Growth factors in cystic fibrosis

Document Type: Systematic review

Authors

1 Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Abstract

Introduction: Cystic fibrosis is one of the most common autosomal recessive diseases that affects sweat glands and mucosa. CF is a hereditary disease with annual incidence of about 2500 new cases in United Kingdom. Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 levels decrease in CF. The aim of this study was to assess the role of growth peptides in patients with CF.
Method: We searched PubMed, Google scholar, IranMedex, and Scientific Information Database (SID) in September 2012 to April 2014. We included clinical studies with available abstracts and full texts that were in English or Persian languages. Manual searching was conducted within the reference lists of articles. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data.
Result: The earliest study was published in 1997 and the most recent one was in 2014. Study participants were adults in 3 studies (20%) and 12 studies (80%) were conducted in children. Patients with CF have lower levels of IGF-1 and there is a significant correlation between IGF-1 levels and growth index in patients with CF.
Conclusions: IGF-1 decreases in children with CF and might be the cause of poor growth and low body mass index in these children. 

Keywords


Introduction
Cystic fibrosis (CF) is one of the most common autosomal recessive diseases that affects sweat glands and mucosa. It is a life-threatening condition which presents with malfunction of exocrine glands in various organs in childhood (1). Failure to thrive, meconium ileus, abdominal distention, intestinal obstruction, increased frequency of stool, jaundice, gastrointestinal bleeding, salty-tasting skin and delayed puberty are some signs and symptoms of CF (2). However, the main manifestation of the disease is chronic respiratory infections (3). Respiratory symptoms occur in about 90% of children survived after neonatal period. Respiratory failure is the main cause of children mortality.
CF is also known as mucoviscidosis that involves lungs, pancreas, liver, and intestine. Most patients are infertile (4).
CF occurs due to mutation in a protein called cystic fibrosis transmembrane conductance regulator (CFTR) gene. This protein acts as a chloride channel and its functional regulator is cyclic adenosine monophosphate (cAMP). CFTR mutations first were described in 1932 (4). Such mutations cause defect in chloride transport system in epithelial cells especially on mucosal surfaces. Reduction in chloride secretion leads to sodium and water reabsorption that decreases mucosal thickness and promotes bacterial overgrowth and invasion risk (5). High viscosity of pulmonary secretion results in difficulty clearing of small airway. Although the relation between CF and CFTR is clear, the cause of chronic inflammation and recurrent infection in this disease remains doubtful. Some studies revealed that alveolar macrophages could phagocytose bacteria, but enable to kill them in CF (2). Such impairment might be the cause of recurrent respiratory infections (6).
Insulin-like growth factor-1 (IGF-1) is a hormone with a similar structure to insulin and is produced by the liver. It has been considered that this peptide has a fundamental role in growth (7). IGF-1 has an antiapoptotic role. IGF-1 is associated with growth, development, and various metabolic actions. The body skeleton is the main target organ for IGF-1 deposition (8). IGF-1 is secreted by tissues and liver. The cortical bone size, bone growth, and bone mass are affected by IGF-1.
 This hormone binds to one of six IGF-binding proteins. It is demonstrated that 80% of IGF-1 is attached to IGF binding protein-3 (IGFBP-3). Increasing the number and size of the alveolus is one of the probable effects of IGF-1 on lung growth. Studies showed that there was a relation between low level of IGF-1 and impaired macrophage function in CF patients. Other studies distinguished IGFBP-3 stimulation of fibroblasts to synthesize collagen and fibronectin (8-10). The aim of this study is to systematically review the articles about the relation between growth peptides and CF.
Methods
In this systematic review, we assessed all papers published in  September 2012 to April 2014 about growth peptides and CF. Electronic databases were searched with a detailed search strategy to find relevant studies. We entered studies from PubMed, Google Scholar, IranMedex, and Scientific Information Database (SID) in 2012 to 2014. Search strategy was designed as follows: (“cystic fibrosis” OR CF) AND “growth factor” AND child. Retrieved articles were assessed to identify additional related articles from their reference lists. Possible duplicate publications were discussed and only the most recent studies were assessed. We included articles with available abstracts, full texts, and those in English or Persian languages. Exclusion criteria were in vivo or animal articles, article published in other languages (other than English and Persian), case reports, commentaries, and review articles. Finally, following CONSORT checklist (11), quality assessment was performed for each study.

Results
In the first step, abstracts were reviewed by two independent researchers. First search was started with 323 topics, 22 were withdrawn due to duplication, and 259 out of 301 reviewed abstracts were excluded due to no relevance to the topic. Full texts of remained articles were evaluated by the reviewers for more accurate selection if necessary.
We used a structural data extraction tool. However, meta-analysis was not performed due to heterogeneity in hormone and outcome measurements. Figure 1 shows the PRISMA flowchart of study selection.
The earliest study was published in 1997 and the most recent one was in 2014. Study participants were adults in 3 studies (20%) and 12 studies (80%) were conducted in childhood. Table 1 shows the general characteristics of the included studies. In terms of study sample size, two studies evaluated more than 100 patients and other studies (86.6%) assessed less than 100 patients. One study was a clinical trial and other were cohort studies.
IGF1- enhances lean body mass in children and increases linear growth (7). Body mass index (BMI) was correlated with IGF1- bioavailability (8). Serum concentration of IGF1- decreases in children with CF and is associated with BMI (9). Combination of IGF1- and BMI Z-scores may be useful for identifying children with CF who are at risk of impaired bone accretion (4). IGF1- and IGFBP3- are useful parameters in determination of growth retardation in children with CF. Some studies suggested that IGFBP3- was more sensitive for growth monitoring (10). Others proposed that IGF1- level could predict CF clinical outcome and respiratory function (11).
It was revealed that insulin secretion abnormalities were presented in 65% of children with CF even if their glucose tolerance test was normal. Growth retardation is multifactorial in these children; impaired insulin secretion and impaired glucose tolerance are two passible causes of poor growth especially in puberty (12). Insulin insufficiency or resistance might be the cause of low IGF1- level in CF, and a decrease in IGF-1 bioactivity may result in poor growth in these children (1).
Growth hormone (GH) therapy might be useful in children with CF, have anabolic effect on total body protein, and bone accretion and can promote growth (13). IGF1- treatment in a -6month period showed no effect on linear growth, but an increased glucose/insulin ratio (insulin sensitivity) (14). Long-term studies are needed to identify GH and IGF1- efficacy and side effects. Some studies showed that short-course antibiotic therapy, brief exercise, and hyperalimentation increase IGF1 and IGFBP3- levels in CF patients and promote their clinical outcome (15,16). A study revealed isoenergetic exercise effects on IGF-1 levels as an anabolic stimulus in patients who suffer from CF (17).

Discussion
CF is a hereditary disease with annual incidence of about 2500 new cases in United Kingdom (1). CF incidence is estimated about 1/2500 to 1/3900 in live births. CF heterozygote frequency in white population is higher (about 1 in 20). In family with 2 heterozygote parents, 25% of children develop CF. Disease is more severe in blacks than whites because of poor nutritional status and poor pulmonary function. Moreover, CF is more severe in females and they die at younger age in comparison with males (22).  
Thirty to 80% of patients with CF have ΔF508 mutation in defective CFTR gene. Epidemiologic studies in Iran showed 16%-23% of patients with this mutation (23). CF could be confirmed by genetic testing, or sweat testing, and one of the following: chronic obstructive pulmonary disease, insufficiency of pancreas exocrine part, and positive family history (4).
Additional assessments in CF patients include radiologic studies (chest X-ray or computer tomography scan (CT), abdominal ultrasonography, and barium study), genotype, bronchoalveolar lavage, and pulmonary function tests (6,7).
Serum IGF-1 concentration decreases in patients suffered from CF with unclear cause. IGF-1 is an insulin-like molecule and has a crucial role in children growth and anabolic function in adults (24).
Serum concentration of insulin is in normal range in CF patients, while basal insulin level is higher in comparison with healthy people (25). Various studies have been performed to determine the correlation between growth peptides and CF. Impaired insulin secretion and glucose tolerance are common in cystic fibrosis (26). Although GH increases in many inflammatory conditions, IGF-1 and IGFBP-3 levels decrease in CF and lower levels correlate with poor prognosis. IGF-1 and GH are two therapeutic options which should be considered at puberty. On the other hand, exocrine pancreatic insufficiency (EPI) is reported in 90% of patients with CF that might lead to malabsorption and poor growth (27).
IGFs activate by local elements expressed in tissues and circulating IGFBP within body tissue. This circulating system is regulated by insulin, growth hormones, nutrition, and systemic disorders, such as cancer (28). Some recent evidences revealed that bone fractures and osteopenia are associated with decreased level of IGF-1 (29). This protein plays an important role in cellular homeostasis and repair. Moreover, IGF-1 is produced by fibroblasts and correlates with wound healing process and granulation tissue formation. Despite the low level of IGF-1 in normal skin, damaged skin has higher concentration of this peptide (30).
Many studies indicated that patients with CF suffer from growth defects; growth problems in CF patients are multifactorial (31). Chronic lung infections and malnutrition in childhood are the predisposing factors for growth retardation in childhood (32). Changes in GH regulation and release are the other probable causes of growth defects in CF.

Conclusion
We concluded that IGF-1 and related binding protein levels decrease in children with CF and might be the cause of poor growth and low BMI in these children.

Acknowledgement
We would like to thank Clinical Research Development Unit of Ghaem Hospital for their assistant in this manuscript.

Conflict of Interest
The authors declare no conflict of interest.

  1. Taylor AM, Thomson A, Bruce-Morgan C, et al. The relationship between insulin, IGF-I and weight gain in cystic fibrosis. Clin Endocrinol (Oxf). 1999;51:659-665.
  2. Bessich JL, Nymon AB, Moulton LA, et al. Low levels of insulin-like growth factor-1 contribute to alveolar macrophage dysfunction incystic fibrosis. J Immunol. 2013;191:378-385.
  3. Farjadian S, Moghtaderi M, Zuntini R, et al. Rare large homozygous CFTR gene deletion in an Iranian patient with cystic fibrosis. World J Clin Cases. 2014;2:395-397.
  4. Schulze KJ, Cutchins C, Rosenstein BJ, et al. Calcium acquisition rates do not support age-appropriate gains in total body bone mineral content in prepuberty and late puberty in girls with cystic fibrosis. Osteoporos Int. 2006;17:731-740.
  5. Falany CN, He D, Li L, et al. Regulation of hepatic sulfotransferase (SULT) 1E1 expression and effects on estrogenic activity in cystic fibrosis (CF). J Steroid Biochem Mol Biol. 2009;114:113-119.
  6. Savage MO, Simon D, Czernichow PC. Growth hormone treatment in children on chronic glucorticoid therapy. Endocr Dev. 2011;20:194-201.
  7. Mauras N. Can growth hormone counteract the catabolic effects of steroids? Horm Res. 2009;72:48-54.
  8. Street ME, Spaggiari C, Volta C, et al. The IGF system and cytokine interactions and relationships with longitudinal growth in prepubertal patients with cystic fibrosis. Clin Endocrinol (Oxf). 2009;70:593-598.
  9. Boguszewski MC, Kamoi TO, Bento Radominski R, et al. Insulin-like growth factor-1, leptin, body composition, and clinical status interactions in children with cystic fibrosis. Horm Res. 2007;67:250-256.
  10. Ozen M, Cokugras H, Ozen N, et al. Relation between serum Insulin-like growth factor-I and insulin-like growth factor-binding protein-3 levels, clinical status and growth parameters in prepubertal cystic fibrosis patients. Pediatr Int. 2004;46:429-435.
  11. Moreno-Ramírez D, Arias-Santiago S, Nagore E, et al. CONSORT, STROBE, and STARD. Tools to Improve the Reporting of Research. Actas Dermosifiliogr. 2015;106:79-81.
  12. Gifford AH, Nymon AB, Ashare A. Serum insulin-like growth factor-1 (IGF-1) during CF pulmonary exacerbation: trends and biomarker correlations. Pediatr Pulmonol. 2014;49:335-341.
  13. Switzer M, Rice J, Rice M, et al. Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. J Pediatr Endocrinol Metab. 2009;22:417-424.
  14. Schnabel D, Grasemann C, Staab D, et al. A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the metabolic and respiratory effects of growth hormone in children with cystic fibrosis. Pediatrics. 2007;119:e1230-8.
  15. Gordon CM, Binello E, LeBoff MS, et al. Relationship between insulin-like growth factor I, dehydroepiandrosterone sulfate and proresorptive cytokines and bone density in cystic fibrosis. Osteoporos Int. 2006;17:783-790.
  16. Hardin DS, Ahn C, Prestidge C, et al. Growth hormone improves bone mineral content in children withcystic fibrosis. J Pediatr Endocrinol Metab. 2005;18:589-595.
  17. Sermet-Gaudelus I, Souberbielle JC, Azhar I, et al. Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients. Arch Dis Child. 2003;88:956-961.
  18. Lebl J, Zahradníková M, Bartosová J, et al. Insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in cystic fibrosis: a positive effect of antibiotic therapy and hyperalimentation. Acta Paediatr. 2001;90:868-872.
  19. Laursen EM, Lanng S, Rasmussen MH, et al. Normal spontaneous and stimulated GH levels despite decreased IGF-I concentrations in cystic fibrosis patients. Eur J Endocrinol. 1999;140:315-321.
  20. Dooghe C, Grizard G, Labbe A, et al. Decrease in insulin and insulin-like growth factor I (IGF-I) binding to erythrocytes from patients with cystic fibrosis. Diabetes Metab. 1997;23:511-518.
  21. Taylor AM, Bush A, Thomson A, et al. Relation between insulin-like growth factor-I, body mass index, and clinical status in cystic fibrosis. Arch Dis Child. 1997;76:304-309.
  22. Ripa P, Robertson I, Cowley D, et al. The relationship between insulin secretion, the insulin-like growth factor axis and growth in children with cystic fibrosis. Clin Endocrinol (Oxf). 2002;56:383-389.
  23. Gulmans V, van der Laag J, Wattimena D, et al. Insulin-like growth factors and leucine kinetics during exercise training in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2001;32:76-81.
  24. Tirakitsoontorn P, Nussbaum E, Moser C, et al. Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis. Am J Respir Crit Care Med. 2001; 164:1432-1437.
  25. Lai HC. Nutritional status of patients with cystic fibrosis with meconium ileus: A comparison with patients without meconium ileus and diagnosed early through neonatal screening. Pediatrics. 2000;105:53–61.
  26. Zhu G, Liu S, Jiang Y, et al. Growth hormone pathway gene expression varies in porcine cumulus-oocyte complexes during in vitro maturation. In Vitro Cell Dev Biol Anim.2008;44:305–308.
  27. Brennan AL, Gyi KM, Wood DM, et al. Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis. J Cyst Fibros. 2007;6:101-109.
  28. De Silva B, Banney L, Uttley W, et al. Pseudoporphyria and nonsteroidal antiinflammatory agents in children with juvenile idiopathic arthritis.Pediatr Dermatol. 2000;17:480–483.
  29. Ionescu AA1, Nixon LS, Luzio S, et al. Pulmonary function, body composition, and protein catabolism in adults with cystic fibrosis. Am J Respir Crit Care Med. 2002;165:495–500.
  30. Le Henaff C, Gimenez A, Haÿ E, et al. The F508del mutation in cystic fibrosis transmembrane conductance regulator gene impacts bone formation. Am J Pathol. 2012;180:2068-2075.
  31. Phung OJ, Coleman CI, Baker EL, et al. Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients With Cystic Fibrosis [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Oct.
  32. Hardin DS, Rice J, Rice M, et al. Use of the insulin pump in treat cystic fibrosis related diabetes. J Cyst Fibros. 2009;8:174-178.