How Cystic Fibrosis and Fabry Disease Affect the Gut
Cystic Fibrosis
When you think of cystic fibrosis (CF) and the parts of the body it affects, the lungs and respiratory system will likely come to mind. However, it also affects other parts of the body.
CF is a rare, life-shortening genetic disease caused by mutations in both copies (one from each parent) of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Those who have a single working copy are carriers, but are otherwise normal. CFTR controls the production of sweat, digestive fluids, and mucus. When it is not functional, mucus secretions that are usually thin become thickened. The condition is diagnosed by a sweat test, genetic testing and, in some countries, by screening of infants at birth.1,2,3,4
Although a rare condition, about one in every 25 Caucasians is a CFTR carrier.2 It is most common among those of Northern European ancestry and affects about one out of every 3,600 newborns, with more than 4,200 individuals in Canada living with CF.5 It is least common in those of African and Asian descent. There are at least 2,000 identified mutations in the CFTR gene, and more than 89% of individuals in Canada with CF carry at least one copy of the most common mutation, deltaF508.5 The name cystic fibrosis refers to the characteristic fibrosis and cysts that form within the pancreas.6,7 Cystic fibrosis patients have decreased lung function with the potential for frequent respiratory infections.
Cystic fibrosis has a negative effect on the gastrointestinal (GI) system, particularly interfering with the function of the pancreas. Fortunately, with the help of modern treatment options, patients with cystic fibrosis are living longer, healthier lives. This longer lifespan is likely the result of ensuring patients take in enough nutrition to make up for the nutrients their bodies are unable to absorb, and by the increasing use of new medical treatments.
The pancreas produces most of the digestive enzymes used to break food down into absorbable components. The increased mucus production blocks digestive enzymes released by the pancreas from assisting the body in absorbing nutrients, which can lead to vitamin deficiencies and malnutrition.8 A person with CF will likely need to take digestive enzymes with each meal, and consume more calories than average, because so much food can pass through the digestive tract unabsorbed. This inefficient absorption causes stools to become bulky and contain excessive fat.
Due to decreased pancreatic function, proper nutrition is vital to cystic fibrosis patients’ health and wellness. Patients can work with their physicians, registered dietitians, and other specialists to determine a dietary plan that best promotes their health within the spectrum of their disease.
In addition to malnutrition, individuals with cystic fibrosis are more likely to develop gastroesophageal reflux disease (GERD),9 which occurs when there is backflow of digestive juices and stomach acid due to a malfunction in the sphincter between the esophagus and the stomach (lower esophageal sphincter), causing discomfort and pain (heartburn). Individuals with cystic fibrosis can develop GERD as a result of their under-functioning GI systems.
Changes in diet can help greatly in combatting malnutrition in cystic fibrosis patients, but GERD is somewhat harder to remedy. By paying attention to which foods trigger their GERD and worsen symptoms, patients can more accurately determine which foods they should avoid.10 It’s likely that most will require medicinal help.
A small number of CF patients, approximately 1%, also suffer from intussusception. Intussusception is a medical condition in which a part of the intestine folds into the section next to it. It typically involves the small bowel and less commonly the large bowel. Symptoms include intermittent abdominal pain, vomiting, abdominal bloating, and bloody stool. It often results in a small bowel obstruction, with the majority of patients requiring surgical intervention.11
Fabry Disease
Another rare disease with associated GI manifestations is Fabry disease. This is a genetic disorder that results in loss or reduction of a-galactosidase enzyme activity, which is necessary for breaking down specific fatty substances found in cell membranes (globotriaosylceramide or Gb3).12 Disease progression is caused by the build-up of Gb3 in the compartments within the cell serving as recycling centres (lysosomes) and can lead to impairment of several major organs.
Fabry disease is an X-linked disorder, as the gene encoding a-galactosidase is found on the X-chromosome (one of the two chromosomes determining sex), with clinical onset typically occurring during childhood or adolescence.12,13,14 If a mother has Fabry disease, then all of her sons (XY) will develop the disease and her daughters (XX) will each receive one copy of the gene. If the mother has only one copy (carrier status), then her male and female children have a 50% chance of inheriting her defective gene and any males who receive the gene will develop Fabry disease. If the father carries the gene, then he has Fabry disease and all of his female children and none of his male children will inherit the defective gene. A woman must receive a copy of the gene from each of her parents to develop Fabry disease. The severity of Fabry disease is also sex-dependent, with males, in the majority of cases, more severely affected than females.12,13 Approximately 1 in 40,000 to 60,000 individuals in Canada has Fabry disease.14
Nerve cells, cardiac cells, renal (kidney) cells, and cells lining the blood vessels (endothelium) are particularly affected by the accumulation of Gb3 resulting in an increased morbidity and mortality due to kidney failure, heart disease, and/or early onset of stroke.12 Individuals left with untreated Fabry disease have significantly decreased life expectancy with many males succumbing to the disease by the fifth decade of life, and most females’ lifespans reduced by 15 years compared to the general population.12 Therefore, timely and accurate diagnosis followed by commencement of disease-altering therapy is paramount in achieving optimal outcomes.
Gastrointestinal symptoms can be amongst the first to present in individuals with Fabry disease. In the European Fabry Outcome Survey of 342 individuals in 2007, 52% of adult patients reported experiencing GI issues.15 Severe pain within minutes of eating and diarrhea devoid of blood or mucus are the most commonly reported issues, with almost all patients experiencing these symptoms at some point during the course of disease.13,14,15 Although diarrhea is common in up to 20% of patients, there is a subset of mostly female patients who also experience debilitating constipation.16 Additional, but less frequent, upper GI symptoms include bloating, nausea, and vomiting.
The similarity of digestive symptoms to those encountered in other disorders leads to frequent misdiagnoses – such as irritable bowel syndrome, appendicitis, and autoimmune diseases, among others – as well as mistreatment.13,16 As such, physicians should pay special attention to individuals who experience long-term GI issues who don’t have a concrete diagnosis, particularly exploring their family history, so that treatment can begin if these patients have Fabry disease.
Dysregulation of the gut nervous system caused by Gb3 accumulation in its neurons likely drives many of the gut symptoms associated with Fabry disease.13,16 Decreases in the wave-like contractions moving contents through the digestive tract (peristalsis) as well as spastic contractions of the muscular intestinal wall result in many of these observed symptoms.13,16 Slower movement of contents through the intestines can also result in bacterial overgrowth, which may contribute to reported diarrhea. In addition, alterations in the blood vessels of the gut, due to Gb3 accumulation in the endothelium further perpetuate GI issues.12,16
Medical interventions exist to target the many digestive issues associated with Fabry disease. Metoclopramide treatment offers significant improvement in patients experiencing nausea and vomiting due to dysregulated stomach emptying.13,17 In some cases, neuromodulators such as carbamazepine might help reduce abdominal pain.16 Antibiotics such as tetracycline for bacterial overgrowth could combat persistent diarrhea, along with probiotics, specific food elimination, and modified timing and quantity of meals.16,17 When there are severe complications, such as bowel obstructions or perforations, surgery may also be required.
In the event of a positive Fabry disease diagnosis, treatment should focus on the underlying issue driving complications: the accumulation of Gb3 in various cell types. Initiation of enzyme replacement therapy (ERT) as early as possible is necessary to prevent multiorgan progression and damage in the long term. The Canadian Fabry Disease Initiative (CFDI) was created in 2007 as a national registry to monitor the natural history of disease as well as the outcomes of ERT intervention.14 Several reports now suggest that long-term treatment with ERT can lead to stabilization of patients, potential reversal of disease, as well as improved health outcomes and resolution of gastrointestinal symptoms.18,19,20,21
