Progressive Familial Intrahepatic Cholestasis (PFIC) and Related Forms

A family of monogenic hepatocellular cholestatic disorders, almost always autosomal recessive, caused by defects in canalicular bile acid and phospholipid transport, tight junctions, nuclear regulation or hepatocyte polarity; the same variants, in heterozygosity or with residual function, contribute to recurrent intrahepatic cholestasis, intrahepatic cholestasis of pregnancy and low phospholipid-associated cholelithiasis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definitions and scope

Cholestasis denotes reduced or absent bile flow, and primary cholestatic liver diseases are inherited disorders in which cholestasis is the main manifestation, owing to defects in bile acid and phospholipid transport, bile acid synthesis or bile acid metabolism [3]. Transport disorders were historically grouped under progressive familial intrahepatic cholestasis (PFIC), with onset in infancy or childhood, and the same variants, in combinations with greater residual function or in heterozygosity, contribute to later-onset forms: benign recurrent intrahepatic cholestasis (BRIC, from benign recurrent intrahepatic cholestasis), with intermittent cholestatic episodes of variable severity, and intrahepatic cholestasis of pregnancy (ICP, from intrahepatic cholestasis of pregnancy), with pruritus and liver dysfunction during pregnancy that usually resolve after delivery [3]. The review by Vitale and colleagues groups paediatric forms and adult-onset cholestatic disease under familial intrahepatic cholestasis (FIC), because the same genes are involved [6].

In this article, PFIC denotes autosomal recessive monogenic hepatocellular cholestasis caused by biallelic variants in a gene involved in canalicular transport, tight junctions, transcriptional regulation of transporters, or hepatocyte polarity and apical trafficking. FIC1 deficiency (ATP8B1) encompasses a continuum between severe disease (PFIC1, Byler disease) and mild-to-moderate disease (BRIC1); BSEP deficiency (ABCB11) ranges from PFIC2 to BRIC2; MDR3 deficiency (ABCB4) ranges from biallelic PFIC3 to LPAC (low phospholipid-associated cholelithiasis, low phospholipid-associated cholelithiasis) and ICP in heterozygotes [2, 4, 7]. ICP, BRIC and LPAC are addressed as related forms, and Alagille syndrome, bile acid synthesis defects and biliary atresia as differential diagnoses.

1.2. Historical overview

The classic description of recurrent cholestasis is by Summerskill and Walshe, who in 1959 published benign recurrent intrahepatic “obstructive” jaundice in the Lancet [32]. Ten years later, Clayton, Iber, Ruebner and McKusick described Byler disease, fatal familial intrahepatic cholestasis in an Amish lineage; the bibliographic record includes no abstract, and Vitale's review reports that the study included 11 children from 6 families descended from Jacob Byler [5, 6]. Greenland familial cholestasis in Inuit children was described in the 1980s and 1990s and proved to be the same disease [4]. The earliest PFIC forms were separated by immunohistochemistry and Sanger sequencing; next-generation sequencing enabled expansion from three to thirteen types [6].

The year 1998 brought three milestones. Bull and colleagues showed that BRIC and PFIC1, previously mapped to 18q21, shared an interval of less than 1 cM and were caused by variants in the same gene, then named FIC1 and now ATP8B1, the first human member of a subfamily of P-type ATPases involved in aminophospholipid transport and expressed in several epithelia, more in the small intestine than in the liver [33]. Strautnieks and colleagues showed that the PFIC subgroup with normal cholesterol and GGT was genetically heterogeneous, with a locus on 2q, and identified variants in the liver-specific transporter BSEP (sister of P-glycoprotein), the human bile salt export pump [34]. De Vree and colleagues described high-GGT PFIC resembling the mdr2−/− mouse, lacking biliary phospholipids, in two patients with negative canalicular MDR3 staining and homozygous ABCB4 variants (a 7-bp deletion at codon 132 and a nonsense variant at codon 957) [35].

The next expansion was genomic. In 2014, truncating TJP2 variants were associated with severe cholestasis due to failed localisation of ZO-2 and disruption of tight junctions, contrasting with the embryonic lethality of the murine knockout [36]. In 2016, Gomez-Ospina and colleagues described four individuals from two families with NR1H4 (FXR) variants, rapidly progressive neonatal cholestasis, vitamin K-independent coagulopathy, low-to-normal GGT, elevated alpha-fetoprotein (AFP) and undetectable hepatic BSEP [37]. In 2017, Gonzales and colleagues described five children with a normal-GGT PFIC phenotype and MYO5B variants without microvillus inclusion disease, and Qiu and colleagues expanded the spectrum to previously undiagnosed low-GGT cholestasis [38, 39]. In 2019, exome sequencing in seven Saudi Arabian families added KIF12, USP53, LSR, WDR83OS and PPM1F [40]; that same year, two children born to consanguineous parents with high-GGT cholestasis confirmed KIF12 [41]. These were followed by USP53 in a Shanghai series [42], ZFYVE19 as a biliary ciliopathy [43], SEMA7A [44] and, in 2026, PSKH1 as a hepatorenal ciliopathy designated PFIC13 [45].

1.3. Nomenclature and reclassification

PFIC numbering is not uniform and should not be read as a stable classification. European experts and the EASL (European Association for the Study of the Liver) guideline recommend naming the deficient protein (FIC1, BSEP, MDR3 deficiency), and GeneReviews records the proposal to use gene-based rather than phenotype-based names, such as “ATP8B1 deficiency”, encompassing the entire severity continuum [1–3, 46, 47]. OMIM-based numbering, used by Vitale and the Italian real-world cohort, calls SLC51A deficiency PFIC6 and MYO5B deficiency PFIC10; in contrast, FDA (Food and Drug Administration) and EMA (European Medicines Agency) prescribing information and the PEDFIC and MARCH trials call MYO5B deficiency “PFIC6”, as does GeneReviews [3, 6, 26, 48, 49]. The Orphanet record for the PFIC group (ORPHA:172) also links OMIM numbers 619484 and 620010, whose gene-by-gene correspondence could not be established in the sources consulted because OMIM was inaccessible during source collection [13]. This article uses the protein- or gene-based designation and gives the number when quoting it from a source.

The practical consequence of this divergence is direct: when prescribing information or a trial reports results in “PFIC6”, this means patients with MYO5B variants rather than OSTα deficiency; data from the 2 “PFIC6” patients in the pooled odevixibat analysis and 4 in MARCH-PFIC should be interpreted accordingly [25, 26, 49].

1.4. Related forms and clinical reclassification

BRIC was initially understood as intermittent cholestasis without fibrosis; it is now known that early fibrosis may occur and that some patients progress over time from episodic to persistent disease, leading some authors to prefer recurrent intrahepatic cholestasis (RIC) [4, 6]. The genetic contribution to ICP risk is estimated at around 20%, with heterozygous variants in ABCB4, ABCB11, ATP8B1, TJP2 and NR1H4 [2, 6]. LPAC is the expression of partial MDR3 deficiency in young adults, with intrahepatic cholesterol stones and recurrence after cholecystectomy [2, 7]. The October 2026 review by Liebe and colleagues proposes regrouping severe paediatric PFIC and later forms under genetic cholestasis, with genotype-directed treatment [50].

2. Molecular Genetics and Pathophysiology

2.1. Bile secretion, enterohepatic circulation and the meaning of GGT

Bile acid-dependent bile flow begins at the hepatocyte canalicular membrane, where the bile salt export pump (BSEP, bile salt export pump, encoded by ABCB11) transports conjugated bile acids against a gradient in the rate-limiting step of bile secretion [2, 7]. Phosphatidylcholine is moved to the outer leaflet of the canalicular membrane by the MDR3 floppase (ABCB4) and extracted by mixed micelles, thereby protecting cholangiocytes from the detergent effect of bile salts; the FIC1 flippase (ATP8B1) moves lipids in the opposite direction and maintains the lipid asymmetry that makes the membrane resistant to that effect [2, 7]. The tight junction, organised by ZO-2 (TJP2), seals the canaliculus and prevents bile backflow; the nuclear receptor FXR (NR1H4) induces BSEP and other transporter expression; myosin Vb (MYO5B) delivers BSEP to the apical membrane through vesicular recycling [7]. In the terminal ileum, the apical sodium-dependent bile acid transporter (ASBT or IBAT, ileal bile acid transporter) reabsorbs bile acids, which return to the liver through enterohepatic circulation (EHC); interruption of this circulation, surgically or pharmacologically, is the rationale for biliary diversion and IBAT inhibitors [1, 24].

Serum GGT separates the groups. When the defect involves the canalicular pump or its regulation (FIC1, BSEP, TJP2, FXR, MYO5B, USP53), insufficient bile salts reach the biliary tree to injure the ductal epithelium and release GGT, so it remains low or normal despite marked cholestasis; when bile salts are present without sufficient phosphatidylcholine (MDR3), or when the defect involves cholangiocytes or cilia (KIF12, ZFYVE19), ductal injury raises GGT [1, 3, 7]. In bile acid synthesis defects, GGT is also normal, but because primary bile salts are absent from bile, although the enzyme is well expressed in canaliculi [4].

2.2. FIC1 deficiency (ATP8B1)

ATP8B1 (18q21.31; OMIM gene 602397) encodes a P4-subfamily P-type ATPase, the catalytic subunit of a flippase complex that translocates phospholipids from the outer to the inner leaflet; early studies identified phosphatidylserine as the substrate, whereas more recent work suggests phosphatidylcholine [4, 7]. Loss of function alters bilayer lipid composition, increases canalicular membrane vulnerability to bile acids, impairs membrane proteins including BSEP and possibly vesicular trafficking; roles in FXR signalling, with discordant findings, and innate immunity have been described [4]. The asymmetry maintained by FIC1 also supports the apical localisation of CDC42, CFTR and the ileal transporter SLC10A2, and the protein is required for microvillus formation and preservation of cochlear hair cells [7]. Expression is widespread (liver, small intestine, colon, pancreas, stomach, bladder, heart, lung, kidney, gallbladder and inner ear), explaining diarrhoea, pancreatitis, abnormal sweat testing and sensorineural deafness [4, 6]. The mechanism is loss of function.

Variants severely impairing the protein (nonsense, frameshift and large deletions) predominate in severe disease, and missense variants in mild disease [4, 51]. Nevertheless, in severe disease, the number of predicted truncating variants (0, 1 or 2) does not predict native liver survival: in the NAPPED consortium (NAtural course and Prognosis of PFIC and Effect of biliary Diversion), with 130 patients, 10-year survival was 67%, 41% and 59% in the groups with no, one and two truncating variants (p=0.12) [52]. The variant NM_001374385.1:c.1982T>C p.(Ile661Thr) is frequent in Europeans with mild disease, occasionally non-penetrant, but also occurs in compound heterozygosity in severe disease; c.923G>T p.(Gly308Val), an Amish founder variant, and c.1660G>A p.(Asp554Asn), found in Inuit people, are associated with progressive disease often requiring surgery [4, 51, 53–55]. In 2025, ClinVar contained 554 ATP8B1 variants [6]. Apart from the PFIC1, BRIC1 and ICP phenotypes in heterozygotes, no other phenotypes associated with germline ATP8B1 variants are known; variants have been described in adults with cryptogenic cirrhosis [4, 56].

2.3. BSEP deficiency (ABCB11)

ABCB11 (2q31.1; OMIM gene 603201) encodes the canalicular ABC transporter exporting conjugated bile salts, particularly taurine- or glycine-conjugated cholic acid [7]. As BSEP is present only in the canalicular membrane, extrahepatic manifestations are rare [6]. Strautnieks' series, with 109 families with severe BSEP deficiency, identified 82 variants (52 novel: 9 nonsense, 10 small insertions or deletions, 15 splice variants, 3 whole-gene deletions and 45 missense); in 7 families only one heterozygous variant was found despite complete sequencing, and NM_003742.4:c.890A>G p.(Glu297Gly) and/or c.1445A>G p.(Asp482Gly) were present in 58% of European families (52/89) [57]. Immunohistochemistry showed abnormal or absent BSEP in 93% of 88 patients, but detected some protein in 45% (19/42) of carriers of p.(Glu297Gly) or p.(Asp482Gly) [57].

Genotype is the main determinant of prognosis. Odevixibat prescribing information and the NAPPED consortium define three subgroups: BSEP1, with at least one p.(Asp482Gly) (NM_003742.4:c.1445A>G) or p.(Glu297Gly) (NM_003742.4:c.890A>G) variant; BSEP2, with at least one other missense variant; and BSEP3, with variants predicting non-functional or absent protein (PPTM, predicted protein-truncating mutations), with approximate frequencies of 27%, 52% and 21% in a global consortium of severe BSEP deficiency [24, 58]. Felzen's analysis refined this division: compound heterozygosity for p.(Asp482Gly) or p.(Glu297Gly) with a PPTM (BSEP1/3) behaves like two PPTMs rather than BSEP1 [59]. According to Vitale, adult cholestasis, such as drug-induced liver injury (DILI, drug-induced liver injury) or ICP, arises when BSEP function falls below around 25% [6]; EASL associates adult ABCB11 heterozygosity with BRIC, chronic cholestasis, ICP and DILI, often with an environmental trigger [2]. The common variant p.(Val444Ala) (NM_003742.4:c.1331T>C, rs2287622) is a susceptibility factor for ICP and drug-induced cholestasis [6, 60]. An August 2026 functional study showed that two missense variants at the same residue, NM_003742.4:c.1388C>T p.(Thr463Ile) and c.1387A>C p.(Thr463Pro), give opposite phenotypes (mild with response to diversion, or transplantation before 1 year because of a folding defect), and that pharmacological modulators increase expression or transport of these proteins in vitro [61].

2.4. MDR3 deficiency (ABCB4)

ABCB4 (7q21.12; OMIM gene 171060) encodes MDR3 (also called MDR2, PGY3 or GBD1), the canalicular phosphatidylcholine floppase; despite its name, it does not confer drug resistance [7]. Deficiency causes bile salts to circulate without sufficient phosphatidylcholine, injuring cholangiocytes (ductal injury in severe deficiency) and reducing cholesterol solubility (crystals and stones in partial deficiency) [7]. The phenotype depends on the amount of residual transporter, in a more linear relationship than for ABCB11: biallelic variants cause high-GGT PFIC3; mild or heterozygous states cause LPAC, ICP, chronic cholestasis, DILI and, according to genome data, stones, bile duct carcinoma and cirrhosis [2, 6, 7]. In Iceland, NM_000443.4:c.1865G>A p.(Gly622Glu) heterozygotes had a higher risk of fibrosis or cirrhosis (odds ratio, OR, 5.52), and carriers of NM_000443.4:c.1529A>G p.(Asn510Ser) (OR 4.74) and of the frameshift variant p.(Leu445GlyfsTer22) (OR 3.07) had a higher risk of hepatocellular carcinoma (HCC) or cholangiocarcinoma; the frameshift variant is described in the source only in protein notation (published designation, without c. mapping) [2]. The common variant NM_000443.4:c.711A>T p.(Ile237=) was associated with cirrhosis in primary biliary cholangitis in a Polish cohort of 867 patients [6]. There are no clear genotype–phenotype correlations in the heterozygous form, and intrafamilial variation is wide [62]; in biallelic deficiency, however, the response to UDCA depends on genotype (section 7).

2.5. TJP2 deficiency

TJP2 (9q21.11; OMIM gene 607709) encodes ZO-2, a MAGUK-family scaffolding protein of tight and adherens junctions [7]. Biallelic truncating variants prevent ZO-2 localisation and disrupt the junction, with bile backflow into the paracellular space [7, 36]; claudin-1 is no longer positioned at the membrane [6]. The murine knockout is embryonically lethal and does not model the disease [7]. Two weak associations should not be conflated with PFIC4: familial hypercholanaemia, with complex inheritance involving BAAT, and autosomal dominant non-syndromic deafness DFNA51, caused by a 270-kb duplication including the gene (ClinGen validity “limited”); heterozygosity for TJP2 variants should therefore not be reported as a cause of deafness [7, 63].

2.6. FXR deficiency (NR1H4)

NR1H4 (12q23.1; OMIM gene 603826) encodes FXR, a bile acid nuclear receptor that heterodimerises with RXR and represses synthesis (through SHP and CYP7A1), restricts uptake (NTCP) and induces conjugation and export (BAAT, SLC27A5, BSEP, MRP2, MDR3) [7]. Without FXR, BSEP is not induced although the ABCB11 gene is intact; immunohistochemistry shows absent BSEP, as in BSEP deficiency [7, 37]. The variant NM_001206979.2:c.887C>T p.(Thr296Ile) prevents ligand-induced activation, and in a series of 13 patients, 5 of 12 variants were located in exon 5 [7, 64]. No clinical assay of FXR activity exists [7].

2.7. MYO5B deficiency

MYO5B (18q21.1; OMIM gene 606540) encodes myosin Vb, an actin motor acting with RAB11A, RAB8A and RAB25 in apical vesicular recycling; in enterocytes it forms the brush border, and in hepatocytes it places BSEP at the canalicular membrane [7]. The gene has two recessive presentations: microvillus inclusion disease (MVID, microvillus inclusion disease), with congenital secretory diarrhoea, and cholestasis without enteropathy [7]. Variants abolishing expression are much more frequent in typical MVID than in isolated cholestasis, suggesting that residual protein spares the intestine [7, 39]. Liver biopsy shows mislocalised BSEP and coarse granular displacement of MYO5B [39]; Orphanet also lists MYO5B in the PFIC1 record, reflecting phenotypic overlap [14].

2.8. Genes described after 2017

The USP53 protein interacts with TJP2; ultrastructure shows elongated tight junctions between hepatocytes [4, 40, 42]. In a Shanghai cohort (2011–2018), exome sequencing of 69 children with low-GGT cholestasis without biallelic variants in ATP8B1, ABCB11, NR1H4, MYO5B or TJP2 identified 7 patients from 7 families with biallelic USP53 variants, including NM_001371395.1:c.169C>T p.(Arg57Ter), c.1012C>T p.(Arg338Ter) and c.569+2T>C; around 20% of low-GGT cholestasis remained without an aetiology [42]. KIF12 encodes a kinesin, also ciliary, whose expression depends on HNF-1β and which is required for hepatocyte polarity; loss alters functional polarity and causes high-GGT cholestasis [7, 40, 65]. ZFYVE19 causes a biliary epithelial ciliopathy with ductal plate malformation [43]. Homozygous SEMA7A NM_003612.5:c.442C>T p.(Arg148Trp) was described in a Han Chinese child, with a probable gain of function reducing canalicular BSEP and MRP2 in the mouse model [6, 44]. SLC51A encodes OSTα, a subunit of the OSTα-OSTβ bile acid transporter [1, 6]. Biallelic VPS33B or VIPAS39 variants cause ARC syndrome, and some VPS33B variants cause low-GGT cholestasis without the full syndrome [4, 6]. PSKH1 encodes a kinase whose loss results in long, tortuous cilia in renal tubules and bile ducts [45]. LSR and WDR83OS (the latter interacting with ATP13A2 and BSEP) have been described in individual families [40].

2.9. Notable variants and HGVS nomenclature (Human Genome Variation Society)

The variants below were normalised using VariantValidator against MANE Select transcripts on 10 October 2026; for ATP8B1, the MANE transcript NM_001374385.1 and historical NM_005603.6 give the same c./p. numbering for all tested variants, and GeneReviews uses NM_005603.5 [4, 9]. Phenotypic associations come from clinical sources rather than VariantValidator.

In historical notation, the ABCB11 variants appear as E297G and D482G, and the Icelandic ABCB4 variant as p.L445GfsX22; the EASL guideline twice writes “p.D487G”, a typographical error for p.(Asp482Gly) [2].

2.10. Inheritance, penetrance, expressivity and modifiers

The great majority of primary paediatric genetic cholestatic disorders are autosomal recessive; exceptions are Alagille syndrome (dominant), some ABCB4-associated liver disease (dominant) and α1-antitrypsin deficiency (codominant) [3, 62]. Expressivity varies within families: siblings with the same ATP8B1 variants do not always have the same severity, and severity may change over a lifetime [4]. In late-onset disease, the phenotype results from interaction of one or more variants with environmental factors such as drugs, pregnancy, infections or other liver diseases [2]. In a German cohort of 427 patients, 154 variants were found in FIC1, BSEP and MDR3 (25 novel), and BSEP and MDR3 polymorphisms were overrepresented in patients without a causal variant [6]. Multigenic burden is frequent: in a series of 26 children with monoallelic variants of uncertain significance (VUS) in PFIC genes, 73.1% had variants in other cholestasis genes [70]. In an Italian cohort of 48 patients with cryptogenic cholestasis, multiple variants were associated with a more aggressive phenotype [6].

2.11. Allelic diseases and overlap

3. Clinical Spectrum and Manifestations by Organ System

3.1. Common manifestations of cholestasis

Cholestasis manifests as jaundice, pruritus related to elevated serum bile acids, malabsorption of vitamins A, D, E and K (with poor weight gain, bruising and bleeding due to vitamin K deficiency), hepatosplenomegaly and pale or acholic stools [3]. The first episode may occur in childhood in any of these disorders, and the natural history of many is progressive fibrosis leading to cirrhosis, with portal hypertension, loss of synthetic function and HCC risk [3]. Pruritus is the symptom with the greatest impact on families' lives: in the PFIC Network patient registry, with 161 patients at baseline, pruritus severity correlated with sleep disturbance, poorer family quality of life and poorer overall health, and direct costs exceeded those of the general US population [72]. The table summarises gene-specific phenotypes according to the European expert opinion.

3.2. FIC1 deficiency (ATP8B1)

FIC1 deficiency is a continuum between severe disease (PFIC1), with infantile-onset cholestasis progressing to cirrhosis, liver failure and early death without treatment, and mild-to-moderate disease (BRIC1) [4]. Severe disease typically presents in the first year with intense pruritus and jaundice; because pruritus onset depends on the ability to scratch in a coordinated way, irritability may be the first manifestation, and some patients were treated for prolonged periods as having chronic dermatoses [4, 54, 73]. Coagulopathy, malabsorption and poor weight gain may arise before 3 months, and cirrhosis usually develops by the end of the first decade [4]. Vitale describes onset within the first 3 months, normal GGT and AFP, alanine aminotransferase (ALT) below five times the upper limit of normal (ULN), moderate jaundice and a sometimes enlarged gallbladder [6]. Cholestasis may begin with episodes separated by symptom-free intervals but becomes constant; triggers include intercurrent illness, drugs, hormonal changes (contraceptives, pregnancy) and malignancy [4]. Pruritus is disproportionate to bilirubin and proportional to bile acids, and jaundice is frequently intermittent [4].

Nutritional deficiencies manifest as bruising and bleeding (vitamin K), rickets (vitamin D) and neurological abnormalities (vitamin E); vitamin A is frequently normal or high, and supplementation is rarely necessary [4, 54, 55]. Growth failure exceeds that expected from cholestasis alone [73]. Diarrhoea, due to pancreatic insufficiency and ileal dysfunction, may be profound and persist or worsen after transplantation [4, 74, 75]. Extrahepatic manifestations include high-frequency sensorineural deafness, often detected in late adolescence, progressive and common across the spectrum [4, 76]; pancreatitis or exocrine pancreatic insufficiency; and, rarely, parathyroid hormone resistance, renal stones, acute renal failure, delayed puberty, epistaxis without coagulopathy and nail dystrophy [4, 77]. In a comparison of 42 patients with FIC1 deficiency and 60 with BSEP deficiency, FIC1 deficiency was associated with diarrhoea, graft steatosis, pancreatic disease and less catch-up weight gain after transplantation [6].

The table follows GeneReviews [4]. NAPPED natural history data, with 130 patients with biallelic variants, show native liver survival of 44% at age 18; patients with serum bile acids below 194 µmol/L at presentation had 10-year survival of 49%, versus 15% with values at or above this threshold (p=0.03) [52]. This group includes patients treated with biliary diversion and is not a pure natural history cohort. After transplantation, two children with chronic diarrhoea and short stature, followed for 9.5 to 11 years, had worsening diarrhoea, no catch-up growth in height and graft steatosis [78].

3.3. BSEP deficiency (ABCB11)

BSEP deficiency generally presents earlier than FIC1 deficiency, with jaundice, severe and frequently intractable pruritus, hepatomegaly, growth failure and fat malabsorption; serum bile acids and AFP are elevated and GGT low [6, 7]. Progression is rapid in the first 5 years, with portal hypertension and early cirrhosis [3]. Extrahepatic manifestations are less common than in FIC1 deficiency, gallstones are more frequent in severe disease, and transaminases, albumin, bile acids and AFP tend to be higher [4, 73, 74]. After transplantation, diarrhoea, pancreatitis and graft steatosis are not described, but the immunological problem of anti-BSEP alloimmunisation arises (section 7.8) [2, 4].

Childhood hepatobiliary neoplasia is the most distinguishing feature of BSEP deficiency. In Strautnieks' series, 15% of patients (19/128) had HCC or cholangiocarcinoma, with a risk of 38% (8/21) in carriers of two PPTMs versus 10% (11/107) in the remainder (relative risk 3.7; 95% confidence interval, 95% CI, 1.7–8.1) [57]. Knisely described 11 children with HCC between 13 and 52 months, of whom 9 (and the sibling of a tenth) had immunohistochemical BSEP deficiency; risk is not explained by cirrhosis alone [7, 79].

NAPPED described genotype-specific natural history in 264 patients with biallelic ABCB11 variants: median native liver survival of 20.4 years in BSEP1, 7.0 in BSEP2 and 3.5 in BSEP3 (p<0.001), and HCC by age 15 in 4%, 7% and 34%, respectively (p=0.001) [58]. In Felzen's analysis, 10-year native liver survival was 75% in BSEP1/1 (n=31), 21% in BSEP1/3 (n=30) and 23% in BSEP3/3 (n=77) (p<0.001), with median age at presentation between 0.7 and 1.3 years [59]. These figures include patients with and without diversion and describe a period before IBATi.

3.4. MDR3 deficiency (ABCB4)

Biallelic MDR3 deficiency presents in infancy, childhood or young adulthood, sometimes only at 2–3 years, with jaundice, diarrhoea, fever, pruritus and hepatosplenomegaly; GGT is high, cholesterol normal and bile acids normal or slightly elevated [6]. Histology shows true ductular proliferation, portal fibrosis and biliary cirrhosis; cholangiography is normal, excluding sclerosing cholangitis, and biliary phospholipids are low [6]. Untreated progression is cholestasis, fibrosis, cirrhosis and end-stage disease before adulthood, with risk of HCC, cholangiocarcinoma and intrahepatic stones [3, 7]. Patients with two severe variants generally require transplantation before 10 years, and UDCA responders, particularly with at least one missense variant, may reach adulthood with their native liver [2]. Cognitive abnormalities, growth retardation and reduced bone density have been described [1, 6].

3.5. TJP2, FXR and MYO5B deficiencies

TJP2 deficiency presents in infancy with severe cholestasis and pruritus, elevated transaminases and bilirubin, low GGT and rapid progression; neurological and respiratory manifestations (subdural haematomas and chronic respiratory disease in 2 patients) and increased childhood HCC risk have been described [6, 7, 80]. Orphanet records 14 cases or families [17].

FXR deficiency is the most rapid form. In Li and colleagues' synthesis of 13 patients, neonatal jaundice occurred in 12, with median onset at 7 days; cholestasis in 13/13; elevated AFP in 11/11; coagulopathy in 11/11; hypoglycaemia in 9/13 (69%); growth retardation in 8/13 (62%); splenomegaly and hyperammonaemia in 7/13 (54%); and hepatomegaly in 6/13 (46%) [64]. The 7 non-transplanted patients died at a median of 5 months (1.2–8 months); of the 6 transplanted patients (median 6.2 months), all survived except one who died from acute infection a year later [64]. Himes described three children from two families with rapidly progressive liver failure, one well 6 years after transplantation [81].

MYO5B deficiency has two recessive presentations. MVID causes intractable secretory diarrhoea from the first days or after 3–4 months, with dehydration and acidosis, not stopping with fasting and requiring lifelong parenteral nutrition (PN) [7]. Cholestasis without enteropathy was described in 10 children without recurrent diarrhoea or PN, with progressive, recurrent or transient courses; an estimate from two cohorts suggests MYO5B accounts for approximately 20% of low-GGT cholestasis without a prior diagnosis [7, 39]. Cholestasis is a primary hepatic gene manifestation rather than only PN-associated liver disease; the bile acid profile resembles BSEP deficiency [7]. Some patients have language delay or pyramidal syndrome [6].

3.6. Other genes

USP53 deficiency begins between childhood and adolescence, with generally mild intermittent cholestasis, normal GGT, frequent fibrosis, intractable pruritus, hypocalcaemia and sometimes progressive deafness; in the Shanghai series, jaundice appeared before 7 months and cholestasis was transient, resolving [3, 6, 42, 82]. KIF12 deficiency ranges from complete remission to transplantation: six children from four families, homozygous for truncating variants, ranged from transient neonatal cholestasis to progressive disease with cirrhosis, and fewer than 20 patients are recorded, mainly from consanguineous families [6, 7, 65]. In ZFYVE19 deficiency, all 9 Han Chinese children described had portal hypertension and ductal plate malformation or congenital hepatic fibrosis with small-duct sclerosing cholangitis, and 4 underwent transplantation for recurrent gastrointestinal bleeding [43]. OSTα deficiency causes chronic malabsorptive diarrhoea, elevated GGT and alkaline phosphatase, portal fibrosis, coagulopathy, severe vitamin deficiencies and rickets (one Pakistani child and two Palestinian siblings) [6]. VPS33B deficiency combines neonatal jaundice, intense pruritus and low GGT, with arthrogryposis and renal dysfunction in those with ARC syndrome [6]. PSKH1 deficiency was identified by exome sequencing in 4 families from a cohort of 299 patients from 279 families with intrahepatic cholestasis, with chronic liver disease in childhood or adolescence with or without renal failure [6, 45]. LSR deficiency caused transient neonatal cholestasis with intellectual disability and short stature, and WDR83OS deficiency intractable pruritus, hypercholanaemia, short stature and intellectual disability [40]; Uehara and colleagues subsequently described biallelic LSR variants as a cause of infantile intrahepatic cholestasis [83]. The French PNDS on bile acid synthesis defects also groups with the genetic hepatocellular cholestases close to PFIC the UNC45A deficiency and osteo-oto-hepato-enteric syndrome, alongside BRIC, MYO5B deficiency and ARC syndrome [29].

3.7. Recurrent intrahepatic cholestasis (BRIC)

BRIC is defined by at least two jaundice episodes with elevated bilirubin and alkaline phosphatase and normal or near-normal GGT, without extrahepatic obstruction [4, 6]. The first episode occurs between 1 and 59 years; attacks last weeks to months, separated by asymptomatic intervals of months to years, and are triggered by pregnancy, drugs or infections, although often no cause is identified [4, 6]. Between episodes, bile acids and bilirubin normalise [4]. The genes are ATP8B1 (BRIC1) and ABCB11 (BRIC2), with cases attributed to MYO5B and USP53; ABCB4 causes episodic cholestasis only anecdotally [2, 6]. In a Japanese series of 7 patients, 5 were compound heterozygotes and 2 simple heterozygotes, suggesting dominant inheritance of some variants [6]. The adjective ‘benign’ means only absence of progressive liver disease and may mislead: quality of life is affected during episodes, some patients have fibrosis and others progress to chronic cholestasis [4, 6].

3.8. Intrahepatic cholestasis of pregnancy (ICP)

ICP presents in the late 2nd and especially 3rd trimester with increasing pruritus on normal skin, with elevated bile acids, and regresses after delivery [6, 7]. Frequency estimates depend on population: 0.5–4% of pregnancies according to GeneReviews, 0.1–2% according to Vitale, approximately 1 in 140 United Kingdom pregnancies according to Dixon and 0.7% in the United Kingdom according to RCOG, with 1.2–1.5% in women of Indian Asian or Pakistani origin [4, 6, 22, 66]. Fetal risk is associated with bile acids rather than transaminases. In Ovadia's meta-analysis, with aggregate data from 23 studies (5,557 cases and 165,136 controls) and individual data from 27 studies (5,269 cases), stillbirth occurred in 0.83% of ICP pregnancies versus 0.32% of controls (OR 1.46; 95% CI 0.73–2.89); in singleton pregnancies it was associated with peak total bile acids (area under the curve 0.83), not ALT (0.46) [84]. Stillbirth prevalence was 0.13% with bile acids below 40 µmol/L, 0.28% between 40 and 99 µmol/L (hazard ratio, HR, 2.35; 95% CI 0.52–10.50) and 3.44% with values of 100 µmol/L or higher (HR 30.50; 95% CI 8.83–105.30) [84]. Adverse outcomes also include spontaneous preterm birth and fetal distress [6, 7].

Genetic contribution is heterogeneous. In United Kingdom (n=333) and continental European (n=158) cohorts with 261 controls, heterozygosity for common ABCB11 variants accounted for approximately 1% of European ICP, and the p.(Val444Ala) polymorphism was associated with ICP (allelic OR 1.7; 95% CI 1.4–2.1; CC versus TT genotype, OR 2.8; 95% CI 1.7–4.4) [60]. Sequencing 147 patients identified 26 potentially damaging variants, all heterozygous (12 in ABCB4, 4 in ABCB11, 5 in ATP8B1, 2 in ABCC2 and 3 in TJP2) [66]. ICP has occasionally been reported in mothers of PFIC patients, and heterozygous sisters may have increased risk [3, 4]. A Finnish study showed long-term survival similar to controls, but EASL reports greater subsequent hepatobiliary and immune-mediated disease risk [2].

3.9. LPAC, drug-induced cholestasis and adult cryptogenic cholestasis

LPAC presents with recurrent biliary symptoms from young adulthood, with intrahepatic and gallbladder cholesterol stones and recurrence after cholecystectomy; a heterozygous missense ABCB4 variant is found in 40–50% of patients [2, 7]. In a cohort of 308 LPAC patients (122 ABCB4 variant carriers), hepatobiliary malignancy occurred in 10.1% of carriers versus 2.2% (multivariable OR 5.0; 95% CI 1.2–25.5) [2]. Drug-induced cholestasis accounts for approximately 30% of idiosyncratic DILI; up to 50% of patients have ABCB4 variants, antibiotics are the main cause, and women with prior ICP are susceptible to contraceptives and hormone therapy [6]. In an exploratory Japanese study of 19 adults with intrahepatic cholestasis, 4 (21%) had rare heterozygous PFIC gene variants, all with DILI diagnoses [68].

In a cohort of 356 sequenced adults, 101 (28.4%) had ATP8B1, ABCB11 or ABCB4 variants (9 in more than one gene), with median presentation age 36.2 years; ABCB4 was associated with ICP (75%) and chronic liver disease (71.7%), with earlier onset in severe genotypes; ABCB11 with acute or episodic cholestasis (40%) or ICP (82.4%); and ATP8B1 with chronic disease (75%) with low-pathogenicity variants; more than 70% of ABCB11 or ABCB4 variant carriers had fibrosis [6]. In an Italian cohort of 48 patients with cryptogenic cholestasis from 6 years, 21% had ATP8B1, ABCB11, ABCB4 or TJP2 variants, with higher bile acids, more fibrosis and more neonatal jaundice [6]. Adult cryptogenic cholestasis is defined by GGT and/or alkaline phosphatase above 1.5 times ULN in at least two tests, or pruritus with bile acids above 10 µmol/L, for more than 6 months [6]. Heterozygotes may have elevated liver tests, stones, episodic or chronic cholestasis, ICP, DILI, greater hepatobiliary malignancy risk and progressive cholestasis with age [2].

4. Clinical Recognition and Warning Signs

4.1. Newborn and infant

Cholestatic jaundice, that is, with conjugated or direct hyperbilirubinaemia, is always pathological, and jaundice persisting beyond 2–4 weeks requires investigation; early detection may save lives or avoid transplantation [8]. The joint NASPGHAN and ESPGHAN guideline (North American and European paediatric gastroenterology, hepatology and nutrition societies) estimates cholestatic jaundice affects approximately 1 in 2,500 term infants, with biliary atresia in 25–40% and monogenic diseases in approximately 25%, and recommends assessment of every infant jaundiced after 2 weeks with total and direct bilirubin; direct bilirubin above 1.0 mg/dL (17 µmol/L) requires timely assessment and referral to paediatric gastroenterology or hepatology [23]. Other authors propose a 0.3 mg/dL (5 µmol/L) threshold, and conjugated bilirubin may be an unreliable cholestasis marker in low-GGT forms [3, 85]. The first priority is excluding biliary atresia, whose jaundice may be unapparent during the first 2–3 weeks, through a structured protocol [1, 8].

PFIC warning signs in infancy are continuous cholestasis from the first months with jaundice, clinically significant diarrhoea, growth retardation, vitamin K deficiency bleeding, hepatosplenomegaly, pruritus and pale stools [4]. Cholestatic jaundice with growth retardation, intractable pruritus and normal GGT is the classic Byler disease picture [86]. Vitamin K-unresponsive coagulopathy with very high AFP, hypoglycaemia or hyperammonaemia should suggest FXR deficiency and expedite transplant referral [7, 64]. Intractable secretory diarrhoea from the first days, with cholestasis, suggests MYO5B [7].

4.2. Child, adolescent and adult

In older children, the most frequent sign is unexplained pruritus, prompting measurement of bilirubin, serum bile acids, GGT and fat-soluble vitamins and ultrasound to exclude obstruction [1]. Excoriations, irritability and sleep disturbance without a primary skin lesion may be the only clue, and some patients are treated for years as chronic dermatoses [4]. High-GGT cholestasis with intrahepatic stones, portal hypertension or small-duct sclerosing cholangitis in an adolescent or young adult suggests MDR3 deficiency [2, 6]. In adults, genetic cholestasis should be suspected with chronic cholestasis after excluding primary biliary cholangitis (PBC; autoantibodies) and primary sclerosing cholangitis (PSC; magnetic resonance cholangiopancreatography, MRCP), antimitochondrial- and antinuclear-antibody-negative PBC, small-duct PSC, early stones, recurrent jaundice episodes, severe or recurrent ICP and severe or recurrent DILI [2, 6].

4.3. Family history and population context

History should include a three-generation pedigree with consanguinity, ethnic origin, prolonged neonatal jaundice in siblings or parents and maternal ICP, found in some carriers [3, 8]. Absence of family history does not exclude recessive disease [3]. Membership of founder-variant populations (Amish, eastern Greenland Inuit) increases pretest probability [4].

4.4. Emergencies and newborn screening

Urgent situations include coagulopathy with vitamin K deficiency bleeding, acute liver failure in FXR deficiency and hepatic decompensation (variceal bleeding, ascites, encephalopathy) [4, 24, 64]. No PFIC-targeted newborn screening exists in the sources consulted; neonatal vitamin K is considered essential in ATP8B1 deficiency [4]. In East Greenland, p.(Asp554Asn) carrier frequencies of 0.16 in Ittoqqortoormiit and 0.23 in Kuummiut justify routine screening in those communities [4].

The French PNDS on bile acid synthesis defects sets out the first-line approach to any newborn who remains or becomes jaundiced at or after 14 days of life: careful clinical examination with inspection of stool and urine colour (preferably with a stool colour card), simple tests with total and conjugated bilirubin, and fasting abdominal ultrasound [29]. Once cholestasis is confirmed, the child is referred urgently to a reference or competence centre, because the most frequent cause at this age (around 45% of cases) is biliary atresia, whose prognosis depends on early Kasai surgery, and receives parenteral vitamin K as soon as possible, at the 10 mg dose indicated by the PNDS, to prevent bleeding from coagulopathy [29]. The same document defines biochemical cholestasis as conjugated bilirubin above 17 µmol/L (10 mg/L) or above 20% of total bilirubin, notes that jaundice becomes clinically visible from 40–50 µmol/L of total bilirubin, and treats complete stool discoloration for more than 7 days, with a firm hepatomegaly, as biliary atresia until proven otherwise [29]. The 20% proportional criterion no longer appears in the 2017 NASPGHAN/ESPGHAN guideline, which defines as abnormal any direct or conjugated bilirubin above 1.0 mg/dL (17 µmol/L), whatever the total bilirubin, because the fraction is physiologically and clinically difficult to apply; the absolute threshold is the reference criterion [23]. Among the errors to avoid in the first month, it lists regarding as physiological a jaundice that persists beyond day 10, over-attributing jaundice to breast milk, being reassured as a matter of principle by a normal growth curve or by the presence of a gallbladder on ultrasound, and mistaking dietary or drug-related colouring for pigmented stools [29].

The PNDS gives neonatal cholestasis, often transient owing to immaturity of bile acid synthesis and transport, an estimated incidence of 1 in 2,500 births, matching that of NASPGHAN/ESPGHAN, and regards as always pathological any cholestasis that persists or appears after 10–15 days of life; pruritus becomes apparent only after 4–5 months, so its absence in the newborn does not rule out PFIC [23, 29]. In the newborn, the document gives priority to causes requiring urgent treatment (biliary atresia, urinary tract infection or sepsis, cortisol deficiency) and to those easily detected (Alagille syndrome, choledochal cyst, cystic fibrosis, α1-antitrypsin deficiency) [29]. The proposed initial panel includes a full blood count with reticulocytes, PT and factor V, total and conjugated bilirubin, transaminases, GGT, total bile acids, blood glucose, confirmation of the newborn screening immunoreactive trypsin result, serum α1-antitrypsin, syphilis and TORCH serology, and cultures when there are signs of infection [29]. Liver biopsy is performed when the cause is not identified quickly and, interpreted by an experienced pathologist, gives the diagnosis in more than 90% of cholestatic jaundice cases; the childhood cholestasis gene panel is a rapid tool whose interpretation requires correlation with clinical, biochemical, imaging and histological findings [29]. In biliary atresia, Kasai surgery before 30 days allows around 40% of operated children to be expected to be alive with their native liver at 20 years, and after 45 days success decreases and complications increase [29]. If investigations do not clarify the cause and the stools regain colour within about 15 days, transient neonatal cholestasis may be accepted (around 10% of neonatal cholestasis, resolving by about 1 year of age), with clinical and biochemical surveillance for at least 1 year; if colour does not return, biopsy is repeated or the bile ducts are opacified, which may reveal sclerosing cholangitis [29]. In hepatocellular failure, which the PNDS defines as PT below 70% without vitamin K deficiency, severe if PT or factor V falls below 50%, grave if there is clinical encephalopathy and fulminant if encephalopathy arises less than 8 weeks after jaundice, transfer to a paediatric centre with liver transplantation is discussed from PT below 50% and carried out before signs of encephalopathy [29].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no published consensus clinical criteria for FIC1 deficiency, and diagnosis rests on suggestive findings and identification of biallelic pathogenic variants; two VUS, or one pathogenic variant and one VUS, neither establish nor exclude diagnosis [4]. Odevixibat labelling allows clinical PFIC diagnosis without a known pathogenic variant [24]. For LPAC, EASL uses three criteria: biliary symptom onset before 40 years, recurrence after cholecystectomy and intrahepatic hyperechoic foci or comet-tail artefacts on ultrasound [2]. For ICP, RCOG (Royal College of Obstetricians and Gynaecologists) requires pruritus on normal skin and a random peak total bile acid level of 19 µmol/L or higher, confirmed at least 4 weeks postpartum by normalisation of pruritus and tests [22]; SMFM (Society for Maternal-Fetal Medicine) recommends measuring bile acids and transaminases in suspected cases [30]. For BRIC, at least two jaundice episodes with normal or near-normal GGT are required [6].

5.2. Biochemistry

In mild FIC1 deficiency, bile acids are very high during episodes and normal between them, and GGT may rise at episode onset or resolution [4]. Alkaline phosphatase is of limited use in children because it reflects growing bone [3]. Ultrasound is non-specific (coarse texture, nodularity, hepatomegaly, ductal and gallbladder changes, splenomegaly, ascites) and mainly excludes obstruction [3]. In MDR3 deficiency, the defect may be demonstrated by biliary phospholipid analysis; values above 6.9% of biliary lipids are associated with better UDCA response [6, 7].

5.3. Histology and immunohistochemistry

Liver biopsy underpinned diagnosis for decades, and OXF 2017 still described it as usually necessary; molecular testing now replaces it, and biopsy remains for excluding obstruction or atresia, when genetic testing is unavailable or the molecular result inconclusive [4, 8]. EASL does not recommend routine biopsy in Alagille syndrome [2]. FIC1 deficiency shows ‘bland’ intracanalicular cholestasis, with preserved architecture, orderly-appearing hepatocytes and coarsely granular canalicular bile on electron microscopy (‘Byler bile’), without paucity or significant ductular reaction; BSEP is usually well expressed [4, 69]. BSEP deficiency shows giant cell transformation, hepatocellular necrosis, bile pigment in hepatocytes and canaliculi, bile without coarse granularity, GGT expressed along canaliculi and frequently absent BSEP [4, 57]. Canalicular MDR3 staining is negative in severe MDR3 deficiency [35]. In TJP2 deficiency, ZO-2 immunostaining is absent or mislocalised [7]. In MYO5B deficiency, there are giant cells, weak canalicular GGT expression and mislocalised BSEP [4, 39]. BSEP immunohistochemistry has a pitfall: the protein is also absent in FXR deficiency because it is not induced, so absent BSEP does not distinguish transporter from regulator; as the IBATi use limitation applies only to ABCB11 variants, molecular confirmation is mandatory [7]. In MVID, small intestinal biopsy with CD10 (diffuse cytoplasmic inclusions), EpCAM and chromogranin and electron microscopy distinguish it from tufting enteropathy and enteroendocrine dysgenesis [7].

5.4. Genetic testing

EASL recommends early genetic testing when investigating cholestasis without a clear cause in infants and children, and in adults after excluding common causes, especially with atypical features or failure to respond to initial treatment [2]. It recommends next-generation sequencing (panel or exome) and discourages Sanger sequencing of individual genes, perhaps excepting ABCB4 in young patients with small-duct sclerosing cholangitis [2]. If exome sequencing is negative, genome sequencing should be considered, and undiagnosed patient data should be reanalysed at least every 3 years [2]. Genetic counselling should precede testing, with prior discussion of incidental findings [2]. GeneReviews proposes a cholestasis multigene panel, limiting VUS in irrelevant genes, or exome sequencing; if exome sequencing is non-diagnostic, an exome array may detect deletions and duplications of one or more exons [3, 4].

In the 77-gene panel, the most common definitive diagnoses were JAG1, SERPINA1, ABCC2, ABCB11, CFTR, POLG and NOTCH2, and 2,917 patients had at least one pathogenic or likely pathogenic variant, many monoallelic in SERPINA1, CFTR, DHCR7, ABCB4 and PKHD1 [87]. These figures concern a referral population and do not measure prevalence.

5.5. Test limitations, VUS and reporting

A negative genetic test does not exclude disease: commercial panels may lack newly described genes, deletions of one or more exons require dedicated methods, in 7 of 109 families with severe BSEP deficiency only one variant was found despite complete sequencing, and a second deep intronic or regulatory variant may escape exome sequencing, a possibility acknowledged in the case in section 10 [4, 6, 57, 69]. VUS are very frequent in these genes. In a series of 26 children with 37 monoallelic VUS in ATP8B1, ABCB11, ABCB4, TJP2 or NR1H4, 42.3% had a PFIC-like biochemical pattern, frequently transient, none met monogenic PFIC criteria during follow-up, and severe outcomes (2 transplants) occurred with ABCB4 and/or ATP8B1 VUS and concurrent factors; the authors conclude that monoallelic VUS should not be taken alone as a monogenic cause [70]. In silico prediction is weak: in 253 women with ICP from Genomics England, only 4 of 9 rare missense ABCB4 variants had concordant classification between five tools, and p.(Asn510Ser), with a demonstrated functional effect, was classified benign by AlphaMissense [88]. Reclassification rests on prediction, family segregation, functional studies and other-family data [2].

The report should state the gene, versioned reference transcript (preferably MANE Select), HGVS variant at c., p. and g. levels with genome assembly, zygosity, confirmation of phase (cis or trans) through parental testing, and class according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) standards: 1–2 benign or likely benign, 3 VUS, 4–5 likely pathogenic or pathogenic [2, 3, 9]. In BSEP deficiency, the report should allow classification into BSEP1, BSEP2 or BSEP3 and identification of BSEP1/3 combinations, because HCC surveillance, diversion indication and IBATi eligibility depend on these [2, 24, 59]. Parental testing confirms phase and heterozygosity; when only one parent is a carrier, possibilities are a de novo variant, postzygotic parental mosaicism or uniparental isodisomy [3].

5.6. Algorithm

The European experts' proposed algorithm starts in newborns and infants with conjugated hyperbilirubinaemia by excluding biliary atresia; with unexplained pruritus, it measures bilirubin, bile acids, GGT and fat-soluble vitamins and performs ultrasound; it suspects PFIC with cholestasis, high bile acids and low GGT, and also suspected MDR3 deficiency with high GGT, after excluding differentials requiring urgent treatment [1]. A panel is requested, and the authors allow empirical IBATi initiation while awaiting results; if the panel is negative with high suspicion, exome sequencing follows, maintaining odevixibat [1]. This proposal is Albireo/Ipsen-funded expert opinion and differs from labels restricting use to diagnosed PFIC and excluding the non-functional BSEP subgroup identifiable only by genotype [1, 24]. The classical textbook approach adds, according to context, α1-antitrypsin, very-long-chain fatty acids, 7-dehydrocholesterol, urinary bile acid mass spectrometry, vertebral radiography, echocardiography and ophthalmological assessment for differential diagnoses [8].

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when familial pathogenic variants have been identified; molecular confirmation is the prerequisite, and professionals and families may have different perspectives on their use [3, 8].

6. Differential Diagnosis

6.1. Differential within the low-GGT group

The first step is distinguishing recessive low- or normal-GGT cholestases from each other, because genotype determines treatment. The table adapts GeneReviews, based on Bull and Thompson [4, 89].

Residual locus heterogeneity exists: some patients with clinical and histological low-GGT PFIC or BRIC diagnoses lack variants in known genes [4, 42].

6.2. Differential diagnoses outside the group

6.3. Bile acid synthesis defects

Synthesis defects are the most important metabolic differential because they also have normal GGT but are treatable with cholic acid [2, 67]. 3β-dehydrogenase deficiency usually presents in the first year: in a London series of 18 cases, neonatal conjugated hyperbilirubinaemia occurred in 11, rickets in 8, hepatomegaly in 7, pruritus in 3 and steatorrhoea with growth retardation in 3, and low 25-hydroxyvitamin D in 10 [67]. The feature most distinguishing it from PFIC is absent pruritus, because primary bile acids do not accumulate, and enzymatic measurement of total plasma 3α-hydroxy bile acids is normal or low [67]. In a 2017 European survey of 55 patients, estimated incidence was 0.99 per 10 million; EASL estimates European prevalence at 1.13 per 10 million [2, 67]. Without treatment, death from cirrhosis complications occurs before 5 years [67]. The case of two Pakistani sisters with SLC27A5 deficiency, one also homozygous for ABCB11 p.(Asn591Ser) and with prolonged PN, shows that concurrent cholestatic causes may coexist [67].

Synthesis of the primary bile acids from cholesterol (cholic acid, around two thirds of the pool in adults, and chenodeoxycholic acid, around one third) involves nearly twenty enzymes distributed across the endoplasmic reticulum, cytosol, mitochondria and peroxisomes, in four stages: initiation by hydroxylation of cholesterol, modification of the steroid nucleus, oxidation and shortening of the side chain, and conjugation with glycine or taurine [29]. The classical, or neutral, pathway begins with cholesterol 7α-hydroxylase (CYP7A1), exclusive to the liver, predominates in adults and produces mainly cholic acid; the alternative, or acidic, pathway predominates in the first months of life and produces mainly chenodeoxycholic acid [29]. Bile acids repress 7α-hydroxylase by negative feedback; when primary bile acids are lacking, this feedback disappears, dysregulated synthesis accumulates hepatotoxic atypical precursors and the bile acid-dependent component of bile flow decreases, which explains cholestasis without accumulation of primary bile acids and, therefore, without pruritus [29]. The lack of primary bile acids in bile also increases its lithogenicity [29]. The PNDS lists ten characterised primary defects, which differ in the stage affected and in the dominant phenotype.

Steroid nucleus defects are expressed mainly as exclusive and severe liver disease; side-chain defects (sterol 27-hydroxylase, AMACR, D-bifunctional protein) classically present with neurological signs and malabsorption of fats and vitamins, with liver disease in the background, because residual primary bile acid synthesis persists [29]. As side-chain modification and conjugation take place in peroxisomes, some peroxisomal disorders, especially Zellweger syndrome, can reproduce the hepatic picture of the latter defects [29]. The PNDS focuses on 3β-HSD and Δ4-3-oxo-R deficiencies because they are the two most frequent forms with chronic liver disease, potentially fatal without treatment, simple to diagnose when considered, probably underdiagnosed and treatable orally [29]. Synthesis defects account for around 1–2% of childhood cholestasis; the international survey cited by the PNDS estimates a minimum prevalence of 1.13 per 10 million for the two defects, much higher for 3β-HSD deficiency, and of 4.02 per 10 million in France, the country with the most cases described, partly because of the recruitment of patients of foreign origin [29]. EASL breaks down the same figure of 1.13 per 10 million into 0.99 for 3β-HSD deficiency and 0.14 for Δ4-3-oxo-R deficiency, and presents it as prevalence, whereas Saudubray presents 0.99 per 10 million as incidence [2, 67].

In 3β-HSD deficiency, with more than 70 published cases and around fifteen HSD3B7 variants described in homozygosity or compound heterozygosity, without a demonstrated genotype–phenotype correlation, 7α-hydroxycholesterol accumulates in the hepatocyte [29]. The PNDS advises considering it in the presence of cholestatic jaundice in the newborn or gradually developing cholestasis in the infant or young child, chronic liver disease of unknown aetiology progressing to cirrhosis, or lipid malabsorption without gastrointestinal or pancreatic disease, with symptomatic or asymptomatic fat-soluble vitamin deficiencies: bleeding from vitamin K deficiency, rickets or symptomatic hypocalcaemia from vitamin D deficiency, absent tendon reflexes from vitamin E deficiency and, more rarely, ocular signs from vitamin A deficiency [29]. Pruritus is absent, palpation finds hepatomegaly or hepatosplenomegaly, and the context frequently includes consanguinity or unexplained chronic liver disease in siblings [29]. This description of hepatomegaly or hepatosplenomegaly differs from the differential table in section 6.2, which, following Saudubray and GeneReviews, records absence of hepatosplenomegaly; in the London series, 7 of 18 patients had hepatomegaly [3, 29, 67]. Tests show (moderately) raised conjugated bilirubin and transaminases, normal GGT and, as a key finding, normal total serum bile acids (around 10 µmol/L), in contrast with the clinical signs of cholestasis; cholesterol is normal or low, 25-hydroxyvitamin D and vitamins E and A are often low and prothrombin time is prolonged [29]. Ultrasound contributes little to the positive diagnosis and serves to exclude biliary tract disease; biopsy is not essential and shows hepatocellular or canalicular cholestasis without signs of obstruction, sometimes giant cell hepatitis, and portal and lobular fibrosis of variable severity [29]. Besides the typical infantile form, the following have been described: neonatal liver disease that resolves spontaneously or runs a course of flares and remissions, a “digestive” form dominated by steatorrhoea and vitamin deficiencies, a paucisymptomatic form with hepatomegaly and faltering weight gain with nearly normal tests, asymptomatic forms discovered by family screening and, in isolated cases, diagnoses in adolescence, young adulthood and the fourth decade [29].

Δ4-3-oxo-R deficiency is considerably rarer, begins earlier (around 3 months), is more severe and progresses more rapidly to liver failure, which makes it necessary to confirm the diagnosis and treat as early as possible [29]. It presents with neonatal conjugated hyperbilirubinaemic jaundice, raised transaminases and normal GGT, signs of fat-soluble vitamin malabsorption (rickets, low vitamin E, coagulopathy corrected by parenteral vitamin K) or acute liver failure in the newborn or infant [29]. The PNDS and EASL describe normal GGT in both defects, whereas the table in section 6.2, based on GeneReviews, records raised GGT in 5β-reductase deficiency [2, 3, 29]. Urinary mass spectrometry shows atypical metabolites with a predominance of conjugated hydroxy-oxo bile acids and allo bile acids (5α-H); this profile is not pathognomonic, because enzyme activity decreases in any advanced liver disease (for example, in neonatal haemochromatosis), and confirmation requires analysis of AKR1D1 [29].

Confirmation of both defects relies on analysis of urinary (and serum) bile acids by gas or liquid chromatography coupled with mass spectrometry (with electrospray ionisation, ESI), performed in a few highly specialised laboratories: total excretion is increased, consistent with cholestasis, but the profile is qualitatively abnormal, with absence or traces of primary bile acids and abundance of atypical intermediates specific to each defect; the result allows the primary bile acid to be started, and sequencing of HSD3B7 or AKR1D1 confirms the diagnosis in a second stage [2, 29]. Other causes are excluded simultaneously, in a specialised setting [29]. In the sequence proposed by the PNDS, once cholestasis is confirmed, ultrasound looks for bile duct dilatation; without dilatation, a normal GGT points to hepatocyte disease, and the absence of pruritus in this context suggests a synthesis defect, especially 3β-HSD deficiency, whereas a raised GGT points to Alagille syndrome, cystic fibrosis, α1-antitrypsin deficiency, parenteral nutrition-associated cholestasis or sclerosing cholangitis [29]. As cholestasis is always accompanied by fasting total bile acids above 10 µmol/L, except in synthesis defects, raised serum bile acids exclude these defects; the distinction from PFIC, which share normal GGT (except for MDR3 deficiency), rests on pruritus, which in PFIC becomes intense after a few months, on histology, on GGT and serum bile acids, on the urinary profile by mass spectrometry and on molecular genetics [29]. Some forms of PFIC were, in the past, confused with synthesis defects [29]. In chronic cholestasis or cryptogenic cirrhosis with diarrhoea and malabsorption, the differential of 3β-HSD deficiency centres on cystic fibrosis, which also causes cholestasis and cirrhosis and is clarified by newborn screening, the sweat test, faecal elastase and CFTR analysis [29]. In Δ4-3-oxo-R deficiency, the differential widens to the causes of liver failure in infancy, among which metabolic disorders predominate at this age and 20–50% remain undiagnosed [29].

6.4. Alagille syndrome

Alagille syndrome is the main high-GGT differential. It is distinguished by dominant inheritance, high cholesterol, and cardiac, vertebral and ocular manifestations [3, 8]. It shares IBATi treatment for pruritus with PFIC, with its own indications and doses (odevixibat 120 µg/kg once daily in the USA from 12 months, up to 7,200 µg/day above 55.5 kg in the weight-band table of the prescribing information, and, in the EU, as Kayfanda® from 6 months; maralixibat 190 µg/kg once daily, increased after one week to 380 µg/kg/day, up to 28.5 mg/day with the solution or 30 mg/day with tablets in the US prescribing information, from 3 months in the USA and 2 months in the EU), and EASL recommends IBATi for pruritus in Alagille syndrome (evidence level 2, strong recommendation) [2, 24–27]. EASL does not recommend statins for xanthomas [2].

6.5. Differential diagnosis of adult forms

In adults with cholestasis, primary cholestasis due to hepatocellular retention is distinguished from cholangiopathies; common causes are excluded first, and histology and/or genetic testing used only with uncertain aetiology, with multidisciplinary discussion [90]. PBC is excluded by autoantibodies and PSC by MRCP [6]. In a pregnant woman with pruritus, ICP is characterised by pruritus on normal skin with elevated bile acids; RCOG reserves additional investigations for atypical presentations, comorbidities or severe early-onset disease and recommends discussing severe, very early or atypical forms with a hepatologist [22]. BRIC episodes require exclusion of extrahepatic obstruction [4].

7. Treatments and Risk Management Strategies

7.1. Goals and organisation of care

Treatment has four goals: controlling pruritus and sleep, ensuring nutrition and growth, delaying progression to cirrhosis and detecting HCC and transplantation indications promptly [1, 2]. Children with chronic liver disease should be under paediatric hepatology, and European experts recommend therapeutic decisions in specialist centres [1, 8]. EASL 2024, developed with PICO (population, intervention, comparison, outcome) questions validated by Delphi with 32 participants (including patient representatives), systematic review and grading using the Oxford Centre for Evidence-Based Medicine system (CEBM; levels 1 to 5) with ‘strong’ or ‘weak’ strength, covers FIC1, BSEP and MDR3 deficiencies; other types are outside scope because of insufficient data, although common-type recommendations probably apply [2]. The 2021 ATP8B1 GeneReviews noted that no guidelines had been published for that deficiency [4].

7.2. Nutritional support

Supplementation of vitamins A, D, E and K and medium-chain triglycerides (MCT), absorbed without bile acids, in formula (for example Alimentum® or Pregestimil®) or oil, underpin support [3]. In severe cholestasis, vitamin E preparations as TPGS (tocopherol polyethylene glycol 1000 succinate) are useful, and neonatal vitamin K (first 28 days) is considered essential; in FIC1 deficiency, vitamin A is often normal or high and rarely needs supplementation [4]. Nasogastric feeding helps some patients, and FIC1 deficiency growth retardation may not respond to transplantation [4]. MDR3 deficiency with decompensated cirrhosis may require oral, enteral and sometimes parenteral support [2]. The sources consulted do not give PFIC-specific fat-soluble vitamin doses; dose is adjusted to serum levels and INR (international normalised ratio), measured before and during IBATi treatment [24, 25].

7.3. Classical drugs for pruritus and cholestasis

Drugs used before IBATi are almost all off-label and have limited efficacy. EASL Table 3 classifies them as follows [2]:

European experts summarise that UDCA is the most used off-label treatment, minimally effective with few adverse effects; rifampicin has little sustained success; and sertraline, colestyramine, antihistamines, sodium 4-phenylbutyrate and naltrexone have limited success and do not modify disease [1]. In mild FIC1 deficiency (BRIC1), rifampicin, UDCA, sertraline, naltrexone and resins may be effective during episodes [4, 91]. In USP53 deficiency, rifampicin was more effective than UDCA [3, 40, 92]. In the United States, ursodiol is approved for gallstone dissolution and prevention during rapid weight loss and, as URSO, for PBC, so paediatric genetic cholestasis use is off-label [7]. The sources consulted give no UDCA, rifampicin, naltrexone or sertraline doses for paediatric PFIC; the only UDCA doses in the sources are LPAC (8–10 mg/kg/day, up to 13–15 mg/kg/day) and ICP (500 mg twice daily in PITCHES), presented in sections 7.11 and 7.12 [2, 93].

7.4. Ileal bile acid transporter inhibitors (IBATi)

Odevixibat and maralixibat are reversible IBAT (ASBT) inhibitors reducing terminal ileal bile salt reabsorption and thus the bile acid load returning to the liver; the antipruritic mechanism is not fully known [24]. Because effect depends on preserved EHC and some canalicular transport, BSEP-deficient patients without functional protein (BSEP3) do not respond: the European odevixibat summary of product characteristics (SPC) states these patients ‘will not respond’, maralixibat's states they ‘are not expected to respond’, and United States labels consider both ‘not recommended’ in this subgroup [24–27]. United States wording has become more restrictive: the original 2021 Bylvay® label stated only that the drug ‘may not be effective’ in BSEP3 [94]. In the 33-patient phase 2 INDIGO trial, none of the 6 with biallelic truncating ABCB11 variants or 8 with FIC1 deficiency had a bile acid response to maralixibat, and all 7 responders with non-truncating variants were transplant-free after more than 5 years [95]. Felzen's analysis indicates BSEP1/3 patients behave like BSEP3/3 and are unlikely to benefit from IBATi [59]. Therefore, ABCB11 genotype should be known before initiation, and BSEP immunohistochemistry does not replace genotype [7].

The use limitation does not apply to other genes: FIC1, MDR3, TJP2, FXR and MYO5B deficiencies fall within labels' ‘PFIC’ indication, extended by FDA extrapolation to all subtypes except BSEP3 because rare-subtype trials are impractical and the mechanism is not gene-specific [7, 96]. In FXR deficiency, IBATi treats pruritus rather than disease, whose rapid progression requires transplantation [7, 64].

7.4.1. Odevixibat (Bylvay®)

The 40 µg/kg/day dose corresponds in both labels' tables to 200 µg up to 7.4 kg (EU: from 4 kg), 400 µg at 7.5 to 12.4 kg, 600 µg at 12.5 to 17.4 kg, 800 µg at 17.5 to 25.4 kg, 1,200 µg at 25.5 to 35.4 kg, 1,600 µg at 35.5 to 45.4 kg, 2,000 µg at 45.5 to 55.4 kg and 2,400 µg from 55.5 kg; the 120 µg/kg dose uses 600 and 1,200 µg capsules in the same bands, up to 7,200 µg [24, 25]. Pellets may be mixed in up to 30 mL of soft food at room temperature or below (apple puree, oatmeal, banana or carrot puree, pudding), or in 5 mL liquid administered by syringe, without dissolving them; capsules for swallowing are not crushed or chewed [24]. Sequestrant resins (colestyramine, colesevelam, colestipol) should be taken at least 4 hours before or after [24]. Odevixibat is a P-glycoprotein substrate (itraconazole increases exposure by 50–60%, without clinical relevance) and an in vitro CYP3A4/5 inhibitor (reduces midazolam concentration area under the curve, AUC, by 30%); it reduces ethinylestradiol AUC by 17%, without relevance; there are no studies with UDCA or rifampicin [25]. Single doses up to 10,000 µg in volunteers had no consequences [25].

The most frequent adverse effect is diarrhoea. In PEDFIC1, it occurred in 10% (2/20) with placebo, 39% (9/23) with 40 µg/kg and 21% (4/19) with 120 µg/kg; 2 patients had 3–7-day interruptions and one withdrew for persistent diarrhoea [24]. In the EU, among PFIC patients aged 4 months to 25 years, adverse reactions were diarrhoea (30.6%), increased bilirubin (24.8%), increased ALT (14%), vomiting (16.5%), increased aspartate aminotransferase (AST) (9.1%), abdominal pain (11.6%) and decreased vitamins D (11%) and E (5%), with diarrhoea generally mild to moderate and lasting up to 5 days [25]. Management of diarrhoea is to treat dehydration, interrupt if persistent, restart at 40 µg/kg on resolution and permanently discontinue if persistent without another cause [24]. New or worsened fat-soluble vitamin deficiency occurred in 5% with placebo, 0 with 40 µg/kg and 16% with 120 µg/kg; vitamins A, D, E and INR should be measured before and during treatment, with supplementation and possible discontinuation if deficiency persists [24]. In two post-marketing open-label studies, fractures occurred in 5% of PFIC and 4% of Alagille syndrome patients, and bleeding requires interruption, vitamin optimisation and restarting when stable [24].

Hepatotoxicity is the main warning. In PFIC and Alagille syndrome trials, six patients had DILI, two transplanted; the United States label requires baseline liver tests (ALT, AST, total and direct bilirubin, INR) and frequent monitoring during the first 6 to 8 months, interruption for new abnormalities or clinical hepatitis, restarting when values return to baseline, and permanent discontinuation if abnormalities persist or recur, hepatitis occurs on rechallenge or decompensation develops [24]. Post-marketing reports include gastrointestinal and gingival bleeding, liver transplantation, increased GGT, decreased haemoglobin, subdural haemorrhage and epistaxis [24].

7.4.2. Maralixibat (Livmarli®)

The 19 mg/mL solution volume per dose at 285, 428 and 570 µg/kg is: 5 kg 0.1/0.1/0.15 mL; 6–7 kg 0.1/0.15/0.2 mL; 8 kg 0.1/0.2/0.25 mL; 9 kg 0.15/0.2/0.25 mL; 10–12 kg 0.15/0.25/0.3 mL; 13–15 kg 0.2/0.3/0.4 mL; 16–19 kg 0.25/0.4/0.5 mL; 20–24 kg 0.3/0.5/0.6 mL; 25–29 kg 0.4/0.6/0.8 mL; 30–34 kg 0.45/0.7/0.9 mL; 35–39 kg 0.6/0.8/1 mL; 40–49 kg 0.6/0.9/1 mL; 50–59 kg 0.8/1/1 mL; from 60 kg 0.9/1/1 mL [26]. The opened bottle is stored below 30 °C and discarded after 100 days [26].

The solution contains 364.5 mg/mL propylene glycol; at 570 µg/kg twice daily, exposure is 21.9 mg/kg/day with the 19 mg/mL solution, and the European SPC reports up to 26 mg/kg/day at 285 µg/kg and 50 mg/kg/day at 570 µg/kg twice daily with the 9.5 mg/mL solution; the risk of haemolysis, hyperosmolarity, anion-gap acidosis, acute kidney injury and central nervous system toxicity is greatest below 5 years (07/2024 warning) [26, 27]. In MARCH-PFIC, diarrhoea occurred in 57.4% (27/47) with maralixibat versus 19.6% (9/46) with placebo, lasting a median of 5.5 versus 3 days and 7 days or longer in 40.4% versus 4.3%, without serious events; abdominal pain occurred in 27.7% versus 15.2%, increased transaminases in 17% versus 6.5%, haematochezia or rectal bleeding in 8.5% versus 2.2%, fractures in 6.4% versus 0 and a haemoglobin decrease of 2 g/dL or more in 17% versus 2.2% [26]. Cholangitis or cholecystitis occurred in 2 patients within 3 weeks after discontinuation and 4 during extension, and treatment-emergent fat-soluble vitamin deficiency was 28% (13/47) versus 35% (16/46) with placebo [26]. Two DILI cases in the controlled phase and 2 in extension were attributed to maralixibat, one transplanted and another deceased; monitoring is the same as for odevixibat [26]. Gastrointestinal management is dose reduction or interruption for persistent diarrhoea or pain, bloody diarrhoea, vomiting, dehydration or fever; the drug was not assessed in patients with chronic diarrhoea requiring intravenous fluids [26, 27]. Maralixibat inhibits OATP2B1 in vitro (potentially reduced absorption of statins such as fluvastatin and rosuvastatin) and CYP3A4 (midazolam, simvastatin), and interaction with UDCA has not been fully assessed [26, 27]. Single doses up to 500 mg in adults had no consequences, and propylene glycol is removed by dialysis [27]. Post-marketing reports include haematemesis, transplantation and bleeding after endoscopy and liver biopsy [26].

7.5. Comparison of regulatory status

The practical implication is that minimum age, indication target (pruritus or disease) and maximum doses differ between jurisdictions: in the EU, odevixibat starts at 6 months and maralixibat at 3 months, unlike the USA (3 and 12 months); maximum maralixibat doses are higher in the EU; and the hepatic decompensation contraindication exists only in the USA [24–27]. Swissmedic restricted maralixibat to pruritus because the trial included no patients without pruritus and the placebo-free extension cannot establish a disease-modifying effect; it considered the clinical relevance of bile acid reduction uncertain and recorded 13 serious hepatic events in extension, mainly transplant listing, without a trend towards reduced incidence on drug, and 2 deaths after discontinuation of uncertain causality [49]. An FDA class safety communication, dated by the medical press to 27 June 2025, added contraindication for prior or active hepatic events, monitoring and discontinuation recommendations and data on bleeding associated with fat-soluble vitamin deficiency; this communication was consulted only through a secondary source, and the Bylvay® label records the contraindication as a March 2025 amendment (supplement S-006 of 20-03-2025) [24, 100]. In Canada, the health technology assessment agency (CDA-AMC, Canada's Drug Agency) recommended public reimbursement in May 2026 for maralixibat for PFIC cholestatic pruritus from 12 months, with conditions (clinically significant pruritus and high bile acids, no initiation after transplantation or biliary surgery and discontinuation if either occurs, benefit after an adequate trial, specialist follow-up and price reduction) [101]. The sources consulted contain no INFARMED, ANVISA or CONITEC decisions on these drugs, and regulatory status in Japan and China was not confirmed in an official source.

7.6. Clinical trials

These trials require cautious interpretation. The paediatric cholestasis GeneReviews supported IBATi efficacy with a case report [3, 106]; current evidence comes from the tabled trials. Controlled trials lasted 24 to 26 weeks and measured pruritus and bile acids, intermediate endpoints: FDA used bile acids as pharmacodynamic support rather than a benefit surrogate, and neither EASL nor Swissmedic considers an effect on native liver survival or HCC demonstrated [2, 49, 96]. PEDFIC1 included only FIC1 and BSEP deficiencies and excluded BSEP3; MARCH-PFIC included other genes in very small numbers (7 TJP2, 4 MYO5B and no FXR), and gene-specific responses come from statistically underpowered subgroups [26, 49, 102]. Response is lower in FIC1 deficiency: in the pooled analysis, 25% of PFIC1 patients had a bile acid response at 72 weeks versus 49% with PFIC2 [25]. Final PEDFIC2 and MARCH-ON results were not published in a peer-reviewed journal in October 2026; figures come from ClinicalTrials.gov, the European SPC and FDA approval letter, and open-label extensions lack a control group [25, 97, 103]. The two drugs have not been compared directly. Lacey's anchored indirect comparison, funded by maralixibat's manufacturer, reported a higher bile acid responder proportion with maralixibat than odevixibat 120 µg/kg (difference 32.3%; 95% CI 1.1–63.4; p=0.043), but used 16 patients from one trial and aggregate data from the other, with different endpoints and populations, and CDA-AMC did not consider it conclusive [101, 107]. A systematic review of 75 records found no clear dose–response relationship for either drug; suggesting dose reduction in responders is a hypothesis, not a label recommendation [108]. Another systematic review, of 114 publications, confirmed improvement in pruritus, bile acids, quality of life and hepatic markers, particularly in BSEP deficiency, with genotype-heterogeneous responses and limited long-term and economic data [109].

7.7. Real-world data and practical choice

GeneReviews 2021 emphasised the lack of real-world experience with the IBATi then approved [4, 110]. In a prospective Italian cohort of 24 children (median 6.6 years), including 8 with rare types and 3 with MDR3 deficiency outside trial criteria, odevixibat reduced bile acids from a median of 317.1 to 45.6 µmol/L at 6 months (p<0.001), with 75% bile acid responders and 73% pruritus responders; 30% required escalation, baseline bile acids above 333.5 µmol/L increased the risk of non-response 17-fold, and no serious adverse effects occurred [48]. In the same cohort, a bile acid reduction of 48% or more at month one (area under the curve 0.771; sensitivity 0.75; specificity 0.83) or of 52% or more at month three (0.885; 0.81; 1.00) predicted pruritus improvement at 6 months [111]. In a French series of 5 children with MYO5B deficiency and pruritus refractory to rifampicin and UDCA, odevixibat (37.2–120 µg/kg/day) reduced bile acids below 10 µmol/L and bilirubin below 15 µmol/L within 6 months, with a sustained response for 22 to 39 months in 4; in one patient, discontinuation after gastroenteritis was followed by recurrence unresponsive to reintroduction [112]. A high odevixibat response rate is described in TJP2 deficiency and a response in one case of ZFYVE19 deficiency [6]. European experts propose odevixibat 40 µg/kg/day for 12 weeks, defining response as a bile acid reduction greater than 70% or a pruritus reduction of at least 1 point; without response or with partial response, 120 µg/kg/day for a further 12 weeks (maximum of 6 mg/day in the US prescribing information and 7,200 µg/day in the European SmPC [24, 25]); and, without improvement, discontinuation and sequential trials of other drugs and biliary diversion, after quantifying pruritus before initiation [1]. This sequence is shorter than that of the European label, which considers an alternative only after 6 months [25]. EASL recommends considering IBAT inhibition to reduce pruritus before transplantation in BSEP-deficient patients with missense variants (level 2, strong; 100% consensus), and does not yet consider it possible to recommend medical instead of surgical interruption to prolong native liver survival (level 5, weak) [2]. In PEDFIC1, patients maintained UDCA, rifampicin and antihistamines, that is, odevixibat was tested as an adjunct [2, 25].

7.8. Biliary diversion and liver transplantation

Surgical EHC interruption is performed through partial external biliary diversion (PEBD), with an intestinal conduit between gallbladder and a stoma draining 30–50% of bile; partial internal biliary diversion (PIBD); or partial ileal exclusion, bypassing the terminal ileum and potentially causing severe malabsorption, particularly of vitamin B12, and diarrhoea [3]. No study has demonstrated superiority of one technique, although PEBD response may be more durable; long-term outcome is excellent when bile acids normalise in the first year, and cirrhosis at surgery is associated with worse outcome [3, 55]. In a meta-analysis of 424 children cited by European experts, pruritus resolved in 59.5% and 27% subsequently required transplantation; complications include stoma problems, malabsorption, diarrhoea, recurrent pruritus and progression [1].

Benefit depends on gene and genotype, and EASL makes distinct recommendations:

Diversion is effective in FIC1 deficiency and mild to moderate BSEP deficiency with residual function, may be ineffective in severe BSEP deficiency and is not used in FXR deficiency because of rapid progression [3, 113]. In mild FIC1 deficiency, nasobiliary drainage and extracorporeal liver support may shorten episodes, diversion benefit is unknown and transplantation difficult to justify [4]. In KIF12 and USP53 deficiencies, diversion's role is unknown [3].

Liver transplantation is indicated in end-stage liver disease and refractory symptoms, including intractable pruritus after medical and surgical treatment, and frequently has good outcomes but does not prevent extrahepatic complications [1, 3, 113]. In FXR deficiency, it is the only intervention shown to change outcome in observational series [7, 64]. In TJP2 deficiency, it may be required earlier because of neonatal severity, and in MYO5B deficiency with refractory pruritus; in KIF12 and USP53 deficiencies experience is limited to reports [3, 40, 65]. In MVID, treatment involves lifelong total PN and intestinal and/or liver transplantation, with pharmacological interventions described only in case reports [7].

7.9. Specific post-transplant problems

In FIC1 deficiency, secretory diarrhoea (without steatorrhoea) may persist or worsen and graft steatohepatitis may progress to cirrhosis, because intestinal disease is not corrected by the new liver and graft bile reaches a diseased intestine [4, 75, 78]. Diversion at transplantation may be considered; bile acid sequestrants may improve diarrhoea, clonidine has palliated it in some patients and intravenous fluids are sometimes necessary [4]. In a series from 6 European centres, 9 transplanted boys with FIC1 deficiency received odevixibat 30–120 µg/kg/day off-label for a median 13 months for diarrhoea and/or steatosis: most improved in diarrhoea and daily activities, and steatosis improved in 3 of 5 with data [114]. An August 2026 case described post-transplant protein-losing enteropathy treated with surgical diversion causing severe fat malabsorption; after IBATi initiation, diversion was reversed without enteropathy recurrence [115].

In BSEP deficiency without canalicular protein expression, the recipient may form IgG alloantibodies against donor BSEP, mimicking original disease (cholestasis, pruritus, low GGT) without rejection or biliary complication; biopsy shows cholestasis with giant cell transformation and sometimes fibrosis [2]. Jara and colleagues described three children with high-titre antibodies inhibiting transport in vitro who remitted with intensified immunosuppression, and Keitel described recurrence in two successive grafts in one patient whose three homozygous missense variants caused complete BSEP absence [116, 117]. In a multicentre cohort published in July 2026, 10 of 35 patients (29%) transplanted for severe BSEP deficiency and screened after 2010 had anti-BSEP antibodies, all with alloimmune liver disease, at a median of 5 years (1.5–14) post-transplant; remission was achieved in 9, with decreased or negative titres in 6, all treated with rituximab or plasmapheresis or immunoadsorption; relapse occurred in 6 of 9, and maintenance rituximab and/or immunoglobulins prolonged relapse-free survival [118]. Retransplantation was required in 6 (60%) and 3 deaths (30%) occurred among patients with alloimmune disease, versus 1 death (4%) and 1 retransplantation (4%) in the 25 without disease; severe genotype (biallelic PPTM) was present in 80% versus 28% (p=0.008), and negative native-liver BSEP immunostaining, cytomegalovirus infection, anastomotic stenosis and rejection were not associated [118]. The authors recommend structured post-transplant anti-BSEP antibody screening, particularly with biallelic PPTM [118]. A 2026 case had four relapses over 24 years, the first 12 years post-transplant, all controlled with plasmapheresis, intravenous immunoglobulin, rituximab and optimised immunosuppression, without retransplantation [119].

The sources consulted give no rituximab or plasmapheresis dosing regimen for this situation; management should be defined by the transplant centre.

7.10. Gene-specific treatment

In MDR3 deficiency, UDCA is the mainstay and response depends on genotype: none of 8 patients with a premature termination codon normalised biochemistry, compared with 21 of 23 with at least one missense variant, and interruptions are associated with biochemical relapse [2]. Approximately two thirds of PFIC3 patients respond well; those without MDR3 expression do not respond, and response is better with at least one missense variant, canalicular MDR3 present and biliary phospholipids above 6.9% of biliary lipids [6]. EASL recommends using genetics to predict phenotype and UDCA response (level 2, strong; 92%), UDCA with at least one missense variant and a clinical phenotype (level 3, strong; 100%), UDCA even with biallelic PPTM because partial response is possible (level 4, weak; 100%), and long-term UDCA in graft recipients with an MDR3 variant (level 4, strong; 96%) [2]. Adherence is critical and UDCA is maintained until transplantation [2]. MDR3 deficiency pruritus is treated with rifampicin, colestyramine, naltrexone, sertraline or IBATi, the latter within the PFIC indication; diversion is an option for refractory pruritus [3, 7]. Chaperones (4-phenylbutyrate, curcumin) and transcriptional induction through FXR agonists or PPAR-α ligands are experimental [7].

In FXR deficiency, obeticholic acid should not be used: it was never approved for PFIC, and its mechanism is useless when the receptor is the defect [7]. Ocaliva® had EU conditional authorisation on 12-12-2016, revoked on 30-08-2024, and appears as discontinued in Drugs@FDA [120, 121]. In a Tunisian infant with FXR deficiency, UDCA was ineffective and the child died at 6 months from liver failure [7]. TJP2 deficiency has no specific therapy: pruritus treatment with usual drugs or IBATi, PEBD with good outcomes if bile acids normalise in the first year, and HCC surveillance [3, 7]. In SEMA7A deficiency, the described child improved with UDCA and glutathione [44]. CFTR correctors improved mutant FIC1 trafficking in cell culture, without clinical data [4].

Primary bile acid synthesis defects (HSD3B7, AKR1D1). In the differential diagnosis with PFIC, these defects have effective medical treatment, and EASL recommends treating them with an oral primary bile acid (evidence level 3, strong recommendation, strong consensus), cholic acid being the agent of choice [2]. According to the PNDS, replacement has three objectives: to reconstitute a physiological bile acid pool that restores absorption of fats and fat-soluble vitamins and growth, to re-establish bile acid-dependent bile secretion, and to restore negative feedback on 7α-hydroxylase, which cholic acid exerts through FXR, to halt production of the toxic metabolites [29]. Treatment begins without delay and in a specialised setting, is lifelong because it does not correct the enzyme defect, and at diagnosis may require oral or parenteral supplements of vitamins A, D, E and K [29]. The PNDS recommends cholic acid rather than chenodeoxycholic acid because it accounts for two thirds of physiological production, and because chenodeoxycholic acid is more detergent, is hepatotoxic at high doses and in severe liver failure, is metabolised to lithocholic acid (hepatotoxic in overdose and potentially carcinogenic in the colon), is not authorised for these indications in any country and is contraindicated in pregnancy because of teratogenicity [29]. EASL considers both capable of restoring bile flow and repressing endogenous synthesis, but recognises cholic acid as the agent of choice because it is neither hepatotoxic nor embryotoxic [2]. UDCA may be used transiently while confirmation of the diagnosis is awaited, but is not indicated as monotherapy, because it exerts no feedback on 7α-hydroxylase and does not reduce the atypical metabolites [29]. Cholic acid has been authorised in the EU since 2013 (Orphacol®) and in the USA since 2015 (Cholbam®) [29, 122, 123].

The lack of correlation between dose and efficacy of feedback requires individual adjustment: at each review, the lowest dose is chosen that reduces the atypical metabolites (in 3β-HSD deficiency, 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-5-cholenoic acids; in Δ4-3-oxo-R deficiency, 3-oxo-7α-hydroxy- and 3-oxo-7α,12α-dihydroxy-4-cholenoic acids) to values as close to zero as possible [29, 122]. Overdose is suspected from pruritus, diarrhoea or a simultaneous rise in GGT and transaminases and is confirmed by raised total serum bile acids; the SmPC adds that transient rises in transaminases at initiation do not require dose reduction if GGT does not rise and serum bile acids are falling or normal [29, 122]. The SmPC contraindicates phenobarbital and primidone, which antagonise cholic acid, advises against ciclosporin, requires a 5-hour separation from bile acid sequestrants and aluminium-containing antacids, and requires separation from UDCA doses (one in the morning, the other in the evening), because UDCA competes for absorption and reduces feedback [122]. Both labels warn of severe hepatotoxicity, including fatal cases in the EU and serious cases in patients with cirrhosis after marketing in the USA; the SmPC requires treatment to be stopped if prothrombin time does not improve within 3 months, and the US prescribing information if liver function does not improve within 3 months, if complete biliary obstruction develops or if there is persistent deterioration [122, 123]. In the Cholbam® trials, six patients with a single enzyme defect underwent transplantation, four with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency [123].

With treatment instituted in time, according to the series gathered by the PNDS, all patients improve, with nearly normal growth (weight recovery may exceed height recovery) and normal sexual maturation; jaundice regresses within a few months, splenomegaly and then hepatomegaly within a few years, bilirubin and transaminases normalise within months, coagulopathy and vitamins A, D and E are corrected (supplements should then be stopped to avoid overdose), and histology improves in almost all, with disappearance of cholestasis and inflammation and stabilisation or regression of fibrosis [29]. Neurological deficits due to vitamin E deficiency are classically irreversible, although improvement of areflexia has been observed [29]. The effect remained stable in series with mean follow-up of up to 12.5 years (5.6–15 years); in a series with more than 180 patient-years there were no serious adverse effects, and in another with mean follow-up of almost 3 years (0–10) there were no deaths or serious effects; adverse effects, mild to moderate, are mainly pruritus and diarrhoea, which subside with dose reduction [29]. In a series of 15 patients (13 with 3β-HSD deficiency and 2 with Δ4-3-oxo-R deficiency) followed for a mean of 12.5 years, adherence, assessed by the urinary profile, was always good, even in older children [29]. In pregnancy, the PNDS gathers nine pregnancies in four patients on cholic acid with healthy newborns; the SmPC reports fewer than 20 pregnancy outcomes without adverse effects, considers it essential to continue treatment under close surveillance, does not require contraception and allows breastfeeding, and the US prescribing information, without studies in pregnant women or animals, cites case reports with healthy newborns and maintains a pregnancy surveillance programme [29, 122, 123]. Δ4-3-oxo-R deficiency requires closer surveillance, because dose adjustment is more difficult than in 3β-HSD deficiency [29].

7.11. Intrahepatic cholestasis of pregnancy

ICP treatment is where guidelines diverge most. PITCHES, in 33 English and Welsh maternity units (December 2015 to August 2018), randomised 605 women to UDCA 500 mg twice daily (1 to 4 tablets daily) or placebo until delivery; the composite endpoint of perinatal death, birth before 37 weeks or neonatal admission for at least 4 hours occurred in 23% (74/322) versus 27% (85/318), with adjusted relative risk 0.85 (95% CI 0.62–1.15), concluding that UDCA does not reduce adverse perinatal outcomes [93]. An individual-data meta-analysis cited by Vitale confirmed pruritus reduction without a significant stillbirth effect [6].

The UDCA divergence has an explanation: RCOG, published after PITCHES, assessed UDCA by fetal outcome and does not routinely recommend it for that purpose, whereas SMFM and EASL recommend it for maternal symptoms and, for EASL, also because of its relationship with ABCB4-associated liver disease [2, 22, 30, 93]. Delivery thresholds also differ, particularly with bile acids above 100 µmol/L (36 weeks in SMFM, 35–36 in RCOG) [22, 30]. Vitale also cites colestyramine and S-adenosylmethionine as options, proposing genetic testing in ICP with bile acids of 40 µmol/L or higher or onset by 32 weeks [6]. Volixibat, an unauthorised IBATi, was given to 4 pregnant women with ICP (20 or 80 mg twice daily until delivery) in a study with more than 1,000 invited and 26 screened: 3 had reduced pruritus, all reached bile acids below 6 µmol/L and had healthy newborns, with mainly gastrointestinal adverse effects; this is a very small experimental series [124].

7.12. LPAC, ABCB4 carriers and adult cholestasis

In LPAC, lifelong UDCA 8–10 mg/kg/day up to 13–15 mg/kg/day is widely used, with transplant-free survival above 90% in retrospective data [2]. In a study of 67 heterozygous adults, 93% treated with UDCA, transplant-free survival was 91% over a median 14 years, with 3 deaths (2 from cholangiocarcinoma, 1 from biliary cirrhosis) and normal elastography (<6.3 kPa) in 75% [2]. In 60 carriers with LPAC compared with 65 LPAC patients without an ABCB4 variant, MRI complications were 35% versus 15% (OR 2.9; 95% CI 1.1–7.8) [2]. EASL recommends follow-up of pathogenic ABCB4 variant carriers for complications, including malignancy (level 2, strong; 100%), tailored to presentation and variant (level 5, strong; 96%), with history, tests and non-invasive fibrosis assessment at least six-monthly (level 3, strong; 96%) and ultrasound and/or MRI with MRCP at least annually (level 4, strong; 100%) [2]. In adults, pharmacological EHC interruption offers a specific intervention in primary cholestasis, and UDCA is essential when biliary epithelium is the main injury site [90]. Plasmapheresis has been explored in severe adult acute intrahepatic cholestasis triggered by drugs, pregnancy or intercurrent illness [6].

7.13. Agents and circumstances to avoid

In FIC1 deficiency, susceptibility to deafness may argue against aminoglycosides and other ototoxic drugs, and oral contraceptives may induce or worsen cholestatic episodes [4]. In women with prior ICP, contraceptives and hormone therapy trigger cholestasis, and antibiotics are the main drug-induced cholestasis cause in carriers [6]. Obeticholic acid is not a therapeutic option [7, 120]. With IBATi, sequestrant resins should be separated by 4 hours, and maralixibat may reduce statin absorption [24, 26]. IBATi are contraindicated in the USA after hepatic decompensation, and safety is unestablished in clinically significant portal hypertension [24, 26].

7.14. Pregnancy, lactation, perioperative care and transition

For odevixibat, human pregnancy data are insufficient; fetal cardiovascular malformations occurred in rabbits (five-chambered heart, ventricular septal defect, right-sided or retro-oesophageal aortic arch) at all doses, with maternal exposure 2.1 times the maximum recommended dose, and the drug crosses the placenta in rats without embryo-fetal effects in this species up to 272 times exposure [24]. The United States label requires fat-soluble vitamin monitoring and supplementation in pregnancy, and a pregnancy registry exists; the European SPC considers odevixibat not recommended in pregnancy, requires effective contraception in women of childbearing potential and, for breastfeeding, a decision between stopping breastfeeding or treatment, whereas the United States label does not expect infant exposure because of low absorption [24, 25, 96]. For maralixibat, measurable fetal exposure is not expected, rat and rabbit studies at 1,200 to 12,000 times maximum exposure showed no effects, and the United States label does not expect infant exposure; the EU considers it preferable to avoid in pregnancy and avoid the solution during breastfeeding as a propylene glycol precaution [26, 27]. In women with PFIC or carriers, pregnancy triggers cholestasis and ICP [2, 4].

Perioperatively and before invasive procedures, coagulation and fat-soluble vitamin status should be known, because bleeding after endoscopy and liver biopsy has been reported with IBATi, and bleeding requires drug interruption and vitamin optimisation [24, 26]. European experts leave paediatric-to-adult transition outside scope and recommend specialist centre referral; Vitale notes that transition grows in importance with IBATi because more patients reach adulthood with their native liver [1, 6].

For transition, the French PNDS on synthesis defects adopts the 2017 framework of the FILFOIE network, which applies to all young people with chronic liver disease or liver transplantation and therefore also to PFIC [29]. The framework divides transition into three periods. In the preparation phase (14–18 years), the patient is informed well in advance about the transfer, which generally takes place at around 18 years; consultations are adapted to promote autonomy, therapeutic education is offered, knowledge and skills are assessed, multidisciplinary consultations are organised (psychology, social work, dietetics, liaison nursing, paediatrics and surgery), and the referring adult physician is chosen at least one year beforehand, receiving the reports and an explanation of the disease, surveillance and treatment [29]. Therapeutic education covers knowledge of the disease and its complications, the importance of follow-up and treatment, and the risks of poor adherence and risk behaviours (alcohol and other toxic substances), with annual assessment by questionnaire and a guide for parents; the adolescent learns to manage appointments, obtain treatment from the pharmacy, renew prescriptions and certificates and arrange transport, and the choice of a general practitioner at 16 years, required by French regulations, serves as a first step [29]. The transfer phase (16–20 years) takes place during a period of clinical, psychological and social stability, with joint or alternating consultations with the adult physician, a liaison form or summary letter and confirmation of contact, to avoid loss to follow-up; on arrival in adult care, a first consultation with sufficient time and an introduction to the team are planned, and each report is sent to the general practitioner and to the paediatrician, who are informed of missed appointments [29].

7.15. Developments over the last 12 months (October 2025 to October 2026)

The 4-phenylbutyrate trial in BSEP deficiency (NCT04531878) was withdrawn in 2023 before recruitment [103]. Gene therapy has encouraging results in animal models, particularly for ABCB4, and potentiators, correctors, combinations and RNA interference are under basic investigation [2, 6]. A 2025 review anticipates extension of IBATi indications to other paediatric and adult cholestases as ongoing trials finish [126]. Experts listed other IBATi in 2023 (elobixibat, approved in Japan for chronic constipation; linerixibat and volixibat, unapproved) [1]. The searches performed did not identify journal publication of the final PEDFIC2 and MARCH-ON results, which does not exclude later publication.

7.16. Synthesis of recommendations and divergences

The most relevant divergence in paediatric practice concerns diversion in FIC1 deficiency: GeneReviews 2021 described surgical EHC interruption as primary therapy, whereas EASL 2024, based on NAPPED data, ceased recommending it routinely to prolong native liver survival [2, 4, 52]. For HCC surveillance, EASL genotype-specific intervals replace the single 6–12-month interval of GeneReviews [2, 3]. In the treatable differential of synthesis defects, the reference cholic acid dose is that of the PNDS, which coincides with the European SmPC (5–15 mg/kg/day, up to 500 mg/day in adults); the lower limit of the US prescribing information (10 mg/kg/day) is higher, and the monitoring proposed by the labels relies on liver function, whereas the PNDS adjusts the dose mainly by the urinary bile acid profile [29, 122, 123].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In paediatric forms, inheritance is autosomal recessive. A patient's parents are presumed heterozygotes and should be tested after molecular diagnosis to confirm variant phase and enable reliable risk calculation [3, 4]. When only one parent is a carrier, with paternity and maternity confirmed, possibilities are a de novo variant in the proband, a postzygotic variant in a mosaic parent or uniparental isodisomy [3]. Each sibling has a 25% chance of being affected, 50% of being a carrier and 25% of being a non-carrier; siblings with the same variants do not always have the same severity, and severity may change over time [4]. A patient's children are obligate heterozygotes unless the other parent is affected or a carrier, in which case disease risk is 50%; this probability is low in the general population but not founder-variant populations (Amish, Greenland Inuit) [4]. A patient's aunts and uncles have a 50% chance of being carriers [3].

8.2. Heterozygotes

Heterozygotes are usually asymptomatic, but ICP has been reported in mothers of PFIC patients, heterozygous brothers may have greater transient neonatal cholestasis risk and heterozygous sisters greater ICP risk [3, 4, 71]. For ABCB4, heterozygotes may develop LPAC, ICP, chronic cholestasis, DILI and hepatobiliary malignancy [2]. EASL recommends offering genetic testing to first-degree relatives of patients with ABCB4 variants (level 2, strong; 100%) and proposes, for heterozygous parents and first-degree relatives of severe MDR3-deficient patients, individualised follow-up approximately every 3 years if asymptomatic with normal tests, without advanced fibrosis or stones, and annual follow-up with consideration of UDCA if they have ICP, stones, LPAC, cholestasis or DILI [2].

8.3. Cascade testing and minors

GeneReviews recommends clarifying the genetic status of apparently asymptomatic at-risk relatives, older and younger, to initiate treatment, surveillance and trigger avoidance early [4]. In a patient's siblings, testing has immediate medical utility because the disease may manifest in childhood; carrier testing, by contrast, requires the familial variants to be known, and the ideal time to discuss it is before pregnancy, with counselling of affected, carrier or at-risk young adults [3]. In women carrying ABCB4, ABCB11 or ATP8B1 variants, knowing their carrier status allows targeted surveillance in future pregnancies because of the risk of ICP [2, 4]. In East Greenland Inuit communities, carrier frequency justifies routine screening [4]. In bile acid synthesis defects, also autosomal recessive, the PNDS recommends family genetic investigation after each new case, because systematic screening of siblings, prompted by a confirmed defect or by early deaths from cirrhosis, has identified asymptomatic siblings who benefit from early treatment [29].

8.4. Prenatal and preimplantation diagnosis

When familial pathogenic variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; carrier detection and prenatal diagnosis depend on that molecular confirmation [3, 8]. Perspectives on prenatal diagnosis vary between professionals and families, and counselling should respect this diversity [3]. In heterozygous women's pregnancies, ICP surveillance follows obstetric guidelines (section 7.11).

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The most repeated figure, an incidence of 1/50 000 to 1/100 000 births for PFIC overall, is an estimate from Srivastava's 2014 review, stating exact prevalence is unknown and disease affects both sexes in all regions [21]. European expert opinion, Vitale's review and Swissmedic repeat this estimate from the same source, so repetition adds no validation [1, 6, 49]. The ATP8B1 GeneReviews has a syntactically ambiguous sentence apparently assigning this value to high-GGT PFIC and PFIC3; Srivastava's text shows it concerns PFIC overall [4, 21]. Exact FIC1 deficiency prevalence is unknown and may be underestimated through misdiagnosis [4]. Orphanet assigns PFIC1, 2 and 3 a European prevalence class of 1–9/100 000, unvalidated and without a mean value, and PFIC4, PFIC5 and MYO5B PFIC a class below 1/1 000,000, based on 14, 4 and 5 published cases or families [14–19]. For the PFIC group, BRIC, ICP and LPAC, Orphanet gives prevalence as ‘unknown’ [10–13].

9.2. Founder populations and consanguinity

FIC1 deficiency was first described in Old Order Amish, with founder variant p.(Gly308Val), and eastern Nunavut and Greenland Inuit with p.(Asp554Asn); outside these populations, no increased-risk groups are known, and disease has been reported in all ethnicities [4, 5, 53]. Lancaster County Amish also have high carrier frequencies of TJP2 and BAAT variants [3, 63]. ATP8B1 p.(Glu665Ter) was described in the Dominican population, and the allele with p.(Pro209Thr) and c.627+5G>T in eastern China [4]. In Europeans, p.(Ile661Thr) in ATP8B1 and p.(Glu297Gly) and p.(Asp482Gly) in ABCB11 are the most frequent variants [4, 57]. KIF12, USP53, LSR and WDR83OS series come mainly from Saudi Arabian consanguineous families, and USP53, ZFYVE19 and SEMA7A series from Chinese cohorts [40, 42–44]. Consanguinity increases local risk of all recessive forms [7]. Iceland contributes genome data on fibrosis and malignancy risk in ABCB4 heterozygotes [2].

9.3. Portugal and Brazil

The sources consulted do not describe PFIC frequency in Portugal or Brazil, which does not demonstrate absence of published data. Portugal participates in the maralixibat phase 4 LEAP-EU study through Unidade Local de Saúde de Coimbra, which was not yet recruiting in October 2026 [103]. In Brazil, a São Paulo centre (Hospital Sírio-Libanês) participated in MARCH-PFIC, MARCH-ON and MRX-801, and G. Porta from São Paulo co-authored MARCH-PFIC and the 2026 Latin American consensus, highlighting regional difficulties in access to specialist care and genetic testing [31, 103, 105]. The sources consulted contain no INFARMED, ANVISA or CONITEC reimbursement or incorporation decisions for IBATi.

9.4. Special populations

In infants younger than 3 months, IBATi efficacy and safety are unestablished, and in the EU odevixibat is indicated only from 6 months [24, 25]. Patients younger than 5 years are most vulnerable to propylene glycol in maralixibat solution [26, 27]. There are no patients aged 65 years or older in odevixibat trials [24]. Women with PFIC, BRIC or carrier status require pregnancy planning and appropriate contraception (sections 7.11 and 7.14). Adults with cryptogenic cholestasis, LPAC, recurrent DILI or severe ICP are an underdiagnosed population [2, 6].

9.5. Reference networks and patient organisations

In Europe, genetic cholestasis reference centres are organised within ERN RARE-LIVER (https://rare-liver.eu/), including, for example, Hospital Bicêtre's centre in Paris [28, 112]. The NAPPED consortium brings together members of ERN and the North American ChiLDReN network (Childhood Liver Disease Research Network, https://childrennetwork.org/), funded by the United States National Institutes of Health (NIH), conducting the LOGIC study of genetic intrahepatic cholestasis causes [52, 103, 129]. The PFIC Network (https://www.pfic.org/) is the international patient and family organisation and maintains PNPR (PFIC Network Patient Registry) [72, 130]. ICP Support (https://www.icpsupport.org/) is the British cholestasis of pregnancy organisation [131]. GeneReviews also lists the American Liver Foundation, Liver Canada, Liver UK and Alagille Syndrome Alliance, and OXF the United Kingdom Children's Liver Disease Foundation [3, 8].

In France, according to the 2019 PNDS, genetic cholestases and bile acid synthesis defects are followed in the network of the rare disease reference centre for biliary atresia and genetic cholestasis (CRAVB-CG): coordinating centre at Bicêtre Hospital (AP-HP, Le Kremlin-Bicêtre), constituent centres in Lyon (Hôpital Femme-Mère-Enfant) and Paris (Necker-Enfants malades), paediatric hepatology competence centres in Lille, Marseille and Rennes, a paediatric and adult centre in Toulouse, and adult hepatology centres in Clichy (Beaujon) and Villejuif (Paul Brousse) [29]. The network belongs to the FILFOIE rare disease healthcare network (rare liver diseases of adults and children, https://www.filfoie.com/), and patients are represented by the AMFE association (Association maladies foie enfants, http://www.amfe.fr/) [29]. The diagnostic approach and the initiation and adjustment of cholic acid are the responsibility of the centre physician, with paediatric hepatology (and, if necessary, neonatology and intensive care), a specialised biochemistry laboratory, pathology and molecular biology; between consultations, the paediatrician or general practitioner manages intercurrent illnesses in liaison with the centre [29]. The PNDS also serves as a reference for the attending physician in establishing the care protocol with the medical adviser of the Caisse d'assurance maladie, when applying for exemption from patient co-payment as a condition outside the list of long-term illnesses [29].

10. Illustrative Clinical Case

Kehler and colleagues from Regensburg and Erlangen published in 2025 the case of a boy with BSEP deficiency treated with odevixibat from 3 months; medical writing was funded by Ipsen, the drug's manufacturer [69]. The newborn had prolonged jaundice with initially non-acholic stools. At 6 weeks, he had direct hyperbilirubinaemia documented before propranolol initiation for a cutaneous haemangioma, very high transaminases and no GGT increase, and started UDCA [69]. At 9 weeks, he had hepatomegaly with increased echogenicity and now-acholic stools; endoscopic retrograde cholangiography showed normal extrahepatic bile ducts, excluding biliary atresia [69].

Liver biopsy, with 22 portal tracts, showed giant cell transformation with marked cholestasis, early septal fibrosis (Ishak 2–3 of 6), regular bile ducts in some portal tracts and immunohistochemical BSEP absence (Figure 1 of the article: histology with haematoxylin-eosin, cytokeratin 7 and BSEP); electron microscopy described in the Figure 2 legend showed amorphous bile without ‘Byler bile’ [69]. Primary and total bile acids were very high despite UDCA. Trio exome sequencing identified, on the paternal allele, ABCB11 NM_003742.4:c.1966_1967del p.(Leu656AlafsTer9) (NC_000002.12:g.168969395_168969396del), likely pathogenic (class 4), and on the maternal allele ATP8B1 NM_001374385.1:c.208G>A p.(Asp70Asn) (NC_000018.10:g.57706561C>T), VUS (class 3); no second ABCB11 variant was found, and genome sequencing was ongoing [9, 69].

With BSEP deficiency diagnosed on immunohistochemical protein absence despite a monoallelic genotype, the child started odevixibat 40 µg/kg once daily at 3 months and UDCA was discontinued [69]. Bilirubin, transaminases and bile acids normalised within weeks, with a transient initial AST increase and no other adverse effects (Figure 3 of the article: laboratory course and growth) [69]. On visual inspection of Figure 3, total bile acids peaked at approximately 380 µmol/L and total bilirubin at approximately 8.5 mg/dL; the transaminase axis is labelled ‘mg/dl’, probably a typographical error for U/L. After 2.5 years of treatment, the child was asymptomatic, without pruritus or jaundice, without fibrosis on acoustic radiation force impulse (ARFI) elastography and without portal hypertension (portal flow 37 cm/s and normal spleen at 3 years), with height 104 cm (98th centile) and weight 18.2 kg (96th centile), maintaining 40 µg/kg/day, folic acid and vitamin D 1,000 IU/day in winter, as summarised in the Figure 4 timeline [69].

The authors acknowledge that the second ABCB11 variant may be deep intronic or regulatory, note that the same truncating variant occurred in a PEDFIC1 patient and recall that, in the Italian series, 2 of 11 PFIC2 patients with a truncating variant, both homozygous, did not respond [69]. The case illustrates diagnostic reasoning with an incomplete genotype and possible response with a genotype containing one truncating variant, but should not be generalised: initiation at 3 months follows the United States label and is outside the European indication (from 6 months), the genotype does not meet molecular diagnostic criteria, and labels do not recommend the drug in patients with non-functional BSEP, potentially suggested by immunohistochemical protein absence [24, 25, 69]. This patient's response does not change EASL's recommendation to base BSEP deficiency management on genotype [2].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, severe forms progress to cirrhosis, liver failure and childhood death [3, 4]. In FIC1 deficiency, native liver survival is 44% at 18 years, fewer than half reach adulthood with their native liver and approximately 70% underwent diversion; presenting bile acids below 194 µmol/L are associated with 10-year survival of 49%, versus 15% above that value [6, 52]. European expert opinion summarises this as survival ‘three times greater at 15 years’; this article uses the values of the primary study [1, 52]. In BSEP deficiency, median native liver survival is 20.4, 7.0 and 3.5 years in BSEP1, BSEP2 and BSEP3, and 10-year survival ranges from 22% to 75% by genotype [1, 58]. In a series of 48 PFIC2 patients cited by Vitale, 18 underwent diversion and 22 transplantation [6]. In MDR3 deficiency, survival depends on UDCA response, and patients with two severe variants generally need transplantation before 10 years [2]. In FXR deficiency, death occurs in the first months without transplantation [64]. In treated LPAC, transplant-free survival exceeds 90% [2].

Preliminary data comparing PEDFIC with NAPPED suggest odevixibat native liver survival benefit, but the controlled phase lasted 6 months and long-term results are awaited; initial data suggest IBATi delay transplantation for pruritus in responders, without knowing whether they alter progression and HCC risk [2]. In MRX-503, Swissmedic found no trend towards fewer serious hepatic events with maralixibat [49]. Bile acid reduction correlates with pruritus reduction, and follow-up instruments are ItchRO(Obs) and PRUCISION for pruritus, APRI (AST-to-platelet ratio) and FIB-4 (fibrosis 4 index) for fibrosis, and a dedicated histological scale for BSEP deficiency [1]. Clinically evident portal hypertension, in the ChiLDReN network operational definition, requires splenomegaly (spleen palpable more than 2 cm below the costal margin) with platelets below 150 × 10⁹/L, or one manifestation (clinically evident ascites or oesophageal or gastric varices on endoscopy); isolated splenomegaly or thrombocytopenia defines possible portal hypertension [132]. GeneReviews, citing this definition, writes ‘hepatomegaly’, which does not correspond to the original [3, 132].

11.2. Surveillance

There are no established cholangiocarcinoma screening guidelines [3]. EASL notes no prospective studies of HCC screening impact in BSEP deficiency, and starting at diagnosis is based on very early cases (7 of 10 Knisely patients were younger than 2 years) [2, 79]. Initial assessment after diagnosis also includes audiology in all FIC1-deficient patients, endocrinology with low calcium and high phosphorus (parathyroid hormone resistance), dedicated pancreatic imaging with high amylase or lipase and excessive faecal fat, genetic counselling and family and social support [4].

12. Summary and Final Considerations

Progressive familial intrahepatic cholestases are a group of recessive diseases defined by the affected gene and protein rather than numbering, which differs between OMIM, labels and trials, especially for MYO5B. The common mechanism is failure of canalicular bile acid or phosphatidylcholine secretion, the junctional barrier, transporter induction or hepatocyte polarity; GGT separates pump and regulatory defects, with low GGT, from defects with ductal injury, with high GGT. The same variants, with residual function or in heterozygosity, explain BRIC, ICP, LPAC and some DILI and adult cryptogenic cholestasis.

Diagnosis rests on early next-generation sequencing, with exome or genome when the panel is negative, requiring attention to limitations: a negative test does not exclude disease, monoallelic VUS are insufficient for monogenic diagnosis, and immunohistochemical BSEP absence does not distinguish BSEP from FXR deficiency. In BSEP deficiency, genotype (BSEP1, BSEP2, BSEP3 and BSEP1/3) determines prognosis, diversion response, IBATi eligibility and HCC surveillance frequency; in MDR3 deficiency, it determines UDCA response.

IBAT inhibitors changed pruritus treatment: odevixibat and maralixibat reduced pruritus and bile acids in 24- to 26-week controlled trials, with diarrhoea and risks of hepatotoxicity and fat-soluble vitamin deficiency as the main adverse effects. Indications, minimum ages and maximum doses differ between the USA, EU and Switzerland, BSEP3 is excluded, and an effect on native liver survival and HCC remains undemonstrated in controlled trials. Biliary diversion retains a place in responsive BSEP deficiency genotypes, but EASL no longer routinely recommends it in FIC1 deficiency; transplantation resolves liver disease but not FIC1 deficiency extrahepatic manifestations, and in BSEP deficiency without protein exposes to anti-BSEP alloimmunisation risk, present in 29% of a recent cohort. In ICP, guidelines differ regarding UDCA, and bile acids above 100 µmol/L mark fetal risk guiding delivery timing. Genetic counselling should include heterozygotes, especially women because of ICP risk, and ABCB4 carriers, warranting dedicated follow-up.

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