Cystic fibrosis

Cystic fibrosis (CF) is a genetic condition that affects the exocrine glands and, secondarily, most physical systems. Genetic conditions like CF are inherited and often begin to exert their effects before birth and continue throughout the lifespan; since in many cases the underlying cause of the condition is unknown, cure is difficult or impossible and care usually restricted to treating its symptoms. As of 2023, the Cystic Fibrosis Foundation stated that approximately 40,000 people were living with the disease in the United States and about 105,000 worldwide; every year in the United States, close to one thousand new cases are diagnosed.

Quick Facts

ANATOMY OR SYSTEM AFFECTED: Chest, lungs, respiratory system, most bodily systems

DEFINITION: A disease that affects the exocrine glands and, secondarily, most physical systems

CAUSES: Genetic mutation

SYMPTOMS: Severe malnutrition, production of bulky stools, chronic respiratory infections, constant coughing, compromised fertility

DURATION: Chronic and progressive

TREATMENTS: Alleviation of symptoms with dietary supplements, balanced diet, therapies to break up mucus, antibiotics

Causes and Symptoms

The genetic mutation that causes cystic fibrosis is recessive. A recessive trait is one that must be inherited from both the mother and the father in order to take effect. When two carriers of the genetic mutation procreate, their children may be born with the condition. Based on the rules of genetics, in such a union, each child has a 25 percent chance of inheriting cystic fibrosis and a 50 percent chance of being an asymptomatic carrier like his or her parents.

The CFTR gene in humans controls some normal cellular function related to the transport of chloride from the inside of a cell to the outside. The affected gene product, a protein called cystic fibrosis transmembrane conductance regulator (CFTR), creates an ionchannel that allows cells to move chloride ions across their cell membranes. CFTR is an enormous protein consisting of 1,480 aminoacids linked end to end and is embedded in the membranes of cells found in the lungs, pancreas, and reproductive tracts. The CFTR found in 70 percent of individuals with cystic fibrosis is identical to that produced by a nonmutated CFTR gene, except that the amino acid at position 508 is missing. Other mutations that cause cystic fibrosis affect different parts of this protein; in all cases, they reduce the ability of the CFTR protein to carry out its normal function. When that ion channel does not work properly, it disturbs both the salt and the water balance of the affected cell, and ultimately of the whole tissue, and the affected person exhibits symptoms of cystic fibrosis.

Cystic fibrosis has several major effects on an individual. These effects begin before birth, extend into early childhood, and become progressively more serious as the affected individual ages. Major symptoms include the blockage of several important internal ducts, which occurs because the underlying genetic mutation has a critical effect on the ability of certain internal tissues, called secretory epithelia, to transport normal amounts of salt and water across their surfaces. These epithelia are often found in the ducts that contribute to the digestive and reproductive systems.

The blockage of ducts resulting from the production and export of overly viscous secretions reduces the delivery of digestive enzymes from the pancreas to the intestine. Thus, proteins in the intestine are only partly digested. Fat-emulsifying compounds, called bile salts, are often blocked on their way from the pancreas to the intestine as well, so the digestion of fats is often also incomplete. These two conditions may occur before birth. According to the Johns Hopkins Cystic Fibrosis Center in 2023, approximately 18 percent of newborns with cystic fibrosis have a puttylike plug of undigested material in their intestines called the meconium ileus (MI), which prevents the normal movement of food through the digestive system and can be very serious. All babies born with MI should be tested for cystic fibrosis, as approximately 98 percent of full-term infants with such a plug have the disease.

Because of their overall inefficiency of digestion, young children with cystic fibrosis can seem to be eating quite normally yet remain severely undernourished. They often produce bulky, foul-smelling stools as a result of the high proportion of undigested material. This symptom serves as an indicator of the progress of the disease; as such, digestive problems often increase as the affected person ages.

As individuals with cystic fibrosis grow older, their respiratory problems also increase because of a thick mucus on the inner lining of the lungs. This viscous material traps white blood cells that release their contents when they rupture, which makes the mucus all the thicker. This mucus buildup is a direct consequence of the ion disturbance. The affected individuals constantly cough in an attempt to remove this material. More importantly, the mucus forms an ideal breeding ground for many types of pathogenic bacteria, and the affected individual experiences continual respiratory infections.

Male patients are almost always infertile as a result of the blockage of the ducts of the reproductive system, while female fertility is sometimes reduced as well. Affected individuals also tend to have a high salt concentration in their perspiration.

Treatment and Therapy

Advances in treatments for cystic fibrosis have drastically improved an affected individual’s chances of survival and quality of life. In the 1950s, a child with cystic fibrosis usually lived only a year or two. Thus, cystic fibrosis was originally described as a children’s disease and was intensively studied only by pediatricians.

Aggressive medical intervention has since increased survival rates dramatically. Affected individuals are treated with a package of therapies designed to alleviate the most severe symptoms of the disease, and taken together, these therapies have allowed many patients with cystic fibrosis to live well into adulthood. It is difficult to calculate an average life expectancy for individuals with cystic fibrosis, as data from some regions is largely unavailable. In addition, life expectancy varies greatly depending on the age at which a patient was diagnosed, the extent of medical care available, and various environmental factors. Individuals with access to the necessary treatments may live into middle age. According to the Cystic Fibrosis Foundation in 2023, more than 75 percent of individuals with cystic fibrosis are diagnosed by the age of two; however, racial and ethnic disparities in diagnosis remain.

The available treatments, however, do not constitute a cure for the disease. The major roadblock to developing a cure was that the primary genetic defect remained unknown. All that was clear until the mid-1980s was that many of the secretory epithelia had a problem transporting salt and water. By the late 1980s, the defect had been further narrowed down to a problem in the transport of chloride ions, one of the two constituents of ordinary salt and a critical chemical in many important cellular processes. Because individuals who had severe forms of cystic fibrosis could still live, however, this function was deemed important but not absolutely essential for survival. Furthermore, only certain tissues and organs in the body seemed to show abnormal functions in a cystic fibrosis patient, while other organs—the heart, brain, and nerves—seemed to function normally. Thus, the defect was not uniform.

The treatment of cystic fibrosis typically focuses on preventing or delaying lung damage and optimizing growth and nutrition. Traditional treatments usually include daily dietary supplements that contain the digestive enzymes and bile salts that cannot pass through the blocked ducts. Individuals with cystic fibrosis are also placed on balanced diets to ensure proper nutrition despite their difficulties in digesting fats and proteins. One characteristic of cystic fibrosis treatment is the long daily ritual of backslapping, which is designed to help break up the thick mucus in the lungs; individuals may also use high-frequency chest-wall oscillation vests for the same purpose. Aggressive antibiotic therapy can keep infections of the lungs from forming or spreading. In the 1990s, a therapy was introduced that uses a genetically engineered enzyme, deoxyribonuclease I (DNase I), to break down DNA in the lung mucus. Many white blood cells rupture while trapped in the thick mucus lining of the lungs, and the release of their DNA adds to the high viscosity of the mucus. DNase I, also called dornase alfa, has been found to help degrade this extra DNA, thus making it easier for affected patients to cough out the mucus.

Therapies for cystic fibrosis, as for many genetic diseases, are largely limited to treating the symptoms. Since every cell in the affected individual lacks a particular metabolic function due to the condition, there is no easy way to replace these functions. Gene therapy involves either replacing a defective gene with a normal one or inserting an additional copy or copies of the normal gene in the affected cells, in an attempt to restore the same functional enzymes and thus reestablish a normal metabolic process. In the case of cystic fibrosis, animal studies have shown that it is possible to produce normal lung function when either genes or genetically engineered viruses containing normal genes are sprayed into the lungs of affected animals. However, there is no similar direct route to the cells in the pancreas or the reproductive system. Research into integrating or non-integrating gene therapies for CF remains ongoing.

Perspective and Prospects

Patients with the symptoms of cystic fibrosis were first described in medical records dating back to the eighteenth century. The disease was initially called mucoviscidosis and later cystic fibrosis of the pancreas. It was not clear that these symptoms were related to a single specific disease, however, until the work of Dorothy Anderson of Columbia University in the late 1930s. Anderson studied a large number of cases of people who had died with similar lung and pancreas problems. She noticed that siblings were sometimes affected and thus suspected that the disease had a genetic cause. Anderson was responsible for naming the disease on the basis of the fibrous cysts on the pancreas that she often saw in autopsies performed on affected individuals.

Researchers later located the gene responsible for cystic fibrosis on chromosome number 7; humans typically have twenty-three pairs of chromosomes. In 1989, two independent groups, led by Lap-Chee Tsui of the Hospital for Sick Children in Toronto and Francis Collins of the University of Michigan at Ann Arbor, announced that they had identified the precise location of the gene. DNA from more than thirty thousand individuals with cystic fibrosis was analyzed, and surprisingly, more than 230 differences between the normal and the mutated genes were found. While the same gene and gene product were affected in each case, the type and extent of the mutations varied widely in about 30 percent of the affected individuals, which accounts for the range in severity of symptoms. Since then, several more mutations in this single gene have been discovered to cause cystic fibrosis; according to the Cystic Fibrosis Foundation, there are more than 1,800 known mutations of the gene.

Because treatment of cystic fibrosis is largely confined to managing the disease's symptoms, a premium has been placed on the development of inexpensive and accurate diagnostic procedures, which, along with genetic counseling, could greatly reduce the incidence of cystic fibrosis in the population.

Every US state has screened newborns for cystic fibrosis since at least 2010. However, due to the longstanding misconception that CF affects only those of European descent, screening tools have looked primarily for mutations common among White Americans, resulting in false-negative results and delayed diagnoses for more than two-fifths of Asian children with the condition, one-fifth of Black children, and about one-seventh of Hispanic and Indigenous children.

Bibliography

"About Cystic Fibrosis." Centers for Disease Control and Prevention, 15 May 2024, www.cdc.gov/cystic-fibrosis/about/index.html. Accessed 8 Aug. 2024.“About Cystic Fibrosis.” Cystic Fibrosis Foundation, 2023, www.cff.org/intro-cf/about-cystic-fibrosis. Accessed 31 Mar. 2024.

Allen, Julian L., et al., editors. Cystic Fibrosis. Informa, 2010. Lung Biology in Health and Disease, 242.

Blankenship, Sarah, et al. “What the Future Holds: Cystic Fibrosis and Aging.” Frontiers in Medicine, vol. 10, 8 Jan. 2024, doi.org/10.3389/fmed.2023.1340388. Accessed 31 Mar. 2024.

‌“Cystic Fibrosis.” MedlinePlus, National Library of Medicine, 17 Feb. 2024,medlineplus.gov/ency/article/000107.htm. Accessed 25 June 2024.

“Cystic Fibrosis.” MedlinePlus Genetics, National Library of Medicine, 6 July 2021, medlineplus.gov/genetics/condition/cystic-fibrosis/. Accessed 25 June 2024.“Dispelling Misconceptions about Cystic Fibrosis.” Cystic Fibrosis Foundation, 2023, www.cff.org/intro-cf/dispelling-misconceptions-about-cystic-fibrosis. Accessed 25 June 2024.

Kepron, Wayne. Cystic Fibrosis: Everything You Need to Know. Firefly, 2004.

“Neonatal Cystic Fibrosis Screening Test.” MedlinePlus, National Library of Medicine, 17 June 2022, medlineplus.gov/ency/article/003409.htm. Accessed 25 June 2024.

Orenstein, David M., et al. Cystic Fibrosis: A Guide for Patient and Family. 4th ed., Lippincott, 2012.

Parker, James N., and Philip M. Parker, editors. The Official Parent’s Sourcebook on Cystic Fibrosis: A Revised and Updated Directory for the Internet Age. ICON Health, 2005.

Pierce, Benjamin A. The Family Genetic Sourcebook. Wiley, 1990.

“Prenatal Diagnosis.” Johns Hopkins Cystic Fibrosis Center, 2023, hopkinscf.org/knowledge/presentations. Accessed 1 Aug. 2023.

Riordan, John R., et al., editors. Cystic Fibrosis: A Trilogy of Biochemistry, Physiology, and Therapy. Cold Spring Harbor Lab., 2013.Szabo, Liz. “For Some Families of Color, a Painful Fight for a Cystic Fibrosis Diagnosis.” The New York Times, 12 June 2024, www.nytimes.com/2024/05/29/well/live/cystic-fibrosis-screening.html. Accessed 25 June 2024.

Thomson, Anne H., and Ann Harris. Cystic Fibrosis: The Facts. 4th ed., Oxford UP, 2008.

Tsui, Lap-Chee. “Cystic Fibrosis, Molecular Genetics.” Encyclopedia of Human Biology. Edited by Renato Dulbecco. 2nd ed., vol. 2., Academic, 1997.

United States. Cong. Office of Technology Assessment. Cystic Fibrosis and DNA Tests: Implications of Carrier Screening. GPO, 1992.

United States. Cong. Office of Technology Assessment. Genetic Counseling and Cystic Fibrosis Carrier Screening: Results of a Survey. GPO, 1992.

Watson, Ronald Ross, editor. Diet and Exercise in Cystic Fibrosis. Academic, 2015.

Yankaskas, James R., and Michael R. Knowles, editors. Cystic Fibrosis in Adults. Lippincott, 1999.