Recent Advances in the Management of Pediatric Cholestatic Liver Diseases

Abstract

Pediatric cholestatic liver diseases are rare conditions that can result from multiple specific underlying etiologies. Among the most common etiologies of pediatric cholestatic liver diseases are biliary atresia, Alagille syndrome, and inherited disorders of bile acid transport. These diseases are characterized by episodic or chronic unremitting cholestasis. Due to the chronicity of these conditions, it is imperative to optimize medical management to improve patient quality of life, provide nutritional support, and reduce bile acid toxicity in efforts to slow disease progression. Cholestatic liver diseases remain the leading cause for pediatric liver transplantation as many underlying disease etiologies have no curative medical therapies. In the present review, we provide an update on the nutritional, medical, and surgical management for pediatric cholestatic liver diseases. As recent advances have occurred in the field with the addition of ileal bile acid transporter (IBAT) inhibitors, we also review the results from prospective clinical trials including their strengths and limitations. While recent clinical trials have demonstrated improved pruritus using IBAT inhibitors in Alagille syndrome and progressive familial intrahepatic cholestasis, establishing medical therapies proven to slow disease progression remains an area of unmet need.

Introduction

Pediatric cholestatic liver diseases are characterized by obstruction of bile flow and accumulation of toxic bile acids, resulting in hepatic injury. The severity and chronicity of liver injury varies based on the etiology of cholestasis. In addition, age of onset can differ by etiology of pediatric cholestatic liver disease and may impact outcome. For example, certain metabolic conditions may present with cholestasis as infants but promptly resolve with appropriate dietary or medical therapy. In contrast, infants diagnosed with biliary atresia (BA) or Alagille syndrome (ALGS) commonly experience more chronic sequelae of cholestatic liver injury throughout childhood. Disease severity can also vary within the same disease based on timing of diagnosis and treatment. Furthermore, specific mutations in the same gene can cause differences in disease severity and progression as has been observed in progressive familial intrahepatic cholestasis.¹ Effective treatment of pediatric cholestatic liver diseases therefore includes careful consideration of factors contributing to disease heterogeneity in addition to nutritional management, medical therapies, and disease-specific surgical options. In the present review, we provide an update on the current management of pediatric cholestatic liver diseases focused on those with onset in infancy including a description of new medical therapies and areas of unmet need.

Nutritional assessment and management

Malnutrition is a prevalent and major modifiable risk factor for adverse outcomes in infants and children with cholestasis (Figure 1).² Factors contributing to malnutrition include reduced intake/retention (e.g. malabsorption), increased caloric demands, and abnormal regulation of energy utilization. Reduced intake may occur due to nausea and vomiting triggered by chronic inflammation, reduced gastric capacity due to ascites and organomegaly, and less palatable formulas. In addition, malabsorption can occur in the setting cholestasis and portal hypertensive gastropathy due to altered motility, anorexia from systemic inflammation, early satiety and poor lymphatic drainage.^3–5 Furthermore, the impact of reduced intake and malabsorption is enhanced due to increased caloric utilization that can occur in a chronic diseased state, and associated complications (sepsis, peritonitis, and bleeding), although not all patients are catabolic. Patients may also exhibit impaired regulation of energy utilization and storage including decreased hepatic glycogen stores and preferential use of fatty acid oxidation as an energy source that impairs growth.⁶ Lastly, abnormal protein utilization can occur secondary to decreased production of insulin-like growth factor (IGF)-1 and IGF binding protein 3 (IGF-BP3), proteins responsible for anabolic actions of growth hormone (GH) important to establish adequate muscle mass.⁷

Figure 1: Graphic representation of pediatric cholestatic management.

Most common etiologies of pediatric cholestasis are listed. Comprehensive approach to the management of pediatric cholestatic liver diseases including nutritional management, fat soluble vitamin supplementation, targeted medical therapies and other medications including chloretics like ursodeoxychoic acid are listed. Medications to manage pruritus including the newer class of ileal bile acid transport inhibitors. Limited surgical options for pediatric cholestatic liver diseases are summarized.

MCT - medium chain triglycerides, TPGS - D-alpha-tocopheryl polyethylene glycol succinate, UTI - urinary tract infection, CMV - cytomegalovirus, HSV - herpes simplex virus, PFIC - progressive familial intrahepatic cholestasis, BASD - bile acid synthesis defects. Created with BioRender.com.

A comprehensive nutritional assessment and physical exam with anthropometric measurements are essential to identify patients at risk for malnutrition. Weight for age and body mass index underestimate the degree of malnutrition in children with end-stage liver disease due to ascites and organomegaly. Length is not a sensitive measure for acute changes in chronic malnutrition.⁶ More reliable indicators of nutritional status include mid-upper arm circumference (MUAC) that measures the amount of muscle and subcutaneous fat stores, and triceps skin fold thickness (TSF) that assesses the amount of subcutaneous fat. Both MUAC and TSF are sensitive to acute changes in nutrition and are not affected by organomegaly or ascites, however skin fold thickness is not accurate in infants under 3 months of age due to differences in fluid compartments.⁸ Prior research has shown an association between low MUAC and higher PELD scores in children with BA.⁹ MUAC and TSF measurements can be repeated every 2 weeks to 3 months to assess changes in growth. However, standardization of technique is important to minimize inter-operator variability in the anthropometric measurements.⁸ Assessment of muscle mass (lean mass) and function (frailty) by methods such as bioimpedance analysis and cross sectional imaging may also be considered, although standard functional tests are difficult to apply to infants and young children and there is scarcity of normative data in a developing child.^{6, 10}

Sarcopenia is the unintentional loss of muscle or lean mass and is a key feature of malnutrition in children with cholestatic liver diseases. Sarcopenia is associated with poor quality of life and increased mortality on the pediatric LT wait list or post-transplant.^{11, 12} Tools to assess muscle mass include dual x-ray absorptiometry, bioimpedance analysis air displacement plethysmography, and cross-sectional imaging. CT scan-based psoas muscle measurements at L3 are a gold standard for the assessment of sarcopenia in adults.¹³ However, studies in children are more heterogeneous as additional factors such as age and pubertal growth must be accounted for to determine normative values for pediatric sarcopenia.¹⁴

Children with cholestatic liver disease have increased caloric needs with requirements up to 130–150% of age-based requirements.^{6 10} Energy sources are comprised of 60–70% carbohydrates (Polymers) and 30–40% lipids. In cholestatic liver diseases, lipids should include a high proportion of medium chain triglycerides (MCT) since they can be directly absorbed to the portal circulation without the need for emulsification by bile salts. The optimal MCT percentage should be 30–50% of the total fat to avoid the risk of essential fatty acid deficiency.⁶ Protein intake should be about 2–4 g/kg/day aiming for a positive nitrogen balance. Laboratory screening for essential fatty acid deficiency should be considered every 3–6 months based on the duration and severity of cholestasis, if the MCT % is >70%, or if clinical signs/symptoms such as dry/scaly skin, poor wound healing, or sub-optimal growth. The composition of many commercial formulas fulfills these requirements although formula must often be concentrated to meet the energy requirement within a reasonable volume.¹⁰ Supplemental or continuous nasogastric feeds as well as total parenteral nutrition might be needed for nutritional optimization prior to LT.^{6, 10, 15} Recommendations for addressing challenges associated with each method of supplemental feeds is beyond the scope of the current review but well described in prior studies.^{6, 10, 16}

Fat-soluble vitamin deficiency in cholestasis occurs due to malabsorption in the setting of impaired bile flow. Close monitoring of serum vitamin levels and prothrombin time should be done regularly at intervals of every 1–2 months until stable levels are achieved and then a minimum of every 3–6 months (Table 1). D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is a synthetic derivative of vitamin E (alpha-tocopheryl) that improves the absorption of vitamins A and D and is therefore included in multivitamins such as TPGS-based AquADEKs or TPGS-based DEKAs Plus.¹⁷ Water-soluble vitamins should be supplemented at twice the recommended dietary allowance for age.¹⁰ Zinc and selenium levels should be measured as clinically indicated and supplemented if needed, and copper levels should be monitored both for toxicity and deficiency in the setting of cholestasis.¹⁰

Table 1.

Recommendations for monitoring and supplementation of fat-soluble vitamins

Vitamin+	Laboratory monitoring	Supplementation	Deficiency	Toxicity
A	Serum retinol: goal > 20 ug/dl Retinol/RBP ratio*: goal >0.8	< 10 kg 5000 IU/day PO > 10 kg 10,000 IU/day PO Alternate IM dosing 50,000 IU	Night blindness Xerophthalmia Follicular keratosis	Hypercalcemia Pseudotumor Hepatic fibrosis
D	25-Hydroxyvitamin: goal 20–60 ng/ml	Cholecalciferol (D3) ⴕ‖ 2000–5000 IU/day PO Ergocalciferol (D2) 50,000 IU weekly PO	Hypocalcemia Hypophosphatemia Decreased bone mineral density Rickets	Hypercalcemia Hypercalciuria Nephrocalcinosis
E	Tocopherol/total lipid ratio‡: goal > 0.6 mg/g in < 1 year or > 0.8 mg/g in > 1 year	15–25 IU/kg/d as TPGS §	Hyporeflexia, ataxia, neuropathy Hemolytic anemia	Abnormal neutrophil chemotaxis Diarrhea
K	INR: goal ≤ 1.2	< 1.5: 2–5 mg PO daily to every other day > 1.5: 5 mg IV, IM, SC every 2 weeks	Bleeding	None

^*Retinol/retinol binding protein molar ratio

^ⴕCholecalciferol (D3) is more potent and better bioavailability

^‡In cholestasis high increased lipoprotein levels may falsely elevate serum Vit E levels

^§TPGS = D-alpha-tocopheryl polyethylene glycol-succinate

^‖Co-administration of TPGS for better absorption of other fat-soluble vitamins

⁺Commercially available liquid multivitamins:

1) DEKAs Plus liquid 1 ml: Vitamin A: 5751 IU (1727 mcg); Vitamin D₃: 750 IU (18.8 mcg); Vitamin E: 50 IU (33.6 mg); Vitamin K: 500 mcg (formulary also in softgels, capsules and chewables)

2) DEKAs Essential liquid 1 ml: Vitamin A: 2500 IU (750 mcg); Vitamin D₃: 2000 IU (50 mcg); Vitamin E (100% TPGS): 75 IU (50 mg); Vitamin K: 2000 mcg (formulary also in capsules)

Medical therapies and their mechanism of action

Medical therapies for neonatal cholestasis can be tailored to underlying etiologies of cholestasis as well as patient symptoms (Table 2 and Figure 1). Early initiation of life saving therapies is of paramount importance to prevent progression of disease or decompensation in infectious and metabolic (e.g., tyrosinemia, galactosemia) etiologies of cholestasis (Table 2a). However, several diseases causing neonatal cholestasis have limited targeted therapeutic options. Furthermore, many newer medications used for pediatric cholestatic liver disease have limited data on long-term efficacy and there is a lack of comparative studies or evaluation of combination therapy. These challenges highlight the need for ongoing studies to expand upon the current treatment landscape described below.

Table 2.

Treatment of pediatric cholestatic liver disease.

2a. Treatment by disease etiology
Underlying cause	Treatment
Infections
Cytomegalovirus	Ganciclovir
Syphilis	Penicillin
HSV	Acyclovir
Sepsis, UTI	Antibiotics (based on cultures)
Metabolic/genetic
Tyrosinemia	NTBC, low tyrosine diet
Galactosemia	Galactose-free formula
Niemann-Pick C	Miglustat
BASD	Cholic acid (10–15mg/kg/d)
Zellweger syndrome	Cholic acid (10–15mg/kg/d)
Endocrine
Hypopituitarism	Hormonal replacement
Hypothyroidism	Thyroid hormone
Other
Neonatal lupus	Corticosteroids
Parenteral nutrition associated cholestasis	Enteral feedings as able, modified lipid emulsions
2b. Medical therapies for cholestatic pruritus
Medication	Pediatric dose	Mechanism of action
Ileal bile acid transport inhibitors
Maralixibat*	ALGS: 380mcg/kg/day PFIC: 570mcg/kg BID	Blocks the reuptake of bile acids in the terminal ileum
Odevixibat*	ALGS: 120mcg/kg/day PFIC: 40mcg/kg/day
Ursodiol	15–20mg/kg/day	Facilitate bile flow & reduces toxic bile acids
Bile Acid Sequestrants
Cholestyramine	4–12g/day	Anion exchange to sequester systemic bile acids
Colestipol	2–16g/day
Rifampin	10–20mg/kg/day	Decreases LPA production
Antihistamines
Diphenhydramine	5mg/kg/day	Blocks the action of histamine
Hydroxyzine	50–100mg/day
Opioid Antagonists
Naltrexone	1–2mg/kg/d	Blocks opioid receptors in the CNS & PNS
Naloxone	1mcg/kg/hour
Antidepressants
Sertraline	2.2mg/kg/d	Not established

^*Recommended dosing reported; see manufacturer guidelines for dosing titrations and maximum dosing per age

Treatment strategies used across multiple etiologies of pediatric cholestatic liver diseases are summarized in Table 2b and Figure 1. Bile acids such as ursodeoxycholic acid (UDCA) are frequently used for general treatment of pediatric cholestatic liver diseases although it is not approved by FDA for pediatric usage. UDCA is a hydrophilic bile acid with various complementary mechanisms to reduce toxic bile acid pools and facilitate bile flow, as well as possible anti-inflammatory and anti-fibrotic properties.^{18, 19} The oral administration of UDCA has been shown to be safe and well tolerated but there is limited data on its impact on patient outcomes. Cholic acid is a FDA approved primary bile acid used in bile acid synthesis defects and Zellweger syndrome. ²⁰

One of the central goals for medical management of pediatric cholestasis is treatment of symptoms to improve quality of life, particularly pruritus.^{21, 22} Historically, there have been limited options for the treatment for cholestatic pruritus, and even fewer that have pediatric-specific data. The newest drug class on the market is the ileal bile acid transporter (IBAT) inhibitors, including maralixibat and odevixibat. IBAT inhibitors interrupt the enterohepatic recirculation of bile acids resulting in decreased absorption and greater intestinal excretion of bile acids thereby decreasing the systemic bile acid pool as measured by serum bile acids.²³ This class has rigorous data showing an early and sustained reduction in both pruritus and serum bile acids in patients with ALGS and Progressive Familial Intrahepatic Cholestasis (PFIC).^23–28

Rifampin has been commonly considered as 2nd line treatment for cholestatic pruritus after UDCA although this paradigm may shift with greater use of IBAT inhibitors.²¹ Proposed mechanisms for rifampin in the treatment of cholestatic pruritus include downregulation of autotaxin resulting in less production of the potential pruritogen lysophosphatidic acid. As a pregnane X receptor agonist, rifampin may also enhance hepatic elimination of bile. While there is minimal data on the efficacy of rifampin in pediatrics, meta-analysis in adults has shown reasonable short-term efficacy, but there is concern for hepatotoxicity with long-term use.²⁹ Bile acid binding resins, e.g. cholestyramine, can treat cholestatic pruritus by sequestering intestinal bile acids and preventing their reabsorption to decrease the systemic bile acid pool. However, specific data on efficacy is lacking and their use is limited by side effects (constipation, diarrhea, bloating) and strict dosing recommendations to prevent interaction with other medications. Other medications acting on central nervous system such as antihistamines (e.g. hydroxyzine), opioid antagonists (e.g. naltrexone) and ani-depressants (e.g. sertraline) have been used off-label with variable success to improve quality of life of patients with refractory pruritus but are limited due to their side effects.²¹ Newer drugs targeting bile acid receptors such as farnesoid X receptor, the G protein-coupled bile acid receptor 1, and peroxisome-proliferator activator receptor agonists³⁰ are under development to alter bile acid production in cholestasis, but none have been used in children with cholestasis. As new therapies are developed, it remains critical to ensure equitable access to avoid disparities in medical treatment.

Surgical management

The indication and timing of surgical intervention varies both due to patient phenotypic heterogeneity within diseases as well as center practices. In the current review we provide a summary of general surgical management strategies for pediatric cholestatic liver diseases prior to consideration of LT including hepatoportoenterostomy (HPE), partial external biliary diversion (PEBD), and management of choledochal cyst (Figure 1).

In infants with suspected BA, an intraoperative cholangiogram should be performed followed by HPE to re-establish bile flow. The success of HPE is most dependent on age at intervention, anatomic pattern of extrahepatic biliary remanent, associated malformations, presence of cirrhosis, and expertise/experience of the surgeon/center. Multiple studies have confirmed that earlier age at HPE is associated with better outcomes including infants under 30 days of age.^31–33 Success of HPE is often measured by improvement of the total bilirubin level to < 2 mg/dl at 3 months post HPE.³¹ After HPE, therapies typically aim to prevent complications such as cholangitis, growth failure, and portal hypertension or control pruritus as described above. Children with non-draining HPE (e.g., total bilirubin > 6 mg/dl) will typically progress to liver transplant by 2 years of age. Liver transplant is necessary when complications of cirrhosis occur, with about 40% of patients needing a LT by two years of age and > 70% of all the patients requiring transplant before adulthood.^31–34 In contrast to BA, HPE is not indicated in ALGS as it is associated with worse outcomes.^{35, 36} It remains unclear whether the HPE operation directly deteriorates liver outcome due to complications such as cholangitis, or if children progress to transplant more quickly due to a more severe phenotype of ALGS.^{36, 37}

For children and adults with ALGS or PFIC with intractable pruritus refractory to medical management, surgical intervention with PEBD can be considered to disrupt the enterohepatic circulation of bile acids, prevent intestinal re-uptake of bile acids and decrease total body bile acids. PEBD uses a jejunal conduit to drain the gallbladder externally and allow 30–70% of bile to drain out of an ostomy³⁸. While PEBD can improve quality of life in both ALGS and PFIC^{39, 40}, PEBD is reportedly less effective to slow disease progression in ALGS perhaps due to the hypoplastic biliary tree in ALGS.⁴¹ Improvement in pruritus after PEBD can occur in up to 81% of patients with PFIC1 and 76% of those with PFIC2.⁴² A variant of this procedure consists of an internal diversion to the colon by partial ileal exclusion to reduce the need for an ostomy bag, however this procedure is less commonly performed despite no definitive evidence of superiority between surgical options.^{43, 44} Success of surgical biliary diversion and native liver survival in patients with PFIC2, is strongly correlated with genotype severity (e.g. worse outcome in BSEP truncating mutations) and reduction in serum bile acid levels after biliary diversion.⁴⁵ Complications of biliary diversion can include persistent or recurrent pruritus, electrolyte imbalances secondary to stoma losses (PEBD), and bile acid-driven diarrhea (internal diversion).⁴⁶ Biliary diversion is becoming a less common intervention for cholestatic pruritus given medical therapy with IBAT inhibitors that simulate the surgical mechanism of action although direct comparative studies regarding cost and efficacy have not been performed. Further studies are needed to define guidelines integrating emerging medical therapies with surgical management.

Despite medical management, some patients with ALGS or PFIC may still require LT. In the Global Alagille Alliance (GALA) study of children with ALGS, the median age of transplant is 2.8 years with the most common indication related to complications from chronic cholestasis (72%).⁴⁷ For those with PFIC, liver transplant can be considered when they have end-stage liver disease, hepatocellular carcinoma, or refractory pruritus. It is important to note that for those with FIC1 disease, liver transplant may lead to further complications such as pancreatitis, allograft steatosis and diarrhea, related to extrahepatic expression of ATP8B1⁴⁸.

If initial diagnostic evaluation of cholestasis identifies a choledochal cyst, surgical excision of the choledochal cyst is indicated to prevent long-term risk of malignancy, particularly cholangiocarcinoma.⁴⁹ The precise timing of choledochal cyst excision during childhood may vary based on the patient’s symptoms, the type of choledochal cyst, and the presence of possible complications such as cholangitis. Surgical approaches for alternate etiologies of pediatric cholestatic liver disease including certain types of choledochal cyst excision, e.g. Caroli Disease with congenital hepatic fibrosis, and inborn errors of metabolism can be limited, and timely LT should be considered for optimal outcomes. Full description of indications for LT, detailed guidelines for choledochal cyst excision, and surgical management in these alternate etiologies is beyond the scope of the current review.

Review of clinical trials to advance medical therapies in pediatric cholestasis

As new medical therapies are emerging, it is important to evaluate clinical trials based on the study’s endpoint(s) to integrate these therapies into clinical practice (Table 3). Evaluating efficacy of medical therapies in pediatric cholestasis is complex as clinically significant endpoints can range from improvement in quality of life (e.g., pruritus), reduction in biochemical markers of cholestasis, or slow/reverse disease progression. Recent clinical trials on IBAT inhibitors highlight challenges in assessment of therapeutic efficacy in pediatric cholestatic liver disease (Table 3). Initial evaluation of IBAT inhibitors in ALGS and PFIC used assessment of pruritus as a primary endpoint in addition to biochemical paraments, e.g. reduction in serum bile acids.^{25–28, 50} Improvement in both pruritus and serum BAs/bilirubin levels has been associated with improved event-free survival and 6-year transplant-free survival in ALGS patients treated with Maralixibat.⁵¹ Additionally, this class of medication improved overall growth of the patient by improving mean height and weight Z scores that may be related to reduced impact of high serum bile acid levels on the growth axis although further studies are needed to better define the mechanism responsible for this outcome^{27, 52}. This finding suggests these parameters could be used as surrogate end-points for disease severity in diseases like ALGS or PFIC where the time-course to develop the need for LT commonly occurs over many years. Further studies are needed to better define the strength of this correlation.

Table 3.

Overview of completed clinical trials in pediatric cholestatic liver disease.

3A. Clinical Trials for BA Outcomes
Study (Start Year)	Trial Design	Patient population	Intervention	Outcome
PRIME (2013) NCT01854827 PMID 30664564	Prospective multicenter, single-arm, open-label Phase 1/2 trial with historical controls	Cholestatic infants with biliary atresia ≤ 120 days old and within 3 days of HPE	3 doses of IVIG starting at days 3–5 post-HPE vs placebo arm of START trial	No improvement in TB or survival with native liver
START (2005) NCT00294684 PMID 24794368	Prospective randomized, multicenter, double-blind, placebo-controlled trial	Cholestatic infants with biliary atresia ≤ 180 days old at time of HPE	13 week course of steroids (IV and PO) vs placebo	No improvement in biliary drainage or survival with native liver
N-Acetylcysteine in Biliary Atresia (2018) NCT03499249 PMID 31193715	Open label Phase 2 prospective study	Infants with biliary atresia < 24 hours after HPE	7 days of IV N-Acetylcysteine post-HPE	Did not achieve normalization in total serum BAs within 24 weeks of HPE (12 patients)
3B. Clinical Trials of IBAT inhibitors for Pruritus
Study (Start Year)	Trial Design	Patient population	Intervention	Outcome
ASSERT (2021) NCT04674761 PMID 38670135	Prospective randomized, double-blind, placebo-controlled Phase 3 clinical trial	ALGS patients with a history of pruritus and elevated serum BAs	Oral odevixibat vs placebo for 24 weeks	Improvement in pruritus (PRUCISION instrument) and reduction in serum BAs
ITCH (2014) NCT02057692 PMID 30288474	Prospective randomized, double-blind, placebo-controlled Phase 2 clinical trial	ALGS patients with a history of pruritus and cholestasis	Oral maralixibat vs placebo for 13 weeks	Dose-dependent reduction in pruritus (ItchRO)
ALGS GALA-Maralixibat (not applicable) PMID 38146932	Combined retrospective and prospective	Matched cohorts from GALA and prospective clinical trials	Oral maralixibat vs standard medical care	Statistically improved event-free survival in maralixibat-treated patients
PEDFIC1 (2018) NCT03566238 PMID 35780807	Prospective randomized, double-blind, placebo-controlled Phase 3 clinical trial	PFIC1 or PFIC2 patients with a history of pruritus and elevated serum BAs	Oral odevixibat vs placebo for 24 weeks	Improvement in pruritus (PRUCISION instrument) and reduction in serum BAs
MARCH-PFIC (2019) NCT03905330 PMID 38723644	Prospective randomized, double-blind, placebo-controlled Phase 3 clinical trial	Two Cohorts: 1) non-truncated BSEP deficiency without prior surgery and without low or fluctuating BA levels, 2) all-PFIC cohort without prior surgery regardless of BA levels	Oral maralixibat vs placebo for 26 weeks	Improvement in pruritus (ItchRO(Obs) severity score) and reduction in serum BAs in both BSEP and all PFIC cohorts

In contrast to ALGS and PFIC, trials in biliary atresia have commonly focused on endpoints more directly related to disease progression and outcome after HPE (Table 3). Prospective studies in BA have included immune modulatory therapy with intravenous immunoglobulin and steroids, as well as anti-oxidant treatment with N-acetylcysteine, however, none have shown any benefit in biliary drainage or native liver survival.^53–55 More recently, use of Maralixibat in BA has evaluated both change in total serum bilirubin levels until week 26 (primary endpoint) in addition to liver-related clinical events such as death or liver transplant as a secondary endpoint (NCT04524390). A similar clinical trial of Odevixibat in BA is assessing outcomes of liver transplant or death until 104 weeks from baseline (NCT04336722). Completion and publication of these trials may inform medical management of BA at the time of diagnosis.

While transplant/death is one of the most clinically meaningful endpoints in pediatric cholestatic liver disease, these outcomes do not capture smaller changes that may significantly impact disease progression prior to LT. Newer technologies such as transient elastography (FibroScan) have more recently offered a non-invasive method for assessment of liver fibrosis in children⁵⁶, lack of comparison to the gold-standard liver biopsy limits the ability to fully define this test’s predictive accuracy. Improvement in nutritional status and patient growth is another important goal central to our care of children with cholestatic liver disease. Poor growth/malnutrition itself can be an indication for pediatric LT or it can be a clinical sign that parallels disease progression. Furthermore, several cholestatic liver diseases are characterized by altered growth independent of their liver disease (e.g., short stature in ALGS) making various markers of growth difficult to interpret as clinical endpoints in specific diseases. However, as described above, the mechanism of malnutrition in pediatric cholestatic liver disease is closely linked to the burden of cholestasis. Ongoing identification of novel biomarkers to predict disease progression and assess nutritional status in pediatric patients will be critical to fully assess treatment efficacy of future clinical trials.

Conclusion and future directions

While recent advances in the treatment for chronic pediatric cholestatic liver disease have occurred, there remain critical knowledge gaps in our clinical management. There remains an unmet need to identify therapies proven to slow disease progression, apply pharmacogenomics to personalize medical treatment, establish guidelines to integrate medical and surgical therapies, and develop novel biomarkers to guide treatment decisions. The heterogenous group of conditions may need additional unique therapies based on the severity and chronicity of liver injury, the underlying etiology, timing of diagnosis, and genetic variability. The pediatric liver community can develop better strategies to improve clinical management, particularly nutritional assessment and intervention, which is critical for the outcomes of these patients. Innovative application of state-of-the-art technology such as large-scale serum proteomics and liver tissue spatial transcriptomics may ultimately help establish non-invasive markers to accurately assess levels of fibrosis and avoid the gold standard of liver biopsy. In the meantime, multidisciplinary teams can continue to support the nutritional, surgical, and medical management of children with cholestatic liver diseases to improve patient quality of life and long-term outcomes for children with cholestatic liver diseases.

What is known:

• Pediatric cholestatic liver diseases are rare conditions that carry high morbidity.

• The current treatment landscape aims to optimize nutrition, alter the bile acid pool, and treat complications of progressive liver disease prior to possible liver transplantation.

What is new:

• IBAT inhibitors have emerged as a new drug class proven to reduce pruritus. As IBAT inhibitors simulate the mechanism of biliary diversion, greater use of these medications may decrease the use of surgical interventions for patients with cholestatic pruritus.

• Further data is needed to define long-term safety and efficacy data for IBAT inhibitors and determine if this drug class improves disease outcomes beyond their impact on pruritus.

• Ongoing clinical trials are needed to establish new medical therapies proven to slow disease progression in pediatric cholestatic liver disease.

Abbreviations:

IBAT

ileal bile acid transporter

LT

liver transplantation

IGF

insulin-like growth factor

IGF-BP3

insulin-like growth factor binding protein 3

GH

growth hormone

ALGS

Alagille syndrome

PFIC

Progressive familial intrahepatic cholestasis

MUAC

mid-upper arm circumference

TSF

triceps skin fold thickness

MCT

medium chain triglycerides

TPGS

D-alpha-tocopheryl polyethylene glycol succinate

UDCA

ursodeoxycholic acid

HPE

Hepatoportoenterostomy

PEBD

partial external biliary diversion