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1
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Raevens S, Boret M, De Pauw M, Fallon MB, Van Vlierberghe H. Pulmonary Abnormalities in Liver Disease: Relevance to Transplantation and Outcome. Hepatology 2021; 74:1674-1686. [PMID: 33636019 DOI: 10.1002/hep.31770] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/17/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.
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Affiliation(s)
- Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University-Ghent University Hospital, Ghent, Belgium
| | - Maxine Boret
- Department of Gastroenterology and Hepatology, Ghent University-Ghent University Hospital, Ghent, Belgium
| | - Michel De Pauw
- Department of Cardiology, Ghent University-Ghent University Hospital, Ghent, Belgium
| | - Michael B Fallon
- Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University-Ghent University Hospital, Ghent, Belgium
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Sasame A, Stokes D, Bourke B, Connolly L, Fitzpatrick E, Rowland M. The impact of liver disease on mortality in cystic fibrosis-A systematic review. J Cyst Fibros 2021; 21:202-211. [PMID: 34380590 DOI: 10.1016/j.jcf.2021.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 07/12/2021] [Accepted: 07/24/2021] [Indexed: 01/25/2023]
Abstract
BACKGROUND There is conflicting evidence on the impact of liver disease (CFLD) on life expectancy in CF. Therefore the aim of this systematic review was to evaluate the impact of liver disease (CFLD) on mortality in CF. METHODS The protocol was published at (https://hrbopenresearch.org/articles/3-44/v3) using PRISPMA-P guidelines and registered in Prospero 2020 (CRD42020182885). Three databases were searched for publications (1938-2020) where the outcome was all-cause mortality (defined as death and transplantation) or CF-specific mortality in participants with CFLD. Studies with and without a comparator group were included. Studies were divided into 2 groups based on the definition of CFLD: Group 1 used 2 categories of liver disease (i) liver disease with portal hypertension (PH) (ii) non-specific abnormalities which did not meet the criteria for PH, Group 2 studies only included participants with PH. RESULTS All 14 eligible studies were observational, with a moderate-high risk of bias, Six of the 14 studies directly compared mortality between those with CFLD and those with no liver disease, and 5/6 demonstrated that those with CFLD had at least 3 time the risk of death compared to those with no liver disease. Pulmonary complications were the primary cause of death. CONCLUSION This SR demonstrates that liver disease shortens life expectancy in CF, and that pulmonary complications are the primary cause of death in those with CFLD. There has been no improvement in survival for persons with CFLD despite significant improvements in life expectancy for persons with CF who have no evidence of liver disease.
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Affiliation(s)
- Ao Sasame
- School of Medicine University College Dublin, Belfield, Dublin 4, Ireland
| | - Diarmuid Stokes
- UCD Library, University College Dublin, Belfield, Dublin 4, Ireland
| | - Billy Bourke
- School of Medicine University College Dublin, Belfield, Dublin 4, Ireland; Children's Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland; King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Lucy Connolly
- School of Medicine University College Dublin, Belfield, Dublin 4, Ireland
| | - Emer Fitzpatrick
- School of Medicine University College Dublin, Belfield, Dublin 4, Ireland; Children's Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland; King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Marion Rowland
- School of Medicine University College Dublin, Belfield, Dublin 4, Ireland.
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Fridell JA, Bozic MA, Ulrich BJ, Lutz AJ, Powelson JA. Pancreas transplantation for cystic fibrosis: A frequently missed opportunity. Clin Transplant 2021; 35:e14371. [PMID: 34032335 DOI: 10.1111/ctr.14371] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 11/29/2022]
Abstract
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.
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Affiliation(s)
- Jonathan A Fridell
- Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Molly A Bozic
- Department of Pediatric Gastroenterology, Riley Hospital for Children, Indianapolis, IN, USA
| | - Benjamin J Ulrich
- Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrew J Lutz
- Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - John A Powelson
- Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Cipolli M, Fethney J, Waters D, Zanolla L, Meneghelli I, Dutt S, Assael BM, Gaskin KJ. Occurrence, outcomes and predictors of portal hypertension in cystic fibrosis: A longitudinal prospective birth cohort study. J Cyst Fibros 2020; 19:455-459. [DOI: 10.1016/j.jcf.2019.09.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 08/29/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022]
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Lascano-Vaca Y, Ortiz-Prado E, Gomez-Barreno L, Simbaña-Rivera K, Vasconez E, Lister A, Arteaga-Espinosa ME, Perez GF. Clinical, genetic and microbiological characterization of pediatric patients with cystic fibrosis in a public Hospital in Ecuador. BMC Pediatr 2020; 20:111. [PMID: 32143663 PMCID: PMC7060626 DOI: 10.1186/s12887-020-2013-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 02/27/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND To carry out a complete clinical, pathological, genetic and microbiological characterization of pediatric patients with molecular confirmed cystic fibrosis (CF) attending the Carlos Andrade Marín Hospital (HCAM) within the study period. METHODS A cross-sectional analysis of the pediatric population with a confirmed diagnosis of CF disease who attended HCAM, one of the largest tertiary-level hospitals in Ecuador, between 2017 and 2018 was performed. All demographic, clinical and genetic variables were obtained from the electronic medical records (EMR) stored by the hospital. RESULTS Forty seven patients with CF were included in the study. Gender distribution was similar between male (48.9%, n = 23) and female patients (51.1%, n = 24). The Tiffeneau-Pinelli index (FEV1/FVC) changed significantly after nine months post-diagnosis (85.55 ± 13.26; p < 0.05). The most common pathogenic genetic variants were F508del, found in 52.78% of the cohort (n = 19); H609R, found in 36.11% (n = 13); g.204099A > C, found in 14.1% (n = 7), followed by G85E and the N1303K with 11.11% (n = 3) each. CONCLUSIONS To our best knowledge, this is the first study exploring the clinical, genetic and bacteriological profile of CF's patients in Ecuador. Within the cohort of patients, an important and unique genetic feature was characterized by the presence of the g.204099A > C and the c.206359C > A homozygous polymorphism as well as the presence of the H609R variant, a mutation only reported among Ecuadorians.
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Affiliation(s)
- Yazmina Lascano-Vaca
- Pediatric Pneumology Service, Pediatric Unit of the Carlos Andrade Marin Specialties Hospital, Quito, Ecuador
| | - Esteban Ortiz-Prado
- One Health Research Group, Universidad de Las Americas, José Queri and Av. de los Granados, Quito, Ecuador.
| | - Lenin Gomez-Barreno
- One Health Research Group, Universidad de Las Americas, José Queri and Av. de los Granados, Quito, Ecuador
| | - Katherine Simbaña-Rivera
- One Health Research Group, Universidad de Las Americas, José Queri and Av. de los Granados, Quito, Ecuador
| | - Eduardo Vasconez
- One Health Research Group, Universidad de Las Americas, José Queri and Av. de los Granados, Quito, Ecuador
| | - Alexander Lister
- Faculty of Medicine, University of Southampton, Southampton, England
| | | | - Geovanny F Perez
- Division of Pulmonary and Sleep Medicine, Children's National Health System, Washington, DC, USA
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Lemoine C, Lokar J, McColley SA, Alonso EM, Superina R. Cystic fibrosis and portal hypertension: Distal splenorenal shunt can prevent the need for future liver transplant. J Pediatr Surg 2019; 54:1076-1082. [PMID: 30792095 DOI: 10.1016/j.jpedsurg.2019.01.035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 01/27/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The management of portal hypertension (PHT) in children with well compensated cirrhosis and cystic fibrosis (CF) is controversial. We present our experience with distal splenorenal shunting (DSRS) for the treatment of PHT as an alternative to liver transplantation (LT). METHODS Between 2008 and 2017, 5 CF children underwent a DSRS at a pediatric hepatobiliary and transplantation referral center. LT (n = 9) was reserved for patients with decompensated cirrhosis. Statistical analysis was done using the paired t-test (p < 0.05 considered significant). RESULTS Mean PELD/MELD score was significantly lower for DSRS patients than LT (3 ± 6 vs 28 ± 4, p < 0.001). All 5 DSRS patients had grade III-IV varices. One bled prior to surgery. After DSRS, spleen size decreased significantly from 8.4 ± 1.5 cm to 4.4 ± 1.8 cm (p = 0.019). Mean platelet count remained stable (87.8 ± 48 to 91.8 ± 35, p = 0.9). There were no postoperative complications. No DSRS patient experienced variceal bleeding following shunt creation. Liver function tests remained stable in the DSRS group, and no patient required a liver transplant (median follow up 4.65 years, range 1.24-7.79). CONCLUSIONS Patients with cystic fibrosis who have well-compensated cirrhosis and symptomatic portal hypertension can be palliated with distal splenorenal shunting and do not need liver transplants. These patients can undergo shunting with minimal morbidity. TYPE OF STUDY Case series with no comparison group. LEVEL OF EVIDENCE IV.
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Affiliation(s)
- Caroline Lemoine
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Joan Lokar
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Susanna A McColley
- Division of Pulmonary Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Estella M Alonso
- Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Riccardo Superina
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Nascimento FDS, Sena NA, Ferreira TDA, Marques CDF, Silva LR, Souza EL. Hepatobiliary disease in children and adolescents with cystic fibrosis. J Pediatr (Rio J) 2018; 94:504-510. [PMID: 28888897 DOI: 10.1016/j.jped.2017.07.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 06/29/2017] [Accepted: 06/30/2017] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVES The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic, clinical, and laboratory profile of these patients. METHODS This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with cystic fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted and sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies were registered. RESULTS Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of cystic fibrosis in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p=0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p=0.007). CONCLUSION The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood.
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Affiliation(s)
| | - Nelson A Sena
- Universidade Federal da Bahia (UFBA), Salvador, BA, Brazil
| | - Tatiane da A Ferreira
- Complexo Hospitalar Professor Edgard Santos, Serviço de Pneumologia Pediátrica, Salvador, BA, Brazil
| | - Cibele D F Marques
- Universidade Federal da Bahia (UFBA), Faculdade de Medicina, Salvador, BA, Brazil; Complexo Hospitalar Professor Edgard Santos, Programa de Residência Médica em Gastropediatria, Salvador, BA, Brazil
| | - Luciana R Silva
- Universidade Federal da Bahia (UFBA), Serviço de Gastroenterologia e Hepatologia, Salvador, BA, Brazil
| | - Edna Lúcia Souza
- Universidade Federal da Bahia (UFBA), Salvador, BA, Brazil; Universidade Federal da Bahia (UFBA), Faculdade de Medicina, Departamento de Pediatria, Salvador, BA, Brazil.
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8
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Nascimento FDS, Sena NA, Ferreira TDA, Marques CD, Silva LR, Souza EL. Hepatobiliary disease in children and adolescents with cystic fibrosis. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2018. [DOI: 10.1016/j.jpedp.2017.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Ayoub F, Trillo-Alvarez C, Morelli G, Lascano J. Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease. World J Hepatol 2018; 10:34-40. [PMID: 29399276 PMCID: PMC5787682 DOI: 10.4254/wjh.v10.i1.34] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/06/2017] [Accepted: 12/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis (CF) patients with hepatic steatosis as compared to normal CF controls.
METHODS We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging (ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls.
RESULTS Data was collected on 114 patients meeting inclusion criteria. Seventeen patients (14.9%) were found to have hepatic steatosis on imaging. Being overweight (BMI > 25) (P = 0.019) and having a higher ppFEV1 (75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level (27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.
CONCLUSION Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher ppFEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.
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Affiliation(s)
- Fares Ayoub
- Department of Medicine, University of Florida, Gainesville, FL 32608, United States
| | - Cesar Trillo-Alvarez
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL 32608, United States
| | - Giuseppe Morelli
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL 32608, United States
| | - Jorge Lascano
- Department of Medicine, Adult Cystic Fibrosis Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL 32608, United States
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Abstract
The survival of patients with cystic fibrosis (CF) has progressively increased over recent decades, largely attributable to early diagnosis through newborn screening and advances in nutritional and respiratory care. As the life expectancy of patients with CF has improved, non-respiratory complications such as liver disease have become increasingly recognized. Biochemical derangements of liver enzymes in CF are common and may be attributed to a number of specific hepatobiliary abnormalities. Among them, Cystic Fibrosis-associated Liver Disease (CFLD) is clinically the most significant hepatic complication and is believed to have a significant impact on morbidity and mortality. However, there remains much conjecture about the extent of the adverse prognostic implications that a diagnosis of CFLD has on clinical outcomes. The purpose of this review is to give an overview of the current knowledge regarding liver disease in children with CF.
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Affiliation(s)
- Lisette Leeuwen
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia; Medical School, University of Groningen, Groningen, The Netherlands
| | - Dominic A Fitzgerald
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Australia
| | - Kevin J Gaskin
- Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Australia; Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, Australia; James Fairfax Institute of Paediatric Nutrition, University of Sydney, Sydney, Australia.
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Parisi GF, Di Dio G, Franzonello C, Gennaro A, Rotolo N, Lionetti E, Leonardi S. Liver disease in cystic fibrosis: an update. HEPATITIS MONTHLY 2013; 13:e11215. [PMID: 24171010 PMCID: PMC3810678 DOI: 10.5812/hepatmon.11215] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 06/16/2013] [Accepted: 08/05/2013] [Indexed: 12/11/2022]
Abstract
CONTEXT Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emerged especially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. RESULTS CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause of mortality in CF (the third after pulmonary disease and transplant complications), only about the 33%of CF patients presents clinically significant hepatobiliary disease. CONCLUSIONS Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed at delaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of fibrosis prevention and to avoid its progression prior to development its related complications.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Giovanna Di Dio
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Chiara Franzonello
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Alessia Gennaro
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Novella Rotolo
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Elena Lionetti
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Salvatore Leonardi
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
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12
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Behrens CB, Langholz JH, Eiler J, Jenewein R, Naehrlich L, Fuchs K, Harth S, Krombach GA, Alzen GFP. A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging. Pediatr Radiol 2013. [PMID: 23192669 DOI: 10.1007/s00247-012-2560-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. OBJECTIVE To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. MATERIALS AND METHODS ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. RESULTS Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. CONCLUSION Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD.
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Affiliation(s)
- Christopher B Behrens
- Department of Pediatric Radiology, University Hospital Giessen, Feulgenstrasse 10-12, 35392, Giessen, Germany.
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Flass T, Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros 2013; 12:116-24. [PMID: 23266093 PMCID: PMC3883947 DOI: 10.1016/j.jcf.2012.11.010] [Citation(s) in RCA: 136] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 11/14/2012] [Accepted: 11/15/2012] [Indexed: 12/25/2022]
Affiliation(s)
- Thomas Flass
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics University of Colorado School of Medicine and The Pediatric Liver Center, Children's Hospital Colorado, Aurora, CO, USA
| | - Michael R Narkewicz
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics University of Colorado School of Medicine and The Pediatric Liver Center, Children's Hospital Colorado, Aurora, CO, USA.
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14
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Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode. Int J Mol Sci 2012; 13:8882-8914. [PMID: 22942741 PMCID: PMC3430272 DOI: 10.3390/ijms13078882] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 07/03/2012] [Accepted: 07/06/2012] [Indexed: 12/14/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.
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Miller MR, Sokol RJ, Narkewicz MR, Sontag MK. Pulmonary function in individuals who underwent liver transplantation: from the US cystic fibrosis foundation registry. Liver Transpl 2012; 18:585-93. [PMID: 22271602 DOI: 10.1002/lt.23389] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Severe liver disease affects 4.5% to 10% of individuals with cystic fibrosis (CF) and is the third-leading cause of death. Liver transplantation (LT) is an accepted therapy, but the effects of liver disease and LT on pulmonary function in patients with CF are controversial. Our aim was to characterize changes in pulmonary function in LT patients with CF. Using mixed effect models, we analyzed pulmonary function before and after transplantation in 168 LT patients and 840 non-LT patients with CF who were matched by age, sex, pancreatic status, infections with US CF Foundation Patient Registry data (1989-2007). The primary outcome was the change in the forced expiratory volume in 1 second (FEV(1); percent predicted) in LT and non-LT in the 3-years periods before or after transplantation; second we compared FEV(1) changes. In the 3 years before transplantation, LT had lower initial FEV(1) values (71.5% ± 1.9%, P < 0.001) and a slower decline (+0.1% ± 0.4%/year, P < 0.001) than non-LT (79.6% ± 1.3% and -1.3% ± 0.2%/year, respectively). There was no difference in the FEV(1) decline after transplantation (-1.4% ± 0.4%/year for LT versus -2.1% ± 0.2%/year for non-LT, P = 0.14). Both the (P = 0.003) and (P = 0.001) had a slower FEV(1) decline in the period before transplantation versus after transplantation. In conclusion, pulmonary function is lower and declines more slowly in patients with CF before LT versus, but parallels the decline in non-LT after transplantation. LT is neither beneficial nor detrimental to pulmonary function in CF but returns FEV(1) decline to the same trajectory found for matched non-LT individuals with CF.
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Affiliation(s)
- Melissa R Miller
- Colorado School of Public Health at University of Colorado Denver, Aurora, CO, USA
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16
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Chryssostalis A, Hubert D, Coste J, Kanaan R, Burgel PR, Desmazes-Dufeu N, Soubrane O, Dusser D, Sogni P. Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. J Hepatol 2011; 55:1377-82. [PMID: 21703187 DOI: 10.1016/j.jhep.2011.03.028] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Revised: 03/23/2011] [Accepted: 03/24/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Increased life expectancy in patients with cystic fibrosis (CF) allows better knowledge of non-pulmonary complications like liver disease (CFLD). However, few data have been published in large adult cohorts. The aim of this study was to estimate the prevalence and the prognosis of CFLD in adult CF patients. METHODS A retrospective analysis of a monocentric cohort of adult CF patients prospectively followed, at least every year, was performed. CFLD was diagnosed using published composite criteria. If cirrhosis was suspected, upper digestive endoscopy was realized to assess the presence of portal hypertension. RESULTS A cohort of 285 adult CF patients was followed during 4.8 ± 3.6 years. Among them, 90 had CFLD at the beginning of follow-up and 23 a suspicion of cirrhosis. Factors independently associated with liver disease at baseline were history of meconium ileus, pancreatic insufficiency, chronic colonization with Burkholderia cepacia and the number of IV antibiotic courses per year. Nine patients developed liver decompensation during follow-up, all with a suspicion of cirrhosis at baseline. Six patients underwent liver transplantation alone and three patients combined liver and lung transplantation. Factors independently associated with death or lung transplantation at baseline were liver disease, BMI, forced expiratory volume in 1 second and number of IV antibiotic courses per year. CONCLUSIONS CFLD was present at baseline in one third of adult patients with CF with a marked risk of liver decompensation during follow-up. Moreover, CFLD at baseline appears as an independent factor associated with death or lung transplantation.
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Wree A, Bechmann LP, Kumarasamy N, Sommerwerck U, Jochum C, Jakob H, Baba HA, Gerken G, Kamler M, Canbay A. Elevated gamma-glutamyltransferase is associated with mortality in lung transplantation for cystic fibrosis. Transpl Int 2011; 25:78-86. [DOI: 10.1111/j.1432-2277.2011.01376.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Arnon R, Annunziato RA, Miloh T, Padilla M, Sogawa H, Batemarco L, Willis A, Suchy F, Kerkar N. Liver and combined lung and liver transplantation for cystic fibrosis: analysis of the UNOS database. Pediatr Transplant 2011; 15:254-64. [PMID: 21219560 DOI: 10.1111/j.1399-3046.2010.01460.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
A proportion of patients with CF develop cirrhosis and portal hypertension. LT and combined LLT are rarely performed in patients with CF. To determine the outcome of LT and LLT in patients with CF. Patients with CF who had LT or LLT between 10/1987 and 5/2008 were identified from UNOS database. A total of 182 children (<18 yr) and 48 adults underwent isolated LT for CF. Seven more children and eight adults with CF underwent combined LLT. One- and five-yr patient and graft survival were not significantly different in patients who underwent LT in comparison with patients who underwent LLT (patient survival: LT; 83.9%, 75.7%, LLT; 80%, 80%; graft survival: LT; 76.1%, 67.0%, LLT; 80.0%, 80.0%, respectively). The two major causes of death after LT were pulmonary disease (15 patients, 22.7%) and hemorrhage (12 patients, 18.2%). Bilirubin was identified as a risk factor for death, and previous liver transplant and prolonged cold ischemic time were identified as risk factors for graft loss in LT patients. LT is a viable option for children and young adults with CF and end-stage liver disease. Outcome of LLT patients with CF was comparable to the outcome of patients with CF who underwent isolated LT.
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Affiliation(s)
- Ronen Arnon
- Mount Sinai School of Medicine, Department of Pediatrics, New York, NY, USA.
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Darwish AA, McKiernan P, Chardot C. Paediatric liver transplantation for metabolic disorders. Part 2: Metabolic disorders with liver lesions. Clin Res Hepatol Gastroenterol 2011; 35:271-80. [PMID: 21376696 DOI: 10.1016/j.clinre.2011.01.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Liver based metabolic disorders account for 10 to 15% of the indications for paediatric liver transplantation. In the last three decades, important progress has been made in the understanding of these diseases, and new therapies have emerged. Concomitantly, medical and surgical innovations have lead to improved results of paediatric liver transplantation, patient survival nowadays exceeding 80% 10 year after surgery with close to normal quality of life in most survivors. This review is a practical update on medical therapy, indications and results of liver transplantation, and potential future therapies, for the main liver based metabolic disorders in which paediatric liver transplantation may be considered. Part 1 focuses on metabolic based liver disorders without liver lesions, and part 2 on metabolic liver diseases with liver lesions.
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Affiliation(s)
- Ahmed A Darwish
- University of Geneva Children's hospital, Paediatric Surgery Unit, Geneva, Switzerland
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20
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Abstract
OBJECTIVES Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD. METHODS This is a 7-year follow-up of 42 children with CFLD and their age- and sex-matched controls. Participants were reviewed clinically, biochemically, and radiologically at follow-up. RESULTS Overall, 85% (72 of 84) of the original cohort were included, 36 CFLD participants and 36 CF controls. There was no significant difference in the number of deaths/transplants between groups (7 of 36 (19.4%) CFLD participants, 3 of 36 (8.3%) CF controls). There was a tendency for participants with CFLD to die younger than their respective CF controls. There was no difference in height, weight, body mass index, or pulmonary function between the groups. Nutritional parameters (sum skinfold thickness 31.6 vs. 42.3, P=0.03; mean upper arm fat area 15.08 vs. 10.59, P=0.001; Shwachman score 43.7 vs. 32.1, P=0.001) were worse among CFLD participants than among CF controls. Cystic fibrosis-related diabetes was more common in CFLD participants (11 of 27 (40.7%) vs. 5 of 33 (15.2%), P=0.02). Eight children (22.2%) with evidence of CFLD at baseline had no clinical evidence of liver disease as adults. CONCLUSIONS Patients with CFLD have a more severe CF phenotype than do CF patients without liver disease. However, a subgroup of children with CFLD will not manifest clinically significant liver disease as adults.
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Nightingale S, O'Loughlin EV, Dorney SFA, Shun A, Verran DJ, Strasser SI, McCaughan GW, Jermyn V, Van Asperen P, Gaskin KJ, Stormon MO. Isolated liver transplantation in children with cystic fibrosis--an Australian experience. Pediatr Transplant 2010; 14:779-85. [PMID: 20557476 DOI: 10.1111/j.1399-3046.2010.01341.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
CF liver disease is an uncommon indication for pediatric LT. Determining optimal timing and type (isolated liver versus multi-organ) of transplantation for those with severe liver disease can be challenging and involves consideration of the extent of liver disease (PHT, synthetic dysfunction) and extrahepatic factors such as pulmonary function. We present the experience of isolated LT for CF at our center. Eight children received one allograft each (3.9% of all grafts). One- and four-yr survivals are both 75%. The two deaths occurred within the first two months after LT, and in both cases, invasive fungal infections were implicated, one following treatment for acute severe rejection. All had significant PHT, and six had synthetic dysfunction. All had roux-en Y biliary anastomoses and none developed long-term biliary complications. Seven had pulmonary colonization with Pseudomonas aeruginosa and six with fungus at time of transplantation. Mean pre-LT FEV1 was 80% (range 59-116%) predicted, and lung function post-LT was stable. Isolated LT in children with CF is successful in those with relatively preserved pulmonary function, which does not appear to deteriorate as a consequence. Roux-en Y biliary anastomosis and antifungal prophylaxis should be a part of management of these patients.
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22
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Transient elastography in patients with cystic fibrosis. Pediatr Radiol 2010; 40:1231-5. [PMID: 20135110 DOI: 10.1007/s00247-009-1531-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Revised: 11/04/2009] [Accepted: 11/28/2009] [Indexed: 01/14/2023]
Abstract
BACKGROUND Hepatic involvement is frequent in patients with cystic fibrosis (CF), with focal biliary cirrhosis being the pathognomonic hepatic manifestation. In around one-quarter of CF patients, it results in CF-associated liver disease (CFLD). This occurs as a relatively early complication with the majority of patients presenting in childhood or their early teens. However, a normal US does not preclude significant liver fibrosis and liver biopsy is an invasive procedure that is hampered by potential sampling errors. Transient elastography (TE) (Fibroscan) is a non-invasive, user-friendly and quick technique that provides an objective and reproducible measure of liver stiffness. This is accomplished with a device using an US probe mounted in the axis of a vibrator. Vibrations are transmitted by the transducer, inducing an electronic shear wave that propagates through the underlying tissue. OBJECTIVES We aimed to prospectively compare TE and transabdominal US scanning in children and adults attending a CF clinic. MATERIALS AND METHODS A total of 134 consecutive patients with documented CF were prospectively studied. In each case, transient elastography measurement was performed immediately after the routine annual US evaluation of the liver. Sonographic appearance of the liver was classified from 1 to 5. Ten validated TE measurements were performed in each patient with the result expressed in kilopascals (kPa). The median value was considered representative of the elastic modulus of the liver. RESULTS Measurements were performed in 59 CF adults, 75 CF children and 31 control children. There was no relationship between age and liver stiffness in either the control group or CF patients. Elasticity values of controls, CF pancreatic sufficient (PS) patients and pancreatic insufficient (PI) CF patients with a US score <3 were comparable and significantly lower than in CF patients with a US score > or = 3 (all PI) (P < 0.002). Median elasticity in CF patients was significantly higher in males (4.7 kPa) than in females (3.9 kPa) (P = 0.0013). CONCLUSION Considering the limitations of US and the low risk-benefit rate of liver biopsy in most CF patients, this preliminary study suggests that TE is an attractive non-invasive way to assess and follow-up liver disease in these patients.
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O'Donnell DH, Ryan R, Hayes B, Fennelly D, Gibney RG. Hepatocellular carcinoma complicating cystic fibrosis related liver disease. J Cyst Fibros 2009; 8:288-90. [PMID: 19473889 DOI: 10.1016/j.jcf.2009.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Revised: 04/14/2009] [Accepted: 05/03/2009] [Indexed: 12/22/2022]
Abstract
Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.
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Affiliation(s)
- D H O'Donnell
- Department of Radiology, St Vincent's University Hospital, Dublin 4, Ireland.
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24
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Abstract
PURPOSE OF REVIEW This review explores the recent advances in knowledge regarding hepatobiliary disease in patients with cystic fibrosis. RECENT FINDINGS Hepatobiliary abnormalities associated with cystic fibrosis are varied in nature and range from defects attributable to the underlying genetic defect to those related to systemic disease and malnutrition. Novel research into the underlying pathogenesis of cystic fibrosis liver disease and the primary role of cystic fibrosis transmembrane conductance regulator in biliary secretory epithelium is presented. This work has been fostered by the development of new animal models of cystic fibrosis transmembrane conductance regulator dysfunction. Of the wide range of hepatobiliary complications associated with cystic fibrosis the most clinically relevant problem is progression of focal biliary cirrhosis to multilobular cirrhosis with its attendant complications of portal hypertension and potentially end-stage liver disease. However, recent studies suggest that liver transplantation may not improve survival in patients with cystic fibrosis and significant portal hypertension. SUMMARY Hepatobiliary disease is a common finding in patients with cystic fibrosis; the pathogenesis is multifactorial in nature. As new therapeutic strategies emerge, life expectancy will continue to increase as will the impact of liver disease on quality of life and survival of patients with cystic fibrosis. This review will discuss novel insights into pathogenesis as well as diagnostic and management options.
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25
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Abstract
The aim of this article is to provide essential information for hepatologists, who primarily care for adults, regarding liver-based inborn errors of metabolism with particular reference to those that may be treatable with liver transplantation and to provide adequate references for more in-depth study should one of these disease states be encountered.
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Affiliation(s)
- Keli Hansen
- Division of Transplant Surgery and Division of Gastroenterology, Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA
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26
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Abstract
The aim of this article is to provide essential information for hepatologists, who primarily care for adults, regarding liver-based inborn errors of metabolism with particular reference to those that may be treatable with liver transplantation and to provide adequate references for more in-depth study should one of these disease states be encountered.
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Affiliation(s)
- Keli Hansen
- Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA.
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27
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Abstract
PURPOSE OF REVIEW This review highlights recent developments in liver disease associated with cystic fibrosis. RECENT FINDINGS The broad spectrum of hepatobiliary problems in cystic fibrosis includes specific alterations ascribable to the underlying defect as well as lesions of iatrogenic origin or that reflect the effects of a disease process occurring outside the liver. Focal biliary cirrhosis, resulting from biliary obstruction and progressive periportal fibrosis, is the most clinically relevant problem, because extension of the initially focal fibrogenic process may lead to multilobular biliary cirrhosis, portal hypertension and eventually liver failure. Cystic fibrosis associated liver disease is presently classified among genetic cholangiopathies and results from lack or dysfunction of the cystic fibrosis transmembrane regulator at the apical membrane of bile duct cells. Major advances have been achieved regarding characterization of natural history, risk factors, diagnostic modalities and treatment options. SUMMARY Liver disease is a relatively frequent and early complication of cystic fibrosis. The pathogenesis is apparently multifactorial, with contributions from environmental and genetic determinants. Its impact on quality of life and survival will increase in future years, and its early detection and treatment will become increasingly important issues. Ursodeoxycholic acid is the only treatment currently available, but novel therapeutic options are being evaluated.
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Affiliation(s)
- Carla Colombo
- Department of Pediatrics, CF Center, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.
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28
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Nash KL, Collier JD, French J, McKeon D, Gimson AES, Jamieson NV, Wallwork J, Bilton D, Alexander GJM. Cystic fibrosis liver disease: to transplant or not to transplant? Am J Transplant 2008; 8:162-9. [PMID: 17973959 DOI: 10.1111/j.1600-6143.2007.02028.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Biliary cirrhosis complicates some adults with cystic fibrosis (CF) and may require transplantation. Cardio-respiratory disease severity varies such that patients may require liver transplantation, heart/lung/liver (triple) grafts or may be too ill for any procedure. A 15-year experience of adults with CF-related liver disease referred for liver transplantation is presented with patient survival as outcome. Twelve patients were listed for triple grafting. Four died of respiratory disease after prolonged waits (4-171 weeks). Eight underwent transplantation (median wait 62 weeks); 5-year actuarial survival was 37.5%. Four died perioperatively; only one is alive at 8-years. Eighteen patients underwent liver transplant alone (median wait 7 weeks); 1- and 5-year actuarial survival rates were 100% and 69%. Three long-term survivors required further organ replacement (two heart/lung and one renal). Two others were turned down for heart/lung transplantation and four have significant renal impairment. Results for triple grafting were poor with unacceptable waiting times. Results for liver transplant alone were satisfactory, with acceptable waiting times and survival. However, further grafts were required and renal impairment was frequent. The policy of early liver transplantation for adults with CF with a view to subsequent heart/lung or renal transplantation needs assessment in the context of long-term outcome.
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Affiliation(s)
- K L Nash
- Liver Transplant Unit, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
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Louis D, Duc MLP, Reix P, Chazalette JP, Durieu I, Feigelson J, Bellon G. Partial splenectomy for portal hypertension in cystic fibrosis related liver disease. Pediatr Pulmonol 2007; 42:1173-80. [PMID: 17968998 DOI: 10.1002/ppul.20713] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIMS To review the middle- and long-term effects of partial splenectomy (PS) on portal hypertension (PHT) and its complications in patients with cystic fibrosis (CF) related liver disease risky PHT. METHOD Over a 20 years period, 19 patients aged 7-23 years underwent partial PS for massive splenomegaly, hypersplenism, and/ or severe PHT. RESULTS In all but three cases, PHT and hypersplenism have improved for long periods. Noticeable improvement of hepatic tests occurred simultaneously. In all patients PS resolved abdominal discomfort. Fifteen patients are alive and a stabilization of the liver disease occurred with a follow-up of 1-20 years (mean 7.9). One patient died following respiratory insufficiency 10 years after PS although PHT was stable. Manifestations recurred in 2 patients 5 and 6 years after PS. In two patients, the course of the disease evolved to hepatic insufficiency without recurrence of PHT 3 and 8 years after PS. PS did not give the expected results in three cases only, in which PHT was not modified or reoccurred during the following year. No severe complication was observed. Early (three patients) or late (one patient) eventration required surgical procedure. CONCLUSIONS Our results show that PS is a reliable and well-tolerated technique. Therefore, it is a therapeutic option for the management of PHT in CF patients with a preserved liver function. It can prevent and significantly delay a liver transplantation and its constraints.
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Affiliation(s)
- Dominique Louis
- Pediatric Cystic Fibrosis Centre, Hospices Civilis de Lyon, Université Claude Bernard Lyon 1, Hôpital Debrousse, Lyon, France
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Desmond CP, Wilson J, Bailey M, Clark D, Roberts SK. The benign course of liver disease in adults with cystic fibrosis and the effect of ursodeoxycholic acid. Liver Int 2007; 27:1402-8. [PMID: 18036103 DOI: 10.1111/j.1478-3231.2007.01570.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The life expectancy of patients with cystic fibrosis (CF) has been increasing and the associated liver disease has emerged as a significant medical issue. Our aim was to describe the clinical features, course and effect of ursodeoxycholic acid (UDCA) on liver disease in an adult CF population. STUDY From 1983 to 2005, 278 patients with CF were followed up at the Alfred Hospital, an adult tertiary referral centre. Twenty-seven patients (9.7%) satisfied the criteria for liver disease and their clinico-pathological features were assessed. The effect of UDCA on hepatobiliary symptoms and biochemical parameters was determined. RESULTS The mean age at liver disease diagnosis was 23 years (range 8-47 years). Portal hypertension was present in 18 (67%) patients. During a median follow-up of 7 years (range 1.5-15), variceal haemorrhage occurred in two patients and ascites in three (one spontaneously). Nine (33%) patients died and five (19%) underwent lung transplantation. There was no encephalopathy, liver transplantation or liver-related deaths. UDCA was taken by 22 patients and was associated with a significant improvement in hepatobiliary symptoms [11/22 (50%) in the pre-UDCA period vs 1/22 (4%) in the post-UDCA period; P=0.0003] and a significant reduction in aspartate aminotransferase (P=0.005); alanine aminotransferase (P<0.001); gamma-glutamyltranspeptidase (P=0.021); and alkaline phosphatase (P<0.001). CONCLUSIONS Liver disease in adults with CF is commonly complicated by portal hypertension, but morbidity and mortality associated with this in our small patient population were low. UDCA is associated with improvement in hepatobiliary symptoms and liver function tests.
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31
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A single centre experience of liver disease in adults with cystic fibrosis 1995-2006. J Cyst Fibros 2007; 7:252-7. [PMID: 18042441 DOI: 10.1016/j.jcf.2007.10.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 09/24/2007] [Accepted: 10/18/2007] [Indexed: 12/14/2022]
Abstract
BACKGROUND Liver disease is an important cause of death in adults with cystic fibrosis (CF). Ursodeoxycholic acid (UDCA) may slow progression. Managing varices and timely evaluation for liver transplantation are important. METHODS Adults with CF underwent annual review. Abnormalities of liver function tests or ultrasound prompted referral to the CF/liver clinic where UDCA was commenced. Endoscopic surveillance for varices was undertaken if ultrasound suggested portal hypertension. RESULTS 154 patients were followed for a median 5 years. 43 had significant liver disease, 29 had cirrhosis with portal hypertension and 14 had ultrasound evidence of cirrhosis without portal hypertension. All started UDCA. Only one patient developed chronic liver failure and none required liver transplantation. 27 underwent endoscopy; 1 required variceal banding, the others had insignificant varices. Ultrasound was normal in 97 patients while five had steatosis; nine further patients had splenomegaly but no other evidence of portal hypertension. Neither spleen size nor platelet count correlated with portal hypertension. CONCLUSIONS Liver disease was common in adults with CF but disease progression was rare. Thus liver disease detected and closely monitored in adults appeared to have a milder course than childhood CF. Splenomegaly, unrelated to portal hypertension may be a consequence of CF.
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32
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Abstract
Liver transplantation has become an accepted treatment for several metabolic liver diseases. With advances in organ transplantation and immunosuppressive strategies, survival rates following liver transplantation are generally excellent. When the primary metabolic defect is hepatic in origin, liver transplantation not only replaces the dysfunctional organ but also cures the underlying metabolic defect. For conditions in which the primary metabolic defect is extrahepatic, liver transplantation is usually performed for hepatic complications, although disease recurrence may occur. This article reviews common metabolic liver diseases treated with liver transplantation in the adult population.
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Affiliation(s)
- Kristine Y Zhang
- Division of Gastroenterology and Hepatology, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195, USA
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33
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Akata D, Akhan O. Liver manifestations of cystic fibrosis. Eur J Radiol 2006; 61:11-7. [PMID: 17174503 DOI: 10.1016/j.ejrad.2006.11.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2006] [Accepted: 11/02/2006] [Indexed: 12/11/2022]
Abstract
Chronic liver disease is one of the major complications of cystic fibrosis (CF). Significant liver disease is seen in 13-25% of children with CF. Improved life expectancy and prolonged follow-up have favored better characterization of the hepatic manifestations of CF and allowed direct observation of an increasing number of liver-related events. Liver disease typically develops in the first decade of life, with the incidence dropping rapidly after the age of 10 years. The wide spectrum of liver disease ranging from asymptomatic gallbladder abnormalities to biliary cirrhosis will be reviewed in this article.
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Affiliation(s)
- Deniz Akata
- Department of Radiology, Hacettepe University Medical School, 06100 Ankara, Turkey.
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Lamireau T, Martin S, Lallier M, Marcotte JE, Alvarez F. Liver transplantation for cirrhosis in cystic fibrosis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2006; 20:475-8. [PMID: 16858500 PMCID: PMC2659915 DOI: 10.1155/2006/539345] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Liver disease is the third most common cause of death in children with cystic fibrosis (CF). Liver transplantation is an effective treatment in children with hepatic failure. AIMS The objective of the present study was to review the indications and postoperative course of hepatic transplantation in a cystic fibrosis population. PATIENTS Five children with CF, at a mean age of 16.5 years, underwent liver transplantation. RESULTS All patients showed cirrhosis, portal hypertension and hepatic failure. The main postoperative complication was ascites refractory to treatment in two patients. No significant deterioration of the pulmonary function was noted. Two patients died, one of Hodgkin lymphoma and the other of progressive pulmonary failure. CONCLUSION Liver transplantation was indicated in children with CF when hepatic failure and/or severe portal hypertension was present with well-preserved pulmonary function.
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Affiliation(s)
- T Lamireau
- Division of Pediatric Gastroenterology, Hôpital Sainte-Justine, Montreal, Quebec
| | - S Martin
- Division of Pediatric Gastroenterology, Hôpital Sainte-Justine, Montreal, Quebec
| | - M Lallier
- Division of Pulmonology, Hôpital Sainte-Justine, Montreal, Quebec
| | - JE Marcotte
- Division of Surgery, Hôpital Sainte-Justine, Montreal, Quebec
| | - F Alvarez
- Division of Pediatric Gastroenterology, Hôpital Sainte-Justine, Montreal, Quebec
- Correspondence: Dr Fernando Alvarez, Division of Pediatric Gastroenterology, Hôpital Sainte-Justine, 3175 chemin de la Côte Sainte-Catherine, Montreal, Quebec H3T 1C5. Telephone 514-345-4931, fax 514-345-4999, e-mail
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35
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Melzi ML, Kelly DA, Colombo C, Jara P, Manzanares J, Colledan M, Strazzabosco M, DeLorenzo P, Valsecchi MG, Adam R, Gridelli B, Assael BM. Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry. Transpl Int 2006; 19:726-31. [PMID: 16918533 DOI: 10.1111/j.1432-2277.2006.00344.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Liver Transplant (LTx) has been rarely performed in cystic fibrosis (CF) patients and indications and outcomes are not well defined. A questionnaire was sent to all European CF and LTx centers to collect data on CF transplanted patients. We obtained information regarding 57 CF patients. LTx has been performed prevalently in males and in pediatric age. The main complication of cirrhosis was portal hypertension with hypersplenism. In the majority of cases the decision to transplant was based on the contemporary presence of various factors. Post-LTx survival was high and comparable with that expected for more common pediatric LTx indications. Poor respiratory function was the main risk factor for early death. In the short-term, respiratory function significantly improved after LTx. LTx is the appropriate treatment for patients with advanced CF-related liver disease and preserved pulmonary function (Forced Expiratory Volume at 1 s, FEV(1) >50%). This poll reveals that most European liver centers perform LTx prior to the development of end-stage liver disease or overt pulmonary or other clinical decompensation.
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Affiliation(s)
- Maria L Melzi
- Liver Transplant Unit, Ospedali Riuniti, Bergamo, Italy.
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Robberecht E, Van Biervliet S, Vanrentergem K, Kerremans I. Outcome of total splenectomy with portosystemic shunt for massive splenomegaly and variceal bleeding in cystic fibrosis. J Pediatr Surg 2006; 41:1561-5. [PMID: 16952592 DOI: 10.1016/j.jpedsurg.2006.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Multilobular biliary cirrhosis and portal hypertension are frequent complications of cystic fibrosis liver disease, leading to esophageal varices and splenomegaly. Therapy is focused on variceal bleeding control; however, reduction of spleen volume is also important to restore gastric volume and resolve invalidating abdominal discomfort. We report long-term follow up (median duration, 5.5 years; range, 14 months-21.5 years) of 6 patients with cystic fibrosis (4 men, 2 women; median age, 14 years; range, 8-18 years) who underwent splenectomy with a splenorenal shunt operation. Three patients received elective surgery for massive splenomegaly with important abdominal discomfort, recurrent variceal bleeding, and hypersplenism. Three were urgently treated to control variceal bleeding after several sessions of sclerotherapy. All but 2 received antipneumococcal vaccination before surgery. Four patients had a weight gain of 10% within 3 months of surgery, and 3 developed spontaneous puberty. Lung function remained stable, and there was an overall reduction of respiratory tract infections. The youngest patient, however, died of overwhelming septicemia during treatment with steroids. Although total splenectomy has important risks, in well-selected cases, it can have benefits. Immuno- and chemoprophylaxis, combined with patient awareness of supplementary risk of infections is indispensable to minimize septic complications.
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Affiliation(s)
- Eddy Robberecht
- Department of Pediatric Gastroenterology, University Hospital of Ghent, 9000 Ghent, Belgium
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Abstract
Liver involvement in Cystic Fibrosis (CF) is much less frequent than both pulmonary and pancreatic diseases that are present in 80-90% of CF patients; liver disease (LD) affects only one third of CF patients, however, because of the decreasing mortality from extrahepatic causes, its recognition and management is becoming a relevant clinical issue. Recent observations suggest that clinical expression of LD in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of patients at risk for the development of LD at the time of diagnosis of CF and early institution of prophylactic strategies. Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated LD. However, the impact of this therapy on the natural history of LD remains to be defined and long-term effectiveness on clinically relevant outcomes should be further investigated. Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival. The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.
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Affiliation(s)
- Carla Colombo
- Department of Pediatrics, CF Center, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.
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Abstract
Vanishing bile duct syndromes (VBDS) are characterized by progressive loss of small intrahepatic ducts caused by a variety of different diseases leading to chronic cholestasis, cirrhosis, and premature death from liver failure. The majority of adult patients with VBDS suffer from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and anticholestatic effects have been reported for several other cholestatic syndromes. Several potential mechanisms of action of UDCA have been proposed including stimulation of hepatobiliary secretion, inhibition of apoptosis and protection of cholangiocytes against toxic effects of hydrophobic bile acids.
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Affiliation(s)
- Thomas Pusl
- Department of Medicine II, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany
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Sogni P, Hubert D, Chryssostalis A. [Liver complications in cystic fibrosis. Specific questions in adults?]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2005; 29:1207-10. [PMID: 16518272 DOI: 10.1016/s0399-8320(05)82201-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
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40
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Fridell JA, Vianna R, Kwo PY, Howenstine M, Sannuti A, Molleston JP, Pescovitz MD, Tector AJ. Simultaneous Liver and Pancreas Transplantation in Patients With Cystic Fibrosis. Transplant Proc 2005; 37:3567-9. [PMID: 16298663 DOI: 10.1016/j.transproceed.2005.09.091] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND Improved survival in patients with cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, cirrhosis and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality. Liver transplantation is the treatment of choice for cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CFRD has not been reported. METHODS Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both had pancreatic insufficiency, CFRD, cirrhosis, and preserved renal function. In each case, the liver and pancreas were procured from a single cadaveric donor. The liver transplant was performed first. A lower midline extension was added for improved exposure of the iliac vessels. The donor pancreas transplant was performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and early steroid withdrawal. RESULTS Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, they are now independent of supplemental pancreatic enzymes. CONCLUSIONS Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CFRD who require liver transplants.
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Affiliation(s)
- J A Fridell
- Department of Surgery, Indiana University, 550 N. University Boulevard #4258, Indianapolis, IN 46202, USA.
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41
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Lamireau T, Monnereau S, Martin S, Marcotte JE, Winnock M, Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol 2004; 41:920-5. [PMID: 15582124 DOI: 10.1016/j.jhep.2004.08.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2004] [Revised: 07/12/2004] [Accepted: 08/01/2004] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS To describe the prevalence of liver disease in a cohort of 241 cystic fibrosis (CF) patients. METHODS 241 CF patients were followed-up every 3 months with clinical and biological assessment, and every year with ultrasonography of the liver. The presence of liver disease was studied using a multivariate Cox's regression analysis including variables such as history of meconium ileus, pulmonary function, pancreatic insufficiency and CFTR gene mutations. RESULTS The prevalence of liver disease was 18, 29, and 41% after 2, 5 and 12 years, respectively, and did not increase thereafter. In multivariate analysis, the probability of liver disease was independently associated with history of meconium ileus (P = 0.001) and pancreatic insufficiency (P = 0.004). CFTR mutations and severity of pulmonary disease were not associated with liver disease. Cirrhosis occurred in 19 (7.8%) patients at a median age of 10 years, and liver transplantation was required in five patients. CONCLUSIONS This study shows that CF related-liver disease occurs mainly in the first decade of life with a prevalence of 41% of patients at 12 years of age. A history of meconium ileus and pancreatic insufficiency are predictive of liver disease. Preventive treatment with ursodesoxycholic acid could be considered in patients with meconium ileus.
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Affiliation(s)
- Thierry Lamireau
- Division of Pediatric Gastroenterology, Hospital Sainte-Justine, 3175 chemin de la Côte Sainte-Catherine, Montreal, Canada H3T 1C5
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42
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Corbett K, Kelleher S, Rowland M, Daly L, Drumm B, Canny G, Greally P, Hayes R, Bourke B. Cystic fibrosis-associated liver disease: a population-based study. J Pediatr 2004; 145:327-32. [PMID: 15343185 DOI: 10.1016/j.jpeds.2004.05.051] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The aim of this study was to explore the clinical factors associated with the development of cystic fibrosis-associated liver disease (CFALD). STUDY DESIGN This was a case-control study of all children (age 5-18 years) with established CFALD in the Republic of Ireland between January 1999 and June 2000. Each child was pair matched for age and sex with a patient with cystic fibrosis (CF) without evidence of liver disease. Only children with clinically overt liver disease were enrolled in the disease group. RESULTS Patients with established CFALD (n = 42; 26 boys) were enrolled. Children with CFALD had worse forced expiratory volume in 1 second values than those without CFALD. However, chest radiography and clinical scores did not differ between groups. Height (mean difference, -4.2 cm [95% confidence interval [CI], -7.41 to -0.90], P =.014), weight (mean difference, -3.21 kg [95% CI, -6.03 to -0.40], P =.026), and mid-upper arm circumference (mean difference, -1.23 cm [95% CI, -2.35 to -0.12], P =.031) were significantly lower among children with CFALD. Children with CFALD were given diagnoses of CF later than children without liver disease. There were more children with meconium ileus in the control group (14 vs 4) than among those with CFALD. CONCLUSIONS Children with established CFALD have impaired growth and nutrition, altered body composition, and worse forced expiratory volume in 1 second values. CFALD is associated with later age of diagnosis of CF.
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Affiliation(s)
- Katie Corbett
- Department of Paediatrics and Children's Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Crumlin, Dublin 12, Ireland
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Efrati O, Barak A, Modan-Moses D, Augarten A, Vilozni D, Katznelson D, Szeinberg A, Yahav J, Bujanover Y. Liver cirrhosis and portal hypertension in cystic fibrosis. Eur J Gastroenterol Hepatol 2003; 15:1073-8. [PMID: 14501614 DOI: 10.1097/00042737-200310000-00002] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Liver disease is the second cause of death in cystic fibrosis. The most deleterious complication of liver disease is portal hypertension, which has an estimated prevalence of up to 8%. Portal hypertension may manifest itself by splenomegaly, hypersplenism, gastro-oesophageal bleeding and ascites. The aim of our study was to determine the prevalence, risk factors and invasive management of portal hypertension at our centre. METHODS One hundred and fifty patients with cystic fibrosis were followed up between 1975 and 2000 in the national cystic fibrosis centre in Israel. Forty patients (27%) had liver disease. All underwent clinical evaluation and laboratory and imaging studies. RESULTS Portal hypertension was diagnosed in 10 patients (7%), of whom eight were male. The mean age at diagnosis was 11 years (range, 4-17 years). All had severe mutations of the cystic fibrosis transmembrane conductance regulator gene (the CFTR gene), pancreatic insufficiency, meconium ileus or distal intestinal obstruction syndrome and variceal bleeding. Seven patients underwent sclerotherapy to control acute bleeding. Four underwent portosystemic shunting (functioning up to 37 years). Two patients with severe lung and liver disease underwent transjugular intrahepatic portosystemic shunting, which provided bleeding control, but both died while waiting for lung/liver transplantation. One patient underwent liver transplantation due to liver failure and still had good liver and lung function 10 years later. CONCLUSIONS Portal hypertension is more common among Israeli patients with cystic fibrosis. The unique genetic composition of our population may explain this phenomenon. Risk factors include male gender, pancreatic insufficiency, severe CFTR mutations, meconium ileus and meconium ileus equivalent. Sclerotherapy is the main option to control oesophageal variceal bleeding, while portosystemic shunts offer a prolonged alternative treatment for refractory bleeding. A transjugular intrahepatic portosystemic shunt and liver transplantation may also be effective, but further research is required in order to establish their role.
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Affiliation(s)
- Ori Efrati
- Paediatric Department, The Chaim Sheba Medical Centre, Tel Hashomer, Israel.
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44
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Slieker MG, Deckers-Kocken JM, Uiterwaal CSPM, van der Ent CK, Houwen RHJ. Risk factors for the development of cystic fibrosis related liver disease. Hepatology 2003; 38:775-6; author reply 776-7. [PMID: 12939606 DOI: 10.1053/jhep.2003.50403] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Fridell JA, Bond GJ, Mazariegos GV, Orenstein DM, Jain A, Sindhi R, Finder JD, Molmenti E, Reyes J. Liver transplantation in children with cystic fibrosis: a long-term longitudinal review of a single center's experience. J Pediatr Surg 2003; 38:1152-6. [PMID: 12891484 DOI: 10.1016/s0022-3468(03)00260-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Improved long-term survival in cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, end-stage liver disease is a significant cause of morbidity and mortality with liver transplantation being the only effective therapy. METHODS Records of all CF pediatric liver transplant recipients were reviewed. RESULTS Twelve children with CF were the recipients of 16 allografts. The 1- and 5-year survival was 91.6% and 75%, respectively. There were 5 deaths at a mean interval of 6.8 +/- 6.3 years. All of these deaths were related to pulmonary disease. Pulmonary function improved or remained stable in 8 of 9 patients tested. Despite an 83% incidence of positive sputum cultures, there was only one early mortality related to pulmonary sepsis in the setting of primary liver allograft nonfunction. CONCLUSIONS Liver transplantation is acceptable treatment for children with CF and end-stage liver disease. Long-term survival is comparable to liver transplantation performed for other indications. Although posttransplant morbidity and mortality is related to lung disease, the authors speculate that as therapeutic improvements prolong the survival in CF, it is expected that longer survival after liver transplantation in this patient population may also be anticipated.
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Affiliation(s)
- Jonathan A Fridell
- Department of Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA
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Debray D. Question 5 Quelle prise en charge de l'átteinte hepatobiliaire au cours de la mucoviscidose? Stratégie thérapeutique spécifique de 1' atteinte hépatobiliaire au cours de la mucoviscidose. Arch Pediatr 2003; 10 Suppl 3:490s-494s. [PMID: 14671965 DOI: 10.1016/s0929-693x(03)90016-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- D Debray
- Service d'hépatologie pédiatrique, hôpital de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France
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Molmenti EP, Squires RH, Nagata D, Roden JS, Molmenti H, Fasola CG, Prestidge C, D'Amico L, Casey D, Sanchez EQ, Goldstein RM, Levy MF, Benser M, McPhail W, Andrews W, Andersen JA, Klintmalm GB. Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Pediatr Transplant 2003; 7:93-7. [PMID: 12654048 DOI: 10.1034/j.1399-3046.2003.00021.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The most common hepatic complications of cystic fibrosis (CF) are steatosis, fibrosis, biliary cirrhosis, atretic gallbladder, cholelithiasis, and sclerosing cholangitis. Cholestatic liver disease is a slow progressive disorder, but will stabilize for many patients. CF patients may suffer from the consequences of their liver disease and without liver transplantation, variceal hemorrhage, malnutrition, or end-stage liver disease can lead to death. Prospective data were collected and reviewed on 311 liver transplants performed in 283 patients at the Children's Medical Center of Dallas between October 1984 and November 2000. Ten children received an orthotopic liver transplant (OTLX) for end-stage liver disease associated with cystic fibrosis. Pulmonary function tests were obtained preoperatively in all cases. There were nine boys and one girl. Six are currently alive, and four are dead. Both patient and graft survival was 5.75 yr. Among those currently alive, mean patient and graft survival is 7.71 yr (range 0.10-12.62 yr). Mean patient and graft survival of those who died was 2.35 yr (range 0.78-5.33 yr). No survivor required re-transplantation and currently, all have normal serum aminotransferase values. Chronic sinusitis was not a significant pre- or post-transplant morbidity, although systematic radiographic evaluation of the sinuses did not occur. Pulmonary deaths occurred in three patients from pulmonary hemorrhage, pulmonary infection with Aspergillus and Candida glabrata, and acute bronchopneumonia associated with polymicrobial sepsis because of Pseudomonas, Klebsiella, and Candida albicans 1.44, 0.78, and 1.83 yr, respectively, after transplantation. The fourth death was associated with chronic rejection, and occurred 5.33 yr after transplantation. All non-survivors were below the 5th percentile for height and weight at the time of liver transplantation. Mean age at transplantation was 9.72 yr (range 1.23-19.09, median 9.61). Survivors were transplanted at a younger age than non-survivors (mean of 9.21 yr vs. 10.66 yr), and had shorter waiting times from diagnosis of end-stage liver disease to transplantation (6.87 months vs. 13.83 months). Eighty percentage (n = 8) of patients had pretransplant variceal bleeds (83% of survivors, 75% of non-survivors). While all non-survivors had a history of meconium ileus and preoperative need of pancreatic enzymes, only 67% of those alive experienced these complications. Preoperative forced vital capacity FVC was 103% for survivors and 95% for non-survivors. The corresponding numbers for forced expiratory flow (FEF) 25-75 were 74-84% respectively. Preoperative Aspergillus was identified in 30% of patients (n = 3). Two of these patients are alive. Cystic fibrosis constitutes an indication for 3.5% of pediatric liver transplants. Evaluation and transplantation for end-stage liver disease associated with cystic fibrosis should be undertaken at an early age. Most deaths were associated with pulmonary/septic events, and occurred less than 2 yr after OLTX. Those children who did not survive had poor growth and nutrition, prolonged waiting times prior to transplantation, were transplanted at an older age, and had a higher incidence of pancreatic insufficiency and meconium ileus. The presence of Aspergillus in the sputum does not constitute a contraindication for OLTX.
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Thalhammer GH, Eber E, Uranüs S, Pfeifer J, Zach MS. Partial splenectomy in cystic fibrosis patients with hypersplenism. Arch Dis Child 2003; 88:143-6. [PMID: 12538318 PMCID: PMC1719430 DOI: 10.1136/adc.88.2.143] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We report three cystic fibrosis (CF) patients with hypersplenism who underwent partial splenectomy. The postoperative course was uneventful in two patients; one patient developed a complication necessitating resection of the rest of the spleen. Haematological parameters improved and oesophageal varices regressed in all patients. On follow up, one patient showed a normal spleen, the other a normally functioning accessory spleen; the third patient again developed splenomegaly with hypersplenism. Partial splenectomy is a promising therapeutic option for CF patients with hypersplenism.
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Affiliation(s)
- G H Thalhammer
- Respiratory and Allergic Disease Division, Paediatric Department, University of Graz, Austria
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Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Hepatology 2002. [PMID: 12447862 DOI: 10.1002/hep.1840360613] [Citation(s) in RCA: 163] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.
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Affiliation(s)
- Carla Colombo
- CF Center, Department of Pediatrics, University of Milan, Italy.
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50
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Williams SM, Goodman R, Thomson A, McHugh K, Lindsell DRM. Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Clin Radiol 2002; 57:365-70. [PMID: 12014933 DOI: 10.1053/crad.2001.0861] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
AIM To review 9 years of annual assessment data in cystic fibrosis (CF) and evaluate the frequency of hepatobiliary abnormalities and the correlation between ultrasound and biochemical findings. MATERIALS AND METHODS Over a 9-year period (1990-99), 168 children (age range 1-18 years) with CF have undergone an annual assessment which has included clinical, biochemical and ultrasonographic evaluation of the hepatobiliary system. We have retrospectively reviewed the sequential ultrasound reports and correlated them with the contemporaneous biochemical results. RESULTS A total of 725 ultrasound examinations were performed over the review period. Sixty patients had at least one examination showing an abnormality of liver echo texture and in 39 patients this was a persisting finding. Seven patients (4.2%) developed frank cirrhotic change on ultrasound criteria, while 15 patients (8.9%) had evidence of persistent splenomegaly. Gall-bladder calculi were present in 4.8%. In 176 examinations (24%) there was disparity between the ultrasound findings and aspartate aminotransferase (AST) levels. In 3.0% of cases (five patients) there were persisting abnormalities of liver echo texture and persisting splenomegaly with a normal range AST value. CONCLUSION No perfect method of assessing hepatobiliary involvement in CF is currently available. Ultrasonographic and biochemical assessment may reflect different aspects of disease progression. Routine use of ultrasound in annual assessment allows identification of a minority of patients with liver changes but with normal biochemistry.
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