Educational aims
The reader will come to appreciate that:
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Severe cystic fibrosis liver disease (CLFD) commonly presents in early childhood years, and affects up to 10 % of people with cystic fibrosis by age 30 years.
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United States CF Foundation (USCFF) guidelines have recently further defined CF hepatobiliary involvement (CFHBI) and advanced CF liver disease (aCFLD).
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Familiarity with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators monitoring guidelines is essential in clinical practice, particularly while their role in aCFLD is not established.
Abstract
Summary
Cystic fibrosis liver disease (CFLD) is characterised by a wide heterogenity of manifestations and severity. It represents a major cause of morbidity in people with cystic fibrosis (PwCF), which will be of increasing relevance as survival increases in the new era of cystic fibrosis care. No medical therapy currently available has evidence to treat or prevent progression of liver disease. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators may be transformative on pulmonary, nutritional and quality of life, but direct effect on long term liver disease outcomes is not yet established. Drug-associated hepatic adverse effects may be common, and clinician familiarity with drug-monitoring recommendations is essential. Longitudinal studies are required to understand the effect of CFTR modulators on the incidence and natural history of CFLD, including with early treatment initiation, in established advanced liver disease, and post liver transplantation.
Overview of CFLD
Cystic fibrosis is a severe, multi-system recessive disease caused by mutations in the gene for cystic fibrosis transmembrane conductance regulator (CFTR), which encodes for a chloride channel expressed in epithelial cells . Abnormal CFTR function in the hepatobiliary tree results in absent or aberrant flow of bicarbonate, viscous bile and obstruction resulting in inflammation and fibrogenesis. This, along with dysbiosis and endothelial dysfunction, contributes to complex mechanisms underlying cystic fibrosis liver disease (CFLD) . CFLD is a major cause of morbidity, and represents the third most common cause of mortality after lung failure and lung transplantation . Neonatal screening programs and improved medical care have significantly improved life expectancy of people with cystic fibrosis (PwCF), with median survival of at least 40 years . Recent widespread availability of CFTR modulators have been transformative in cystic fibrosis care, but their direct effect on long term liver disease outcomes is not yet established. Irrespective, the impact of this new era on CFLD will have important implications in PwCF who are experiencing longer lifespans where pulmonary complications may not be as dominant.
Prevalence, natural history & definition
CFLD manifests in nearly one third of individuals with cystic fibrosis by 25 years of age . Severe liver disease, manifesting with cirrhosis and/or portal hypertension, may be seen in up to 10 % of PwCF by age 30 years . Most severe CFLD presents in early childhood, at median age years . This presents opportunity for targeted screening in the first decade of life prior to and during disease progression. Severe CFLD is more commonly associated with male sex . As no specific CFTR mutations are linked to presence or severity of CFLD, modifier genes may play a role. An example of this is SERPINA-1 resulting in a heterozygous (alpha-1-antitrypsin) z allele, which is overrepresented PwCF with severe CLFD . The development of severe CFLD is associated with pancreatic insufficiency, history of meconium ileus, and severe CFTR mutations (e.g. class I, II and III) . The rate of a liver-related adverse event (including death, liver transplantation, variceal haemorrhage) is 20 % over 10 years in severe CFLD . Furthermore, PwCF have higher disease burden, with greater number of hospitalizations and are at higher risk of poor nutrition, CF-related bone disease and diabetes . The clinical spectrum of CFLD is diverse and assessment may be challenging. This has contributed to poor understanding of true disease prevalence. Given many PwCF with CFLD are asymptomatic, varied screening practices may also contribute to underdiagnosis and underestimation of the disease. Clinicians caring for PwCF require understanding of the many nuances in this complex patient group. For example, not all PwCF with CFLD will have abnormal LFTs, as may be seen in some children with multinodular biliary cirrhosis . Half of infants with cystic fibrosis will have abnormal liver function testing, many of whom normalize their biochemistry by 2–3 years of age . PwCF often have other modifying factors, including poor nutrition, drug, infection, steatosis, endocrine, cardio-pulmonary congestion complications, which further impact assessment of liver disease. Considering this, the United States CF Foundation (USCFF)-assembled-multidisciplinary committee recommended new diagnostic terminologies of CF hepatobiliary involvement (CFHBI) and advanced CF liver disease (aCFLD). CFHBI refers to any persistent elevation of liver enzymes above age and sex normative values over 3–6 months (during a period of clinical stability), with or without supportive physical examination, ultrasonography or elastography abnormalities . Diagnosis of aCFLD was recommended with any of liver nodularity, advanced liver fibrosis, multinodular cirrhosis, or non-cirrhotic portal hypertension .
CFLD encompasses both distinct and overlapping patterns of disease (refer Table 1 ). Steatosis is common, seen in 70 % children undergoing liver biopsy in the work up of CFLD , and is frequently found incidentally on imaging. Steatosis may be associated with other factors including diabetes mellitus and medication exposure (including oral, inhaled or intravenous steroid). Malnutrition, essential fatty acid or carnitine deficiency, or evolving metabolic dysfunction-associated fatty liver disease (MASLD) may also contribute to steatosis . Given emerging understanding of MASLD and its natural history of fibrosis and cirrhosis, steatosis in CF may not be considered as benign as initially regarded. This is relevant in PwCF who may have increasing rates of MASLD with CFTR modulator use. Focal biliary cirrhosis (FBC) may be seen in up to 70 % adult cystic fibrosis patients at time of autopsy . In some PwCF, this localised fibrogenic process may undergo a slow, but unpredictable progression to a widespread, multilobular pattern . Multilobular cirrhosis is seen in 2–8 % by 10 years age and is associated with advanced liver disease and portal hypertension . Obliterative venopathy is a now well-recognised pattern of CFLD which may contribute to presinusoidal vascular disease and non-cirrhotic portal hypertension . The cause and prevalence of this phenomenon remains undefined, but likely results from prominent endothelial dysfunction. Obliterative venopathy may occur as a distinct entity or in parallel to fibrotic changes. Finally, biliary manifestations are well recognised in PwCF. Gallbladder abnormalities and cholelithiasis are common and may be seen in up to 25 % patients . A cholangiopathy akin to sclerosing cholangitis may result from inflammation and fibrosis, with strictures seen in 3.9 % adult cystic fibrosis . Biliary tract malignancy risk is increased in PwCF with native liver .
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Pathogenesis
The pathogenesis of CFLD is poorly understood, particularly given the wide heterogeneity of hepatobiliary manifestations and severity seen in PwCF. CFTR is expressed in cholangiocytes and hepatic endothelium . Defective CFTR on the apical membrane of cholangiocytes lining biliary tracts have decreased or absent transport of chloride and bicarbonate ions . This results in increased viscosity of secretions, biliary obstruction with reduced bile flow and toxic bile acid accumulation. However, this mechanism cannot exist in isolation. Abnormal CFTR is universally seen in PwCF, however only one third will go on to develop CFLD with heterogeneity of severity and form that does not correlate with specific CFTR genotypes. It remains unclear why an individual will develop an obliterative venopathy phenotype, whilst another with the same CFTR mutation will develop multinodular cirrhosis. Non-CFTR genetic variability and environmental factors (including dysbiosis) could contribute to underlying pathophysiology and pro-inflammatory burden.
In CFLD presentations where focal and multi-lobular fibrosis are predominant, a progressive periportal inflammatory process with stellate cell activation and fibrogenesis is seen . Mechanisms behind obliterative venopathy is less understood. A pro-inflammatory state driving endothelial dysfunction, platelet activation with micro-thrombosis has been proposed, which may drive subsequent porto-sinusoidal vascular disease or non-cirrhotic portal venous biliopathy .
The gut microbiome likely plays a role in mechanisms underlying both proposed forms of CFLD. Differences between the CF and non-CF microbiome are well described . CFTR dysfunction itself and the altered intestinal milieu, in addition to the high-calorie CF diet, frequent antibiotics and protein-pump-inhibitor (PPI) exposure, impact bacterial diversity . Prolonged small bowel transit in PwCF with cirrhosis has been documented, likely exacerbating small intestinal bacterial overgrowth . Dysbiosis reduces short-chain fatty acids and promotes gut inflammation, which may contribute to ‘leaky gut’; with increased intestinal permeability, bacterial translocation with pathogen-associated molecular patterns (PAMPs) and biliary tree endotoxin exposure . CFTR may play a role in the innate immunity at the cholangiocytes level . Loss of CFTR may result in aberrant innate immune responses to dysbiosis- driven endotoxins, leading to proinflammatory responses and biliary fibrosis . Interaction with bile acid pathways, via farsenoid X receptor (FXR) and fibroblast growth factor 19 activation, may also play a role .
Surveillance and use of diagnostic biomarkers
Recent consensus guidelines suggest annual laboratory screening and physical examination should occur annually in PwCF from CF diagnosis, with biannual abdominal ultrasonography from 3 years of age . Screening for other causes of liver disease is essential when hepatobiliary involvement is identified . If aCFLD is diagnosed; laboratory testing, including assessment of synthetic function, should occur minimum 6 monthly, with annual liver fibrosis index calculation (APRI, FIB-4) or elastography assessment (transient elastography [TE] or ultrasound shear-wave elastography [SWE]),if available .
Utility of diagnostic biomarkers to monitor and predict evolution of severe CFLD is an area of increasing interest. Liver biopsy remains the gold standard in diagnosis of cirrhosis in CFLD, and can help stage degree of fibrosis, document progression of liver disease, and help differentiate between cirrhotic vs. non-cirrhotic portal hypertension . However, this modality remains invasive and impractical, and has further sampling limitations in the setting of focal biliary disease . Consequently, the use of a diagnostic liver biopsy in this setting did not reach sufficient consensus in the recent recommendations document. Whilst several studies suggest persistently high GGT may be associated with development of cirrhosis , in isolation liver biochemistry is unlikely to correlate or predict CLFD severity . Patients with a cholestatic picture on liver function testing should, however, undergo magnetic resonance cholangiopancreatography (MRCP) to exclude cholangiopathy, strictures or biliary obstruction .
Circulating microRNAs have been proposed as a marker to distinguish severe from mild to moderate fibrosis in CFLD, but have not been validated in prospective cohorts and are not available in mainstream clinical practice . Liver fibrosis indices, including alanine to platelet ratio index (APRI), gamma-glutamyl transferase-to-platelet ratio (GPR) and Fibrosis −4 index (FIB-4) have been well-studied in predicting fibrosis in various forms of liver disease, but in isolation are not useful in detecting earlier stages of CFLD . Their utility is strengthened in combination with ultrasound or liver stiffness evaluation . Ultrasonography can identify steatosis, nodularity, homogenous and heterogenous patterns to monitor clinical progression in CFLD over time . Although this modality correlates with some biomarkers of clinical disease and fibrosis , it may underestimate and cannot reliably exclude fibrosis in isolation . It is strengthened with combined use of SWE as a marker of liver stiffness and fibrosis . A prospective multi-centre study by Dana et al. compared various forms of elastography and found good diagnostic performance in discriminating and predicting CFLD with use of both TE and SWE . This is acknowledging not insignificant confounders to these modalities, including presence of steatosis, inflammation and venous congestion, as well as inter-operator and inter-machine variability . MRE could present a more standardised modality to monitor liver stiffness and fibrosis . However, this resource is currently scarce and expensive, with conflicting studies showing both inferiority and superiority compared to TE and SWE .
In PwCF, portal hypertension may manifest via absolute or relative thrombocytopenia, splenomegaly, portosystemic collateral vessels, ascites and/or variceal bleeding. Understanding cirrhotic or non-cirrhotic basis is necessary to help plan treatment approaches. Hepatic venous pressure gradient (HVPG) measurement in PwCF with portal hypertension who lack evidence for cirrhosis may be useful. Non-cirrhotic (intrahepatic/pre-sinusoidal) portal hypertension is associated with normal or slightly increased values (<5-10mmg/Hg) .
Management
There is currently no evidence for any medical therapy to treat or prevent progression of CFLD . Supportive management is the mainstay of CLFD care . Focus on growth and nutritional optimization is paramount, with pancreatic enzymes, fat soluble vitamins and medium chain triglyceride supplementation as applicable . Minimization of liver insults is essential, including early screening for and diagnosis of comorbid liver disease and vaccination against viral hepatitis .
Ursodeoxycholic acid has been proposed to improve bicarbonate secretion, increase bile flow, and modify the bile acid pool to decrease toxicity in cystic fibrosis . However, no difference in liver related and other mortality outcomes has been shown between prescribing and non-prescribing cystic fibrosis centres, and it likely lacks long-term efficacy evidence to justify routine use . Increased risk of death and liver transplantation with high dose use in primary sclerosing cholangitis is also of concern .
Evidence for primary variceal prophylaxis with endoscopic surveillance and band ligation is lacking in CFLD, and in practice may depend on centre-specifical local expertise . Beta blockade should be used cautiously in PwCF with CFLD given risk of paradoxical bronchospasm . Interventional radiologically guided or surgical shunts for treatment of portal hypertension may be considered on a case-by-case basis, as long-term data is lacking . This may offer a standalone approach for complications in obliterative portal venopathy, or as a bridge to liver transplantation in advanced portal hypertension.
Liver transplantation (LT) is an important and viable approach in end stage CFLD. In large paediatric cohorts, transplantation has been required in 10–16 % in patients with CFLD . Five-year survival rates post liver transplantation are up to 85 % in children and 72 % in adults with CFLD . United Network for Organ Sharing (UNOS) data has demonstrated these outcomes are inferior, but acceptable, compared to transplantation for other indications . Furthermore, survival benefit in PwCF with cirrhosis undergoing LT has been demonstrated over those who do not receive LT . Transplantation may further improve quality of life and respiratory status impeded by portal hypertension ‘ . However, decisions surrounding indication for and timing of transplantation can be nuanced, particularly in the setting of respiratory function and organism colonisation. Synthetic dysfunction, hyperbilirubinaemia and liver failure are often late markers of progression in CFLD , but are weighted heavily in scores such as model for end-stage liver disease (MELD) and paediatric end-stage liver disease (PELD) used commonly in graft allocation. Disease status may be underestimated, actively disadvantaging PwCF with CFLD. Superior outcomes in paediatric liver transplantation have been seen compared to adults with CFLD undergoing liver transplantation . In combination, this may support need for earlier consideration of transplant referral . En bloc liver and pancreas transplantation may be an under-ultilised opportunity to abate ongoing pancreatic insufficiency and diabetes .
Based on new insights on the pathophysiology of CFLD, novel therapeutic approaches targeting endothelial dysfunction and inflammation, such FXR agonists, FGF19 analogues and vitamin D receptor activation pathways require further exploration .
CFTR modulators
The advent of CFTR modulators has resulted in a paradigm shift within cystic fibrosis care. Depending on the class of CFTR mutation, the effect of various modulators may improve production, intracellular processing and/or function of defective CFTR protein . Ivacaftor (Kalydeco ©, Vertex Pharmaceuticals) was the first modulator approved for mainstream practice, potentiating activity in gating mutations such as G551D . In more common CFTR mutations, such as F508del , combinations of modulators have proven most efficacious in targeting multiple cellular mechanisms. This may include tezacaftor-ivacaftor or lumacaftor-ivacaftor. The most widespread example of this now used in clinical practice is elexacaftor/ivacaftor/tezacaftor (ETI) [Trikafta©, Vertex Pharmaceuticals], which is available for use in PwCF with at least one F508del in patients greater than 12 years age, representing more than 90 % PwCF . In recent years Trikafta has been approved for younger age groups, most recently in April 2023 with the US FDA approving Trikafta for children down to age 2 years. Substantial improvements in FEV 1 , frequency of pulmonary exacerbations, weight, decreased sweat chloride are documented with ETI therapy . With introduction of ETI, rates of lung transplantation and death may be 85 % and 72 % lower, based on real-world US Cystic Fibrosis Foundation Patient Registry observational data .
Effect of CFTR modulators on CFLD
With improved CFTR function in extra-pulmonary epithelium, it could be hypothesised that CFTR modulators might modify extra-pulmonary organ manifestations and disease progression, particularly in PwCF treated from an early age. An example illustrating this is an improvement of pancreatic function with early use of CFTR modulator therapies in some PwCF with pancreatic insufficient mutations . Effect on pancreatic endocrine function, with improved glycaemic variability has further been reported with use of ETI at 3–12 months . The PROMISE-GI study demonstrated a modest improvement in gastrointestinal symptoms and markers of intestinal inflammation with 6 months of ETI use , supporting similar findings in an earlier multi-centre German study . To date, the impact of CFTR modulators on CLFD remains largely unclarified. CFTR modulators could, in theory, reduce pathophysiological mechanisms at the level of aberrant CFTR in cholangiocytes and hepatic endothelium, to reduce biliary obstruction, and net effects of dysbiosis and inflammation, particularly in patients commenced on therapies at an early age. Proposed effects of CFTR modulators on CLFD incidence, severity and progression are outlined in Table 2 .
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