Cystic fibrosis is the most frequent lethal genetic disease of childhood. Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply “cystic fibrosis” (or “mucoviscidosis” in Europe). Manifestations relate not only to the disruption of exocrine function of the pancreas but also to intestinal glands (meconium ileus), biliary tree (biliary cirrhosis), bronchial glands (chronic bronchopulmonary infection with emphysema), and sweat glands (high sweat electrolyte with depletion in a hot environment). First, CF was considered a childhood disease. The median survival age was 8 years. Today, it is 30 years. (The term “median” means that there is half of the population above that number and half below.)

At first the disease was treated phenomenologically, without understanding of the underlying causes. Recent advances have made the mechanisms responsible for CF much clearer; the lack of CFTR (a protein) causes improper regulation of the chloride channel; chloride (Cl) is prevented from leaving the cell. This affects a wide range of organs in the body, including:

Sweat Gland: CF salt (NaCl) concentration is 5 times normal

Reproductive Organs: Women *can* have children, although poor health of the mother may limit this. 98% of CF males are infertile due to improper transport of sperm to the semen.

GI System: Clogging of pancreatic ducts leads to an enzyme deficiency in the intestines. This is correctable with pancreatic enzyme supplements. CFers are warned against using overly high concentrations of pancreatic enzymes, as these can lead to intestinal blockage and scarring. – these enzymes allow CF patients to eat pretty much what they want – today’s enzymes are much better than in the past – There will be gradual and unavoidable deterioration of the pancreas due to the high concentration of enzymes which remain there instead of being delivered to the intestine. There is currently no known way to deal with this problem. (This may eventually result in a type of diabetes in the CF patient.) – The liver also suffers from gradual deterioration. There has been some work with artificial bile salts. The work is too preliminary to draw conclusions at this time.

Pulmonary complications: The major components of mucus are 1) bacteria, 2) whatever is in regular mucus, and 3) dead white blood cells, which are present in CFers in a concentration about 1000 times larger than in normal people. It was formally believed that the bacteria were the primary cause of airway destruction; it is now believed that the white blood cells, especially the long, viscous strands of DNA from the cell nuclei, are the principle cause of airway clogging and damage. It is these strands that DNAse (an inhaled medication) seeks to chop up. One does not expect DNAse to repair scarred tissue. The advantage is only in lowering the viscosity of the mucus and reducing future damage.

Overall, we’ve seen a lot of improvement over the last 30 years.

30 # # # # # # # MEDIAN # ## # SURVIVAL # # # AGE # # # # # ### # ##### # #### #### 0 #################################

1950’S 1990’s

~ 1994 U.S. Information From the (US) CFF Patient Registry ~

The median survival age is 28.3 yrs. Average age of CF patients is 14.3 Percent of adults over age 18 are 33.9% CF males = 53.8% Reported patients in the U.S. is 19,517 with 1,062 known but not seen at a CF center 96% are Caucasian 7 patients in the U.S. are 60-70 yrs. old Nearly 7,700 patients have had genetic testing 71% have at least one Delta F-508, nearly 50% have two There are over 500 mutations of CF 38.7% of patients had at least one serious respiratory illness in ’94 59.6% have Pseudomonas aeriginosa 3.2% have Berholderia cepacia Over 93% take enzymes 96 patients had lung txs 25% of patients took part in a research study in ’94 300 patients are on tx lists 135 pregnancies reported by CF females 40% patients take Pulmozyme 33% adults are employed full time.

17% adults are employed part time 17% adults are students 5% adults are homemakers 21% adults are not employed Less than 2% of adults had no financial support.

There is an apparent benefit of having a CF gene in surviving cholera (resistance to cholera as a selective advantage of carriers over non carriers). From Discover Magazine, March, 1995, page 30: “Virtues of a Killer Gene”:

“The gene for cystic fibrosis was discovered in 1989. (The normal gene) codes for a protein that forms channels in cell membranes, especially the cells lining the intestines and airways. Normally these channels funnel chloride ions out of a cell, thus making its surroundings saltier; that in turn draws water out of the cell by osmosis. In the lungs this fluid washes away bacteria and other unwanted debris. In the intestines it does the same and also brings digestive enzymes into contact with food. In sweat glands the chloride channels have an additional function; they recycle salt out of the glands and back into the skin before it can be lost to the outside world”.

According to Estivill and his colleagues, the mutation (for CF) known as delta F-508 arose at least 52,000 years ago (in Europe). Researchers reported, from experiments with mice, that the mutation offers increased resistance to cholera, or rather the diarrhea that often kills people with cholera. For people who have just one copy of the mutated gene, that resistance offers an important benefit.

When the bacteria that cause cholera sneak into the intestine, they release a potent toxin that attacks the cells that line the gut. The cells respond by permanently opening their chloride channels, causing the gut to secrete as much as three or four gallons of fluid a day. The point is to flush out the toxin — but the effort often backfires. Unless the lost salts and fluids are fast replaced, the afflicted person can die of dehydration.

Mice that had one mutated gene had only half the chloride channels in the intestines, and secreted only half the amount of fluid… It is speculated that people with one mutated gene still produce enough fluid to wash the cholera toxin out of their gut, but do not die of dehydration.

It is speculated that the mutation held an advantage for other bacterial diseases that afflicted the intestines as well… Why didn’t the mutation spread beyond Europe? It is speculated that in warmer climates, people with the one mutated gene, having only half the chloride channels in their sweat pores, did not retain salt effectively, which is needed in a warm climate. So they did not survive. The mutated gene had a bigger drawback than benefit in warmer climates. Hence, CF is found mainly in people with a Northern European ancestry. Frequency: 1 in 3000 births is CF, 3% of white (Caucasian) are carriers. Many (330) mutations known (Cutting 93); most common: Deletion of F508 (Delta F508)in 70-80% of the cases. The gene locus has been known since 1989 (Riordan et al. Science 245, 1989, pp 1066-1073).