ABCB4 Deficiency Presenting as a Pruritus‐Free Continuous Spectrum From Childhood Cholestasis to Adult Cirrhosis: A Case Report

ABSTRACT

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by biallelic mutations in the ABCB4 gene and typically presents in childhood. However, the full phenotypic spectrum—particularly adult‐onset and pruritus‐free forms—remains under‐recognized. We report the case of a 28‐year‐old male who presented with pruritus‐free decompensated cirrhosis after a 10‐year diagnostic delay. Genetic testing revealed compound heterozygous ABCB4 variants [c.249C>A (p.Asp83Glu) and c.1466A>G (p.Asn489Ser)], which were initially classified as variants of uncertain significance (VUS). Proactive family screening identified his asymptomatic 14‐year‐old sister, who carried the same genotype and exhibited significant gamma‐glutamyl transferase (GGT) elevation (142.1 U/L) but no pruritus. Perfect genotype–phenotype cosegregation in the two siblings, combined with the absence of these variants in population databases (PM2 and PP1 criteria per American College of Medical Genetics and Genomics [ACMG] guidelines), provided decisive evidence for reclassifying the VUS as “Likely Pathogenic.” This family defines a pruritus‐free continuous PFIC3 spectrum and demonstrates that systematic screening of all first‐degree relatives upon proband diagnosis is essential for enabling pre‐symptomatic intervention. The key learning point is that ABCB4 deficiency should be considered in adults with cryptogenic cirrhosis even without pruritus, and family screening can resolve diagnostic uncertainty while facilitating early therapy.

Key Clinical Message

Clinicians should suspect ABCB4 deficiency in adults with cryptogenic cirrhosis, even in the absence of pruritus. Family segregation analysis can both resolve uncertain genetic findings and enable pre‐symptomatic treatment in at‐risk relatives.

1. Introduction

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by biallelic mutations in the ABCB4 gene, resulting in MDR3 protein deficiency and characterized by gamma‐glutamyl transferase (GGT)‐elevated cholestasis [1, 2]. The terms PFIC3 and ABCB4 deficiency are used interchangeably in this report to describe the same disease entity. PFIC3 classically presents in childhood with severe pruritus as a hallmark symptom, often prompting early diagnosis. However, the absence of pruritus in some patients—as in our case—can lead to significant diagnostic delay. Although traditionally considered a pediatric disease, the phenotypic spectrum of PFIC3 is broad [3]. Adult‐onset forms are increasingly recognized but frequently misdiagnosed, and the full natural history, particularly of pruritus‐free presentations, remains poorly defined [4].

The significance of this report lies in three aspects: (1) the rare pruritus‐free presentation in both siblings, (2) the demonstration of a prolonged asymptomatic biochemical phase detectable in childhood, and (3) the practical utility of family screening in reclassifying VUS and enabling early intervention. This case report describes a family that uniquely illustrates the complete disease continuum associated with a specific ABCB4 genotype—from silent childhood biochemical abnormalities to decompensated cirrhosis in adulthood—and underscores the critical role of systematic family screening in both diagnosis and prevention.

2. Case History/Examination

2.1. Patient 1 (Proband)

A 28‐year‐old male was admitted to our hospital with worsening jaundice and fatigue.

2.1.1. Clinical Timeline of the Proband

• Age 18: First diagnosed with “biliary cirrhosis” based on biochemical and imaging findings; no pruritus reported.

• Age 18–28: No specific treatment received; progressive fatigue and jaundice developed gradually.

• Age 28: Admitted with decompensated cirrhosis; genetic testing performed.

Notably, he reported never having experienced pruritus throughout his entire clinical course. His past medical and family histories were unremarkable for liver disease at presentation.

Physical examination on admission revealed signs of decompensated cirrhosis, including scleral icterus, jaundice, and palmar erythema. No spider angioma was observed on the chest. Abdominal examination showed a firm, non‐tender liver edge palpable 4 cm below the costal margin, splenomegaly (palpable 3 cm below the costal margin), and shifting dullness suggestive of moderate ascites.

2.2. Differential Diagnosis, Investigations, and Treatment

2.2.1. Differential Diagnosis

Given the presentation of cholestatic liver disease with elevated GGT in a young adult, the differential diagnosis included:

1. Progressive familial intrahepatic cholestasis (PFIC) type 3: Considered the primary diagnosis due to GGT‐elevated cholestasis in a young adult with a negative viral and autoimmune workup.

2. Primary sclerosing cholangitis (PSC): Considered but excluded by the absence of inflammatory bowel disease, normal magnetic resonance cholangiopancreatography (MRCP) findings (no beading or strictures), and negative perinuclear anti‐neutrophil cytoplasmic antibodies (p‐ANCA).

3. Other cholestatic liver diseases: Such as drug‐induced liver injury, alcoholic liver disease, or viral hepatitis, which were ruled out by detailed history and negative serology.

2.2.2. Investigations

Laboratory tests confirmed severe cholestasis and synthetic dysfunction:

• Liver biochemistry: GGT 317.1 U/L (normal < 40), total bilirubin 85.5 μmol/L, direct bilirubin 45 μmol/L, albumin 31.9 g/L.

• Aminotransferases: Mildly elevated (aspartate aminotransferase [AST] 95 U/L, alanine aminotransferase [ALT] 80 U/L; normal < 40).

• Hematology: Thrombocytopenia (platelets 15 × 10⁹/L).

• Viral/Immune serology: Negative for viral hepatitis (A, B, C, E) and autoimmune markers (antinuclear antibody [ANA], anti‐mitochondrial antibody [AMA], smooth muscle antibody [SMA]).

Abdominal CT imaging demonstrated cirrhosis, features of portal hypertension including collateral circulation and splenomegaly, and moderate ascites.

A liver biopsy was performed to establish the etiology. Histopathology showed:

• Bridging fibrosis linking portal tracts (consistent with advanced fibrosis/cirrhosis).

• Prominent cholangiolar proliferation at the portal tract periphery.

• Immunohistochemistry for MDR3 protein showed positive canalicular staining (Figure 1).

FIGURE 1.

Liver histopathology of the proband. (A) H&E staining (40× magnification) showing portal inflammation and cholangiolar proliferation. (B) Masson's trichrome staining (200×) demonstrating bridging fibrosis. (C) Immunohistochemistry for MDR3 (200×) showing positive canalicular staining.

To identify a genetic cause, whole‐exome sequencing was performed on the proband using the Illumina NovaSeq platform with a targeted liver disease gene panel covering all exons of ABCB4 and 120 other cholestasis‐related genes. This identified compound heterozygous variants in the ABCB4 gene:

• A maternal variant: c.249C>A (p.Asp83Glu) in exon 4.

• A paternal variant: c.1466A>G (p.Asn489Ser) in exon 13.

  Both variants were absent from population databases (gnomAD) and were initially classified as variants of uncertain significance (VUS) according to ACMG guidelines. Family‐based segregation analysis later provided PP1 evidence supporting reclassification.

2.2.3. Treatment

The proband received comprehensive medical management for decompensated cirrhosis. This included diuretics (spironolactone and furosemide) for ascites control, nutritional support, and regular surveillance for complications such as variceal bleeding and hepatocellular carcinoma. Given the underlying diagnosis of ABCB4 deficiency, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day was added to his regimen to improve bile flow and slow disease progression—a standard approach for PFIC3, particularly in patients with residual MDR3 function. However, its efficacy in advanced cirrhosis is limited. Owing to the severity of his liver disease and poor long‐term prognosis, he was formally evaluated and placed on the waiting list for orthotopic liver transplantation.

2.2.4. Family Screening and Genetic Reclassification

Prompted by the genetic findings, we performed proactive clinical and genetic screening of all available first‐degree relatives. The results were as follows:

• Asymptomatic 14‐year‐old sister: Carried the identical compound heterozygous genotype [c.249C>A+c.1466A>G]. Biochemical testing revealed significant, previously unrecognized GGT elevation (142.1 U/L) with mild aminotransferase elevation (AST 73.3 U/L, ALT 76.7 U/L). She also denied any history of pruritus. Her abdominal ultrasound was normal.

• Father (42 years old): Heterozygous carrier of the c.1466A>G variant, clinically asymptomatic with normal liver biochemistry.

• Mother (41 years old): Heterozygous carrier of the c.249C>A variant, clinically asymptomatic with normal liver biochemistry.

The perfect segregation of the compound heterozygous genotype with the biochemical phenotype (GGT‐elevated cholestasis) in both affected siblings, while the heterozygous carrier parents remained unaffected, provided strong evidence for pathogenicity. This cosegregation fulfills the ACMG criterion PP1, which, combined with their absence from population databases (PM2), supported the reclassification of both variants from VUS to “Likely Pathogenic” (Table 1).

TABLE 1.

ABCB4 genevariant analysis and ACMG classification.

Genomic position (GRCh37)	Nucleotide/Protein change	Exon	Population frequency (gnomAD)	Inheritance	ACMG evidence	Proposed classification
chr7:87092111	Nucleotide/Protein change	4	Not found	Maternal	PM2, PP1	Likely Pathogenic
chr7:87069609	c.1466A>G/p.Asn489Ser	13	Not found	Paternal	PM2, PP1	Likely Pathogenic

Note: PM2: absent from population databases; PP1: co‐segregation with disease in multiple family members. Criteria per ACMG/AMP 2015 guidelines.

The identification of asymptomatic carriers (the parents) underscores the importance of genetic counseling. They were informed about their carrier status and the 25% recurrence risk in future pregnancies, and were advised to undergo annual biochemical surveillance.

3. Conclusion and Results (Outcome and Follow‐Up)

Despite medical therapy including UDCA, the proband's liver synthetic function did not show significant recovery due to the advanced stage of cirrhosis at presentation. His condition has been managed supportively while he awaits liver transplantation.

The identification of his sister in a pre‐symptomatic stage was a critical outcome of family screening. She was immediately started on ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day. At her 6‐month follow‐up, she remained asymptomatic, and her liver biochemistry showed improvement, with GGT decreasing from 142.1 to 98 U/L. This early intervention aims to halt or slow disease progression and potentially alter her natural history.

This case provides three key learning points for clinicians: (1) ABCB4 deficiency should be suspected in adults with cryptogenic cirrhosis even in the absence of pruritus; (2) genetic variants initially classified as VUS can be resolved through family segregation analysis; and (3) systematic screening of first‐degree relatives is essential for early diagnosis and pre‐symptomatic intervention. Our findings advocate for a shift from reactive end‐stage management toward proactive, precision‐based prevention in ABCB4 deficiency.

4. Discussion

This family case provides a seminal illustration of the complete phenotypic spectrum of ABCB4 deficiency. It highlights two underappreciated features: the potential for a completely pruritus‐free clinical course and the existence of a prolonged, asymptomatic biochemical stage detectable in childhood [3, 4].

The absence of pruritus in both affected siblings is notable. Previous studies have reported that pruritus is present in over 90% of PFIC3 patients with early‐onset disease [1, 4]. However, adult‐onset cases may present without pruritus, and a prolonged asymptomatic phase has been documented in some families [2]. Our case extends these observations by documenting a 10‐year asymptomatic interval from biochemical abnormalities to clinical decompensation, emphasizing the need for early screening. The absence of pruritus aligns with the “bile duct‐centric” injury model in PFIC3, in which phospholipid deficiency in bile generates toxic bile that primarily damages cholangiocytes. This mechanism may limit the systemic accumulation and recirculation of potential pruritogens, such as lysophosphatidic acid, which are more commonly associated with other forms of PFIC [1]. The specific compound heterozygous variants identified in this family—c.249C>A (p.Asp83Glu) and c.1466A>G (p.Asn489Ser)—are predicted to affect the nucleotide‐binding domains of the MDR3 protein, potentially impairing phospholipid translocation. This functional defect results in phospholipid‐deficient bile, which preferentially injures cholangiocytes, consistent with the “bile duct‐centric” injury model and potentially explaining the absence of pruritus.

The discovery of significant GGT elevation in the asymptomatic 14‐year‐old sister is pivotal. It demonstrates that biochemical liver injury (evidenced by GGT) precedes clinical symptoms by many years, creating a crucial window for therapeutic intervention. This finding challenges the traditional view of PFIC3 as solely a childhood disease and supports the concept of a disease continuum [2].

Most importantly, this case powerfully underscores the imperative for systematic family screening in PFIC3. Our experience demonstrates that identifying a proband should automatically trigger genetic and biochemical screening of all first‐degree relatives. Based on this case, we recommend that upon diagnosis of a proband with ABCB4 deficiency, all first‐degree relatives should undergo: (1) genetic testing for the identified variants, (2) biochemical screening including GGT and liver function tests, and (3) abdominal ultrasound. This strategy offers two major benefits: early diagnosis enabling UDCA therapy before symptom onset, and provision of cosegregation evidence to resolve VUS classification. This strategy serves a dual purpose:

1. Diagnostic: It provides the critical cosegregation evidence (ACMG PP1) needed to resolve the significance of VUS, transforming diagnostic uncertainty into a definitive molecular diagnosis for the entire family.

2. Therapeutic/Preventive: It identifies at‐risk individuals in the pre‐symptomatic phase. Early initiation of disease‐modifying therapy with UDCA during this window aims to alter the disease trajectory, potentially preventing progression to cirrhosis [4].

The main limitation of this report is the relatively short follow‐up period for the sister, although ongoing monitoring will clarify long‐term outcomes. Nevertheless, the clear genotype–phenotype correlation within this family provides robust evidence supporting our conclusions. This case represents a shift from reactive end‐stage management toward proactive, precision‐based prevention in ABCB4 deficiency.

Author Contributions

Rongxia Ma: project administration, resources, writing – original draft. Haojun Zhang: formal analysis, writing – review and editing. Wenjie Zhang: data curation, investigation. Xiaojuan Yang: validation, visualization.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for participation in this study and for publication of the case details. The consent form is retained by the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data supporting the findings of this case report are available from the corresponding author upon reasonable request. Due to patient privacy and confidentiality considerations, the full clinical and genetic data are not publicly available but can be accessed through reasonable request to the corresponding author, subject to institutional review board approval.