What is the management approach for USP53 (Ubiquitin Specific Peptidase 53) deficiency?

Management Approach for USP53 Deficiency

USP53 deficiency should be managed with ursodeoxycholic acid (UDCA) as first-line therapy, with consideration for rifampicin as adjunctive treatment for pruritus, based on the most recent evidence showing good outcomes with medical management. 1

Disease Overview

USP53 (Ubiquitin Specific Peptidase 53) deficiency is a rare genetic form of progressive familial intrahepatic cholestasis (PFIC) classified as PFIC type 7. It is characterized by:

• Disruption of cellular tight junctions leading to cholestasis
• Typically low γ-glutamyltransferase (GGT) levels
• Variable age of onset (early infancy to adolescence)
• Intermittent jaundice and pruritus
• Risk of progressive liver fibrosis

Diagnostic Approach

1. Clinical presentation:

   • Jaundice (occurs in 93% of patients, with 48.8% developing it within 3 months of age) 1
   • Pruritus (occurs in 76% of patients, typically starting around 7 months of age) 1
   • Intermittent cholestasis with fluctuating bilirubin levels 2

2. Laboratory findings:

   • Elevated liver enzymes
   • Elevated total bilirubin
   • Elevated total bile acids
   • Low or normal GGT (characteristic of USP53 deficiency) 2

3. Genetic testing:

   • Next-generation sequencing (NGS) techniques are recommended over Sanger sequencing of individual genes 3
   • Panel sequencing or whole-exome sequencing (WES) should be performed 3
   • Whole-genome sequencing (WGS) may be considered if WES is negative 3
   • Genetic counseling must precede genetic testing 3

4. Liver biopsy:

   • May show evidence of fibrosis (present in all biopsied patients in one study) 4

Treatment Algorithm

First-line therapy:

• Ursodeoxycholic acid (UDCA)
  • High-dose UDCA has been shown to normalize symptoms and bilirubin levels 2
  • Should be initiated promptly upon diagnosis

Management of pruritus:

• Rifampicin
  • Add when pruritus persists despite UDCA therapy 5
  • Monitor liver function during treatment

Monitoring:

• Regular liver function tests to assess response to therapy
• Ultrasound surveillance for:
  • Splenomegaly (reported in 5 of 7 patients in one study) 4
  • Cholelithiasis (may require cholecystectomy) 5
• Long-term follow-up is essential due to risk of progressive liver disease 4

Advanced disease management:

• Liver transplantation
  • Consider for patients with progressive disease not responding to medical therapy
  • Required in approximately 17.3% of patients with USP53 deficiency 1

Prognosis

The prognosis for USP53 deficiency is generally favorable with appropriate management:

• Native liver survival in 82.7% of patients 1
• Jaundice resolves in approximately 72.4% of cases 1
• However, liver fibrosis and evidence of chronic liver disease may develop despite biochemical improvement 4

Important Considerations

• No clear correlation has been found between genotype and clinical outcomes 1
• Both biallelic (most common, 82.7%) and heterozygous mutations can cause disease 1
• Cholestasis tends to be biochemically mild and intermittent but can lead to progressive liver damage if untreated 4
• Reanalysis of genetic data every 3 years is recommended for patients without a definitive diagnosis, as new variants continue to be discovered 3

USP53 deficiency is a relatively newly recognized entity in the spectrum of PFIC disorders, and ongoing research may further refine management approaches. Current evidence suggests that early diagnosis and treatment with UDCA can lead to good outcomes in the majority of patients.