Cystic Fibrosis (CF)

Cystic fibrosis (CF) is due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in dysfunction of the CFTR protein. The disease affects multiple organ systems, including the lungs, pancreas, upper airways, liver, intestine, and reproductive organs, with varying degrees of severity.¹

Age

More than 75% of cases of CF are diagnosed in children younger than 2 years, and the average age at diagnosis is approximately 3 years.² Although clinical signs and symptoms may not develop until later, the median age at diagnosis is 6 to 8 months.³ 

Genetics

The inheritance of CF is autosomal recessive.⁴ Mutations in the CFTR gene on chromosome 7 result in abnormalities of the CFTR protein, which functions as a cyclic adenosine monophosphate (cAMP)-activated transmembrane chloride channel. Individuals with CF carry 2 mutant genes.³

Approximately 2000 distinct mutations have been identified in the CFTR gene that may

cause illness.³ The mutations have been divided into 6 different classes, each corresponding to a specific type of CFTR dysfunction. The mutations of classes I through III are generally associated with more severe disease than the mutations of classes IV through VI.² The most common mutation, delta F508, is a class II mutation that causes aberrant folding of the CFTR protein; as a result, the protein is destroyed prematurely within the Golgi apparatus. Exocrine pancreatic insufficiency and an increased risk for meconium ileus are common effects of the delta F508 mutation.³ 

Ethnicity

The most prevalent mutation in CF, delta F508, is identified in 70% of American whites with CF and two-thirds of all cases of CF in the world.³ In Europe, 82.4% of patients with CF have at least one F508del mutation; however the incidence is higher in northern than in southern Europe: 83% in Denmark vs 40% to 60% in Spain, Italy, and Greece.⁵ The incidence of CF is well documented in Australasia, where a newborn screening (NBS) program has been in place for a long time, and is on average 1 per 3000. In Canada, the incidence of CF is about 1 per 3300, and in the United States, it is about 1 per 4000, with considerable racial differences noted. In small, segregated populations, such as the Amish in Ohio or the population of Saguenay-Lac-Saint-Jean in Quebec, extremely high rates of CF (1 per 569 and 1 per 902, respectively) have been observed, most likely a consequence of genetic drift and founding effects.⁶ 

Complications and Associated Risks

The most common cause of mortality is chronic, progressive lung disease, seen in 77% of cases. Chronic endobronchial bacterial infections, infectious exacerbations, and structural alterations of the lungs (including emphysema/fibrosis) are all features of this condition. Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the bacteria that most commonly cause endobronchial infection.¹

Intestinal involvement is more likely to develop in children with meconium ileus at birth and intestinal obstruction later in life. Chronic mechanical obstruction causes inflammation, scarring, and the formation of strictures. Later in life, fecal impaction or intussusception may exacerbate intestinal obstruction.³ 

Complications of CF include diabetes, spontaneous pneumothorax, and pulmonary hypertension. CF-related diabetes is due to insulin insufficiency; therefore, insulin therapy is the only recommended treatment. A spontaneous pneumothorax occurs in about 3% of patients with CF at some point in their lifetime; it is most common in older adults with end-stage disease. Pulmonary hypertension is very common in older persons, particularly those with severe lung disease, which is linked to poorer outcomes and higher mortality rates.⁷ 

Liver disease is another leading cause of mortality in CF. It occurs as a consequence either of focal biliary cirrhosis, which starts early in life in a few patients and progresses to multilobular cirrhosis, or of obliterative portal venopathy, which starts in adulthood and progresses over time.⁸ 

References

1. Naehrig S, Chao CM, Naehrlich L. Cystic fibrosis. Dtsch Arztebl Int. 2017;114(33-34):564-574. doi:10.3238/arztebl.2017.0564 
2. Chen Q, Shen Y, Zheng J. A review of cystic fibrosis: basic and clinical aspects. Animal Model Exp Med. 2021;4(3):220-232. doi:10.1002/ame2.12180
3. Yu E, Sharma S. Cystic fibrosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; August 11, 2021.
4. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992- 2001. doi:10.1056/NEJMra043184
5. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155
6. Scotet V, L’Hostis C, Férec C. The changing epidemiology of cystic fibrosis: incidence, survival and impact of the CFTR gene discovery. Genes (Basel). 2020;11(6):589. doi:10.3390/genes11060589
7. Brown SD, White R, Tobin P. Keep them breathing: cystic fibrosis pathophysiology, diagnosis, and treatment. JAAPA. 2017;30(5):23-27. doi:10.1097/01.JAA.0000515540.36581.92
8. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3

Reviewed by Kyle Habet, MD, on 1/25/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.