What is the treatment for cholestasis due to inborn errors of metabolism?

Treatment of Cholestasis Due to Inborn Errors of Metabolism

For bile acid synthesis disorders (HSD3B7 and AKR1D1 deficiencies), initiate oral primary bile acid replacement therapy (cholic acid or chenodeoxycholic acid) as early as possible, ideally before significant liver disease develops, as this can result in complete clinical, biochemical, and histologic resolution. 1

Bile Acid Synthesis Disorders (BASD)

Diagnostic Clues

• Hallmark laboratory features that distinguish BASD from other cholestatic diseases include normal or low serum primary bile acid levels, normal gamma-glutamyltransferase (GGT) concentrations, and absence of pruritus 1, 2
• Definitive diagnosis requires fast atom bombardment-mass spectrometry (FAB-MS) or gas chromatography-mass spectrometry (GC-MS) analysis of serum and urine, available only in specialized referral laboratories 1
• These disorders most commonly present as neonatal cholestasis or neonatal hepatitis, but can manifest as chronic liver disease in older children 1

Primary Treatment: Bile Acid Replacement

• Cholic acid is the only FDA-approved primary bile acid with marketing authorization in both the USA and Europe for treatment of bile acid synthesis defects 1, 3
• The recommended dosage is 10-15 mg/kg orally once daily or in two divided doses for both pediatric patients and adults 3
• Patients with concomitant familial hypertriglyceridemia require a 10% dosage increase (11-17 mg/kg daily) to account for malabsorption 3

Mechanism and Expected Outcomes

• Primary bile acid therapy (cholic acid and/or chenodeoxycholic acid) down-regulates endogenous bile acid synthesis, resulting in clinical, biochemical, and histologic improvement when initiated before significant liver disease is established 1
• Treatment is often curative for several bile acid synthesis disorders when started early 1
• In clinical trials, 64% of patients with single enzyme defects responded to cholic acid treatment, with response rates of 59% for 3β-HSD deficiency and 75% for AKR1D1 deficiency 3
• Responders demonstrated resolution of jaundice, steatorrhea, and hepatosplenomegaly, with liver biopsies showing resolution of cholestasis after at least 5 years of treatment 3

Treatment Monitoring

• Monitor serum AST, ALT, GGT, alkaline phosphatase, bilirubin, and INR monthly for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent 3 years, and annually thereafter 3
• Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy 3
• Adequacy of dosing can be determined by monitoring clinical response including steatorrhea and laboratory values 3

Hereditary Tyrosinemia Type 1

Primary Medical Treatment

• NTBC (nitisinone) should be initiated immediately when the diagnosis is established 1
• NTBC results in rapid clinical and biochemical improvement, with undetectable levels of succinylacetone in urine within 24 hours 1
• Combine NTBC with a low tyrosine/low phenylalanine diet 1
• NTBC therapy has reduced early complications and the need for liver transplantation, increasing mean age at transplantation from 1.82 years (1988-1998) to 3.70 years (1999-2008) 1

Surveillance Requirements

• Regular surveillance with AFP and liver imaging is mandatory even with metabolic stability on NTBC, as hepatocellular cancer may still occur 1
• AFP should normalize or fall to levels less than 10 ng/L on NTBC therapy 1

Indications for Liver Transplantation

• Promptly refer for liver transplant evaluation if progressive liver disease occurs despite adequate NTBC dose and compliance, rising AFP while on NTBC, or liver imaging shows a single nodule exceeding 10 mm or increasing number of nodules 1
• Failure to respond to NTBC within one week may indicate noncompliance, subtherapeutic NTBC levels (check for persistent succinylacetone in urine), or fulminant disease course 1

MDR3 Deficiency (PFIC Type 3)

Medical Management

• Ursodeoxycholic acid (UDCA) is the first-line treatment for MDR3 deficiency 1
• Long-term UDCA therapy is recommended for liver transplant recipients with MDR3 monoallelic deficient grafts 1
• UDCA may have no or only partial beneficial effect in patients with biallelic protein-truncating ABCB4 gene variants, but may still be offered 1
• UDCA treatment is specifically recommended for those with at least one missense variant and a clinical phenotype 1

Liver Transplantation

• Liver transplant evaluation is indicated for patients with MDR3 disease whose condition fails to respond to UDCA 1
• Among 28 children with MDR3 disease in an Italian consortium, five underwent successful liver transplantation 1

General Principles for Liver Transplantation

• Liver transplantation is reserved for patients with progressive end-stage liver disease due to inborn errors of bile acid synthesis or those known to be refractory to medical therapy 1
• The use of PFIC heterozygote live donor organs from family members remains viable and feasible for FIC1 and BSEP patients requiring transplantation, though ongoing follow-up is needed 1
• Families of children with BSEP disease requiring transplantation should be cautioned that the disease may recur following liver transplantation 1

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting specialized testing results - if bile acid synthesis disorder is strongly suspected based on clinical presentation (cholestasis with normal GGT and low serum bile acids), consider empiric bile acid replacement therapy 1, 2
• Do not confuse BASD with biliary atresia - the presence of normal GGT despite cholestasis should prompt consideration of BASD rather than proceeding to unnecessary invasive procedures 2
• Do not rely on serum bile acid levels alone - normal or low levels in the context of cholestasis are characteristic of BASD and should trigger urinary bile acid analysis 1, 2
• Early diagnosis is paramount - clinical, biochemical, and histologic improvement occurs only if therapy is initiated before significant liver disease is established 1