Cystic Fibrosis: Causes and Treatment

Symptoms

In cystic fibrosis (CF, cystic fibrosis), different organ systems are affected, resulting in a heterogeneous clinical picture with symptoms of varying severity: Lower respiratory tract:

  • Chronic cough with viscous mucus formation, obstruction, recurrent infectious diseases, e.g., with , inflammation, remodeling of the lungs (fibrosis), pneumothorax, respiratory insufficiency, shortness of breath, wheezing, oxygen deficiency.

Upper respiratory tract:

Digestive tract:

Pancreas:

Failure to thrive:

  • Small body size, underweight

Reproductive tract:

  • Infertility, especially in men

Bones:

  • Osteoporosis

Skin:

Liver:

The disease occurs in childhood and is life-threatening in the longer term, especially because lung function progressively deteriorates. Patients have a shortened life expectancy, but with treatment today can be extended to 50 years or beyond. However, cystic fibrosis remains incurable.

Causes

Cystic fibrosis is an inherited metabolic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on the long arm of chromosome 7. CFTR is an ABC transporter with a chloride channel that transports chloride along the concentration gradient across cell membranes. It is located on the apical membrane of epithelial cells. Gating, i.e. the opening and closing of the channel, is controlled by ATP. However, ATP does not provide the energy as in other transporters. CFTR is found in many organs, including the lungs, liver, pancreas, digestive tract, reproductive tract and skin. The mutations cause chloride and water to be inadequately transported across the cell membrane. This leads luminal to thickening of secretions and impeded clearance, causing inflammation. The viscous secretions make patients susceptible to infections in the lungs. Over 2000 possible mutations have been identified to date. They are usually small alterations. For example, the common F508del mutation lacks only one phenylalanine at position 508 of the protein. The consequence is defective protein folding, with the result that the protein does not reach the cell surface. Inheritance is autosomal recessive from both parents. Only when two defective genes come together, one from the mother and one from the father, does the disease break out in the child.

Diagnosis

Diagnosis is made by medical treatment based on the patient’s history, clinical symptoms, with a chloride measurement in sweat (sweat test), a chest x-ray, a lung function test, and genetic testing, among other tests. A genetic test is a prerequisite for treatment with specifically effective drugs, as these are not suitable for all patients. Newborn screening with a blood test measuring an enzyme (immunoreactive trypsin) has been performed in many countries since 2011.

Nonpharmacologic treatment

  • Loosening and removal of the viscous mucus in the lungs by various methods, respiratory physiotherapy.
  • Daily inhalations
  • Physiotherapy and sports
  • Adjusting the diet
  • Lung transplantation as a last resort

Drug treatment

Causal therapy: CFTR correctors such as lumacaftor (Orkambi + ivacaftor), tezacaftor (Symdeko + ivacaftor), and and elexacaftor (Trikafta + tezacaftor + ivacaftor) stabilize the structure of CFTR, promote transport of the protein to the cell surface, and increase its concentration in the cell membrane. CFTR potentiators such as ivacaftor (Kalydeco) enable chloride transport by increasing the probability that the channel is open. In gene therapy, the functional -gene is temporarily or permanently introduced into the organism.No effective gene therapy agent has yet been approved, but clinical trials are underway. The lung is the primary target organ for gene therapy. Symptomatic therapy: Vitamin preparations such as AquADEKS contain fat-soluble and water-soluble vitamins as well as some trace elements. They are used to prevent or treat vitamin deficiency. Pancreatic enzymes such as pancreatin (e.g. Creon) supply the organism with the necessary digestive enzymes, which are insufficiently secreted by the exocrine part of the pancreas. Antibiotics are used to treat bacterial infectious diseases. Aztreonam, colistimethate, and tobramycin are administered as inhalations. Peroral or parenteral antibiotics are also used. Bronchodilators such as salbutamol (Ventolin, generic) or parasympatholytics dilate the bronchi, temporarily improving breathing. Non-steroidal anti-inflammatory drugs such as ibuprofen and glucocorticoids are effective against the inflammatory processes. Mucolytic agents such as hypertonic saline (3 to 6%), mannitol (bronchitol), or acetylcysteine are used to mobilize secretions. The enzyme dornase alfa (Pulmozyme) cleaves extracellular DNA in the lungs. The DNA makes the mucus viscous and prevents its removal. Vaccines to prevent infectious diseases. Oxygen to treat hypoxia. If a lung transplant is performed, immunosuppressants must be given for life to prevent rejection of the donor lung.