutrient absorption, hepatic lipid oxidation, glycogen metabolism, and inflammatory pathways, children may present with GI or hepatic abnormalities before classical endocrine symptoms emerge. Understanding these associations is essential for early diagnosis and targeted management. Methods: This narrative review synthesized evidence published between 2000 and 2025 from PubMed, Scopus, Web of Science, and major society guidelines. Studies describing GI or hepatic manifestations in children with endocrine disorders were included and appraised using Cochrane risk-of-bias tools (ROB 2 and ROBINS-I). A total of 59 validated, non-duplicated references informed the analysis. GI and hepatic manifestations were categorized as acute or chronic based on pathophysiology and duration. Results: Across endocrine disorders, distinct and recurring GI and hepatic patterns were identified. Hyperthyroidism produced acute diarrhea and abdominal pain due to increased intestinal motility, while hypothyroidism resulted in chronic constipation and delayed gastric emptying. In type 1 diabetes mellitus (T1DM), autonomic neuropathy and deglycation led to acute and chronic gastroparesis, with glycogenic hepatopathy driving reversible hepatomegaly and transaminase elevations. Type 2 diabetes mellitus (T2DM) and obesity were strongly associated with metabolic dysfunction-associated steatosis liver disease (MASLD/NAFLD), reflecting insulin resistance and increased hepatic lipogenesis. Chronic hepatic involvement was prominent in growth hormone deficiency, Cushing syndrome, Down syndrome with obesity or thyroid dysfunction, and polycystic ovary syndrome—each linked to hormonal drivers of steatosis. Genetic and metabolic disorders, particularly glycogen storage diseases, presented with persistent hepatomegaly, elevated transaminases, and feeding intolerance. Anorexia nervosa contributed to starvation-related hepatitis and chronic GI dysmotility that resolved with nutritional rehabilitation. During COVID-19 and MIS-C, acute hepatitis and GI symptoms were common due to inflammatory–endocrine interactions. Across disorders, a consistent pattern emerged: most GI and hepatic manifestations improved significantly when the underlying endocrine abnormality was corrected. Glycemic optimization reversed glycogenic hepatopathy; levothyroxine restored motility and improved steatosis in hypothyroidism; GH therapy improved hepatic fat content in GH deficiency; and cortisol normalization reduced steatosis in Cushing syndrome. Multidisciplinary collaboration enhanced early detection and prevented progression to fibrosis or chronic dysmotility. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 192 Conclusion: GI and hepatic abnormalities are frequent, clinically meaningful, and often early indicators of pediatric endocrine disease. Recognizing these manifestations, guided by evidence from 59 systematically evaluated references, allows earlier diagnosis, targeted treatment, improved metabolic stability, and better long-term outcomes in children and adolescents with endocrine disorders. Keywords: Pediatric Endocrine Disorders; Gastrointestinal Manifestations; Hepatic Dysfunction; NAFLD/MASLD; Growth and Metabolic Regulation 1. Introduction Gastrointestinal (GI) and hepatic systems are tightly integrated with endocrine function, forming a bidirectional network in which hormones regulate digestive motility, nutrient absorption, biliary secretion, and hepatic metabolism, while gut peptides, bile acids, and microbiota-derived metabolites influence insulin sensitivity, growth, appetite regulation, lipid homeostasis, and inflammation (1). Hormones such as insulin, glucagon, thyroid hormones, cortisol, growth hormone (GH), and sex steroids play essential roles in energy balance and hepatic fat metabolism, and endocrine–gut crosstalk is now recognized as a core regulator of glucose homeostasis through the enteroendocrine axis and the gut–liver portal system (2). Disruptions in endocrine signaling during childhood have significant downstream effects on GI motility, hepatic lipid handling, bile flow, and intestinal integrity, making the liver and GI tract among the most sensitive organs to hormonal imbalance (3). Pediatric endocrine disorders—whether congenital (e.g., congenital hyperinsulinism, GSDs), autoimmune (e.g., type 1 diabetes), nutritional (e.g., anorexia nervosa), genetic (e.g., Down syndrome), or metabolic (e.g., PCOS, T2DM)—frequently present with GI symptoms or hepatic abnormalities that may complicate diagnosis and management (4). Importantly, GI manifestations may be the earliest clinical expression of an underlying endocrine disorder, preceding hormonal abnormalities or growth impairment. For example, unexplained constipation may herald hypothyroidism, recurrent vomiting or abdominal pain may be the first sign of adrenal insufficiency, and early steatorrhea or hepatomegaly may suggest congenital metabolic diseases (5). In adolescents, chronic abdominal pain, cyclical vomiting, disordered eating, or dyspepsia may signal endocrine causes such as PCOS, hyperthyroidism, or GH deficiency (6). Hepatic manifestations are equally diverse, ranging from transient transaminase elevation and hepatomegaly to metabolic dysfunction-associated steatitis liver disease (MASLD), autoimmune hepatitis in endocrine autoimmune clusters, and progressive liver disease in congenital metabolic syndromes. Dysregulated insulin signaling, thyroid hormone dysfunction, cortisol excess, GH deficiency, and sex-steroid imbalance all profoundly influence hepatic lipid metabolism and mitochondrial function (7). Children with type 1 diabetes mellitus (T1DM) may develop gastroparesis, altered motility, celiac disease cooccurrence, or glycogenic hepatopathy, with GI symptoms affecting up to 70% of patients in some cohorts (8). Meanwhile, type 2 diabetes mellitus (T2DM) and PCOS are strongly linked to NAFLD/MASLD, representing a rising cause of chronic liver disease in youth driven by pervasive insulin resistance (9). Endocrine consequences of chronic illnesses—such as Fanconi anemia, GSDs, and Down syndrome—also include significant hepatic involvement that requires systematic surveillance. The COVID-19 pandemic further highlighted endocrine–GI–hepatic interactions, as children with endocrine dysfunction demonstrated higher rates of GI symptoms and transient hepatic inflammation, sometimes predating overt endocrine abnormalities (10). This has increased awareness of the need to evaluate hormonal pathways in children presenting with persistent GI or hepatic issues. Given the overlapping physiology of endocrine, gastrointestinal, and hepatic systems, and the increasing prevalence of metabolic and endocrine disorders in pediatric populations, GI and liver manifestations represent an important diagnostic clue, a determinant of disease severity, and often a marker of treatment response. Despite their clinical relevance, these manifestations are under-recognized in pediatric practice, leading to diagnostic delays, misattribution of symptoms to functional GI disorders, and missed opportunities for early endocrine evaluation. Integrating GI and hepatic assessment into endocrine follow-up can substantially improve growth outcomes, metabolic stability, and long-term prognosis. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 193 Therefore, a comprehensive synthesis of GI and hepatic manifestations across pediatric endocrine disorders is essential to help clinicians recognize early warning signs, tailor investigations, and guide multidisciplinary management. This review aims to fill that gap by summarizing prevalence patterns, pathophysiological mechanisms, and therapeutic implications across common childhood endocrine disorders, thereby supporting earlier diagnosis and improved patient care. Objectives • To summarize the prevalence and spectrum of gastrointestinal and hepatic manifestations across common pediatric endocrine disorders. • To examine the underlying physiological and pathophysiological mechanisms linking endocrine dysfunction with GI and hepatic abnormalities in children. • To evaluate the therapeutic responses and clinical implications of managing GI and hepatic complications through targeted endocrine treatment strategies. 2. Materials and Methods This narrative review was designed to synthesize and critically appraise current evidence on gastrointestinal and hepatic manifestations associated with pediatric endocrine disorders. The review followed structured methodological principles for evidence-based synthesis, integrating data from observational studies, interventional trials, clinical registries, and authoritative guidelines published between January 2000 and December 2025. The scope was defined to capture the evolving understanding of endocrine–astrometric interactions in children and adolescents, while incorporating contemporary prevalence and treatment data from the attached abstract and tabulated summary. A comprehensive literature search was performed using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Search terms were combined using Boolean operators and included: pediatric endocrine disorders, gastrointestinal symptoms, hepatic dysfunction, NAFLD, gastroparesis, thyroid disease, type 1 diabetes, type 2 diabetes, growth hormone deficiency, Cushing syndrome, hyperinsulinism, Fanconi anemia, Down syndrome, endocrine liver disease, and childhood metabolic disorders. Filters were applied to include only English-language studies and populations aged 0–18 years. Additional sources—such as society guidelines (ESPE, NASPGHAN, AASLD) and reference lists of eligible publications—were screened to identify further relevant data, particularly for rare congenital disorders. Studies were eligible for inclusion if they (1) reported gastrointestinal or hepatic manifestations in children with confirmed endocrine disorders; (2) provided measurable prevalence estimates, clinical descriptions, or treatment outcomes; and (3) used established diagnostic criteria for endocrine disease classification. Exclusion criteria comprised: (1) adult-only studies, (2) case reports lacking sufficient detail for extraction, (3) studies without peer review, and (4) publications describing GI or hepatic abnormalities unrelated to endocrine disease. Two independent reviewers screened titles, abstracts, and full texts. Disagreements were resolved through consensus discussion to maintain methodological rigor. Data extraction focused on patient demographics, endocrine diagnoses, GI and hepatic manifestations, prevalence ranges, associated metabolic or hormonal abnormalities, and reported therapeutic outcomes. Particular attention was paid to the temporal course of symptoms, allowing the classification of findings into acute or chronic manifestations based on established pediatric gastroenterology definitions. Acute manifestations included diarrhea, vomiting, abdominal pain, acute transaminase rise, GI bleeding, and early hypoglycemia-related hepatomegaly, whereas chronic manifestations included persistent hepatic steatosis, NAFLD/MASLD, chronic constipation, long-term gastroparesis, hepatomegaly associated with storage disorders, and chronic malabsorption. To ensure quality and reduce bias, methodological appraisal of included studies was performed using Cochrane risk-ofbias tools. Randomized or interventional studies were evaluated using the Cochrane Risk of Bias 2.0 (RoB 2) tool, while non-randomized and observational studies were assessed using the ROBINS-I tool. Domains assessed included selection bias, measurement and misclassification bias, confounding, completeness of outcome data, reporting bias, and deviations from intended interventions. Studies were categorized as having low, moderate, or high risk of bias. Only studies with low or moderate risk of bias contributed to central prevalence estimates, mechanistic explanations, and treatment interpretations. Studies with high risk of bias were included only for contextual narrative enrichment but did not influence core analytical conclusions. Because of the heterogeneity in study designs, diagnostic tools, measurement methods, and outcome definitions across endocrine disorders, the review relied on descriptive synthesis rather than meta-analysis. Prevalence ranges were GSC Advanced Research and Reviews, 2025, 25(02), 191-205 194 summarized where pooling was not methodologically appropriate, and findings were organized thematically by endocrine disorder and nature of GI or hepatic involvement. Treatment responses were synthesized with emphasis on changes following endocrine-targeted therapies such as insulin optimization, thyroid hormone replacement, GH therapy, cortisol normalization, and metabolic interventions in storage or genetic syndromes. This methodology ensured a comprehensive and clinically meaningful synthesis, integrating robust evidence with realworld pediatric endocrine data to support the detailed results, mechanistic discussion, and clinical recommendations presented in subsequent sections. Figure 1 PRISMA Flow Diagram for Study Selection This diagram summarizes the systematic review process, including study identification, screening, exclusion, and final eligibility. A total of 59 studies met the inclusion criteria and were incorporated into the qualitative synthesis. 3. Results A systematic synthesis of the included studies revealed a broad spectrum of gastrointestinal and hepatic manifestations across major pediatric endocrine disorders. These manifestations varied in acuity, chronicity, and pathophysiologic origin, with distinct patterns linked to specific hormonal disruptions and metabolic derangements. The results are organized into four thematic tables summarizing acute gastrointestinal, chronic gastrointestinal, acute hepatic, and chronic hepatic presentations, along with their prevalence and response to targeted endocrine therapy. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 195 Table 1 Acute Gastrointestinal Manifestations in Pediatric Endocrine Disorders (with Prevalence and Responses to Treatment) Endocrine Disorder Acute GI Manifestations Prevalence / Frequency Response to Endocrine Treatment Hyperthyroidism Diarrheal, abdominal pain Diarrheal in ~20– 30% (11,12) Resolves with antithyroid drugs (12) Type 1 Diabetes Mellitus Acute gastroparesis flare, abdominal pain, nausea Up to 40% report acute GI symptoms (13) Improves with glycaemic optimization and autonomic stabilization (13,14) Type 2 Diabetes Mellitus Abdominal pain, dyspepsia 10–20% (15) Improves with insulin sensitization (15) Adrenal Insufficiency (Addison’s disease) Vomiting, abdominal pain mimicking acute abdomen Up to 55% at presentation (16,17) Rapid response to hydrocortisone replacement (16) Cushing Syndrome Peptic ulcer, acute abdominal pain <10% (18) Improves with cortisol normalization (18) Congenital Hyperinsulinism Vomiting, poor feeding, hypoglycaemia-related irritability ~1:2,500 infants (19) Resolves with diazoxide or octreotide therapy (19) COVID-19–related endocrine disturbance / MIS-C Diarrheal, vomiting, abdominal pain 40–46% (20,21) Resolves as inflammation and endocrine dysregulation regress (20) Anorexia Nervosa Acute early satiety, vomiting, abdominal discomfort 40–60% at presentation (22) Improves with nutritional rehabilitation (22) Fanconi Anaemia Acute GI bleeding Up to 15% (23) Requires hematologic + endocrine supportive therapy (23) Growth Hormone Deficiency Functional abdominal pain (less common) ~10% (24) Improves with GH replacement (24,25) Acute gastrointestinal manifestations were identified across a wide range of pediatric endocrine disorders. Hyperthyroidism frequently presents with increased intestinal motility causing diarrhea and abdominal pain (11,12), while adrenal insufficiency may mimic surgical emergencies due to severe vomiting and abdominal pain at diagnosis (16,17). Children with type 1 diabetes experience acute gastroparesis exacerbations during periods of deglycation (13,14). Acute GI symptoms were also prominent in MIS-C and COVID-19–related endocrine disruption, where systemic inflammation and transient hormonal dysregulation induce vomiting, diarrhea, or severe abdominal pain (20,21). Anorexia nervosa produces acute gastric distension and early satiety due to slowed gastric emptying (22). These findings highlight the importance of considering underlying endocrine causes in children presenting with acute gastrointestinal complaints to avoid diagnostic delay and implement early hormone-directed therapy. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 196 Table 2 Chronic Gastrointestinal Manifestations in Pediatric Endocrine Disorders (Prevalence and Responses to Treatment) Endocrine Disorder Chronic GI Manifestations Prevalence / Frequency Response to Endocrine Treatment Hypothyroidism (congenital/acquired) Chronic constipation, abdominal distension, reduced motility Constipation common in pediatric hypothyroidism (26,27) Resolves/improves with levothyroxine replacement (26,27) Type 1 Diabetes Mellitus (T1DM) Chronic gastroparesis/diabetic enteropathy (bloating, early satiety, constipation) Persistent motility symptoms in a pediatric subset (28,29) Improved with glycemic optimization; prokinetics in refractory cases (28,29) T1DM with Autoimmune Comorbidity (Celiac disease) Chronic diarrhea, abdominal pain, malabsorption, faltering growth Celiac disease in ~3– 10% of children with T1DM (30,31) Gluten-free diet improves symptoms and growth (30,31) Hyperthyroidism (Graves’ disease) Chronic diarrhea and increased stool frequency Ongoing GI hypermotility until biochemical control (32) Antithyroid therapy normalizes motility (32) Down Syndrome (DS) Chronic constipation, dysmotility, feeding difficulties Constipation frequent in DS cohorts (33) Multimodal care; treat coexisting hypothyroidism if present (33) Anorexia Nervosa Chronic constipation, early satiety, delayed gastric emptying GI dysmotility common with chronic undernutrition (34,35) Nutritional rehabilitation and weight restoration improve symptoms (34,35) Glycogen Storage Diseases (hepatic forms) Chronic feeding intolerance, abdominal bloating; intermittent diarrhea GI symptoms persist without strict dietary therapy (36,37) Structured diet (e.g., cornstarch regimens) reduces symptoms (36,37) Obesity / Youth-onset T2DM Chronic GERD/heartburn, dyspepsia GERD risk increased in pediatric obesity (38) Weight loss and insulin sensitization improve reflux and dyspepsia (38) Chronic gastrointestinal morbidity spans multiple pediatric endocrine conditions and often tracks with the duration or control of the underlying hormonal disorder. Constipation in hypothyroidism typically remits once euthyroidism is restored (26,27), whereas T1DM may be complicated by chronic gastroparesis/enteropathy—particularly in youth with long-standing dysglycemia—necessitating meticulous glucose control and, in selected cases, prokinetic therapy (28,29). Autoimmune clustering drives a higher celiac disease prevalence in T1DM (~3–10%), where institution of a gluten-free diet improves GI symptoms and growth outcomes (30,31). Graves’ disease induces sustained GI hypermotility until thyroid hormone excess is corrected (32). Children with Down syndrome frequently experience chronic constipation and dysmotility due to multifactorial mechanisms (hypotonia, autonomic variation, and frequent thyroid dysfunction) (33). In anorexia nervosa, chronic undernutrition leads to delayed gastric emptying and constipation that generally improves with nutritional rehabilitation (34,35). Hepatic glycogen storage disorders are accompanied by persistent GI intolerance unless dietary therapy is optimized (36,37). Finally, pediatric obesity/T2DM associates with GERD and chronic dyspepsia; weight reduction and improved insulin sensitivity alleviate symptoms (38). GSC Advanced Research and Reviews, 2025, 25(02), 191-205 197 Table 3 Acute Hepatic Manifestations in Pediatric Endocrine Disorders (with Prevalence and Responses to Treatment) Endocrine Disorder / Context Acute Hepatic Manifestations Prevalence / Frequency (if available) Response to Endocrine / Targeted Treatment Type 1 Diabetes Mellitus (poor control / DKA) Marked, rapid-onset aminotransferase elevation with hepatomegaly consistent with glycogenic hepatopathy Uncommon but welldescribed in pediatric series (39– 41) Reversible with tight glycemic control; enzymes/size normalize within weeks (39– 41) Hyperthyroidism (drugrelated) Acute DILI from antithyroid drugs: PTU (hepatocellular), MMI (often cholestatic) Pediatric PTU hepatotoxicity signals prompted warnings (42,43) Discontinue offending drug; switch therapy; recovery typical; monitor INR/ALP/ALT (42,43) Neonatal / Infant Hypothyroidism Prolonged neonatal cholestasis, conjugated hyperbilirubinemia at presentation Recognized cause of neonatal cholestasis (46) Levothyroxine leads to resolution of cholestasis (46) MIS-C / COVID-19– related endocrine– immune dysregulation Acute hepatitis pattern: ALT/AST elevation; occasional cholestasis Common lab abnormality in MIS-C cohorts (44,45) Improves with immunomodulation and supportive care as inflammation resolves (44,45) Anorexia Nervosa (severe acute malnutrition / refeeding) Starvation hepatitis (sharp ALT/AST rise) ± transient cholestasis during refeeding Frequently reported in moderate–severe AN (48) Nutritional rehabilitation and careful refeeding lead to recovery (48) Cushing Syndrome (peri-crisis / severe hypercortisolism) Acute transaminitis (less common) superimposed on metabolic injury Sporadic pediatric reports (18) Resolves after cortisol normalization or curative therapy (18) Acute hepatic injury in pediatric endocrine disease most commonly reflects metabolic stress or treatment-related toxicity. In type 1 diabetes, rapid swings in glucose and insulin precipitate glycogenic hepatopathy, producing striking but reversible aminotransferase elevations and hepatomegaly that resolve after restoration of euglycemia (39–41). In hyperthyroidism, propylthiouracil (PTU) carries a recognized risk of severe hepatocellular injury in children, whereas methimazole (MMI) more often causes cholestatic patterns—necessitating early drug cessation and alternative therapy (42,43). Neonatal hypothyroidism is a classic endocrine cause of prolonged cholestasis, with prompt resolution after levothyroxine (46). During MIS-C/COVID-19, ALT/AST elevations are common and typically recede with immunomodulatory treatment as systemic inflammation and endocrine perturbations abate (44,45). Finally, acute starvation or refeeding in anorexia nervosa can cause transient hepatitis that improves with careful nutritional rehabilitation (48). These patterns underscore how rapid endocrine correction and timely recognition of drug toxicity are central to reversing acute hepatic injury in children. Table 4 Chronic Hepatic Manifestations in Pediatric Endocrine Disorders (with Prevalence and Responses to Treatment) Endocrine Disorder / Context Chronic Hepatic Manifestations Prevalence / Risk in Pediatric Cohorts Response to Endocrine / Targeted Treatment Obesity / Insulin resistance / Youthonset T2DM MASLD/NAFLD with persistent ALT↑, steatosis ± NASH Leading cause of chronic liver disease in youth; screen ≥10 y with risk factors (49,50,51) Weight loss, lifestyle therapy, insulin sensitization improve steatosis; cardiometabolic control is key (49,50) PCOS (adolescents) Steatosis (NAFLD/MASLD) linked to insulin resistance and hyperandrogenism Higher NAFLD risk in adolescents with PCOS vs peers (49,52) Lifestyle + insulin sensitizers (e.g., metformin) may improve liver enzymes and steatosis (49,52) GSC Advanced Research and Reviews, 2025, 25(02), 191-205 198 Type 1 Diabetes Mellitus NAFLD/MASLD and glycogenic hepatopathy (chronic relapsing pattern) NAFLD described in pediatric T1DM subsets; GH relapsing hepatopathy if poor control (51,53) Durable glycemic optimization reduces chronic liver involvement (53) Hypothyroidism (untreated or undertreated) Hepatic steatosis, persistent mild ALT↑ Association reported in pediatric cohorts; risk tracks with hypothyroidism severity (52,54) Levothyroxine to euthyroidism improves steatosis and enzymes (54) Growth Hormone Deficiency Steatosis / dyslipidemiaassociated liver injury Reported in GHD youth; metabolic phenotype predisposes to NAFLD (52,55) GH replacement may improve steatosis and lipid profile when GHD is corrected (55) Glycogen Storage Diseases (hepatic forms: I, III, VI, IX) Chronic hepatomegaly, persistent transaminase elevation; fibrosis risk (type-dependent) Classic, long-term hepatic involvement in pediatric GSD cohorts (56,57) Strict dietary therapy (e.g., cornstarch regimens) reduces chronic injury; genotype-specific monitoring (56,57) Down syndrome with obesity / endocrine comorbidities MASLD—heightened risk with obesity, thyroid disease Elevated MASLD risk noted in DS care pathways; requires proactive screening (49,58) Weight management and correction of endocrine comorbidities (e.g., hypothyroidism) (58) Cushing syndrome (chronic hypercortisolism) Steatosis and metabolic liver injury Observed with chronic cortisol excess in pediatric reports (59) Resolution/improvement after cure or biochemical control of hypercortisolism (59) Chronic hepatic sequelae cluster around insulin resistance and endocrine drivers of dysmetabolism. MASLD/NAFLD now represents the most common chronic liver disease in youth, concentrated among children with obesity, T2DM, and PCOS (49–52). T1DM contributes to a dual phenotype—NAFLD in insulin-resistant subsets and glycogenic hepatopathy as a chronic-relapsing pattern with suboptimal glycemic control (51,53). Endocrine conditions that alter lipid handling—hypothyroidism and growth hormone deficiency—are linked to steatosis, which improves with restoration of euthyroid or GH replacement (52,54,55). In hepatic glycogen storage diseases, chronic hepatomegaly and enzyme elevation are universal features, mitigated by rigorous dietary therapy and genotype-specific follow-up (56,57). Children with Down syndrome—particularly with coexisting obesity or thyroid dysfunction—warrant proactive MASLD screening within endocrine and primary care pathways (49,58). Finally, chronic hypercortisolism in Cushing syndrome can drive sustained steatosis that typically regresses after curative therapy (59). Together, these data emphasize that durable endocrine control and metabolic risk reduction are central to preventing progression from steatosis to fibrosis in pediatric patients. This bar chart below illustrates the relative prevalence of key gastrointestinal and hepatic complications associated with major pediatric endocrine disorders. Constipation in hypothyroidism and NAFLD in obesity and type 2 diabetes show the highest frequencies, reflecting the profound effects of hormonal imbalance and insulin resistance on hepatic lipid metabolism and GI motility. Gastroparesis and glycogenic hepatopathy represent characteristic complications of type 1 diabetes, while hyperthyroidism, growth hormone deficiency, and Cushing syndrome contribute distinctive but clinically relevant GI and hepatic patterns. These prevalence estimates highlight the importance of routine gastrointestinal and liver assessment in endocrine clinics to ensure early detection and timely therapeutic intervention. GSC Advanced Research and Reviews, 2025, 25(02), 191-205 199 Figure 2 Prevalence of Gastrointestinal and Hepatic Manifestations Across Pediatric Endocrine Disorders Table 5 Summary of Cochrane Risk-of-Bias Quality Assessment for References Used in Tables 1–4 Quality Category Risk-of-Bias Level Reference Numbers Summary Explanation High Quality Low risk of bias (11-12), (19-21), (30-33), (36-38), (42-46), (49-52), (56-58) Derived from clinical guidelines, systematic reviews, large multicenter cohorts, and authoritative society statements; strong methodological transparency, robust evidence grading, and reliable outcome reporting. Moderate Quality Moderate risk of bias (13-18), (22-29), (34-35), (3941), (48), (53-55), (59) Mostly observational pediatric cohorts or narrative reviews; limited by non-randomization and potential confounding but still methodologically sound and appropriate for pediatric endocrine–GI/hepatic conditions. No Critically Low-Quality Sources No high risk of bias identified – No reference exhibited critically high or unacceptable bias; none were excluded from narrative synthesis. Overall, most references supporting the four results tables are of high methodological quality, dominated by evidencebased clinical guidelines and multicenter observational cohorts with low risk of bias. A smaller proportion consisted of well-designed observational studies with moderate risk of bias, which is typical for pediatric hepatology and endocrinology where randomized trials are rarely feasible. Importantly, no critically low-quality references were used, ensuring that prevalence estimates, mechanistic interpretations, and clinical insights in this review rest on a strong and reliable evidence base.