Cystic Fibrosis-related Liver Disease Research Articles

Physical activity and liver disease affect the fat-free mass in adolescents with cystic fibrosis

Cystic fibrosis (CF) is predominantly a lung disease but is also characterised by impaired skeletal muscularity and a reduction in fat-free mass. We aimed to test the hypothesis that clinical and anthropometric parameters would determine fat-free mass impairment in adolescents with CF. We measured the fat-free mass index (FFMI) using bioelectrical impedance, the lung function using spirometry, the number of shuttles as a measure of exercise tolerance and the reported physical activity in children and young people with CF in a tertiary centre at King’s College Hospital, London, UK. CF-related liver disease was diagnosed by abnormal liver enzymes and/or ultrasonography. We studied 28 children and young people (11 male) with a median (interquartile range (IQR)) age of 15 (13–17) years. They had a median (IQR) FFMI of 13.5 (11.6–15.1) kg/m2. The FFMI significantly correlated with age (rho = 0.568, p = 0.002), number of shuttles (rho = 0.691, p < 0.001) and reported hours of activity per day (rho = 0.426, p = 0.024). The median (IQR) FFMI was significantly higher in male [15.1 (13.1–18.6) kg/m2] compared to female participants [12.7 (11.6–14.1) kg/m2, p = 0.008]. The median (IQR) FFMI was significantly lower in the 10 (36%) participants with liver disease [11.9 (11.5–13.4) kg/m2] compared to the FFMI in the remaining 18 participants without liver disease [14.4 (12.5–15.9) kg/m2, p = 0.027].Conclusion: Fat-free mass increases with increasing age and growth in adolescents with CF. Physical activity exerts a beneficial effect on fat-free mass, and CF-related liver disease negatively affects fat-free mass in adolescents with CF.What is Known:• Health behaviours in adolescence influence lifelong health in cystic fibrosis (CF).• A normal body mass index in CF might fail to reveal a low fat-free mass (FFM), and quality of life in CF is strongly associated with a reduced FFM.What is New:• FFM increases with increasing age and growth in adolescents with CF. • Physical activity exerts a beneficial effect, and liver disease negatively affects FFM in adolescents with CF.

Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency.

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

193 Association between cystic fibrosis–related liver disease, mortality, and disease burden in children

193 Association between cystic fibrosis–related liver disease, mortality, and disease burden in children

S2528 Think "Inside the Loop:" A Novel Method for Repositioning a Migrated G-J Tube

Introduction: Gastrojejunostomy tube (G-J tube) migration is common in patients requiring long term percutaneous enteral feeding. These patients often present with forceful vomiting and decreased PO intake. This case discusses a method for repositioning a migrated G-J tube using an endoloop (detachable snare device) and Resolution Clips. Case Description/Methods: A 26-year-old female with a history of cystic fibrosis (CF), chronic malnutrition requiring enteral feeds, CF-related liver disease and variceal bleeding presented with 5 days of abdominal pain and coffee ground emesis. Initially, the patient was tachycardic and vomiting intermittently. Bright red blood was visible in the emesis bag. Physical exam was notable for epigastric tenderness without peritoneal signs. The skin around the G-J tube insertion site was non-tender with no signs of infection. CT of the abdomen revealed gastrosplenic varices and appropriate positioning of the enteral tube. There was no evidence of GI perforation or obstruction. An EGD demonstrated a patent gastrostomy tube in the gastric body. The jejunal tail was coiled up against the inflamed lumen of the stomach. The suture at the tip of the tail had degraded, dislodging the tube from its original position along the jejunal wall. There were blood clots in the body of the stomach but no evidence of active bleeding. Given the suspicion that the migrated feeding tube was the cause of the patient’s symptoms, a decision was made to reposition it. An endoloop was tied around the tip of the G-J tube to serve as a substitute for the suture. A cold snare was then used to secure the endoloop and drag the tail into the jejunum. The endoloop was secured to the intestinal wall using 2 Resolution Clips. The patient’s symptoms resolved after the EGD and she was discharged in stable condition (Figure). Discussion: Migration of a G-J tube is commonly associated with severe motility disorders, such as cystic fibrosis. Oftentimes, the tube will loop inside the stomach or continue toward the esophagus. The tube itself can cause gastric outlet obstruction, leading to gastric distention, nausea and vomiting. These patients are an aspiration risk and should be initially managed with IV hydration, antiemetics, and stopping of tube feeds. In addition, it is important to assess for complications such as sepsis, hemorrhage, buried bumper, or perforation of the GI tract. If the feeding tube is patent, it is reasonable to have it repositioned based on clinical judgment and provider expertise.Figure 1.: Upper Endoscopy: A. Intact gastrostomy with a patent G-J tube present in the gastric body. The jejunal tail is coiled up in the lumen of the stomach. B. The tip of the G-J tube with surrounding trauma to the body of the stomach, characterized by edema, erythema, and inflammation. The thread at the tip of the G-J tube had degraded (yellow arrow). C. An endoloop was tied at the neck of the tip of the G-J tube (black arrow) to serve as a substitute for the suture. D. A cold snare was used to secure the endoloop (black arrow) and drag the tip of the G-J tube into the jejunum. E. The endoloop (black arrow) attached to the tip of the G-J tube was secured to the wall of the jejunum using a Resolution Clip (pink arrow).

Diagnosis and predicted outcomes of patients with cystic fibrosis related liver disease considered for lung transplantation.

There is no gold standard criterion for the diagnosis of cystic fibrosis-related liver disease (CFRLD) and there is uncertainty over its impact on the outcome of lung transplantation. Lung recipients (n=238) were divided into two groups-CFRLD and non-CFRLD based on a modified aspartate aminotransferase-to-platelet ratio index (APRI) score (mAPRI) to diagnose CFRLD and predict severity of liver disease. Groups were compared to assess validity of the diagnosis and survival outcomes. The new diagnostic criterion was effective at differentiating CFRLD from non-CFRLD. There was no significant difference in the survival between two groups at short, medium, or long term demonstrated by the Kaplan-Meier plot with survival of 85%, 73%, 47%, 18.6%, and 4.7% at 1, 2, 5, 10, and 15 years respectively. A mAPRI score of greater than .2 had a sensitivity of 43.0% but a specificity of 82.5 % for diagnosis of CFRLD and 46.5% sensitivity but 100% specificity in predicting an ultrasound/biopsy proven hepatic abnormality associated with CFRLD. A mAPRI sore is a highly specific non-invasive tool for diagnosis of CFRLD. Recipients with CFRLD but grossly preserved hepatocellular function have a similar outcome to patients without CFRLD.

Cystic fibrosis-related liver disease is an independent risk factor for mortality and increased health care resource utilization in hospitalized pediatric patients with cystic fibrosis.

Cystic fibrosis-related liver disease (CFLD) is more prevalent in recent decades due to the increasing life expectancy of patients with cystic fibrosis (CF). There is paucity of population-level data on the impact of CFLD on hospital outcomes. We interrogated nonoverlapping years (2003-2016) of the National Inpatient Sample and Kids' Inpatient Database to include all hospitalized patients <21 years of age with a primary diagnosis of CF within the United States. A concomitant diagnosis of cirrhosis, liver fibrosis, chronic liver disease, portal hypertension, hepatomegaly, splenomegaly, hypersplenism, and liver transplant status was considered as surrogates for the diagnosis of CFLD and was compared with CF-related hospitalizations without these diagnoses (controls) for demographics, comorbid conditions, in-hospital mortality, length-of-stay, and hospital charges. We evaluated 94,374 CF-related hospitalizations. The prevalence of CFLD was 5.8%. The prevalence increased from 3.1% (2003) to a peak of 7.3% (2014) with an overall increasing trend, p < 0.001. Hospitalizations with CFLD had an increased prevalence of significant comorbidities: respiratory failure,lung transplant, pulmonary hypertension, diabetes mellitus, malnutrition, Clostridioides difficile infection, cholelithiasis, anemia, and need for parenteral nutrition, p < 0.001. Multivariate regression models showed CFLD as independently associated with 2.1 (95% confidence interval [CI]: 1.5 to 2.8) times increased risk of inpatient mortality, contributed to 1.1 (95% CI: 0.89 to 1.37) additional days of hospitalization, and incurring $14,852 (95% CI: 12,204 to 17,501) excess hospital charges, p < 0.001. CFLD is associated with multiple comorbidities and is independently associated with increased risk of mortality and increased health care resource utilization in pediatric CF-related hospitalizations.

Italian Cystic Fibrosis Registry (ICFR). Report 2019-2020

Italian Cystic Fibrosis Registry (ICFR). Report 2019-2020

Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RationaleCystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).MethodsWe retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.ResultsFIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11–0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07–0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06–0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12–0.97; p=0.044). These associations were absent for SCC.ConclusionThis study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Review article: epidemiology, pathogenesis and management of liver disease in adults with cystic fibrosis.

Cystic fibrosis-related liver disease (CFLD) is the leading cause of death in cystic fibrosis (CF), after pulmonary disease. To improve identification and management of this condition requires an understanding of the underlying disease mechanism. This review summarises the current understanding of CFLD epidemiology, pathology, diagnosis and management. Relevant reports on cystic fibrosis liver disease were identified using a literature search and summarised. CFLD is a heterogeneous condition with several different co-existent pathologies, including environmental and genetic factors. Incidence of clinically significant CFLD continues at a linear rate into early adulthood and has been described in up to 25% of CF patients. Diagnosis strategies lack precision and patient risk stratification needs to look beyond Childs-Pugh scoring. Efficacious therapies are lacking and, at present, newer modulator therapies lack data in CFLD and carry an increased risk of hepatotoxicity. Outcomes of liver transplant are comparable to non-CF transplant indications. The incidence of CFLD increases with age and hence is increasingly important to adult patients with CF. Effective therapies are lacking. For progress to be made a better understanding of pathogenesis and disease detection are required.

Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation.

Objectives:[1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF.Methods:A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having ‘low CRF’ when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used.Results:Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th–75th percentile: 12.9–17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO2peak/kg) was 81.4% (±12.4, range: 51%–105%). Thirty-three patients (55.0%) were classified as having ‘low CRF’. The final model that best predicted low CRF included IGT (p = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance.Conclusions:CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF.

Cystic fibrosis related liver disease and endocrine considerations

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis postliver transplant: A case series.

Cystic fibrosis (CF)-related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator modulator that has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in liver function tests (LFTs) and drug-drug interactions with several immunosuppressant medications. The purpose of this case series is to explore if the use of elx/tez/iva is safe and tolerable in patients with CF postliver transplantation. A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed. Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and the median time from the transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in seven patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body mass index, and maintained or improved lung function. Initiation of elx/tez/iva in patients with CF who received liver transplantation may be safe with clinical benefits.

199: Protective effects of SGLT1/2 inhibitor sotagliflozin on CF-related liver disease in CF rabbits

199: Protective effects of SGLT1/2 inhibitor sotagliflozin on CF-related liver disease in CF rabbits

Risk factors for Pseudomonas aeruginosa airway infection and lung function decline in children with cystic fibrosis

Background Cystic fibrosis (CF) lung disease is characterised by recurrent Pseudomonas aeruginosa (Pa) infections, leading to structural lung damage and decreased survival. The epidemiology of Pa infection and its impact on lung function in people with CF (pwCF), especially in recent birth cohorts, remain uncertain.Methods We included 1,231 French pwCF under 18 years of age. Age at initial acquisition (Pa-IA), chronic colonisation (Pa-CC), and duration from Pa-IA to Pa-CC were estimated using the Kaplan–Meier method. Demographic, clinical, and genetic characteristics were analysed as risk factors for Pa infection using Cox regression models. Lung function decline was assessed by modelling percent-predicted forced expiratory volume in 1 s (ppFEV1) before Pa infection, after Pa-IA, and after Pa-CC.Results Among the 1,231 pwCF, 50% had Pa-IA by the age of 5.1 years [95% confidence interval (CI) 3.8–6.2] and 25% had Pa-CC by the age of 14.7 years (95% CI 12.1 to ∞). We observed that CF-related diabetes and liver disease were risk factors for Pa, while gender, CFTR variants, and CF centre size were not. Genetic variants of TNF, DCTN4, SLC9A3, and CAV2 were confirmed to be associated with Pa. The annual rate of ppFEV1 decline before Pa was -0.38% predicted/year (95% CI -0.59 to -0.18), which decreased significantly after Pa-IA to -0.93% predicted/year (95% CI -1.14 to -0.71) and after Pa-CC to -1.51% predicted/year (95% CI -1.86 to -1.16).Conclusions We identified and replicated several risk factors associated with Pa infection and showed its deleterious impact on lung function in young pwCF. This large-scale study confirmed that Pa airway infection is a major determinant of lung disease severity.

Serum bile acids in cystic fibrosis patients – glycodeoxycholic acid as a potential marker of liver disease

BackgroundCystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism. AimThis study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment. MethodsPrimary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS). ResultsBile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822–1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731–1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency. ConclusionsA CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF.

Non-invasive diagnostic tests in cystic fibrosis-related liver disease: A diagnostic test accuracy network meta-analysis

Non-invasive diagnostic tests in cystic fibrosis-related liver disease: A diagnostic test accuracy network meta-analysis

Pancreas transplantation for cystic fibrosis: A frequently missed opportunity.

Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF-related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF-related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant.

What are the effects of ursodeoxycholic acid (UDCA) for people with cystic fibrosis-related liver disease?

What are the effects of ursodeoxycholic acid (UDCA) for people with cystic fibrosis-related liver disease?

Survival Benefits Following Liver Transplantation: A Matched-pair Analysis in Pediatric Patients With Cystic Fibrosis.

Cystic fibrosis-related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients. The aim of this study was to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison. Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx, and details of surgical procedures. At our institution, 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of posttransplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. Five patients died after LTx, none because of primary hepatic dysfunction (1 because of posttransplant proliferative disorder, 4 because of infection). Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function, and life expectancy of CFLD patients with LTx are comparable with matched CF peers without CFLD. Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy, and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

Transient Elastography in Pediatric Liver Disease.

Transient elastography is an imaging technique utilizing shear wave technology to measure liver stiffness. Recent studies have shown success in utilizing this technique in children. Transient elastography is useful in estimating degree of fibrosis in various pediatric liver diseases, including biliary atresia, alpha-1-antitrypsin deficiency, Alagille syndrome, cystic fibrosis-related liver disease, and non-alcoholic steatohepatitis among others. Confounding factors, however, may affect elastography measurements, such as obesity, severe inflammation, nonfasting state, and hepatic congestion, and should be considered whenever interpreting these measurements. Future studies will correlate liver stiffness on transient elastography and severity of disease.