CYSTIC FIBROSIS

by Hannah Blau MD
Director, Pulmonology and Cystic Fibrosis Unit,
Schneider Children's Medical Center of Israel

These are the questions to be answered

  1. What is Incidence of CF worldwide?
  2. How when and where to suspect and diagnose CF?
  3. How do different gene mutations correlate witht the clinical picture?
  4. What is standard of care and new therapies and prognosis?

Introduction

Cystic Fibrosis (CF) is the most common fatal autosomal recessive genetic disorder that affects the Caucasian population. It reflects mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CF gene was cloned 6 years ago, and since then, over 700 mutations have been described. CFTR functions as a cyclic AMP regulated chloride channel and is important for secretion of sodium chloride by the apical membrane of epithelial cells within affected organs. Secretion of water follows that of sodium chloride. As a result of defective CFTR function in organs lined by epithelium, there is intraluminal accumulation of thick, viscid secretions lacking in water.

What is the incidence of Cystic Fibrosis worldwide?

Cf occurs wherever Europeans have settled. It is extremely rare among Asians. However, it has been found in blacks, and natives of Middle Eastern countries, India and Pakistan. There are about 60,000 CF patients diagnosed worldwide, about 30,000 of these in the US. Incidence among white populations ranges from 1 in 1700 to 1 in 6500 . In the 1990 US CF foundation registry : 1 in 3500 live white births, 1 in 14,000 live black births, 1 in 25,000 live Asian-american births, 1 in 11,500 live Hispanic births.

Suspecting and diagnosing cystic fibrosis - how, when and where?

The most important clinical features are chronic obstructive pulmonary disease and in most cases pancreatic insufficiency. Babies present with recurrent airway obstruction, atelectasis, failure to thrive, steatorhea. Many other organs are effected too:sweat glands, intestinal obstruction at birth (meconium ileus) and later (distal intestinal obstruction syndrome), liver , vas deferens and male infertility, nasal polyps. Two syndromes that can lead to diagnosis in infants are: a) edema with hypoalbuminemia and anemia due to protein malabsorption; b) hypochloremic alkalotic dehydration, especially during hot weather.

The level of chloride and sodium in sweat is usually above 70meq/l (normal less than 40meq/l) and these allows the pilocarpine iontophoresis sweat test accurately performed in experienced hands, to be the standard method of diagnosis. Today, testing for genetic mutations is helpful in populations where most of the mutations are known, eg. US white caucasians, ashkenazy jews.It can be used for borderline cases, and for prenatal diagnosis and even screening of heterozygotes. As chloride remains within the CF epithelial cells, the potential difference across the apical cell membrane is more negative. Measuring nasal potential difference is useful in diagnosing unusual cases, and in the future may be a way of assessing gene therapy!

How do different gene mutations correlate with the clinical picture?

There is a wide variability in the clinical severity of disease expression in CF. Of course, heterozygotes, eg. parents of CF patients, who have one normal allele for CFTR and one mutation, have no clinical disease, as they have sufficient CFTR function in all organs. Some mutations ("severe") cause no functional protein to be produced, while others ("mild") produce a protein allowing some limited transport of chloride ions. About 10% of CF patients are pancreatic sufficient (PS) and this is associated with a "mild" mutation (allowing some CFTR function) on at least one allele. In patients with "severe" mutations on both alleles, there is usually pancreatic insufficiency (PI). Similarly, some patients with a "mild" mutation on one allele, may have borderline or even normal sweat tests. However, the situation is far less clear regarding pulmonary disease, with less correlation between type of gene mutation and severity of lung disease. It is thought that other genes may modify the expression of the CFTR gene, as might the environment.

Standard of care today; future therapies and prognosis

In 1938 when CF was first described, more than 80% of patients died within 1 yr of birth. Today, median survival is about 30 years of age, and projected survival for children born today is about 40 years.Most of this improvement is due to treatment of the secondary effects in end organs ie. aggressive therapy of lung disease (the major cause of mortality) with long term antibiotics orally, by inhalation (aminoglycosides) and IV, as well as daily (often 1 hour!) chest physiotherapy and inhalations. New modalities such as home IV therapy, midlines and central IV catheters, have improved quality of life. In addition, pancreatic enzyme supplementation ( enteric coated) , improved nutrition and high fat, high caloric diet, food supplements and in more severe cases nasogastric or gastrostomy night feeds , have ensured improved growth and prognosis. In end stage lung disease bilateral sequential lung transplantation or even living related donor lung transplantation offers hope. Treatment has also improved for CF liver disease (often ursodeoxycholate; even transplant in end stage) , non invasive management of bowel obstruction at birth and in later life, and microsurgical sperm retreival and in vitro fertilization has successfully treated male sterility.

Newer therapies focus mainly on the lung disease. Neutrophil inflammation with elastase and oxidant destruction of lung tissue, is the hallmark of CF lung disease. This is probably secondary to the permanent bacterial colonization of airways, usually with mucoid Pseudomonas aeruginosa. Today inhalations of Dnase (pulmozyme) depolymerize the extracellular DNA released from degenarating neutrophils in CF sputum. DNase markedly decreases the viscosity of CF secretions and helps sputum clearance. In certain patients this improves lung function. Antiinflammatory therapy eg. ibuprofen, seems promising. Future therapies aim at correcting the basic defect in chloride permeability, by activating alternate channels, improving the function of mutated CFTR or, by inserting corrected versions of CFTR gene (cDNA) into respiratory epithelial cells. This final alternative of gene therapy, is very promising with phase 1 trials ongoing. Gene is delivered using molecular engineered adenovirus (virulence removed), adenoassociated virus, or inert liposomes which may cause less immune response. However, there are still obstacles in translating this therapy which was successful in vitro, to patients. All these modalities promise a bright future and better prognosis for CF.

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