Cystic Fibrosis

The term “cystic fibrosis” refers to the autopsy findings of fibrosis with cyst in the pancreas of children who died early in life with this diseases.  These days, major pulmonary problems are usually seen in older patients with severe CF who are given pancreatic enzyme replacements, so that they can digest food and survive into childhood.

About 80-90% of patients with cystic fibrosis have pancreatic insufficiency, which means that the exocrine pancreas no longer functions at a level needed to digest food.  Most of the remaining patients with pancreatic sufficiency still do not have a normal pancreas, and they are susceptible to acute pancreatitis and progression to chronic pancreatitis with pancreatic insufficiency.

Inside the pancreas, thick mucus blocks the ducts which usually transport critical enzymes to the intestines to digest food. When the enzymes don’t get to the food, the body cannot absorb and metabolize nutrients properly, especially fats. Children with CF often have problems maintaining or gaining weight, even when they have a good appetite and eat a healthful diet.

The cause of CF has been traced to mutations in a gene called the “cystic fibrosis transmembrane conductance regulator” (CFTR).  The CFTR gene codes for a protein that goes to the surface of cells that line the pancreatic duct, airways, gastrointestinal tract, biliary tract, part of the male reproductive tract and cells that are part of sweat glands.  The CFTR protein forms a pore or channel that allows ions, including chloride and bicarbonate, to move from one side of the cell membrane to the other.  The movement of these ions changes the concentration of molecules in the fluid within the ducts or organs that the cells are lining.  The change in ion concentration causes fluid to move by osmosis.  The result is pancreatic fluid secretion, moistening of the airway lining, a contribution to bile secretion, movement of digestive juices in the gastrointestinal track and sweating on the skin surface, among other actions.  Loss or dysfunction of CFTR interferes with these processes, leading to organ damage or dysfunction.

Some of the mutations in the CFTR gene cause partial or limited dysfunction.  In these cases, the organ is weakened – but not damaged. People carrying these mutations do fine – until one of the organs that uses CFTR is stressed.  Under stress, the organ may be injured or begin to fail because it does not have enough reserve function.  In the case of the pancreas, people with some mild CFTR mutations may develop acute pancreatitis or chronic pancreatitis without manifesting lung disease.

In July 2014 a research paper by LaRusch et al was published that demonstrated TWO types of cystic fibrosis.  The second type is caused by pathologic variants in CFTR that prevent the transformation of the CFTR molecule from a chloride-predominate channel to a bicarbonate-predominant channel with WNK1 activation. This results in risk for Pancreatitis, Sinusitis and Male Infertility – likely because these organs use CFTR to transport bicarbonate rather than chloride.

The CF Foundations has taken the lead in helping patients and families with cystic fibrosis find a cure.  The following link to the CF Foundation web site addresses FAQs related to the disease: Link – http://www.cff.org/AboutCF/Faqs/

Key references of CFTR and the pancreas:

  • Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med. 2010;61:413-24.
  • Kerem E. Atypical CF and CF related diseases. Paediatr Respir Rev. 2006;7 Suppl 1:S144-6.
  • Steiner B, Truninger K, Sanz J, Schaller A, Gallati S. The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles. Hum Mutat. 2004 Aug;24(2):120-9.
  • Whitcomb DC, Ermentrout GB. A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice. Pancreas. 2004;29(2):E30-E40.
  • Whitcomb DC, Lowe ME. Hereditary, Familial and Genetic Disorders of the Pancreas and Pancreatic Disorders in Childhood In: Feldman M, Friedman LS, Sleisenger MH, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th Edition ed. Philadelphia: W. B. Saunders Company; 2010.
  • Schneider, A., et al. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis. Gastroenterology 140, 162-171 (2011).
  • LaRusch, J., et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genetics 2014 Jul 17;10(7):e1004376.