Cystic fibrosis is a genetic disease that occurs when a protein that regulates the transmission of salt on the surface of tissues is disrupted by a genetic mutation, severely impairing many essential physiological functions. For most of human history, it was associated with high mortality rates occurring during childhood. But breakthroughs in understanding how the disease works at the cellular level as well as innovations in therapy over the past 20 years have enabled those with the disease to now live much longer and with a higher quality of life.
In this episode of Kentucky Health, host Dr. Wayne Tuckson speaks with a Lexington pulmonologist about cystic fibrosis and exciting developments in treating the disease.
Dr. Jamshed Kanga, M.D., is the chief of the Division of Pediatric Pulmonology at the University of Kentucky Health Care’s Kentucky Children’s Hospital and is a professor in pediatrics at the University of Kentucky College of Medicine.
“Cystic fibrosis has been known through the ages,” Kanga says. “Even the ancient Greeks knew that babies that tasted salty would die early. But it was not until 1938 that a landmark paper by a pathologist who was doing autopsies on these children that died from what used to be referred to as celiac disease found a group of patients that had changes in their pancreas, and they had changes in their lungs, which is called bronchiectasis, and said this must be a different disease.”
Causes and Symptoms of Cystic Fibrosis
That pathologist, Dr. Dorothy Anderson, published a paper that presented the first comprehensive description of what she termed “cystic fibrosis of the pancreas.” Her study ignited further research into the disease that documented its effects on digestion and pulmonary function and, decades later, identified its genetic component.
Kanga shows a chart detailing how cystic fibrosis (CF) is “a multi-organ disease.” Most people associate cystic fibrosis with impaired lung function, but Kanga notes that it also harms digestion as well as liver function, sinuses, and male fertility.
“We now understand what the basic mechanism of this disease is,” Kanga says. “And in laypeople’s terms I would say it’s a problem with salt transport.” Normally, the CFTR (cystic fibrosis transmembrane conductance regulator) protein ensures normal production of secretions in airways, digestive paths, sinuses, and elsewhere in the body. But if that CTFR protein is mutated, salt transport does not occur and thick mucus builds up, resulting in organ damage.
Cystic fibrosis is an autosomal recessive genetic disease. A person with CF will carry two copies of a mutated gene, one transferred from each parent. A person with only one copy of the gene will carry the disease but not actually have it. Therefore, with each pregnancy parents who each carry one copy of the mutated gene and are normal have a one in four chance of passing their copies to a child, giving the infant two copies of the gene and thus the disease.
“Among Caucasians, white people, it is the most common of what we call life-shortening – we used to say fatal – genetic diseases,” Kanga says. “One in 2,000 to 2,500 white babies will be born with the disease. But it’s not just a disease that’s confined to white people. Other races, including African-Americans, Hispanics, people from Asia have it, it’s been described all over the world.”
As noted above, CF affects many parts of the body, but the most severe problems occur in digestion and respiration, Kanga says. In the pancreas, mutated CF genes restrict the production of enzymes that help with food digestion. According to Kanga, this occurs in 80 percent of CF patients.
In the respiratory tract, CF causes thick and sticky mucus buildup in the lumen (inner vessel lining) of the lungs. “And this mucus causes respiratory symptoms that, initially in a child, may be very much like asthma or a viral illness – a little cough and mucus production,” Kanga says.
But this condition progresses over time, he explains. It creates a vicious cycle where the lungs eventually become infected and inflamed, because even after mucus is cleared out, it will build up again. The infection leads to cyst formation in the lungs, and eventually to respiratory failure.
“The majority of patients with CF did die from end-stage lung disease,” Kanga says. “Of course, now we have an option of a lung transplant when patients come to that point.”
Research Breakthroughs Lead to a Transformation in Care
Kanga says the gold standard for diagnosis CF in infants is a sweat test. A drug is administered to a part of a baby’s skin and then stimulated with a mild electric current, causing that area to perspire. The sweat sample is then analyzed for higher concentrations of salt.
Nowadays, genetic CF screening is available for all newborns as well, Kanga says. “For many years, CF was not tested (in infant screening),” he explains. “And there were a lot of controversies why it was not done, even though we had the technology, because truly in the past we didn’t have any treatments to offer these kids… But then it became apparent that early diagnosis does make a difference, as we started getting newer treatments.” About 15 years ago, Kentucky added a CF screen to its panel of tests for newborns – one of the first states to do so.
Kanga notes that this year marks the 30th anniversary of the discovery of the CF gene and the CTFR protein. Since 1989, researchers have identified roughly 2,000 different mutations of the CF gene that have different effects on the body. That means that not all people present with full CF symptoms as infants, and also that early screening and tests on newborns may reveal some, but not all genetic components of CF. Even if certain symptoms aren’t present in infants or they don’t have a complete genetic diagnosis, they are monitored closely going forward.
Kentucky has two cystic fibrosis centers, at the University of Kentucky where Kanga works and at the University of Louisville. “We have a very good protocol for monitoring these patients, we see them in clinic on a regular basis, every three months,” Kanga says. “We check breathing tests, pulmonary function tests, we do chest X-rays, we do labs, and we watch these patients very closely.”
Cystic fibrosis is well-known for requiring very vigilant and time-intensive treatment. Kanga says that in terms of nutrition, CF patients must eat high calorie, high protein diets and take enzymes to aid digestion as well as vitamins. This active digestive routine can lead to problems including constipation, but Kanga notes that improvements in nutrition therapy over the past couple of decades have enabled infants with CF to reach a normal level of body weight after one year and establish a normal growth curve.
“As far as the lungs go, probably the most important part of care is to get that thick mucus out, and to prevent it from staying there and getting infected,” Kanga says. Most patients must follow a breathing exercise regimen lasting 15 to 20 minutes per session and occurring two to three times a day. That is followed by chest therapy, which requires parents or medical staff to clap on the young patient’s chest, sides, and back with cupped hands to loosen up the mucus. This can be done manually or using several specialized devices.
Ongoing genetic research has created new horizon for CF treatment, Kanga says. “Over the last five to 10 years, after the discovery of the CF gene, we found that there were different defects that caused that chloride pump not to work,” he explains. “And so now we have precision medicine: if you have this (specific) gene, this drug will make that CF gene put that salt out.”
Originally, researchers developed a genetically targeted drug that worked for only 5 percent of the CF population, Kanga says, but they have since crafted a two-drug treatment that helps about 16 percent of the CF cohort. Kanga says that a triple-combination drug is currently being examined by the Food and Drug Administration. Researchers believe that if this new triple-combination drug is tested and approved, it has the potential to help over 90 percent of CF patients produce more normal mucus in their respiratory systems.
“So, when people ask me, ‘What is the life expectancy for CF?’ Well, if you look at the average today, the median expectation is about 47 to 50 years, which means half of the CF patients today will be expected to live at least until 50,” Kanga says. “But that’s looking at the whole population – patients born 20, 30, 40, even 50 years ago when we didn’t have any of these treatments. Today, I tell parents with newborn screening that we are expecting a normal life expectancy for children that are born today and diagnosed early and receive appropriate care. It’s a very exciting time in CF.”