Summary
The purpose of this overview is to increase the awareness of clinicians regarding pediatric genetic cholestatic liver diseases, including their clinical characteristics and recommended approaches to diagnosis, management, and genetic counseling. The following are the goals of this overview.
Goal 1.
Briefly describe the common clinical characteristics of inherited cholestatic liver diseases in which cholestasis is a primary manifestation of the underlying causative pathology. Note: Disorders in which cholestasis is a secondary manifestation of the underlying causative pathology are outside the scope of this chapter.
Goal 2.
Review the genetic causes of primary cholestatic liver disease.
Goal 3.
Provide an evaluation strategy to identify the genetic cause of primary cholestatic liver disease in a proband (when possible).
Goal 4.
Inform genetic counseling of family members of an individual with primary genetic cholestatic liver disease.
Goal 5.
Review high-level dietary, medical, and surgical management of primary genetic cholestatic liver disease.
1. Clinical Characteristics of Genetic Cholestatic Liver Disease
For the purposes of this chapter, the term "primary cholestatic liver disease" is used to designate those inherited disorders in which cholestasis is a primary manifestation of the underlying causative pathology (such as transport of bile acids and phospholipids, bile acid synthesis, and bile acid metabolism or transport). Disorders in which cholestasis is a secondary manifestation of the underlying causative pathology are outside the scope of this chapter.
Cholestasis is absent or reduced bile flow associated with a pathologic condition. Cholestasis is suspected in the presence of the following clinical manifestations and is defined by the following laboratory findings.
Clinical manifestations of cholestasis
Jaundice (yellowing of the skin and/or mucous membranes and/or peripheral sclera of the eye – i.e., scleral icterus)
Pruritus or itching (commonly related to the relative elevation of serum bile acids)
Malabsorption of fat-soluble vitamins (i.e., vitamins A, D, E, and K), resulting in:
Hepatosplenomegaly
Discolored and/or pale stools (i.e., acholic stools)
The first episode of cholestasis may occur in infancy in any of the pediatric genetic disorders discussed in this overview, regardless of the natural history of the disorder.
The natural history of many genetic cholestatic disorders is progression to fibrosis (i.e., general scarring of the liver secondary to injury) that can be graded 1-4. Cirrhosis, the most severe form of fibrosis, is generally accompanied by other complications such as portal hypertension, synthetic liver dysfunction, and increased risk for hepatocellular carcinoma.
Laboratory findings of
cholestasis
Conjugated or direct hyperbilirubinemia
Note: (1) While consensus guidelines recommend evaluation of cholestatic disease for conjugated or direct bilirubin concentrations above 1.0 mg/dL (17 µmol/L) [
Fawaz et al 2017], others have proposed a more conservative approach, suggesting investigations in individuals with conjugated or direct bilirubin measurements of 0.3 mg/dL (5 µmol/L) [
Harpavat et al 2016,
Feldman & Sokol 2019]. (2) Conjugated or direct bilirubin levels may not be an accurate marker of cholestasis.
Gamma-glutamyl transferase (GGTP) levels are integral to identifying different causes of cholestatic liver disease, including:
Low-normal GGTP levels in most disorders known as progressive
familial intrahepatic cholestasis (see
Table 1);
Elevated GGTP levels in disorders with abnormal biliary duct morphology or cholangiociliopathies/ciliary development (see
Table 3).
Elevated serum bile acids
Liver and abdominal ultrasound imaging findings in individuals with pediatric genetic cholestatic liver disease may be nonspecific.
Liver ultrasound findings may include [Squires & McKiernan 2018]:
Coarseness, nodularity, or increased echogenicity
Hepatomegaly
Antegrade portal blood flow on Doppler assessment
Bile duct abnormalities including:
Abdominal ultrasound may include:
Extrahepatic clinical manifestations may be observed in certain metabolic or developmental disorders (see Table 3).
2. Causes of Genetic Cholestatic Liver Disease
Note: Pathologic cholestasis occurs in one in 2,500 newborns in North America, 40% of which is attributed to biliary atresia, an inflammatory cholangiopathy that requires immediate diagnosis (suggested by liver ultrasound examination and liver biopsy and confirmed with intraoperative cholangiogram) and life-saving surgical intervention [Karpen 2020].
The subject of this overview is the estimated 25%-50% of pediatric primary genetic cholestasis NOT related to biliary atresia that has an identifiable genetic etiology [Feldman & Sokol 2019].
The genetic disorders discussed in Tables 1, 2, and 3 of this overview are organized by the mechanism of disease causation and presence of extrahepatic findings:
Disorders of transport of bile acids or phospholipids (
Table 1)
Disorders of bile acid synthesis (
Table 2)
Disorders with extrahepatic metabolic or developmental findings (
Table 3)
Disorders of Transport of Bile Acids or Phospholipids
Table 1 summarizes primary cholestatic liver disease caused by defects that impair bile acid transport and result in progressive cholestasis. These disorders, many of which have overlapping clinical findings, are historically referred to as progressive familial intrahepatic cholestasis (PFIC) and are generally associated with onset in early infancy or childhood. However, it is increasingly apparent that pathogenic variants in PFIC-associated genes can also contribute to the adult-onset diseases benign recurrent intrahepatic cholestasis (BRIC) – intermittent episodes of cholestasis of varying severity – and intrahepatic cholestasis of pregnancy (ICP) – cholestasis, pruritus, and hepatic impairment that manifests with pregnancy and usually resolves completely after delivery. See Table 1 for the range of phenotypes observed in association with each PFIC-related gene.
Note: (1) Although some investigators have proposed the use of gene-based nomenclature (e.g., ATP8B1 deficiency) rather than phenotype-based nomenclature (e.g., PFIC1) to enable gene-specific clinical care and facilitate scientific discovery [Biesecker et al 2021, Squires & Monga 2021], this chapter primarily relies on historical phenotype-based nomenclature and classification for consistency with their use in most contemporary medical literature. (2) Table 1 does not include provisionally identified genes for which data available to date are not sufficient to associate variants with a specific phenotype or an underlying disease mechanism.
Table 1.
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Defects in Transport of Bile Acids or Phospholipids
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| Gene 1 | Disorder Designation(s) | Laboratory
Findings | PFIC Clinical Features / Comments | Adult-Onset
Phenotypes |
|---|
| BRIC | ICP |
|---|
| ABCB4 2 | PFIC3; MDR3 deficiency (OMIM 602347) | ↑ AST/ALT; ↑↑↑ GGTP | ↑ risk for HCC & CCA; ↑ risk for intrahepatic stone formation; typically AR inheritance but can be AD | | + |
| ABCB11 2 | PFIC2; BSEP deficiency (OMIM 601847) | ↑ AST/ALT; ↓ or normal GGTP | Jaundice, pruritus, & portal HTN; poor growth & malabsorption; rapid progression in 1st 5 yrs; early-onset cirrhosis; ≤15% rate of malignancy (HCC & CCA) in children as young as 13 mos | + | + |
| ATP8B1 2 | FIC1 deficiency; ATP8B1 deficiency (incl PFIC1 & BRIC1) | ↑ AST/ALT & bilirubin; ↓ or normal GGTP; ↑ electrolytes on sweat chloride test | May have profound diarrhea, poor growth, short stature, pancreatic insufficiency, & hearing loss; 3 carrier frequencies relatively high in Inuit populations of Greenland & northern Canada & Amish kindreds 4, 5 | + | + |
| KIF12 6 | KIF12 deficiency (OMIM 619662) | ↑ GGTP | Rapid progression to liver fibrosis & portal HTN; progressive sclerosing cholangitis w/age | | |
| LSR 7 | LSR deficiency | ↑ AST/ALT, bile acids, & bilirubin; ↓ or normal GGTP | Intractable itching | | |
| MYO5B 2, 8 | PFIC6 | ↑ AST/ALT & bilirubin; ↓ or normal GGTP | Microvillus inclusion disease; liver disease can be transient, progressive, or recurrent. | | |
| NR1H4 2 | PFIC5 (OMIM 617049) | ↑ AST/ALT & bilirubin; ↓ or normal GGTP; ↑↑ AFP; coagulopathy | Rapid progression to ESLD | | |
| TJP2 9 | PFIC4 | ↑ AST/ALT & bilirubin; ↓ or normal GGTP | Severe cholestasis & pruritus; rapid progression; ↑ risk for HCC; neurologic or respiratory deficits; high carrier frequency for TJP2-related genetic cholestatic liver disease among Lancaster County Old Order Amish 10 | | + |
| USP53 9 | USP53 deficiency (OMIM 619658) | ↑ AST/ALT; normal GGTP | Intractable pruritus & hypocalcemia; w/or w/o progressive hearing loss | | |
AD = autosomal dominant; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AR = autosomal recessive; AST = aspartate aminotransferase; BSEP = bile salt export pump; BRIC = benign recurrent intrahepatic cholestasis, CCA = cholangiocarcinoma; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HCC = hepatocellular carcinoma; HTN = hypertension; ICP = intrahepatic cholestasis of pregnancy; PFIC = progressive familial intrahepatic cholestasis
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Genes are listed alphabetically.
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"Byler disease" refers to severe ATP8B1 deficiency in individuals of Amish ancestry; "Greenland childhood cholestasis" or "Greenland familial cholestasis" refers to severe ATP8B1 deficiency in individuals of Inuit ancestry.
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Disorders of Bile Acid Synthesis
Table 2 summarizes primary cholestatic liver disease caused by disorders of bile acid synthesis. These disorders, generally associated with onset in early infancy or childhood, are characterized by fat-soluble vitamin deficiency with growth deficiency.
There are two main mechanisms by which bile acid synthesis defects can damage the liver:
Defective bile acids affect bile-induced bile flow, resulting in cholestasis.
Buildup of intermediates/metabolites from the process of bile acid synthesis are toxic to hepatocytes.
Note: Table 2 does not include provisionally identified genes for which data available to date are not sufficient to associate variants with a specific phenotype or an underlying disease mechanism.
Table 2.
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders of Bile Acid Synthesis
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| Gene 1, 2 | Disorder | Laboratory Findings | Clinical Features / Comments |
|---|
| AKR1D1 3 | CBAS2 (OMIM 235555) | ↑ AST/ALT; ↑ GGTP | No pruritus; HSM |
| AMACR 3 | CBAS4 (OMIM 214950) | ↓ serum bile acids | Motor neuropathy in adult-onset phenotype |
| BAAT 4 | Bile acid conjugation defect 1 (OMIM 619232) | ↑ or normal AST/ALT | Possible ESLD; high carrier frequency of BAAT-related genetic cholestatic liver disease in Lancaster County Old Order Amish community 5 |
| CYP7B1 3 | CBAS3 (OMIM 613812) | ↑ AST/ALT; ↓ or normal GGTP | HSM, synthetic dysfunction |
| CYP27A1 6 |
Cerebrotendinous xanthomatosis
| Cholestasis w/↓ or normal bile acids | Neonatal onset; neurologic findings & diarrhea |
| HSD3B7 3 | CBAS1 (OMIM 607765) | ↑ AST/ALT; ↓ or normal GGTP; ↓ serum bile acids | Most common defect; similar clinically to PFIC1 (see ATP8B1 deficiency in Table 1) but w/o pruritus or HSM |
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBAS = congenital defect in bile acid synthesis; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transpeptidase; HSM = hepatosplenomegaly; PFIC = progressive familial intrahepatic cholestasis
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Genes are listed alphabetically.
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Selected references included
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Disorders with Cholestatic Liver Disease and Extrahepatic Findings
Table 3 includes genetic disorders with extrahepatic metabolic or developmental findings in which cholestasis is the primary manifestation of underlying disease pathology that can be localized to the liver.
Note: Table 3 does not include provisionally identified genes for which data available to date are not sufficient to associate variants with a specific phenotype or an underlying disease mechanism.
Table 3.
Pediatric Genetic Cholestatic Liver Diseases: Genes and Clinical Features of Disorders with Extrahepatic Metabolic or Developmental Findings
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| Gene(s) 1 (Disorder 2) | Age of Onset | Laboratory Findings | Clinical Features / Comments |
|---|
| CFTR 3 (Cystic Fibrosis) | Childhood/
adolescence | Diagnosis requires ≥2 of following findings:
↑ AST/ALT & GGTP for >6 mos HSM, confirmed on ultrasound Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound Liver biopsy w/biliary or multilobular cirrhosis 4
Synthetic dysfunction is usually minimal. | Cystic fibrosis liver disease is diagnosed in 10%-15% of persons w/CF & is cause of mortality in 2%-3% of persons w/CF. 4 Cirrhosis & portal HTN are most clinically significant manifestations. Neonatal cholestasis is possible presenting feature. |
| CLDN1 5 (neonatal ichthyosis-sclerosing cholangitis; OMIM 607626) | Neonatal | ↑ ALT & GGTP | Portal HTN; ichthyosis & alopecia |
| DCDC2 6 (neonatal sclerosing cholangitis; OMIM 617394) | Neonatal | ↑ ALT & GGTP | Acholic stools, HSM, coagulopathy, ascites (variable presentation), renal disease |
JAG1; NOTCH2 7
(Alagille Syndrome) | Infancy | ↑↑↑ GGTP | Cholestasis, progressing to ESLD in some; butterfly vertebrae, xanthomas, CHD, posterior embryotoxon, vascular abnormalities |
| NPC1; NPC2 (Niemann-Pick Disease Type C) | Neonatal to adulthood | | Neonatal features incl cholestasis, HSM, & in some cases ALF; neurodegenerative findings in older groups |
| PEX genes (Zellweger Spectrum Disorder) | Neonatal | Abnormal VLCFA | Cholestasis + hepatomegaly; neurologic deficits |
| PKHD1 8 (Polycystic Kidney Disease, Autosomal Recessive) | Infancy to adulthood | Abnormal lab findings may be absent in newborns w/ARPKD. | Congenital hepatic fibrosis; variable dilatation of intrahepatic bile ducts (Caroli syndrome) & dilatation of common bile duct; nephromegaly, HTN, & varying degrees of renal dysfunction |
| SCYL1 9 (cholestasis, acute liver failure, and neurodegeneration; OMIM 616719) | Infancy | Low GGTP | Cholestasis, fibrosis, & recurrent ALF; DD, neuropathy, cerebellar atrophy, ataxia, chronic anemia, skeletal dysplasia |
| SERPINA1 (Alpha-1 Antitrypsin Deficiency) | Infancy to adulthood | ↑ AST/ALT & GGTP in 20% | Neonatal onset in severe phenotype w/cholestasis & progressive liver disease. HCC possible; chronic obstructive lung disease, panniculitis, & vasculitis; rare in Asian populations |
| SLC25A13 (neonatal intrahepatic cholestasis caused by citrin deficiency; see Citrin Deficiency) | Age <1 yr | Hypoproteinemia, synthetic liver dysfunction; ↑ NH3; ↓ glucose | ↓ birth weight, growth restriction; transient cholestasis; resolves by age 1 yr in most |
| SLC51A 10 (SLC51A deficiency) | Neonatal | ↑ AST/ALT/ALP | Diarrhea & malabsorption, poor weight gain & bleeding; early fibrosis & cirrhosis w/cholestasis |
| SLC51B 11 (primary bile acid malabsorption 2; OMIM 619481) | Neonatal | ↑ AST/ALT & GGTP; ↑ INR, normal albumin; ↓ fat-soluble vitamins | Congenital diarrhea; prolonged jaundice in neonatal period |
| TALDO1 12 (transadolase 1 deficiency) | Neonatal | ↑ AST/ALT/ALP; normal GGTP | Hepatomegaly, pancytopenia, renal defects, cardiac defects, fetal hydrops, & dysmorphic features; ↑ HCC risk |
| TTC26 13 (biliary, renal, neurologic and skeletal syndrome; OMIM 619534) | Neonatal | ↑ liver enzymes; ↑ bilirubin; ↑ GGTP in some cases | Cardiac defects, renal abnormalities (small/echogenic kidneys, hydronephrosis), DD, pituitary stalk interruption syndrome |
| VIPAS39 (VIPAR); VPS33B (arthrogryposis, renal dysfunction, & cholestasis; PS208085) | Neonatal | ↑ AST/ALT & bilirubin; ↓ or normal GGTP | Arthrogryposis, renal tubular acidosis, & ichthyosis; poor growth; largely fatal in 1st yr of life |
| ZFYVE19 14 (ciliopathy of bile duct epithelia; OMIM 619849) | Neonatal | ↑ GGTP & bile acids; hyperlipidemia | Fibrosis/cirrhosis w/o effect on synthetic function; HSM |
ALF = acute liver failure; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ARPKD = autosomal recessive polycystic kidney disease; AST = aspartate aminotransferase; CHD = congenital heart disease; DD = developmental delay; ESLD = end-stage liver disease; GGTP = gamma-glutamyl transferase; HCC = hepatocellular carcinoma; HSM = hepatosplenomegaly; HTN = hypertension; INR = international normalized ratio; VLCFA = very long-chain fatty acids
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Genes are listed alphabetically.
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Link to GeneReview or OMIM entry
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3. Evaluation Strategies to Identify the Cause of a Genetic Cholestatic Liver Disease in a Proband
Establishing a specific cause of pediatric genetic cholestatic liver disease:
Can aid in discussions of prognosis (which are beyond the scope of this
GeneReview) and
genetic counseling;
Usually involves a medical history, physical examination, laboratory testing, family history, and
genomic/genetic testing.
Family history. A three-generation family history should be taken with attention to relatives with manifestations of a genetic cholestatic liver disease and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing. Because the vast majority of genetic cholestatic liver diseases are inherited in an autosomal recessive manner, the family history may show affected sibs and/or parental consanguinity. Absence of a known family history does not preclude the diagnosis.
Molecular genetic testing approaches can include gene-targeted testing (multigene panel) or comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician hypothesize which gene(s) are likely involved, whereas genomic testing does not.
A cholestatic liver disease multigene panel that includes some or all of the genes listed in
Tables 1,
2, and
3 is likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. Of note, given the rarity of some of the genes associated with genetic cholestatic liver disease, some panels may not include all the genes mentioned in this overview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Comprehensive
genomic testing does not require the clinician to determine which
gene(s) are likely involved and may be used if clinical suspicion for a genetic etiology remains high but more targeted investigations have not identified a genetic cause.
Exome sequencing is most commonly used;
genome sequencing is also possible.
For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
4. Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members (Autosomal Recessive Inheritance)
Parents of a proband
The parents of an affected child are presumed to be
heterozygous for one of the pathogenic variants identified in the
proband.
Once a molecular diagnosis is established in the
proband,
molecular genetic testing is recommended for the parents of a proband to confirm that both parents are
heterozygous for a
pathogenic variant and to allow reliable
recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the
proband occurred as a
de novo event in the proband or as a postzygotic
de novo event in a mosaic parent [
Jónsson et al 2017].
The
heterozygous parents of a
proband are typically asymptomatic but may rarely manifest related features. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with progressive
familial intrahepatic cholestasis (PFIC).
Sibs of a proband
If both parents are known to be
heterozygous for a
pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting
biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a
heterozygote, and a 25% chance of inheriting neither of the
familial pathogenic variants.
Heterozygous sibs may be at increased risk for transient neonatal cholestasis. Female sibs who are
heterozygous for a PFIC-associated
pathogenic variant may be at risk for intrahepatic cholestasis of pregnancy.
Offspring of a proband
Offspring of an affected individual and a
carrier have a 50% chance of being affected and a 50% chance of being carriers. Higher carrier frequencies have been reported in some populations.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a cholestatic liver disease-related pathogenic variant.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the PFIC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Alagille Syndrome Alliance
P.O. Box 22
Collierville TN 38027
Phone: 901-286-8869
Email: alagille@alagille.org
American Liver Foundation
Phone: 800-465-4837 (HelpLine)
Canadian Liver Foundation
Canada
Phone: 800-563-5483
Email: clf@liver.ca
Childhood Liver Disease Research Network (ChiLDReN)
Phone: 720-777-2598
Email: joan.hines@childrenscolorado.org
Children's Liver Disease Foundation
United Kingdom
Phone: +44 (0) 121 212 3839
Email: info@childliverdisease.org
PFIC Advocacy and Resource Network, Inc.
Email: emily@pfic.org
5. Management
The interventions discussed here focus on symptomatic treatment of clinical manifestations, surveillance issues, and disease-specific treatments/surveillance.
Symptomatic Treatment of Clinical Manifestations
Nutritional Supplements
Standard nutritional approaches for malabsorption of fat and fat-soluble vitamins that benefit growth and development:
Supplementation of the fat-soluble vitamins A, D, E, and K
Use of dietary medium-chain triglycerides (MCTs), as they are absorbed independent of bile acids. MCTs can be provided either as infant formula (e.g., Alimentum®, Pregestimil®) or as MCT oil.
Pruritus – Medical Management
Synthetic bile acids
Oral ursodeoxycholic acid (UDCA), a hydrophilic bile acid, can both replace circulating toxic hydrophobic bile salts and stimulate hepatobiliary secretion of bile salts to improve bile flow. UDCA, which is FDA approved, may be prescribed by physicians for an "off-label" indication in pediatric cholestatic liver disease (see
Table 4).
Oral cholic acid, available as Cholbam
®, an FDA-approved bile acid, is specifically used in inborn errors of bile acid synthesis (see
Table 5).
Glycocholic acid is a bile acid approved as an investigational drug by the FDA for conjugation defects (see
Table 5).
Antipruritic agents
Pruritis – Surgical Management
Surgical management by either partial external biliary diversion (PEBD) or partial ileal exclusion improves pruritus by interrupting the enterohepatic circulation of bile and decreasing bile reabsorption. Both surgical interventions are generally well tolerated and improve pruritus, normalize serum markers of liver disease, and prevent progression of liver disease (by unknown mechanisms). Of note, cirrhosis at the time of surgical intervention is associated with poorer outcomes [Squires et al 2017].
Although no studies have demonstrated superiority of either of these surgical interventions, the response to PEBD may be longer lasting than the response to ileal exclusion.
Partial external biliary diversion (PEBD), the most common procedure, uses a segment of intestine to form a conduit between the gallbladder and an opening (ostomy) in the abdominal wall. With this approach, the 30%-50% of bile excreted by the liver drains through the ostomy and can be discarded.
Initially described for children with low-GGTP forms of PFIC, PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
Some data suggest that PEBD is effective in PFIC1 (ATP8B1 deficiency) and mild-to-moderate PFIC2 (BSEP deficiency) in which some enzyme function is retained [Henkel et al 2019]; however, it may not be effective in severe PFIC2 (see Table 4). PEBD may also be effective for other forms of cholestasis – namely, Alagille syndrome (see Table 6).
Partial ileal exclusion, a less utilized approach, uses a loop of small intestine to bypass the terminal ileum, the site of most bile acid reabsorption. Complications of bypassing a portion of the small intestine can include severe malabsorption (particularly of vitamin B12) and diarrhea.
Liver Transplantation
When the medical and surgical interventions discussed above fail to provide relief from severe pruritus or prevent progression to end-stage liver disease with cirrhosis, liver transplantation often provides a good outcome.
Note that liver transplantation fails to prevent the extrahepatic complications for any of the disorders described in Tables 1, 2, and 3.
Surveillance Issues
Monitoring for complications of chronic liver disease including fibrosis and cirrhosis can be done by abdominal ultrasound examination as a first step. The presence of hepatomegaly and thrombocytopenia has been used to define clinically evident portal hypertension [Bass et al 2019].
Screening for hepatocellular carcinoma (HCC). While HCC can occur in any individual in whom cirrhosis develops, persons with BSEP deficiency (see Table 1) and alpha-1 antitrypsin deficiency are at the highest risk. In those with significant fibrosis or cirrhosis, lifelong screening is warranted with a serum AFP concentration and abdominal ultrasound examination every six to 12 months.
Screening for cholangiocarcinoma. No guidelines have been established.
Disease-Specific Treatment of Manifestations
Disorders of Transport of Bile Acids or Phospholipids
Nutritional supplements are often required for disorders of transport of bile acids or phospholipids (see Table 1).
UDCA (see Pruritus -- Medical Management) is also used as a synthetic hydrophilic bile acid replacement in all these disorders.
The two indications for liver transplantation in these conditions are disease refractory to medical/surgical supportive treatments and progression to end-stage liver disease [Henkel et al 2019].
Additional treatment is summarized in Table 4.
Table 4.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues For Disorders of Transport of Bile Acids or Phospholipids
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| Gene 1 | Disorder | Pruritus Management | Liver Transplantation | Surveillance |
|---|
| Rx | Biliary diversion 2, 3 |
|---|
|
ABCB4
| PFIC3; MDR3 deficiency | Rifaximin, cholestyramine, naltrexone, sertraline, odevixibat (IBAT) | + | + | For HCC |
|
ABCB11
| PFIC2; BSEP deficiency | + but less helpful in severe PFIC2 | Anti-BSEP antibodies can occur afterward & cause recurrent disease. |
|
ATP8B1
| ATP8B1 deficiency; PFIC1; Byler syndrome | + | Transplant possible, but worsening diarrhea & allograft steatohepatitis are post-transplant complications. | |
|
KIF12
| KIF12 deficiency | Rifaximin, cholestyramine, naltrexone, sertraline | Unknown | Case reports [Maddirevula et al 2019, Stalke et al 2022] | |
|
MYOB5
| Myosin VB deficiency | + | + when pruritus is refractory | |
|
NR1H4
| PFIC5 | Not used due to rapid progression to ESLD 4 | + | |
|
TJP2
| PFIC4 | + | Transplantation possible at younger age due to severity of neonatal disease 4 | For HCC |
|
USP53
| USP53 deficiency | Rifaximin more effective than UDCA 5 | Unknown | Unknown | |
BSEP = bile salt export pump; ESLD = end-stage liver disease; HCC = hepatocellular carcinoma; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid
- 1.
Genes are listed alphabetically.
- 2.
The surgical treatment for pruritus used in most cases is a partial external biliary diversion (PEBD). A partial internal biliary diversion (PIBD) and ileal exclusion have been documented as other methods of surgical treatment of pruritus.
- 3.
PEBD is associated with an excellent long-term outcome when serum bile acid levels normalize within one year.
- 4.
- 5.
Disorders of Bile Acid Synthesis
Nutritional supplements are often required for disorders of bile acid synthesis, since fat-soluble vitamin deficiency is a hallmark of their disease. Additional treatment is summarized in Table 5.
Table 5.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders of Bile Acid Synthesis
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| Gene 1 | Disorder | Treatment (synthetic bile acids) |
|---|
|
AKR1D1
| CBAS2 | Cholic acid |
|
AMACR
| CBAS4 |
|
BAAT
| Bile acid conjugation defect 1 | Glycocholic acid |
|
CYP7B1
| CBAS3 | Chenodeoxycholic acid may be effective. |
|
CYP27A1
|
Cerebrotendinous xanthomatosis
| Cholic acid |
|
HSD3B7
| CBAS1 |
- 1.
Genes are listed alphabetically
Disorders with Cholestatic Liver Disease and Extrahepatic Findings
Management of extrahepatic metabolic or developmental manifestations, which typically persist despite treatment of hepatic manifestations, is outside the scope of this overview.
Nutritional supplements are required. In addition to these supplements, children with cystic fibrosis may benefit from pancreatic enzymes to assist with pancreatic exocrine insufficiency, if present.
Table 6.
Pediatric Genetic Cholestatic Liver Diseases: Treatment of Manifestations and Surveillance Issues for Disorders with Extrahepatic Metabolic or Developmental Findings
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| Gene(s) 1 | Disorder | Synthetic Bile Acids | Pruritus Management | Liver Transplantation |
|---|
| Rx | Biliary diversion |
|---|
|
CFTR
|
Cystic fibrosis
| UDCA, but efficacy uncertain | | | Severe loss of hepatic synthetic function or complications of portal HTN |
|
CLDN1
| Neonatal ichthyosis-sclerosing cholangitis | Usually UDCA | | | For severe progressive liver disease |
|
DCDC2
| Neonatal sclerosing cholangitis | |
Antipruritic agents
| | For severe, progressive liver disease |
| JAG1; NOTCH2 |
Alagille syndrome
| UDCA | Maralixibat (IBAT) | + | Severe loss of hepatic synthetic function, uncontrolled pruritus, or complications of portal HTN 2 |
| NPC1; NPC2; SMPD |
Niemann-Pick disease type C
| | | | |
| PEX genes |
Zellweger spectrum disorder
| Cholic acid | | | − |
|
PKHD1
|
Polycystic kidney disease, autosomal recessive
| UDCA used when intrahepatic ductal dilatation is present (i.e., Caroli syndrome). | | | Severe cases: liver transplant or combined renal-hepatic transplant |
|
SCYL1
| Cholestasis, acute liver failure, and neurodegeneration | | | | |
|
SERPINA1
|
Alpha-1 antitrypsin deficiency
| | | | For progressive liver dysfunction / liver failure 3 |
|
SLC25A13
| Neonatal intrahepatic cholestasis caused by citrin deficiency (See Citrin Deficiency.) | | | | Liver findings typically resolve spontaneously by age 1 yr; liver transplant for severe progressive liver disease |
|
SLC51A
| SLC51A deficiency | |
Antipruritic agents
| | |
|
SLC51B
| Primary bile acid malabsorption 2 | |
Antipruritic agents
| | |
|
TALDO1
| Transadolase 1 deficiency | | | | Liver transplant in early, severe cases; higher risk for early-onset HCC |
|
TTC26
| Biliary, renal, neurologic, & skeletal syndrome | | | | Liver transplant in severe cases w/fibrosis & cirrhosis |
| VIPAS39 (VIPAR); VPS33B | Arthrogryposis, renal dysfunction, & cholestasis 4 | | | | |
|
ZFYVE19
| Ciliopathy of bile duct epithelia | |
Antipruritic agents
| | |
HCC = hepatocellular carcinoma; HTN = hypertension; UDCA = ursodeoxycholic acid
- 1.
Genes are listed alphabetically.
- 2.
For more detailed information about the clinical manifestations of the liver disease in Alagille syndrome and its management, see Childhood Liver Disease Research Network, Alagille Syndrome (pdf).
- 3.
For more detailed information about the clinical manifestations of the liver disease in alpha-1 antitrypsin deficiency and its management, see Childhood Liver Disease Research Network, Alpha-1 Antitrypsin Deficiency (pdf).
- 4.
No specific treatment or management of cholestatic liver disease in arthrogryposis, renal dysfunction, and cholestasis has been recommended.
Chapter Notes
Author Notes
James E Squires, MD, MS, joined the faculty at the Children's Hospital of Pittsburgh in 2015, where he is an associate professor in pediatrics, director of the pediatric advanced/transplant hepatology fellowship, and associate medical director of hepatology. Dr Squires remains active in both clinical and research pursuits. He is a co-investigator in the Childhood Liver Disease Research Network (ChiLDReN), an NIH-funded consortium working to improve the lives of children with rare cholestatic liver diseases. He is also a member of the Society of Pediatric Liver Transplant (SPLIT), a multifaceted organization focused on improving outcomes for children receiving liver transplantation. He is the clinical lead for the Starzl Network for Excellence in Liver Transplantation, a novel learning health network of leading pediatric transplant institutions committed to continuous improvement until every child can achieve a long and healthy life, with funding from the Patient-Centered Outcomes Research Institute (PCORI) to advance this work. Other current interests include metabolic liver disease, acute liver failure, and liver transplant.
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