Sellers ZM, Assis DN, Paranjape SM, et al. Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations. Hepatology. 2024 May 1;79(5):1220-1238. doi: 10.1097/HEP.0000000000000646. Epub 2023 Oct 26. PMID: 37934656
Background and Purpose
The understanding of hepatobiliary disease in people with cystic fibrosis has expanded considerably since the Cystic Fibrosis Foundation’s initial recommendations were published in 19991. Research has provided new insights regarding the pathogenesis of disease and its wide range of clinical manifestations. In addition, more refined diagnostic tools have been developed. These advances have coincided with the development and U.S. Food and Drug Administration approval of CFTR modulator therapies. Changes in clinical practice have prompted new questions regarding the impact of CFTR modifying therapies on liver health in people with CF and suspected or confirmed hepatobiliary disease. The updated guidelines were developed to improve the detection, clinical care, and outcomes of children and adults with CF-associated hepatobiliary disease.
Methodology
The CF Foundation assembled an international multidisciplinary committee including hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, as well as an individual with CF and a parent of a child with CF. Population,
- CFHBI: having one (or more) of the following without features of aCFLD: hepatomegaly, liver fibrosis (<F4), increased liver stiffness by elastography (<F4), hepatic steatosis, focal biliary
cirrhosis , cholestasis, persistent (greater than 3 to 6 months) elevated serum liver function tests (any level above upper limit of normal), abnormal liver imaging, cholelithiasis, sclerosing cholangitis, or hepatolithiasis - aCFLD: having one (or more) of the following: nodular liver, advanced fibrosis (F4), multilobular cirrhosis with or without portal
hypertension , or noncirrhotic portal hypertension
Key Recommendations
| Screening | Vote % (n) |
| S1. The CF Foundation recommends that annual labs (total bilirubin, AST, ALT, alkaline phosphatase, GGT, Platelet Count) should be performed, at a time of clinical stability, for identification of hepatobiliary involvement in all people with CF starting at CF diagnosis. | 100 (22/22) |
| S3a. The CF Foundation recommends abdominal ultrasound to assess the liver and spleen at least every two years in people with CF from childhood until late adolescence, starting at age 3 years or at diagnosis, if diagnosed after age 3 years. | 95% (21/22) |
| S3b. In adults with CF, there is value in baseline screening for CFHBI, but the optimal frequency of subsequent imaging for those with normal baseline findings is unknown and a specific recommendation cannot currently be made. | 95% (21/22) |
| S4. The CF Foundation recommends that people with CF who are found to have hepatobiliary involvement (abnormal physical exam, persistently elevated liver |
100 (22/22) |
| Monitoring | Vote % (n) |
| M1. The CF Foundation recommends that in people with CF and liver involvement, a liver-specific physical examination be performed at least annually and at each in-person visit to monitor for the progression of disease. | 100 (22/22) |
| M2. The CF Foundation recommends that for people with CF and hepatobiliary involvement at least one liver fibrosis index be calculated and followed at least annually. | 95 (21/22) |
| M3. The CF Foundation recommends for people with CF and hepatobiliary involvement an abdominal ultrasound be performed at least every two years to monitor for the progression of disease. | 100 (22/22) |
| M4. The CF Foundation recommends that people with CF and hepatobiliary involvement or advanced liver disease undergo evaluation of liver stiffness with elastography at least annually, if available, to monitor for the progression of disease. | 100 (22/22) |
| M5. The CF Foundation recommends that people with CF hepatobiliary involvement or advanced liver disease receive consultation with a pharmacist with experience in CF and hepatobiliary disease to identify high-risk medications, polypharmacy, therapy modifications, and risk based on their hepatobiliary disease every 6 months, unless there have been no medication changes, to improve morbidity and mortality. | 100 (22/22) |
| M7. The CF Foundation recommends that people with CF and advanced liver disease, receive a nutritional assessment for malnutrition and liver specific macro- and micronutrient deficiencies every 6 months by a dietitian experienced in CF. When abnormalities are identified a treatment plan and monitoring of nutritional rehabilitation should be developed. | 100 (22/22) |
| M8. The CF Foundation recommends for people with CF and advanced liver disease beginning CF-related diabetes (CFRD) screening at the diagnosis of advanced liver disease, even if earlier than age 10 years and then annually thereafter, to provide early diagnosis and treatment of CFRD (using methodologies described in the most current CFRD Guidelines). | 100 (22/22) |
| M9. The CF Foundation recommends that people with CF and advanced liver disease receive multidisciplinary care from pulmonology, gastroenterology/hepatology, endocrinology and when appropriate, a transplant center, to optimize liver outcomes. | 100 (22/22) |
| M10a. The CF Foundation recommends that adults with CF and advanced liver disease with esophageal varices be managed according to the relevant most current published guidelines, such as those from the American Association for the Study of Liver Diseases or the Baveno group. | 100 (22/22) |
| M11b. The CF Foundation recommends that all CF adults with cirrhosis or suspected cirrhosis are screened for hepatocellular carcinoma using the most current screening guidelines as per American Association for the Study of Liver Diseases or European Association for the Study of Liver Disease. | 100 (22/22) |
| Treatment | Vote % (n) |
| T1. The CF Foundation recommends against the routine use of ursodeoxycholic acid to prevent advanced liver disease in all people with CF. | 100* (21/21) |
| T2a. |
100* (16/16) |
| T2b. |
100* (16/16) |
| T2c. Safety: The CFLD Guidelines Committee cannot recommend for or against the use of CFTR modulators in people with CF with advanced liver disease and portal hypertension without decompensation due to insufficient evidence. | 100* (16/16) |
| T2d. Safety: The CFLD Guidelines Committee recommends against CFTR modulator use in people with CF and decompensated advanced CF liver disease, as determined by a consultant Hepatologist based on thresholds such as sustained INR>1.5, abnormal direct bilirubin, low albumin, refractory ascites or encephalopathy. | 100* (16/16) |
| T2e. Transplant: The CFLD Guidelines Committee recommends, based upon expert opinion, for CFTR modulator treatment in people with CF who have received a liver transplant because the benefits to CF lung disease outweigh the liver related risk. There should be close monitoring and collaboration with the transplant team/pharmacist in these individuals as drug-drug interactions need to be noted and monitored. | 100* (16/16) |
| T5b. The CF Foundation recommends that for children with CF and advanced liver disease with portal hypertension, varices, and prior variceal hemorrhage, current guidelines for secondary prophylaxis be followed in consultation with a pulmonologist and anesthesiologist with expertise in CF. | 100 (22/22) |
| T5c. The CF Foundation recommends that adults with CF and advanced liver disease and portal hypertension (with or without prior variceal hemorrhage), should undergo primary or secondary prophylaxis according to current guidelines in consultation with a pulmonologist and anesthesiologist with expertise in CF. | 100 (22/22) |
| T6a. The CF Foundation recommends that for people with CF and cirrhotic or non-cirrhotic portal hypertension with INR ≤1.5, normal direct bilirubin and albumin, no encephalopathy and no refractory ascites, portosystemic shunt or liver transplantation be considered as long-term treatment. | 100 (22/22) |
| T6b. The CF Foundation recommends that for people with CF and cirrhotic or non-cirrhotic portal hypertension with INR>1.5, abnormal direct bilirubin, low albumin, refractory ascites or encephalopathy, liver transplantation be considered as the appropriate long-term treatment. Portosystemic shunt placement may be a bridge to transplantation for management of intractable variceal bleeding. | 100 (22/22) |
Unanswered questions
The long-term impact of CFTR modulator therapy on the liver health of people with CF remains unclear. Additional long-term observational studies of hepatobiliary involvement in people with CF treated with highly effective CFTR modulatory therapy are needed to fully assess this area of concern.
Additional studies identifying methods to prospectively recognize individuals with CF who are at high risk of developing advanced liver disease are needed. Clinical trials evaluating methods for monitoring disease progression and treatment are also necessary.
Further Reading
Bodewes FAJA, Freeman AJ, Weymann A, et al. Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper. J Pediatr Gastroenterol Nutr. 2024 Jan;78(1):153-165. doi: 10.1097/MPG.0000000000003944. PMID: 38291686.
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. The guideline is intended to be location agnostic and are applicable to individuals with CF in all settings including but not limited to outpatient clinics, hospitals, in-home, psychiatric facilities, long-term care facilities, incarceration, detention, and foster care settings.
The guidelines were published in May of 2024 and reviewed in July of 2025. It was determined that no update was needed.
This executive summary was prepared by:
Yonathan Fuchs, MD (Yale University School of Medicine) and Zachary Sellers, MD, PhD (Stanford University School of Medicine)
1. Sokol RJ, Durie PR. Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr. 1999;28(suppl 1):S1–13.
