Cholestasis is indicative of hepatobiliary dysfunction and, in the pediatric population, is uncommon but potentially serious. Cholestasis affects approximately one in 2500 newborn infants, in whom the most frequent cause is biliary atresia.1 Early diagnosis is crucial for its correct management and to improve patient outcomes. The aim of this document is to establish guidelines for the appropriate diagnosis and management of cholestasis, which were developed by consensus by primary care pediatricians and specialists in pediatric gastroenterology, hepatology and nutrition (Fig. 1).

Figure 1.

Diagnostic algorithm for cholestasis.

The first step was the formation of a working group composed of seven members representing the Sociedad de Gastroenterología, Hepatología y Nutrición Pediátrica (Society of Gastroenterology, Hepatology, and Pediatric Nutrition), the Asociación Española de Pediatría de Atención Primaria (Spanish Association of Primary Care Pediatrics), and the Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria (Spanish Society of Outpatient Pediatrics and Primary Care). The group formulated twelve clinical questions regarding the detection, focused diagnostic evaluation and management (nutritional, pharmacological, and surgical) of cholestasis.

The group conducted a literature search in PubMed for “pediatric cholestatic liver disease” restricted to sources published between January 2015 and December 2023 and to ages 0–18 years and for “genetic liver disease” and “histology liver disease” with no age or time restrictions. We used the shared Zotero 5.0 reference management tool. The search yielded 446 articles published in English or Spanish for which we consulted the full text. Other articles considered pertinent by reviewers for answering the formulated questions were added to the search results. Of the total articles considered, 90 were considered relevant for the development of the guideline and selected because they were suitable for answering the clinical questions that the group had formulated for the consensus process. The excluded articles either did not address the pediatric population, covered topics unrelated to cholestasis or had methodological limitations.

Each clinical question was answered by one member of the group (as appropriate based on the expertise of each member) based on the available evidence. The group did not carry out a systematic review or meta-analysis of the evidence. All members of the group reviewed all the answers a total of four times (using Google Drive), and an online meeting was held after each of these review rounds (using Microsoft Teams). All the recommendations in this guideline were established by consensus and approved by the members of the group (informal consensus process). An online vote (Google Forms) was held to rate each recommendation on a six-point Likert scale (1: strongly disagree; 2: disagree; 3: somewhat disagree; 4: somewhat agree; 5: agree; 6: strongly agree). Recommendations were approved once consensus was reached by more than 80% of participants (with ratings of 5–6). The full consensus document is available for consultation at the webpages of each of the participating scientific societies.

Cholestasis is defined as reduced bile formation or flow that may manifest with jaundice (yellowish discoloration of skin, sclera and other tissues resulting from the accumulation of excess bilirubin), partial (hypocholia) or total (acholia) discoloration of feces, choluria (dark-colored urine due to the presence of bilirubin) and pruritus.1–3

At the biochemical level, it is defined as elevated direct/conjugated bilirubin levels (serum bilirubin > 1 mg/dL or direct fraction > 20% of total bilirubin), usually accompanied by elevation of serum bile acids. Other markers of cholestasis are elevation of the enzymes gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) and of substances usually excreted in bile, such as cholesterol.1–3

Reference values for GGT vary with age, and its secretion can be induced by alcohol and drugs, which complicates its interpretation.4 Normal ranges in the healthy pediatric population have not been clearly established.4–8 Adeli et al. proposed the following upper limits of normal stratified by age in the healthy population: 219 U/L in neonates between days 0–15 post birth; 127 U/L in infants aged 15 days to 1 year; 20 U/L from 1 to 18 years.5

Elevation of AP can be difficult to interpret in children, as it is frequently elevated on account of increases in bone isoenzyme levels.9 Consequently, GGT is a more specific marker of cholestasis than PA in the pediatric population.4,9

There are three key elements in the evaluation of a patient with suspected cholestasis: a detailed history-taking, a thorough physical examination and liver function tests.1,16 In the history-taking, emphasis should be placed on the prenatal, perinatal and postnatal history of the patient and the family history (Table 3).16 The most characteristic signs and symptoms of cholestasis are jaundice, acholia or hypocholia, choluria and pruritus, although not all of them are present in every case (Table 4).1 Hypocholia may be underestimated,1,17 so the use of stool color charts1 or mobile applications (eg, PopòApp) is recommended for its assessment.

The physical examination should be thorough and include a body systems review,1,2 assessing for the presence of hepatomegaly, splenomegaly, other signs of portal hypertension and faltering growth, among others (Table 4).14

As regards laboratory tests, the initial diagnostic evaluation should include total and conjugated bilirubin measurement and a full liver function panel. Unless physiologic or breast milk jaundice are suspected, it is also indicated to order first-tier tests for etiological diagnosis in the initial workup, as cholestasis requires an expedited focused investigation.

The differential diagnosis of the various conditions that cause cholestasis can be complex. In infants with confirmed cholestasis, early diagnosis of diseases for which specific treatments are available is a priority. The evaluation should be carried out in stages based on the suspected diagnosis to determine the etiology while assessing the severity of liver disease (Fig. 1). The causes of cholestasis in older children differ significantly from those in infants, so the diagnostic evaluation will be different in these age groups (Fig. 1).

All patients with cholestasis should undergo an initial diagnostic evaluation including a full liver function panel (alanine aminotransferase, aspartate aminotransferase, GGT, AP, total/conjugated bilirubin, glucose, albumin, coagulation). In infants, it is also important to review the newborn screening results.1

Imaging tests are particularly important to rule out anatomical causes of cholestasis.3Abdominal sonography (following a fast of at least 4 h) is a simple, noninvasive technique that is useful as a first step to rule out obstructive causes, lesions of the biliary tree or choledochal cysts. Several sonographic findings are suggestive of biliary atresia, although none allows definitive diagnosis.18Intraoperative cholangiography is considered the gold standard for diagnosis of biliary atresia, so it should not be delayed if the condition is strongly suspected.3

Early detection and etiological diagnosis of cholestasis are of utmost importance, so, once cholestasis has been confirmed, we recommend timely referral for assessment by a pediatric gastroenterologist/hepatologist.1

Under certain circumstances (cholestasis in an infant, clinical or laboratory evidence of associated liver failure, hemodynamic and/or respiratory instability, or suspected neoplastic disease), the patient should be admitted to a referral hospital for immediate evaluation.19

It is estimated that between 25% and 50% of cases of cholestasis are due to identifiable genetic changes. These involve a broad range of genes that have a direct or indirect effect on bile synthesis, transport and flow. Once surgical (AVB, etc.), infectious and secondary causes have been ruled out, cholestasis in children is most likely due to a monogenic liver disease (Tables 1 and 2).10 The geneticist plays a key role in determining the most suitable genetic test for each case.

Advances in noninvasive diagnostic methods (blood chemistry tests, imaging techniques and genetic analysis) have changed the diagnostic use of liver biopsy to a secondary level.20,21 A liver biopsy should be performed in cases in which the findings of previous tests have not allowed identification of specific etiology and cases in which the degree of hepatic involvement needs to be determined more precisely.1,10Table 5 presents the possible biopsy findings in different diseases.

Patients with cholestasis often have associated symptoms and complications secondary to malnutrition, including growth faltering, fat-soluble vitamin deficiency and metabolic bone disease, among others. Malnutrition is common and has a multifactorial etiology in these patients,22 who also exhibit a 30% increase in the basal metabolic rate.11,23 In the presence of portal hypertension, the congestion of the intestinal mucosa causes malabsorption.22

On the other hand, the decreased concentration of bile salts in the bowel results in fat malabsorption.11,13 This can lead to fat-soluble vitamin deficiency, which carry a risk of coagulopathy, rickets and defective neurological, immunological and visual functions.24

When assessing nutritional status in these patients, it must be taken into account that body weight and associated measures may lead to underdiagnosis of acute malnutrition, as they are affected by the presence of ascites, edema or visceromegaly.25,26 The brachial or mid-upper arm circumference is a possible alternative for assessing short-term nutritional status and has been validated as a marker of malnutrition in patients with chronic cholestasis.26

In addition to the customary laboratory tests for assessment of nutritional status, fat-soluble vitamin levels should be monitored in these patients (Table 6).11,24,27

Increasing energy intake is recommended (delivering about 130% of the recommended calorie intake for the patient’s ideal weight),23,25 and modifying fat intake to increasing the proportion of medium chain triglycerides (MCTs), which are absorbed by passive diffusion. Restriction of protein intake is not recommended.22 Maintaining breastfeeding is also recommended, with the possibility of breastmilk fortification and MCT supplementation.20 If the infant requires supplemental formula, a formula containing larger amounts of MCTs should be chosen, with frequent use of formulas with partially or fully hydrolyzed protein.28 Patients with cholestasis require supplementation with fat-soluble vitamins, and the need of calcium supplementation should be considered given the risk of decreased bone mineral density.25,29

Pruritus is one of the most common symptoms in patients with cholestasis. It can be severe enough to be disabling. Its pathogenesis is complex, multifactorial and not well understood. It is caused by the accumulation of pruritogenic substances (bile acids, lysophosphatidic acid, etc), whose circulating levels do not necessarily correlate to the intensity of the pruritus.30 An objective measurement tool is necessary to optimize the management of pruritus. Different scales are available for assessing pruritus, such as the Itch-Ro scale and the PRUCISION scale, that have been validated in the pediatric population.

The pharmacological treatment of pruritus is symptomatic and acts through the promotion of choleresis and the modification of bile acid composition. A combination of drugs is often required to target several of the pathways involved in pruritus.31,32Fig. 2 proposes a possible regimen with the main drugs used for treatment of cholestatic pruritus.

Figure 2.

Algorithm for the treatment of cholestatic pruritus.

When medical treatment fails, invasive treatment is an option in select cases, for instance, biliary diversion, which aims to reduce ileal resorption of bile acids through the surgical interruption of the enterohepatic circulation.33 Another possible treatment is albumin dialysis via the molecular adsorbent recirculating system (MARS), which allows elimination of pruritogenic substances through their binding albumin.34 Intractable pruritus can seriously impair quality of life and is, therefore, an indication for liver transplantation.

Ileal bile acid transporters (IBATs) are proteins located in the luminal surface of terminal ileal enterocytes. Their function is to mediate the resorption of bile acids, completing the enterohepatic circulation cycle. Ileal bile acid transporter inhibitors block this process and promote the fecal excretion of bile acids.35 Two molecules have been developed (odevixibat35 and maralixibat36) that are currently approved for treatment of progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome37 in children, so far limited to hospital use.

In the pediatric age group, cholestasis is an uncommon but potentially serious condition. This consensus document provides guidance for a structured approach to management, including the early detection of signs and symptoms, the differential diagnosis and adequate treatment. Particular emphasis is placed on the early detection of treatable causes, such as biliary atresia, given the potential impact of on patient outcomes. Multidisciplinary collaboration and the use of specific diagnostic tools (e.g., genetic tests) are essential to improve the management of these patients.

This research project did not receive specific financial support from funding agencies in the public, private or not-for-profit sectors.