Category Archives: Pediatric Gastroenterology Liver Disease

Pharmacological Management of Pediatric Steatotic Liver Disease

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RARA Jaoudeh et al. J Pediatr Gastroenterol Nutr. 2025;80:14–24; Pharmacological management of pediatric metabolic dysfunction-associated steatotic liver disease

Key points:

  • Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated efficacy against adult MASLD. “In patients ≥12 years of age with obesity (BMI ≥ 95th percentile), we recommend the use of GLP-1RA—along with dietary and lifestyle modifications—in those who have MASLD or MASH, and 1 additional metabolic comorbidity (hypertension, prediabetes, polycystic ovary syndrome, dyslipidemia, and obstructive sleep apnea) (Figures 1 and 2). Treatment with these agents should only be initiated after other causes of hepatic steatosis are ruled out.”
  • “GLP-1RA are effective in treating pediatric obesity and have shown to decrease liver enzyme levels which is likely indicative of their effect on MASLD.”
  • “It is important to note that phentermine/topiramate combination drug is approved for patients 12 years and older with obesity15 and can be used as a bridge for GLP-1RA therapy in cases where access to GLP-1RA is limited.”
  • GLP-1RA Dosing regimens are provided in Table 1. For example, “Semaglutide for weight loss is initiated at 0.25 mg once weekly subcutaneously and increased every 4 weeks in a stepwise fashion up to a maximum of 2.4 mg once weekly dose. The most common side effects are nausea and/or vomiting and can be worse the first few days a after dose increase. It is acceptable to delay dose escalation or reduce the target dose based on patient tolerance. Medication therapy should be evaluated for effectiveness after 12 weeks on a maximally tolerated dose.” And, “Liraglutide for weight loss is initiated at 0.6 mg daily subcutaneously and increased weekly in 0.6 mg increments up to a maximum 3 mg daily dose.”
  • Adverse effects: “Both liraglutide and semaglutide have been associated with thyroid C-cell tumors in animal studies37 and are contraindicated in patients with a personal or familial history of multiple endocrine neoplasia 2A and 2B and medullary thyroid carcinoma. Patients should be educated on symptoms of thyroid tumors—lump in the neck, difficulty breathing or swallowing, or persistent hoarseness—and treatment should be discontinued if these occur.37 GLP-1RA also increase the risk of pancreatitis and gallbladder disease especially with rapid weight loss.37 Liraglutide is contraindicated in pregnancy due to potential embryo-fetal defects shown in animal studies, and semaglutide should be discontinued if pregnancy occurs.10, 37“

Useful algorithm:

My take: GLP-RAs are likely to be used increasingly in adolescents with MASLD despite issues with insurance/affordability and need for chronic treatment. This is a helpful review.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

ESPGHAN Guidelines for PSC in Children

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PF van Rheenen et al. JPGN 2024; DOI: 10.1002/jpn3.12378. Open Access! Primary sclerosing cholangitis in children with inflammatory bowel disease: An ESPGHAN position paper from the Hepatology Committee and the IBD Porto group

Recommendations:

  • In children with suspected or confirmed IBD, screening for liver disease is usually performed at 3 to 6 months intervals and a work‐up for underlying liver disease is most commonly initiated when liver enzymes exceed 2x the upper limit of normal
  • Use MRCP as the radiological modality of choice for diagnosing PSC
  • Consider performing a liver biopsy in children with IBD and suspected PSC in the following circumstances: i) Normal biliary tree at MRCP, ii) raised immunoglobulin G and the presence of liver-specific autoantibodies, or iii) clinical uncertainty before steroid induction therapy for IBD
  • Perform fecal calprotectin screening at least once yearly in children with isolated PSC and/or AIH to select patients for diagnostic endoscopy for suspected inflammatory bowel disease (panel recommends cutoff of >150 indicating need for ileocolonoscopy)
  • Surveillance colonoscopy should be considered in children with PSC–IBD and the following risk factors of colorectal cancer: i) persistent active colonic inflammation, ii) longstanding colitis (≥8 years), or iii)  a family history of colorectal cancer in a first-degree relative <50 years. (The overall risk of colon cancer in those <18 yrs of age is very low)
  • UDCA may be prescribed at doses of 15–20 mg/kg/day. Despite evidence of improvement of liver enzymes, its long-term effect on disease progression has not been demonstrated. Consider a 6-months therapeutic trial of UDCA, either immediately after PSC diagnosis or when spontaneous normalization of GGT does not occur in the first 6 months postdiagnosis. Continue UDCA treatment if there is a meaningful reduction or normalization of GGT or improvement of symptoms
  • Oral vancomycin may be prescribed for a potential improvement in liver biochemistry as well as bowel inflammation. Its long-term effect on disease progression has not been demonstrated
  • In children with PSC–IBD and biochemical, serological, and histological features of AIH, the use of corticosteroids and antimetabolites may suppress immune-mediated hepatitis. In the absence of convincing AIH features, the use of corticosteroids and antimetabolites is not indicated to manage PSC
  • Children with PSC, relevant bile-duct strictures and cholestatic symptoms should be assessed for liver transplantation. When their symptoms are likely to improve following biliary intervention, ERCP can be considered
  • Recommended blood testing for children with PSC: At diagnosis: Autoantibodies (ANA, anti-SMA, anti-LKM-1, anti-LC1, and anti-SLA), Every 3-6 months: ALT, AST, GGT, Albumin, INR, Platelets, CRP. Every 12 months: IgG, AFP, and Fat Soluble vitamins. Consider f/u autoantibodies in those with elevated IgG at f/u lab testing

My take: This is a useful position paper; it does not have a zillion recommendations like some other ESPGHAN positions papers. Given the frequency of liver enzyme elevation in patients with IBD, mild to modest elevations may need to be observed before launching an extensive evaluation (see related blog posts below).

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Key Advances in 2024: An Overview from GutsandGrowth (Part 2)

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This year I had the opportunity to give a lecture to our group that reviewed much of the important advances that happened in 2024. Here are some of the slides (if you have any trouble reading the slides, you can search for the original blog post using author name).

Limitations of MRE and TE in Assessing Liver Fibrosis in Pediatric MASLD

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N Ravanbakhsh et al J Pediatr Gastroenterol Nutr. 2024;79:1192–1198. Comparing imaging modalities in the assessment of fibrosis in metabolic dysfunction-associated steatotic liver disease

In this retrospective review with 77 patients who had liver biopsy-proven MASLD (2017-2023), the authors examined how well magnetic resonance elastoraphy (MRE) and transient elastography (TE) identified fibrosis.

Key findings:

  • Fibrosis was identified in 90% of liver biopsies
  • The area under the receiver operating characteristic curves (AUROC) of MRE and TE for detection of high-grade fibrosis were 0.817 and 0.750, respectively
  • Only 20% of patients had severe fibrosis on liver biopsy; thus, this is a limitation given the small number
Sensitivity in detecting advanced fibrosis, defined on liver biopsy was defined as Metavir Stage ≥ 3.

Conclusion of authors: “MRE and TE did not accurately predict high-grade fibrosis on liver biopsy. Between the two noninvasive imaging modalities, the correlation of identifying high-grade fibrosis was not statistically different.”

My take: Even MRE is not very accurate at identifying fibrosis. Given the huge numbers of individuals (pediatric and adult) with MASLD, the lack of reliable non-invasive markers is a problematic. As effective treatments become available, being able to determine if they are working is essential.

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Environmental Toxins/Forever Chemicals and Steatotic Liver Disease

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AK Jain et al. JPGN 2024; 79:943–953. Open access: Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis

This study correlated environmental toxins and steatotic liver disease. Four hundred and thirty-five children distributed across MASH (n = 293) and MASLD (n = 142), with 304 (69.9%) males. Toxins analyzed: PFAS chemicals included perfluorohexane-1-sulphonic acid (PFHXS), perfluorononanoic acid, perfluorooctanoic acid, and perfluorooctanesulfonic acid and PBDE included 2,2′,4,4′-tetrabromodiphenyl ether (BDE47), 2,2′,4,4′,5-pentabromodiphenyl ether (BDE99), and 2,2′,4,4′,6-pentabromodiphenyl ether (BDE100).

Key findings:

  • There was an inverse association between PFAS/PBDE mixture and MASH versus MASLD, lobular inflammation (p = 0.026), NAS (p = 0.009, FDR p = 0.04), and log-transformed ALT (p = 0.005, FDR p = 0.025) driven by perfluorohexane sulfonate (PFHXS). 
  • PFASs were detected in 290 (67%) samples, showing the pervasive nature of this chemical exposure in children

My take: Not surprisingly, our environmental exposures influence the severity of steatotic liver disease. There is widespread exposure to pollutants and the full toll on our health is not clear.

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Non-Invasive Studies Often Fail to Detect Advanced Liver Fibrosis in Steatotic Liver Disease

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N Ravanbakhsh et al. JGPN 2024; https://doi.org/10.1002/jpn3.12368. Comparing imaging modalities in the assessment of fibrosis in metabolic dysfunction-associated steatotic liver disease

Key findings:

  • TE and MRE did not have high correlation with liver biopsy in the detection of high-grade fibrosis
  • Fibrosis was identified in 90% of liver biopsies with bridging fibrosis in 15 (19%) and cirrhosis in 1 (1%)
  • AUROC curves of MRE and TE for detection of high-grade fibrosis were 0.817 and 0.750, respectively, and not significantly different.

The authors note that previous adults studies suggest that MRE is more accurate in the identification of liver fibrosis than TE (MRE detected ≥ F1 fibrosis with an AUROC of 0.82, while TE detected fibrosis with an AUROC of 0.67).20 

My take: Trying to identify accurate non-invasive testing is crucial to help identify patients most in need of treatment and for limiting costs.

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Isle of Palms, SC

Markers for Outcomes in Neonates with Acute Liver Failure

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PS Rolfes et al. J Pediatr 2024; 272: 114080. Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

Methods: A single-center, retrospective chart review (n=51) was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction).  This excluded infants who responded to a single dose Vit K injection or fresh frozen plasma. The age at presentation was 4.7 in survival with native liver (SNL) group and 6.9 in the non-SNL group.

Key findings:

  • The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). All three patients with HLH died. Ischemia had the highest survival rate of 64% compared to 40% for infectious ALF, and 50% for GALD-ALF.
  • Overall survival with native liver (SNL) rate was 43% (n = 22).
  • Alpha-fetoprotein levels were higher in SNL group on admission (mean 46,471) compared to transplant/non-survival group (mean 2450). Peak values were 165,000 compared to 17,650. AFP levels remained significant after removing GALD patients with SNL group now with 17,500 mean on admission compared to 1006 in non-SNL group.
  • Ammonia levels were lower in SNL group on admission 48 vs 70 and at peak: 83 vs 172.
  • A neonatal ALF (nALF) model was developed: 1.29 x Admission INR +0.985 x Admission Ammonia (micromol/L). This score was significantly lower (mean 48.1) in SNL group compared to non-SNL group of 76.2.
  • A peak nALF model: 0.982 x Peak PT +0.985 x Peak Ammonia (micromol/L) performed even better than admission nALF model. SNL group had mean value of 118 compared to 223 for non-SNL group (P <0.001)

In the discussion, the authors note that AFP may have high prognostic value at time of admission (similar to neonatal ALF model), especially in Non-GALD patients. AFP Is a “biomarker for hepatic regeneration….Similar to our findings, several adult studies have shown that elevated AFP levels are associated with favorable outcomes in non-oncologic liver diseases…Specifically, it has been shown that in ALF, rising levels of AFP during hospitalization are associated with favorable outcomes.”

My take: Both the AFP and the neonatal ALF score had similar prognostic value for SNL.

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Flowers on Channel Islands (off coast of California)

Autoimmune Diseases in Patients with Primary Sclerosing Cholangitis Plus One

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A Lundberg Bave et al. Hepatology 2024; 80: 527-535. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives

Methods: Using National Swedish registries, the authors evaluated a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives.

Key findings:

  • After excluding inflammatory bowel disease and autoimmune hepatitis, the prevalence of autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77
  • Highest odds were seen for celiac disease [OR: 4.3], sarcoidosis [OR: 2.74], diabetes type 1 [OR: 2.91], and autoimmune skin disease [OR: 2.15]
  • First-degree relatives of individuals with PSC had higher odds of developing IBD [OR: 3.25], autoimmune hepatitis [OR: 5.94], and any autoimmune disease than relatives of the comparators [OR: 1.34] 

My take: Keep an eye out for other autoimmune diseases in patients (& their 1st-degree relatives) with PSC.

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Briefly noted: BB Lai et al. Hepatology 2024; 80: 511-526. Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency–related cholestasis Key finding: “Patients with the TJP2-C genotype carrying PPTMs [predicted protein-truncating mutation] in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.”

Blog Case Report: A Persistent Elevated AST in Teen with IBD and ADHD

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A recent case reminded me of the quote by Helena Ravenclaw in Harry Potter: “”If you have to ask, you’ll never know. If you know, you need only ask.”

One of my colleagues recently diagnosed a teenage boy with ulcerative colitis. His past medical history was notable for ADHD. At the time of his evaluation, he was noted to have an elevated AST.

Labs:

  • June: AST 143, ALT 8, Hepatitis B immune
  • August: AST 190, ALT 10, Albumin 4.7, T protein 7.3, T bili 0.4, D bili 0.1, Alk phos 168; GGT 10, CPK 93

The concern at the time was whether his elevated AST should preclude using his ADHD medicine and whether there was an underlying liver disease. Based on the pattern of liver enzyme abnormalities, it was suspected that the patient had macro AST. A blood test was sent to the Mayo clinic and confirmed this diagnosis:

“”The sample was investigated for the presence of macro AST by polyethylene glycol (PEG) precipitation. Serum AST activity = 316 U/L. The AST result post-PEG precipitation = 22 U/L. The results obtained are positive for the presence of macro AST (93% of activity precipitated with PEG). Based on validation studies performed at the Mayo Clinic, a cut-off of >80% AST activity precipitated by PEG indicates the presence of macro AST.” This test is rarely ordered at the Mayo Clinic and is ordered as a miscellaneous test; it is not on the Mayo Clinic’s regular test menu.

Internet description of macro AST: Macro-aspartate aminotransferase (macro AST) is a rare, benign condition that causes a persistent elevation of aspartate aminotransferase (AST) levels in the blood. It’s caused by the binding of AST to immunoglobulins, which results in a high molecular weight macroenzyme that’s excreted from the serum more slowly than normal.

My take: Macro AST diagnosis is useful –it helps eliminate the concern for other conditions. Since it is quite uncommon, it is easier to think of this problem once you have seen it before.

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Grand Point View Overlook at Canyonlands National Park

Fibrosis and Steatotic Liver Disease -Who Needs to be Followed by Hepatology?

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N Ma et al. JPGN 2024; 79:229–237. Fibrosis and steatotic liver disease in US adolescents according to the new nomenclature

Methods: Among 1410 adolescents (12–19 years) in NHANES (2017-March, 2020), the controlled attenuation parameter (CAP) of transient elastography (TE) was used to define steatosis and fibrosis (TE ≥ 7.4 kPa). Obesity and alanine aminotransferase (ALT) ≥ 80 U/L were used to identify adolescents qualifying for hepatology referral according to practice guidelines.

Key findings:

  • At the supplier (EchoSens)-recommended CAP threshold of 240 dB/m, 30.5% of adolescents had steatotic liver disease (SLD) and about 85% of adolescents with NAFLD met criteria for MASLD. At a CAP threshold of 270 dB/m, SLD prevalence was about 16% in adolescents. The other 15% of NAFLD patients do not meet diagnostic criteria MASLD and would receive a diagnosis of cryptogenic SLD or possible MASLD
  • At higher CAP thresholds, MASLD/NAFLD concordance increased and approached 100%.
  • Among adolescents with MASLD-fibrosis, only 8.8% had overweight/obese and ALT ≥ 80 U/L. Thus, more than 90% of adolescents in this group would not merit hepatology evaluation based on current guidelines.

My take: This study identifies potential problems with current thresholds for which patients need to be seen by pediatric hepatologists. This will be even more important as effective pharmaceuticals become available.

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Channel Islands off the California coast