Cystic Fibrosis Related Hepatobiliary Involvement

Description

Cystic fibrosis (CF) is the most common genetic disorder in Caucasians and is inherited in an autosomal recessive manner. In Europe, the average prevalence at birth is around 1 in 5000 live births. 

In people with cystic fibrosis (pwCF), involvement of the liver and/or biliary tract as a whole is relatively frequent and has a negative impact on life expectancy.

Cystic fibrosis-related hepatobiliary involvement (CFHBI) is diverse, ranging from the common transaminase elevations, biliary strictures, hepatic steatosis, fibrosis, and advanced liver disease with cirrhosis and/or portal hypertension. Non-cirrhotic portal hypertension can also occur (2). Cross-sectional studies report a prevalence of cirrhosis within CFHBI between 2 and 10% depending on the definition and studied cohort, with two-thirds to three-quarters of pwCF and cirrhosis exhibiting portal hypertension (3-6). Similar to other chronic liver diseases, pwCF have an increased risk of developing hepatocellular carcinoma and cholangiocarcinoma.

Genetics

CF is an autosomal recessive condition caused by biallelic pathogenic variants in the CF Transmembrane Conductance Regulator (CFTR) gene. Specifically for CFHBI, genotype-phenotype correlations are incompletely understood. Generally, CFHBI and CFHBI with advanced liver disease are more commonly observed in pwCF who are homozygous F508del-genotypes and other severe genotypes (class I and II variants), are male, and presented with meconium ileus during the neonatal period. Additionally, those with variants predicted to cause pancreatic insufficiency are at a higher risk of developing CFHBI.

Apart from the CFTR-gene, genetic modifiers that significantly influence the likelihood of developing CFHBI. The heterozygous presence of the SERPINA1 Z-allele is the most crucial modifier that increases the probability of CFHBI development.

Clinical presentation

CFHBI is often detected without specific symptoms during routine liver function tests in the follow-up of pwCF. Persistent or significant elevation of transaminases or gamma-GT may suggest the need for abdominal imaging. Such imaging can reveal liver enlargement, steatosis, biliary tract abnormalities, nodular cirrhosis, and spleen enlargement if portal hypertension is present. 

In the absence of cirrhosis and/or portal hypertension, CFHBI is mostly asymptomatic. If cirrhosis and/or portal hypertension are present (CFHBI with advanced liver disease), clinical signs such as liver or spleen enlargement, palmar erythema, spider nevi, and bleeding symptoms can be present. Advanced liver disease, if present, usually develops during childhood.

Risk factors

Maintaining optimal nutritional status is crucial for all patients with CF throughout their growth, development, and beyond. Malnutrition and any form of steatotic liver disease can add additional strain on a liver that is already susceptible to disease. Other risk factors include systemic infections, polypharmacy, an altered gut-liver axis, and alcohol intake.

Diagnosis

CFHBI is very heterogeneous and no diagnostic criteria exist to confirm or exclude involvement of liver or biliary tract in pwCF. Moreover, hepatobiliary involvement can be dynamic over time in this population. The joint NASPGHAN/ESPGHAN standardised classification system incorporates the diverse disease manifestations and allows sequential classification over time (9).

CFHBI can thus be diagnosed by assessment of liver function tests, imaging, liver stiffness measurement, and histopathology. Physical examination is usually nonspecific, unless signs of cirrhosis and/or portal hypertension are present in the context of advanced liver disease.

At baseline, a more comprehensive screening is frequently performed to rule out other causes of chronic liver disease than CF.

Liver biopsy is not a prerequisite for the diagnosis of CFHBI and is not routinely performed in pwCF, unless there are specific indications (eg. to exclude other causes of liver disease that cannot be reliably diagnosed on a non-invasive basis).

Management

Management of CFHBI reflects the diverse possible manifestations. No specific treatment exists for hepatobiliary involvement. 

Non-pharmacologic treatment:

Specialised nutritional care is an important part of the integrated care for pwCF, either with or without CFHBI, CF-related diabetes, or pancreatic insufficiency.

Pharmacologic treatment:

• Ursodeoxycholic acid (UDCA) is frequently prescribed in pwCF with liver abnormalities, although there is currently insufficient evidence to advocate for the routine use of UDCA in all pwCF and CFHBI. UDCA treatment has been reported to improve liver enzymes and can improve liver stiffness measurement in pwCF with mild liver disease. Although some cohorts report a positive impact of UDCA treatment on survival in those with mild liver disease, its use did not result in prevention of advanced liver disease in pwCF.
• CFTR-modulator therapy has proven to be a game changer for many pwCF. Since liver involvement was an exclusion criterion in the initial studies investigating the effect of these modifiers, data on evolution or incidence of hepatobiliary involvement under CFTR-modifier therapy is scarce. CFTR-modifier therapy seems safe in subjects with CFHBI, but whether it also impacts hepatobiliary disease evolution is currently unclear (11, 12). Use of CFTR-modulator therapy in pwCF and CFHBI should be monitored by expert personnel.

Active surveillance: 

Active surveillance involves timely detection of CFHBI and its potential complications. It should be carried out in expert centers with sufficient expertise in management and follow-up of pwCF. 

• Laboratory assessment involves follow-up of transaminases, gamma-GT, total serum bilirubin, alkaline phosphatase, and platelet counts.
• Abdominal imaging assesses liver and spleen size, parenchymal abnormalities, and flow characteristics of the portal vein. It is usually performed by ultrasound. Magnetic resonance imaging (with or without MR cholangiopancreatography) can be indicated for differentiation of nodular lesions or to evaluate biliary tract abnormalities.
• Elastography is utilised to evaluate liver stiffness during longitudinal follow-up.
• Endoscopy can be performed if portal hypertension is present for surveillance of gastroesophageal varices.

Complications

As in all chronic liver diseases, ongoing inflammation can lead to the development of cirrhosis and its complications. It is currently unknown which subjects with CFHBI will go on to develop cirrhosis and/or portal hypertension, and no specific treatment exists for CFHBI. Furthermore, in some pwCF, portal hypertension is present without evidence of cirrhosis. Therefore, active surveillance is key for timely detection and management.

Subjects with cirrhosis have an elevated risk of hepatocellular carcinoma and cholangiocarcinoma. 

CPMS

 If you wish to discuss a patient with cystic fibrosis-related hepatobiliary involvement with experts from the ERN, you can upload cases to the CPMS. 

The CPMS is essential for interaction between healthcare professionals and experts on clinical decision making, and is provided by the European Union to all ERNs. CPMS supports online multidisciplinary meetings (tele-boards) to discuss patients with diagnostic or therapeutic dilemmas in need of expert consultation. CPMS offers the opportunity to upload and share clinical data of patients and pictures such as histological slides or MRI images. Importantly, this is fully in line with European data protection law. It is obligatory to inform patients about CPMS and obtain their informed consent before their data are entered into the system (see CPMS Privacy Statement published by the European Commission on 14 December 2017). The consent form is available in all EU languages in CPMS.