Liver Disease Clinical Care Guidelines

Involvement of the liver and bile ducts in cystic fibrosis can be clinically silent. These guidelines highlight the role of screening in detection of liver involvement in cystic fibrosis.
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Summary
  • The Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group published revised recommendations for management of liver and biliary tract disease in cystic fibrosis in 1999 with a summary of the recommendations outlined below.
  • The recommendations were developed by expert consensus following review of the existing literature at the time.

Liver Disease Clinical Care Guidelines

Recommendations for Management of Liver and Biliary Tract Disease in Cystic Fibrosis. Sokol RJ, Durie PR, Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr. 1999; 28 Suppl 1:S1-S13.

Hepatobiliary complications of cystic fibrosis are increasingly recognized. Liver disease is now the third leading cause of death among people with CF. There is a wide spectrum of liver disease among people with CF, ranging from steatosis and neonatal cholestasis to cholelithiasis and multilobular cirrhosis. However, only 5-10 percent of people with CF develop CF-related cirrhosis.

Characterized predominantly by portal hypertension, CF cirrhosis is a disease of childhood onset with a median age of diagnosis of 10 years. The pathophysiology of liver disease remains uncertain. Advanced liver disease is primarily found in individuals with pancreatic insufficiency. Males and carriers of the Alpha-1 antitrypsin Z allele are at increased risk for advanced CF liver disease. To date, there are no proven therapies to prevent development or progression of CF-related cirrhosis.

Methodology

The Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group published revised recommendations for management of liver and biliary tract disease in cystic fibrosis in 1999 with a summary of the recommendations outlined below. The recommendations were developed by expert consensus following review of the existing literature at the time. There have been several reviews and studies published since these guidelines, some of which are noted at the end of this review.

Recommendations

Diagnostic Evaluation
Recommendations Evaluation of the Evidence
1. Physical exam: evaluation for stigmata of liver disease:
  1. Hepatosplenomegaly
  2. Ascites
  3. Palmar erythema
  4. Spider hemangiomas
  5. Scleral icterus
  6. Digital clubbing
 Consensus Conference 
2. Biochemical evaluation of liver injury and function in those with suspected liver disease:
  1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), albumin, prothrombin time, ammonia, cholesterol, and complete blood count for evaluation of hypersplenism.
  2. Screening for other causes of chronic liver disease when clinically appropriate, including autoimmune hepatitis, Alpha-1 antitrypsin deficiency, Wilson disease, and hemochromatosis.
 Consensus Conference 
3. Radiographic evaluation:
  1. Ultrasonography with doppler imaging can be useful to detect presence of radiographic cirrhosis, signs and/or complications of portal hypertension.
 Consensus Conference 
4. Upper gastrointestinal endoscopy:
Most sensitive method for detecting esophageal and gastric varices as well as portal hypertensive gastropathy. Indicated in those patients presenting with upper gastrointestinal bleeding.
  1. Not routinely recommended for all children with suspected CF liver disease, as varices in children that have not bled are generally not treated unless unusual circumstances exist.
 Consensus Conference 
5. Liver biopsy:
  1. Can be useful to determine extent of fibrosis and exclude otConsensus Conference her causes of liver disease, though not routinely indicated. Risks and benefits of procedure should be carefully weighed before considering.
 Consensus Conference 

Management of Liver Disease
Recommendations Evaluation of the Evidence
6. A multidisciplinary approach is important and should include a pediatric or adult hepatologist, pulmonologist, surgeon experienced in hepatobiliary surgery, radiologist, and registered dietician. Consensus Conference
7. For patients with decompensated cirrhosis, close collaboration with a liver transplant center should be established. Consensus Conference

Screening for Liver Disease
Recommendations Evaluation of the Evidence
8. Careful examination by palpation and percussion of liver and spleen size and texture at each visit. Consensus Conference
9. Yearly panel of liver blood tests (AST, ALT, GGT) should be performed in all CF patients. Consensus Conference

Medical Management
Recommendations Evaluation of the Evidence
10. Hepatic steatosis:
  1. Optimize nutritional status and consider evaluation for deficiencies of essential fatty acids, carnitine, and choline, as well as evaluation for possibility of diabetes mellitus.
 Consensus Conference
11. Hepatic congestion:
  1. Optimize cardiopulmonary function and avoid hypoxia.
 Consensus Conference
12. Cholestasis, fibrosis, cirrhosis:
  1. The goal of therapy is to limit ongoing injury to the liver, prevent complications of cholestasis, such as fat-soluble vitamin deficiency, and manage the complications of portal hypertension.
  2. No therapy is yet known to alter the progression of CF liver disease.
 Consensus Conference
13. Cholelithiasis:
  1. If clinical symptoms are present or liver blood tests remain abnormal, laparoscopic or surgical cholecystectomy should be performed unless end-stage liver disease is present.
  2. Consider liver biopsy and intraoperative cholangiogram in those undergoing cholecystectomy.
 Consensus Conference

Nutritional Therapy
Recommendations Evaluation of the Evidence
14. For those with significant cholestasis, formulas containing medium chain triglyceride (MCT) will help promote absorption of dietary lipids. Consensus Conference
15. Monitoring of fat-soluble vitamin levels should occur every 6-12 months; and 1-2 months after a change in dietary supplementation dosing. Consensus Conference
16. CF patients often require high doses of vitamins A, D, E, and K to obtain optimal serum levels. Consensus Conference

Management of Portal Hypertension
Recommendations Evaluation of the Evidence
17. Bleeding from esophageal varices should be managed as in any other cause of varices (hemodynamic stabilization followed by direct variceal treatment, such as variceal band ligation). Consensus Conference
18. Beta blocker therapy should be used cautiously in those patients with asthma or other airway hyperreactivity syndromes. Consensus Conference
19. Ascites should be treated sequentially with careful salt restriction, diuretic therapy, and, if refractory, paracentesis. Transjugular intrahepatic portosystemic shunt (TIPS) should be considered if severe and unresponsive to medical management. Consensus Conference
20. Hepatic encephalopathy may be treated with dietary protein restriction, lactulose, and use of oral antibiotics. Consensus Conference
21. Spontaneous bacterial peritonitis should be treated with systemic antibiotics once blood and ascetic fluid cultures have been obtained. Consensus Conference
22. Referral to a liver transplant center should be considered for patients with complications from portal hypertension unresponsive to medical management. Consensus Conference

Management of Liver Failure
Recommendations Evaluation of the Evidence
23. Liver failure is rare in cystic fibrosis and when it does occur, usually occurs late in the course of disease. Consensus Conference
24. Referral to an experienced liver transplant center when there is evidence of decompensated cirrhosis: difficult to control ascites, prolonged prothrombin time unresponsive to vitamin K, hyperammonemia, and encephalopathy. Consensus Conference
25. Liver transplantation should be considered especially if pulmonary function is well preserved. Consensus Conference

New Issues

In 2007, the CF Foundation organized a group of hepatologists to further clarify the definition/classification of CF-related liver disease and suggested the following classification (Flass 2013):

  • Liver involvement with cirrhosis/portal hypertension
    • Clinical evidence of portal hypertension
    • Evidence of cirrhosis by histology, imaging, or laparoscopy
  • Liver involvement without cirrhosis or portal hypertension
    • Biochemical abnormalities; persistent elevation of AST, ALT, GGT greater than 1.5 to 2 times the upper limit of normal
    • Steatosis on liver biopsy
    • Fibrosis on liver biopsy
    • Cholangiopathy evidenced on ultrasound, magnetic resonance cholangiopancreatography (MRCP), retrograde cholangiopancreatography (ERCP), computed tomography (CT)
    • Ultrasound abnormalities inconsistent with cirrhosis
  • Preclinical
    • No evidence of liver disease on exam, imaging, or laboratory studies
  • A Cochrane review in 2014 concluded there is insufficient evidence to support routine use of ursodeoxycholic acid in patients with cystic fibrosis. Further randomized controlled studies are needed to assess the safety and efficacy of ursodeoxycholic acid use in cystic fibrosis liver disease (Cheng 2014).
  • While there is not a clear genotype-phenotype correlation for CF-related liver disease (CFLD), there have been advances in genetic modifiers for CFLD. The SERPINA1 Z allele, a mutation associated with Alpha-1 antitrypsin deficiency, has been found to be a risk factor for developing severe CFLD with portal hypertension. However, further studies are needed before routine screening for Alpha-1 antitrypsin deficiency is recommended (Bartlett 2009).
  • A clinical trial called PUSH (NCT01144507) is currently exploring the role of ultrasound in predicting the progression of cirrhosis in patients with cystic fibrosis (Leung 2015).
  • The most recent European best practice guidance for the diagnosis and management of cystic fibrosis-related liver disease was published in 2011 (Debray 2011).

Unanswered Questions

  • What is the role of newly discovered cystic fibrosis transmembrane conductance regulator (CFTR) modulators and potentiators in preventing or altering the progression of fibrosis in CF-related liver disease?
  • Are there novel serum biomarkers that predict liver disease in CF?
  • What is the role of imaging, elastography, or liver biopsy in screening patients for CFLD?
  • What factors are associated with the development of CFLD/CF-related cirrhosis?
  • What are effective medical treatments for CFLD/CF-related cirrhosis?

Further Reading

Relevant manuscripts published after the original guidelines are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

  1. Sokol R, Durie P, Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. Recommendations for management of liver and biliary tract disease in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1999;28 Suppl 1:S1-13.
  2. Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev. 2014 Dec 15;(12):CD000222. doi: 10.1002/14651858.CD000222.pub4.
  3. Bartlett JR, Friedman KJ, Ling SC, et al. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009 Sep 9;302(10):1076-83. doi: 10.1001/jama.2009.1295.
  4. Leung DH, Ye W, Molleston JP, et al. Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis. J Pediatr. 2015 Oct;167(4):862-868.e2. doi: 10.1016/j.jpeds.2015.06.062. Epub 2015 Aug 5.
  5. Debray D, Kelly D, Houwen R, et al. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros. 2011 Jun;10 Suppl 2:S29-36. doi: 10.1016/S1569-1993(11)60006-4.
  6. Flass T, Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros. 2013 Mar;12(2):116-24. doi: 10.1016/j.jcf.2012.11.010. Epub 2012 Dec 20.
  7. Debray D, Narkewicz MR, Bodewes FAJA, et al. Cystic fibrosis-related liver disease: research challenges and future perspectives. J Pediatr Gastroenterol Nutr. 2017 Oct:65(4), 443-48. doi: 10.1097/MPG.0000000000001676.
  8. Bodewes FA, van der Doef HP, Houwen RH, Verkade HJ. Increase of Serum γ-Glutamyltransferase Associated With Development of Cirrhotic Cystic Fibrosis Liver Disease. J Pediatr Gastroenterol Nutr. 2015 Jul;61(1):113-8. doi: 10.1097/MPG.0000000000000758.

Use of These Guidelines

The CF Foundation intends for this executive summary of its guideline to summarize the published guideline. The published guideline summarizes evidence, and provides reasonable clinical recommendations based on that evidence, to clinicians, patients, and other stakeholders. Care decisions regarding individual patients should be made using a combination of these recommendations, the associated benefit-risk assessment of treatment options from the clinical team, the patient's individual and unique circumstances, as well as the goals and preferences of the patients and families that the team serves, as a part of shared decision-making between the patient and clinician.

This executive summary was prepared by:

Michael R. Narkewicz, MD, (University of Colorado School of Medicine) and Molly A. Bozic, MD, (Indiana University School of Medicine)

The guidelines, which were published in 1999, are currently undergoing an update.

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Clinical Care Guidelines | Clinician Resources
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