Cystic fibrosis: symptoms, signs, diagnosis, tests
Cystic fibrosis is a rare autosomal recessive genetic disease caused by a mutation in a gene located on chromosome 7, which codes for a protein that functions as a channel for chlorine, called CFTR (Cystic Fibrosis Transmembrane conductance Regulator)
Cystic fibrosis, once fatal in the first year of birth, is now a disease that can be cured, however it remains a severely debilitating disease that lowers the patient’s quality of life and decreases life expectancy.
Symptoms and signs of Cystic Fibrosis
The hallmarks of cystic fibrosis are sallow skin, poor growth and weight gain despite normal food intake, accumulation of thick, sticky mucus, frequent lung infections and coughing or shortness of breath.
Males may be infertile due to the congenital absence of vas deferens.
Symptoms often appear during childhood, such as intestinal obstruction due to pathological meconium ileus in infants.
As children grow, there are complications in the release of mucus into the alveoli.
The patient’s epithelial hair cells have a mutated protein that leads to the production of abnormally viscous mucus.
Poor growth in children typically presents as an inability to gain weight or height compared to their peers.
The condition is often not diagnosed until the causes of this poor growth are sought.
The causes of growth failure are multifactorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract and increased metabolic demand due to the chronic disease state.
In rare cases, cystic fibrosis can manifest itself as a blood clotting disorder.
Young children are particularly susceptible to vitamin K malabsorption disorders because only a small amount of this vitamin crosses the placenta, leaving the child with very low reserves.
Since factors II, VII, IX and X (coagulation factors) are vitamin K-dependent, low levels of it can cause problems.
Lung pathology is the consequence of airway obstruction caused by mucus accumulation, reduced mucociliary clearance and inflammation.
Lungs in Cystic Fibrosis
Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms.
In the early stages, incessant coughing, profuse sputum production and reduced lung capacity are common conditions.
Many of these symptoms occur when bacteria, which normally inhabit the thick sputum, grow out of control and cause pneumonia.
In later stages, changes in the structure of the lung, such as pathologies of the main airways (bronchiectasis), further aggravate breathing difficulties.
Other symptoms include coughing up blood (haemoptysis), high blood pressure in the lungs (pulmonary hypertension), heart failure, difficulty getting enough oxygen (hypoxia) and respiratory failure requiring support with breathing masks.
Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa are the three most common organisms causing lung infections in patients with cystic fibrosis.
In addition to typical bacterial infections, people with the condition usually develop other types of lung diseases.
These include allergic bronchopulmonary aspergillosis, in which the body’s response to the common fungus Aspergillus fumigatus causes respiratory problems to worsen.
Another disease is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause lung damage and do not respond to common antibiotics.
Mucus present in the sinuses is equally dense and can also cause blockage of the passages, resulting in infection.
This can cause facial pain, fever, nasal discharge, headache and increased breathing difficulties.
Persons with cystic fibrosis may develop excessive growth of nasal tissue (naso-sinus polyposis) due to inflammation from chronic sinus infections.
Recurrent polyps may occur in about 10% to 25% of cystic fibrosis patients.
Cardiorespiratory complications are the most common cause of death (~80%) in patients with the condition.
Gastrointestinal signs and symptoms of Cystic Fibrosis
Before prenatal and neonatal screening, cystic fibrosis was often diagnosed when an infant was unable to expel faeces (meconium). Meconium can completely block the intestine and cause serious illness.
This condition, called meconium ileus, occurs in 5-10% of infants with cystic fibrosis.
In addition, protrusion of the inner rectal membrane (rectal prolapse) is more common, occurring in about 10 per cent of children with the condition, and is caused by increased faecal volume, malnutrition and increased intra-abdominal pressure caused by coughing.
Pancreas
Abnormal secretions in the pancreas block the movement of digestive enzymes in the duodenum and cause irreversible damage to the pancreas, often resulting in painful inflammation (pancreatitis).
In more severe and advanced cases, the pancreatic ducts appear atrophic.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with cystic fibrosis.
It is mainly associated with ‘severe’ mutations in the CFTR gene, in which both alleles are completely non-functional (e.g. ΔF508/ΔF508).
It occurs in 10-15% of patients with one ‘severe’ and one ‘medium’ mutation of the CFTR gene, where there is still mild CFTR activity or where there are two ‘medium’ mutations.
In these milder cases, there is still sufficient exocrine function of the pancreas so that enzyme supplementation is not necessary.
Dense secretions can also cause liver problems.
Bile secreted to aid digestion can block the bile ducts, causing liver damage.
Over time, this can lead to scarring and nodularity (cirrhosis).
The liver fails to clear the blood of toxins and fails to synthesise important proteins, such as those responsible for blood clotting.
Liver disease is the third most common cause of death related to cystic fibrosis.
In addition to pancreas problems, people with cystic fibrosis complain of heartburn, intestinal blockage from intussusception, and constipation.
Elderly individuals with cystic fibrosis may develop distal intestinal obstruction due to thickened stools.
Malnutrition
A lack of digestive enzymes leads to difficulty absorbing nutrients, with their subsequent excretion in the faeces: ‘malabsorption’.
Malabsorption leads to malnutrition by default and poor growth.
The resulting hypoproteinaemia can be severe enough to cause generalised oedema.
Individuals with cystic fibrosis also have difficulty absorbing fat-soluble vitamins A, D, E and K.
Diabetes in cystic fibrosis
Damage to the pancreas can lead to the loss of insular cells, causing a form of diabetes characteristic of cystic fibrosis sufferers.
This is one of the most important non-pulmonary complications of the disease. Diabetes is the most frequent non-pulmonary complication in cystic fibrosis cases.
It is recognised as a distinct entity, and has mixed features of type 1 and type 2.
Although oral diabetes drugs are used, the only recommended treatment consists of insulin injections or the use of an insulin pump.
Unlike classic diabetes, no dietary restrictions are recommended.
Vitamin D, osteoporosis and Hippocratic fingers
Vitamin D is involved in calcium and phosphate regulation.
Poor absorption of vitamin D in the diet, due to malabsorption, can lead to osteoporosis, a condition in which weakened bones are more prone to fractures.
In addition, people with cystic fibrosis often develop so-called hippocratic fingers (also called clubbing) due to low oxygen content in their tissues;
Infertility in patients with Cystic Fibrosis
Infertility affects both men and women.
At least 97% of men with cystic fibrosis are infertile but not infertile and can have children with assisted reproduction techniques.
The main cause of infertility in men with cystic fibrosis is the congenital absence of the vas deferens (which normally connect the testicles to the ejaculatory ducts of the penis), but there may also potentially be additional problems that may cause azoospermia, teratospermia and oligoasthenospermia.
Some women experience difficulties in procreation due to thickening of the cervical mucus or due to malnutrition.
In severe cases, malnutrition interrupts ovulation and causes amenorrhoea.
Diagnosis of Cystic Fibrosis: anamnesis
Cystic fibrosis is initially recognised during childhood or childhood; however, in a small proportion of patients, the diagnosis is made in adulthood.
Patients with cystic fibrosis frequently first manifest recurrent lung infections.
Children with cystic fibrosis have more frequent and prolonged respiratory infections than normal children.
Most children with cystic fibrosis present with chronic coughing and wheezing.
As the disease progresses, symptoms related to bronchiectasis and bronchial hypereactivity become prominent.
Digital hippocratism and dyspnoea on exertion are also observed.
Fever is mostly mild during the exacerbation of bronchiectasis, but can be very high during episodes of pneumonia.
In advanced stages of the disease, complications due to pulmonary involvement include haemophthisis, which is occasionally massive, pneumothorax, atelectasis, pulmonary heart and respiratory failure.
Pancreatic involvement in the presence of cystic fibrosis causes exocrine pancreatic insufficiency.
Lack of pancreatic enzymes causes difficult digestion and malabsorption.
Exocrine pancreatic insufficiency is associated with diarrhoea and stools that contain large amounts of fat.
These symptoms are frequently associated with cramping abdominal pain, malnutrition and inability to maintain an adequate growth rate.
Other less common gastrointestinal symptoms detectable at history include meconium plugs, intussusception (slipping of one part of the intestine into another part); rectal prolapse, intestinal obstruction, prolonged neonatal jaundice, liver cirrhosis, cholelithiasis (gallstones in the gallbladder); recurrent pancreatitis and diabetes mellitus.
Abnormalities in sweat production are manifested by an elevated concentration of salts in sweat.
This increase in salts causes a salty taste in the skin and the development of salt crystals on the skin or inside clothing, particularly in shoes and boots.
Loss of electrolytes during the summer months can result in heat intolerance, heat prostration, electrolyte depletion and dehydration.
On history, symptoms related to the upper respiratory tract include recurrent sinusitis and the development of nasal polyps.
Almost all men and most women with cystic fibrosis are infertile.
If a woman with cystic fibrosis becomes pregnant, it is not certain that she will carry the pregnancy to term.
The unborn child will either have cystic fibrosis or carry the cystic fibrosis gene.
Diagnosis: objective examination
The objective examination of patients with cystic fibrosis is almost always abnormal within a few years of diagnosis of the disease.
Patients are usually thin children or young adults.
If respiratory distress is present, the accessory muscles of respiration are used.
A productive cough is an almost universal finding. examination of the extremities may reveal digital hippocratism.
Examination of the upper airway reveals the presence of nasal polyps or soreness at the paranasal sinuses.
The thorax appears to have a barrel configuration.
The lungs present gross crackles and hisses.
In the advanced stage of the disease, hypoxemia manifests with cyanosis around the mouth.
Auscultation of the heart may reveal a pulmonary component of the second tone, indicative of pulmonary hypertension.
Distention of the jugular veins in the neck and pedidium oedema are associated with the development of right-sided heart failure (pulmonary heart).
Diagnosis: laboratory tests
On haemogasanalysis, blood gas values are almost normal in the early stages of the disease apart from an increase in the alveolar-arterial oxygen gradient.
Hypoxaemia in ambient air increases as the disease progresses, while hypercapnia and severe hypoxaemia only appear in the very advanced stages of lung disease.
In cystic fibrosis, on the other hand, serum biochemical findings and the haemochromocytometric examination do not show typical alterations.
However, an elevation of serum bicarbonates can be observed as a consequence of chronic respiratory insufficiency, while the elevation of the haematocrit may reflect chronic hypoxaemia.
The onset of acute bronchopneumonia may lead to elevation of white blood cells with a subsequent appearance of the more immature forms of granulocytes.
In contrast, serum protein and albumin concentrations may be low in the presence of malnutrition.
Measuring the electrolyte content of sweat has been the standard technique for diagnostic confirmation of cystic fibrosis.
After the secretion of sweat is stimulated, it is collected tightly and after the collection of approximately 0.1 ml of sweat, the electrolyte content is measured.
In paediatric age, the diagnosis of cystic fibrosis is made in the presence of a chlorine concentration in the sweat of more than 60 mEq/l, while in adult age, a chlorine concentration of more than 80 mEq/l is required for this diagnosis to be made.
If the response to this test is doubtful (between 50 and 80 mEq/l), repeating this measurement can resolve the diagnostic doubt.
Although the electrolyte concentration in sweat is useful in confirming the diagnosis of cystic fibrosis, this assessment must be carried out meticulously or the results may be confusing.
Patients with cystic fibrosis typically have pathogenic microorganisms in their sputum; the 3 most frequently encountered are Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa.
The strain of P. aeruginosa found in cystic fibrosis patients typically produces mucin.
This mucoid form of P. aeruginosa is almost only found in patients with cystic fibrosis and is almost exclusively found in the airways of those with advanced forms of the disease.
Severe exacerbations can however be caused by several different mucin-producing strains of P. aeruginosa.
Diagnosis of Cystic Fibrosis: spirometry
Pulmonary function tests are very useful in assessing the extent of the pulmonary disease process and in following the rate of progression.
Following the progression of the disease process allows the clinician to increase therapy if lung function deteriorates unexpectedly.
Spirometry typically shows airway obstruction with a reduction in forced expiration volume in 1 second (FEV1), while in advanced stages of the disease, loss of forced vital capacity (FVC) can be observed.
Both of these changes may, however, improve after administration of bronchodilators.
Residual volume increases early in the course of the disease and can be validly measured using a body plethysmograph.
Diagnosis: imaging
Chest X-ray characteristically shows hyper-expansion, diagnosed by flattening of the hemidiaphragms and increased retrosternal air space.
Thickening of the bronchial wall in the form of parallel lines radiating outwards from the pulmonary hilum and called ‘train track’ is also commonly observed.
Small round opacities are also evident in the periphery of the lung, which may represent small abscesses located distal to the obstructed airway.
These areas usually clear leaving small residual cysts from the infectious process.
Other abnormalities observable on chest X-ray include atelectasis, fibrosis, hilar adenopathy, bronchopneumonia and pneumothorax.
Diagnosis: genetic testing
The discovery of the cystic fibrosis gene has also made it possible to perform genetic diagnostic tests for certain genetic abnormalities associated with cystic fibrosis.
Evaluation of the delta F508 gene alone will, in fact, make it possible to identify around 70% of abnormal genes or around 50% of affected patients.
Since the test cannot, however, identify 100 of the cystic fibrosis genes, it is more appropriately reserved for the evaluation of patients with suspected cystic fibrosis who show doubtful results on the sweat test or individuals who require genetic counselling because they are at high risk for conceiving children with cystic fibrosis.
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