Strategies for management of pediatric cystic fibrosis liver disease


  • Molly Bozic M.D.,

    1. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine Riley Hospital for Children, Indianapolis, IN.
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  • Jean Molleston M.D.

    Corresponding author
    1. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine Riley Hospital for Children, Indianapolis, IN.
    • CORRESPONDENCE Jean Molleston, M.D., Department of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine Riley Hospital for Children, 705 Riley Hospital Drive, Room ROC 4210, Indianapolis, IN 46202. E-mail:

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  • Potential conflict of interest: Nothing to report.


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cystic fibrosis


cystic fibrosis liver disease


cystic fibrosis transmembrane conductance regulator


ursodeoxycholic acid.

Cystic fibrosis (CF) is the most common fatal autosomal recessive disease among Caucasians. Affecting nearly 1 in every 3000 live births, CF results from an inherited defect in the CF transmembrane conductance regulator (CFTR). There are now 1500 different known CFTR mutations, the most common being delta F508.[1] CF is a multisystem disease affecting not only the pulmonary system but also the hepatobiliary, endocrine, and reproductive systems. With increased life expectancy over the past two decades, hepatobiliary complications have become increasingly more common, with liver disease being the third leading cause of death among CF patients.[2]

There is a wide spectrum of liver disease among CF patients, ranging from simple steatosis and benign transient elevation of liver enzymes to cirrhosis and end-stage liver disease with severe portal hypertension (see Table 1). Although many patients with CF will have elevated aminotransferase levels, only 5%-10% percent of CF patients develop severe CF-related multilobular cirrhosis. Although there is no known correlation between CFTR genotype and patients who develop severe CF-related cirrhosis, there are known genetic modifiers for CF liver disease (CFLD). The SERPINA1 Z allele, a known mutation in α1-antitrypsin deficiency, has been found to be a risk factor for CFLD. A multicenter study found that patients with cystic fibrosis who carry this Z allele have an increased risk for developing severe CFLD.[3] CF-related cirrhosis is an early complication, with nearly all cases presenting within the first two decades of life.[4] The complications of CFLD arise mostly from portal hypertension and include hypersplenism, esophageal and gastric varices, and ascites. Liver failure and severe coagulopathy present very late in the course of the disease.[5]

Table 2 summarizes the approach to evaluation of the Child With Suspected CFLD.

There are no proven therapies to prevent the development or progression of CFLD. Treatment focuses on screening for and managing the complications of portal hypertension and optimizing nutritional status.

Ursodeoxycholic Acid

Ursodeoxycholic acid (UCDA) has been used in CF patients in an attempt to delay the progression of CFLD. Thought to improve bile flow, decrease toxic bile acids, and improve bicarbonate secretion, UCDA has been used to treat other cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. A Cochrane review in 2012[6] concluded there was insufficient evidence to justify its routine use in cystic fibrosis. Despite its widespread use for other cholestatic liver diseases, however, harm was noted in a recent study evaluating the safety and efficacy of UCDA in primary sclerosing cholangitis.[7] Further randomized controlled studies are needed to accurately assess its safety and efficacy in CF patients.

Nutritional Support

Because of fat malabsorption, nutritional support for the CF patient with liver disease is a cornerstone of their treatment and management. Patients with CF are recommended to have a caloric intake of 120%-150% of energy requirements for age and sex.[8] CFLD patients are at a further increased risk for fat-soluble vitamin deficiency and often require higher oral doses of vitamins A, D, E, and K.[9]

Screening for Portal Hypertension

In CF patients with known cirrhosis, monitoring for portal hypertension is essential (see Tables 2 and 3). Annual evaluation for hepatosplenomegaly by a pediatric gastroenterologist/hepatologist and monitoring white blood cell count and platelets can provide early indication of portal hypertension. Ultrasound can provide further information on ascites, fibrosis, and direction of portal venous flow in patients with long-standing cirrhosis.[10] In adults, there are clear guidelines for endoscopic surveillance of esophageal varices, but there is insufficient data in children to make this recommendation.[11]

Management of Esophageal Varices

CFLD is characterized primarily by portal hypertension. CF patients with cirrhosis frequently develop esophageal varices and variceal bleeding (see Table 2). Primary prophylaxis of variceal bleeding with beta blockers is generally recommended in adult patients with cirrhosis who have esophageal varices. Pulmonary disease, however, is a relative contraindication for the use of nonselective beta blockers, making pharmacologic primary prophylaxis problematic in CF patients. Prophylactic variceal band ligation can be considered, although repeated procedures requiring general anesthesia may have increased morbidity in the CF patient. Use of pharmacologic therapy for secondary prophylaxis of variceal bleeding is similarly limited in the CF patient; variceal band ligation, however, is often needed to manage difficult gastrointestinal bleeding in CF cirrhosis. Use of transjugular intrahepatic portosystemic shunt for refractory variceal bleeding can be considered when bleeding is intractable or as a bridge to transplantation.[11]

Although controversial given the infection and surgical risks associated with the procedure, splenectomy as a treatment for massive splenomegaly in CF patients with severe portal hypertension has been described.[12]


Development of ascites in the patient with CF can decrease pulmonary vital capacity and potentially increase respiratory infections. Treatment with diuretics such as spironolactone and furosemide can aid in controlling fluid retention. Paracentesis can be considered in cases of refractory ascites or worsening respiratory distress.[13]

Hepatopulmonary Syndrome

Patients with cirrhosis who have CF should be routinely screened for evidence of hepatopulmonary syndrome (see Table 3). Whereas oxygen saturation may be difficult to interpret in chronic lung disease, oxygen saturations performed both in the upright and supine position can screen for hepatopulmonary syndrome. A decrease in oxygen saturation of >5% when moving from the supine to the upright position may be suggestive of the disorder. Confirmation should be obtained with a bubble echocardiogram.[14] Development of hepatopulmonary syndrome can be an indication for liver transplantation.

Liver Transplantation

Liver transplantation is now an established treatment for CF patients with end-stage liver disease (see Table 4).[15-17] Many CF patients who have cirrhosis and portal hypertension maintain normal synthetic function for many years despite significant complications from their portal hypertension. This can present a unique challenge in determining the appropriate timing of liver transplantation in CF patients. Portal hypertension with recurrent variceal bleeding, refractory ascites leading to respiratory compromise, severe malnutrition, and brittle CF-related diabetes can be taken into account in addition to hepatocellular failure when determining timing of transplantation in the CF patient. Successful combined liver/pancreas transplantation has been described in patients with liver disease, pancreatic insufficiency, and CF-related diabetes.[18] Pulmonary disease remains the leading cause of mortality in CF patients and patients with end-stage liver disease often have progressively worsening pulmonary function. Consideration of combined liver-lung transplantation in the CF patient has been performed successfully, albeit on a limited basis.[19]

Future Directions

Research is needed to help identify CFLD early and to characterize its progression to advanced liver disease. Studies such as the ongoing multicenter PUSH study (ClinicalTrials. gov NCT #01144507) will help provide a better understanding of the natural history of this disease. Ultimately, medications that improve biliary CFTR flow or decrease fibrogenesis may help prevent the progression of disease.

Table 1. Hepatobiliary Manifestations of CF
Clinical ManifestationFrequency
  1. Adapted with permission from Journal of Pediatric Gastroenterology and Nutrition.[20] Copyright 2006, Lippincott Williams & Wilkins.

Focal biliary cirrhosis20%-30%
Multilobular biliary cirrhosis5%-10%
Neonatal cholestasis1%-2%
Biliary stricturesRare
Table 2. Evaluation of the Child With Suspected CFLD
  1. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibody; ASMA, anti–smooth muscle antibody; AST, aspartate aminotransferase; GGT, gamma-glutamyltranspepdidase; IgG, immunoglobulin G; INR, international normalized ratio; LKM, liver-kidney microsomal antibody; PT, prothrombin time.

  2. If clinical questions remain, liver biopsy should be considered. Biopsy is not always needed or indicated in the CF patient.

Physical examination evaluation
Laboratory evaluation
PT/INR, albumin
Exclusion of other causes of chronic liver disease
Autoimmune (LKM, ASMA, ANA, IgG)
Wilson disease (ceruloplasmin, serum copper, 24-hour urinary copper)
α1-antitrypsin deficiency (α1-antitrypsin phenotype)
Viral hepatitis (hepatitis A, B, C)
Radiographic evaluation
Doppler ultrasound (heterogeneous echotexture, nodularity, ascites, reversal of portal venous flow)
Histologic evaluation*
Liver biopsy (multilobular cirrhosis, focal biliary cirrhosis, fibrosis, steatosis)
Table 3. Extrahepatic Complications of CFLD
Hepatopulmonary syndrome
Portopulmonary hypertension
Fat-soluble vitamin deficiency
Table 4. Management of CFLD
Identify portal hypertension
Treat variceal bleeding
Optimize nutrition
Provide adequate fat-soluble vitamin supplementation
Immunize against hepatitis A and B
Counsel about alcohol avoidance
Consider liver transplantation if synthetic function declines or severe complications of portal hypertension occur