Cystic Fibrosis

This article was last reviewed on

6 October 2023.

This article waslast modified on 6 October 2023.

What is it?

Cystic fibrosis (CF) is a relatively common inherited disease. In the absence of treatment, from infancy those with CF have recurring chest infections causing progressive lung damage, intestinal malabsorption leading to severe malnutrition and growth failure. There is an excess of salt in the sweat. Without treatment, CF usually causes death during infancy or early childhood.

The disease is caused by mutations in a pair of genes on chromosome 7. Every cell in the body (except the sex cells) has 46 chromosomes (23 pairs, one half inherited from the mother and the other half from the father). Genes on these chromosomes form the body’s blueprint for producing proteins that control body functions. There is a gene on each number 7 chromosome that is responsible for the production of a protein called cystic fibrosis transmembrane regulator (CFTR). Mutations in this gene lead to absent or defective CFTR production, which then causes CF. More than 2,000 different CF mutations have been identified, although some are much more common than others, DF 508 being the most common.

Since CF is recessive, an affected individual must have a mutation in each CFTR gene on each chromosome 7 in order to have the disease (one abnormal copy from each parent). An individual with one normal copy of the gene and one abnormal copy will be a CF carrier. Carriers do not have symptoms and are not ill, but they may pass their abnormal copy of the gene on to their children. Both parents of an affected infant must have the CF gene (be carriers or have CF themselves) for their child to have CF. Caucasian people from Northern Europe and Ashkenazi Jews have the highest population carrier rates (about 1 in 20-25).

Having CF means the absence of or defective production and function of CFTR. This leads to abnormal salt and water movement in and out of the epithelial cells with thick, sticky mucus in the lungs and pancreas leading to chest infections and/or blockages in the pancreatic and liver ducts leading to poor fat and protein digestion. The majority of males with CF are also infertile due to missing or underdeveloped vas deferens, the tubules that transport sperm from the testes. Most people with CF will develop respiratory and pancreatic symptoms very early in their life, although symptom severity will vary from person to person, even in those with the same mutations.

CF is one of the most common recessive genetic disorders in Europe. Currently, there is no prevention or cure, only treatment of the symptoms. However, research is being conducted to develop a cure and to enhance treatments. In fact, great strides have been made over the past 30 years, which are allowing people with CF to live longer lives of improved quality. The median survival in the UK is now over 43 years.

About CF

Signs and Symptoms
CF interferes with electrolyte and fluid balances in the body. In most CF patients, sweat is up to five times saltier than normal and severe salt depletion can occur in very hot weather.

Much of the disease associated with CF is due to chest infections and lung complications. From early childhood the abnormal composition of the fluid lining the airways makes them prone to infection. The lubricating mucus in the lungs becomes thick and sticky, leading to chronic infections, severe inflammation and eventual lung damage. However, with early diagnosis through neonatal screening, early recognition of infection and aggressive treatment of the infections using oral, inhaled and intravenous antibiotics, chronic infection can be delayed or even prevented in many of those affected.

The excessively thick secretion lining the pancreatic ducts leads to obstruction and extensive destruction of pancreatic tissue even before birth. The resulting deficiency of pancreatic enzymes and bicarbonate causes severe intestinal malabsorption of fat and protein and fat-soluble vitamins with foul-smelling, greasy stools. Nutritional support with oral high energy supplements, pancreatic enzyme replacement therapy and supplements of fat-soluble vitamins A, D, E and K can, in many patients, achieve near normal absorption, nutritional state and growth. Although over half of those affected survive into their forties, many develop diabetes mellitus, and some have osteoporosis.

Other problems and symptoms associated with CF include:

Meconium ileus (no stools in the first 24 to 48 hours of life) – intestinal obstruction due to viscid bowel contents, affecting some 15% of newborns with CF

Jaundice due to biliary cirrhosis caused by blocked bile ducts in the liver

Inadequate weight gain, suboptimal growth, delayed puberty and eventual below average stature due to intestinal malabsorption

Recurrent pancreatitis, particularly in the 10-15% with some remaining pancreatic function

Growths (polyps) in the nasal passages

Enlargement or rounding (clubbing) of the fingertips and toes due to a chronic reduced oxygen environment from lung involvement

Rectal prolapse (protrusion of the rectum through the anus)

Male infertility
Tests
1. Newborn screening for Immunoreactive Trypsin (IRT). This newborn screening test for CF is measured using the blood spots collected on Guthrie screening cards on day 4 to 5 of life. In CF, thick mucus plugs can obstruct pancreatic ducts and prevent trypsinogen from reaching the intestine. Blood IRT levels will be elevated in newborns with CF, and a raised second IRT usually combined with DNA testing is used in many countries for neonatal CF screening. Persistently raised blood IRT values after the newborn period usually indicate that the infant has CF. Early diagnosis is essential so that treatment can be started before damage to the lungs with chronic infection and malnutrition become established.

2. CF Genetic Tests. If IRT levels on a newborn screen are raised, a panel of 25 common mutations of the CF gene are investigated to determine if the patient has CF or CF carrier status. Some laboratories have larger panels of 30-88 mutations. These panels check the patient’s DNA for each of the selected CF mutations. If two CF mutations are identified, then the patient has CF; if one is located, the patient is either a carrier or has CF with the second mutation unidentified. Further clinical assessment, genetic testing and a sweat test may be performed. If the patient tests negative for the 25 mutations and is asymptomatic, then the chances are that they do not have CF, but there is still a slight risk of them being a carrier of a rare mutation.

3. The Sweat Test. This is the gold standard confirmatory test for CF diagnosis. It involves measuring sodium and chloride from a sweat sample collected by a special procedure in which local sweating is stimulated by pilocarpine, the sweat is collected and the concentrations of sodium and chloride measured. Since the CFTR protein is altered or missing and chloride travel is restricted, the sweat in a CF person may be up to five times saltier than normal. Positives should be confirmed and followed with CF gene mutation testing. Some people with CF will be diagnosed using only sweat testing, and a few very rare patients with definite CF, often with unusual mutations, may have sweat sodium and chloride levels within the normal range.

4. Faecal Pancreatic Elastase 1. This is a specific human protease produced by the pancreas. Values determined on a small faecal specimen clearly differentiate between sufficient and insufficient pancreatic function and are not influenced by pancreatic enzyme treatment. This is now the best indirect measure of pancreatic function and it has replaced a number of indirect pancreatic function tests including the bentiromide and pancreolauryl tests.

Other laboratory tests used to check lung infection, organ function and fertility include:

Throat swab and sputum cultures

Faecal fat microscopy and measurement

Serum electrolytes

Liver function tests

Fat soluble vitamin levels

Immunoglobulins including IgE

IgE antibody test for aspergillus fumigatus

Pseudomonas antibodies

Semen analysis

Non-laboratory tests that may be done include lung function tests, chest X-rays, lung scans, bronchoscopies, bone scans, upper GI and small bowel X-rays and other gastrointestinal pancreatic and liver investigations.
Prevention, Early Detection, and Treatment
Prevention of CF is not currently possible, except through targeted population screening for carrier status and genetic counselling about CF risk before a couple conceives.

Early detection can be accomplished with CF gene mutation testing prenatally, using amniocentesis or chorionic villi collection procedures. This is offered to parents who are known CF carriers. The newborn screening programme in the UK includes screening for CF. Early identification of CF allows parents to get education, to be referred to a Specialist CF Centre for expert help, and to start early treatments in their infants to prevent or minimise lung damage and nutritional problems.

Treatments are currently aimed at preventing or lessening symptoms and improving quality of life.

Treatments to ease symptoms include:

Medications: Aerosolized and inhaled medications are used to improve breathing, reduce respiratory swelling and thin mucus. These include bronchodilators, rhDNase (Pulmozyme), hypertonic saline and corticosteroids. Oral, intravenous, and aerosolized antibiotics that can be inhaled are used to fight frequent respiratory infections and stabilise those who are chronically infected.

Chest physiotherapy (CPT): Bronchial, or postural, drainage is performed once or more a day by placing the patient in a position that allows mucus to drain from the lungs. The chest or back is then clapped (percussed) to dislodge the mucus. Other techinques include positive expiratory pressure (PEP) masks and high frequency chest compression.

Exercise: Exercise helps loosen mucus and also stimulates coughing to aid in its removal.

Oral pancreatic enzymes, Vitamin A, D, E, and K supplements, and a diet high in fat and protein, and high in calories help with gastrointestinal symptoms and in maintaining an adequate nutritional state..

In vitro procedures in males with missing vas deferens aid in fertility.

Carefully monitored pregnancies are generally well tolerated in CF women with mild to moderate disease.

Lung transplants are an option for those with end stage lung disease, but the demand exceeds the supply of donor organs in some countries. However, the results are increasingly good for long term post-transplant survival.

Ivacaftor is a drug that increases chloride transport in the abnormal CFTR protein and has been shown to be extremely effective for some types of CF (G551D). Ongoing research is exploring gene therapy as a way to replace the defective CF genes and looking for ways around the protein defect, such as finding other chloride channel regulators to compensate.