Understanding Cystic Fibrosis

Researchers at Baylor University Medical Center at Dallas have published the results of three studies on cystic fibrosis (CF) using human subjects. The vast majority of studies done on the disease are conducted on animals or in test tubes.

There is not always agreement between tests performed in intact humans and those done with animal tissues or in test tubes, said John Fordtran, M.D., former chief of the department of medicine at Baylor University Medical Center at Dallas and an international expert in gastroenterology. That's why it is so important to develop experimental methods that are safe to implement in human subjects.

CF is a genetic disease that affects approximately 30,000 children and adults in the United States. A pair of abnormal genes causes the body to produce an abnormally thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections. The thick secretions also obstruct the pancreas, preventing digestive enzymes from reaching the intestines to help break down and absorb food. CF is the most common fatal autosomal recessive genetic defect in white persons of European descent. (Autosomal recessive means that if a child inherits CF, each of his/her parents has one gene with the mutation).

The first study at Baylor was designed to test the theory that people who carry one gene mutation for CF might have a survival advantage. Whenever a gene is very common in the population, the question arises if, in certain environments, there might be some advantage to being a carrier. For example, sickle cell disease is a very common autosomal recessive disease among African-Americans. A major factor contributing to its high prevalence is that people who are carriers of sickle cell disease (i.e., they have one copy of the abnormal gene and one normal gene that prevents sickle cell disease) are more resistant to malaria than normal people (who have two normal genes).

A similar theory has been proposed for CF in regard to diarrheal diseases, including those caused by cholera and certain E. coli infections. In normal people, such infections cause large quantities of chloride to be secreted through special channels in the membranes of intestinal cells. In response to this chloride secretion, a great deal of sodium and water diffuse into the intestine, resulting in severe diarrhea. In patients with CF, these chloride channels do not function properly, and chloride cannot be secreted. Therefore, when infected with cholera or E. coli, patients with CF (who have two abnormal genes) do not develop diarrhea. One hypothesis to explain the high prevalence of the CF carrier state is that carriers (who have one abnormal gene and one normal gene) have only half of the normal amount of chloride channels and therefore would develop only one-half as much diarrhea as a normal person when infected with E. coli or cholera. The carrier state would thereby provide a survival advantage for people living in areas where severe infectious diarrhea is common.

To test this hypothesis, CF carriers (parents of CF patients), as well as a group of normal control subjects, were given prostaglandin, a hormone-like substance that can be used to safely generate a cholera-like diarrhea condition. Results, which were published Oct. 30, 2000, in the American Journal of Human Genetics, showed that the cholera survival advantage theory is probably not correct. As expected, CF patients did not secrete any chloride and did not develop diarrhea in response to the prostaglandin. However, chloride secretion by the parents of CF patients (who carry one normal and one CF gene) increased just as much as normal subjects with two normal genes. Consequently, the high prevalence of the CF gene must have some other explanation.

CF can be induced in mice by genetic engineering. However, CF in mice produces severe intestinal obstruction, rather than the lung and pancreas disease that develops in patients with CF. The second Baylor study was carried out to learn why patients with CF are usually protected from developing severe intestinal obstruction. A study of CF patients led to the discovery of an abnormality in the intestinal paracellular pathway of CF patients. The paracellular pathway, located in the space between cells, is the site where passive absorption of sodium, chloride and other electrolytes occurs. The researchers found an abnormality in the paracellular space of CF patients that inhibits normal passive chloride absorption. This absorption defect offsets or counterbalances the lack of normal chloride secretion by CF patients, which otherwise would cause the intestinal fluid to become thickened and generate blockages. Those findings were published in the July 2003 issue of The Journal of Clinical Investigation.

This was an unexpected finding, said Dr. Fordtran. It is a compensating or protective intestinal mechanism that exists in patients with CF that had not previously been identified.

The most recent Baylor findings on cystic fibrosis were published in Gastroenterology, a leading peer-reviewed journal, in July 2004. In this study, Baylor researchers sought to determine if the results of a widely reported mouse study would prove true in humans with the disease. That study showed that the intestine of mice with CF hyperabsorb sodium in the intestine and that this sodium hyperabsorption cannot be suppressed. In CF mice, this process is so severe, hyperactive and sustained that it probably contributes to the marked dehydration of the intestinal contents, leading to intestinal blockage and death in CF mice.

To test for this sodium absorption abnormality in CF patients, Baylor researchers measured intestinal sodium absorption in patients with CF under normal conditions and after they were given prostaglandin, which suppresses sodium absorption in normal people. They found that prostaglandin reduced the rate of sodium absorption markedly in both the normal control subjects and in patients with CF. Thus, there was no evidence that patients with CF have abnormal intestinal sodium absorption another clear difference between what happens in mice and humans with this disease.

The development of a mouse model of CF was a huge advance and has contributed immensely to our understanding of the disease, said Michael Emmett, M.D., chairman of internal medicine at Baylor Dallas and one of the study investigators. However, our studies demonstrate there are significant differences between the way CF affects the GI tract of mice and the GI tract of people. It may well be the lung defects are different as well, but that is more difficult to study in humans.

The Institutional Review Board for Human Protection at Baylor Dallas approved each research study. Informed consent was obtained from each subject, who received a fee for his or her participation.