Guideline for use of Ursodeoxycholic Acid in Children with Suspected or Confirmed Cystic Fibrosis-Associated Liver Disease

• Summary
• Background
• Clinical Diagnosis
• Investigation
• Management

Summary

Cystic Fibrosis-Associated Liver Disease (CFLD) is a common cause of mortality for patients with Cystic Fibrosis.

Children with Cystic Fibrosis (CF) should have their Liver Function Tests (LFTs), and GGT (gamma-glutamyl transferase) checked annually. This should also be checked when admitted for IV antibiotics or when clinical concerns arise regarding liver disease.

Starting Ursodeoxycholic Acid:

• Consider starting in patients with CF with abnormal liver function and evidence of Cystic Fibrosis LiverDisease (CFLD) on ultrasound scan.
• A raised Alkaline Phosphatase (ALP), in the absence of other normal LFTs, is not specific for CFLD¹.

Ursodeoxycholic Acid Dose:

• 20-30mg/kg/day in 2-3 divided doses^1,2.

Monitoring:

• While taking ursodeoxycholic acid (UDCA), continue regular clinical assessments, LFTs, GGT, and liver ultrasound yearly^2,3.

Stopping Ursodeoxycholic Acid:

• Consider stopping UDCA if liver function blood tests return to normal and clinical assessment and liver ultrasound scan show no liver disease³.
• If ursodeoxycholic acid is stopped, monitor for re-emergence of liver disease using clinical assessment, and annual LFTs³.

Referral to Liver Specialists:

• Consider referral to a Liver Specialist if LFTs or GGT remain persistently abnormal after a further 3 months despite treatment with UDCA³.
• The presence of the following should result in a referral to a Liver Specialist³.
  • Signs of chronic progressive liver disease on clinical assessment, ultrasound, or blood tests
  • Liver failure based on clinical assessment or liver function tests
  • Portal hypertension or splenomegaly on ultrasound.

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Appendix 1 for investigation and treatment algorithm.

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Background

Liver disease is a frequent and early complication of Cystic Fibrosis². The cystic fibrosis transmembrane conductance regulator (CFTR) protein is present in the epithelial cells of the bile duct and gall bladder. CFTR dysfunction leads to inssipated secretions that obstruct bile ducts and bile acid malabsorption results in retention of hepatotoxic conjugated bile acids.² CFLD is currently the 3^rd commonest cause of mortality in patients with CF⁴. Ursodeoxycholic acid is a naturally occurring bile acid which augments bile flow and is used in Cystic Fibrosis related liver disease to help arrest the progression of early focal liver lesions².

The 2017 Nice guideline on diagnosis and management of cystic fibrosis suggest that liver function tests should be measured annually in children with Cystic Fibrosis, and that if they are abnormal a liver ultrasound should be performed and treatment with ursodeoxycholic acid should be considered³. This treatment should then be stopped if liver function tests return to normal and there is no evidence of liver disease on clinical assessment and liver ultrasound. Specialist referral should be considered if there are persistently abnormal liver function tests on ursodeoxycholic acid treatment, or if there is evidence of progressive liver disease, liver failure, portal hypertension, or splenomegaly.

The CF Trust standards of care include that CF clinicians should be able to manage early CF-Associated Liver Disease (CFLD) including when to start ursodeoxycholic acid, and that referral to specialist liver teams should be made for significant liver disease and its complications, including portal hypertension and oesophageal varices³.

Although ursodeoxycholic acid (UDCA) is the main treatment option for CFLD it has remained controversial due to a lack of high-quality randomised control trials⁵. In 2017, a Cochrane review did not recommend prophylactic use of UDCA to prevent CFLD in patients with CF⁶. However, a more recent longitudinal cohort study of over 3000 patients by Toledano et al. suggested an improvement in overall survival in patients taking UDCA⁴.

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Clinical Diagnosis

Clinical assessment for CFLD should be performed at least annually, including assessing for splenomegaly and jaundice.

Investigation

Liver Function Tests (LFTs) and Gamma-glutamyl transferase (GGT):

Children with Cystic Fibrosis should have their LFTs, and GGT checked annually. This should also be checked when admitted for IV antibiotics or when clinical concerns arise regarding liver disease.

A raised Alkaline Phosphatase (ALP), in the absence of other normal LFTs, is not specific for CFLD¹.

If there is a rise above the upper limit of normal of other LFTs, or GGT, a clinical examination of the child should be undertaken, and ultrasound scan of the liver considered.

Liver Ultrasound:

Children aged over 5 years who are pancreatic insufficient should have a routine liver ultrasound every two years to screen for signs of CFLD. Additional ultrasound scans should be considered in patients who have an abnormal clinical examination or deranged liver function testing which is new since the last ultrasound scan or in those who have not had an ultrasound scan.

Ultrasound features of CFLD include^1,7:

• Increased and/or heterogeneous echogenicity.
• Irregular margins.
• Increased nodularity.
• Portal hypertension (splenomegaly, increased thickness of the lesser omentum, spontaneous splenorenal anastomosis, large collateral veins, ascites).
• Biliary abnormalities (bile duct dilatation).

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Management

Ursodeoxycholic Acid (UDCA):

Consider starting in patients with CF with abnormal liver function and evidence of CFLD on ultrasound scan.

Dose: 20-30mg/kg/day in 2-3 divided doses¹.

Available Preparations: 150mg and 300mg tablets, 250mg capsules and 250mg/5ml suspension

Contraindications: Acute inflammation of the gall bladder; frequent episodes of biliary colic; inflammatory diseases and other conditions of the colon, liver or small intestine which interfere with enterohepatic circulation of bile salts; non-functioning gall bladder; radio-opaque stones.

Side Effects: Common – Diarrhoea, pale stools⁸.

Monitoring:

• Continue regular clinical assessments, LFTs, GGT, and liver ultrasound yearly^2,3.

Stopping UDCA:

• Consider stopping UDCA if liver function blood tests return to normal and clinical assessment and liver ultrasound scan show no liver disease³.
• If ursodeoxycholic acid is stopped, monitor for re-emergence of liver disease using clinical assessment, and annual LFTs³.

Referral to Liver Specialists:

• Consider referral to a Liver Specialist if LFTs or GGT remain persistently abnormal despite treatment with UDCA³.
• The presence of the following should result in a referral to a Liver Specialist³.
  • Signs of chronic progressive liver disease on clinical assessment, ultrasound, or blood tests
  • Liver failure based on clinical assessment or liver function tests
  • Portal hypertension or splenomegaly on ultrasound.

Avoidance of further liver disease

• Young people with CFLD should be advised to avoid further liver damage caused by alcohol, obesity, and viral hepatitis.

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