Table of Contents
Definition of Cystic Fibrosis
Cystic fibrosis due to defective chloride channels
Synonyms: Cystic Fibrosis, Fibrosis Cystica, CF
The term Mucoviscidosis (lat. mucus = phlegm, viscidus = tough, sticky) is used to refer to a metabolic disorder caused by an autosomal recessive defect within the CFTR-gene (cystic fibrosis transmembrane conductance regulator), of which there are more than 1,500 known mutations.
This defect causes a disruption in the function of the chloride channel, resulting in the production of sticky secretions in the exocrine glands. The body parts most affected are the epithelia of the respiratory tracts, the biliary tracts, the pancreatic duct, the small intestine, the deferent duct and the perspiratory glands.
Epidemiology of Cystic Fibrosis
Spread of mucoviscidosis
The incidence of mucoviscidosis is higher in Europe than in Africa and Asia. It is about 1 : 2,500 in Central Europe. The frequency of the heterozygous type in Germany is 1 : 25, and about 8,000 people are currently affected in Germany, with another about 3 million healthy individuals carrying a mutated gene that could be passed on.
Etiology and Pathogenesis of Cystic Fibrosis
The mutation of the genetic defect most commonly known in Central Europe and North America is the △F508-Mutation: This deletion in the DNA causes the loss of the amino acid phenylalanine in position 508 in the CFTR-gene.
Discursion: The type of mutation is crucial in determining the severity of the disease. There are four distinct stages:
- No gene expression of CFTR.
- The CFTR channel can be constructed, but cannot be built into the membrane or be located (applies to △F508-Mutation).
- The channel is expressed and built in, but cannot open anymore due to the mutation.
- The protein does not fold correctly, and therefore the channel does not open properly anymore.
As a result of the genetic defect, the chloride channel loses its ability to release chloride and bicarbonate ions from the cell. The increased sodium absorption leads to the formation of tough bronchial mucus in the lung and a backlog of mucus (Mucostasis), due to the lack of osmotic water absorption from the tissue. The obstipation and inflammation resulting from this eventually lead to complete organ destruction and function deficiency.
Impact of mucoviscidosis on various organ systems
- Lung: Blockage of mucociliary clearance; obstruction of the alveoli / bronchioles with an increased risk of infection because of clusters of pathogenic germs; destruction of the lung and reformation into a honeycomb lung because of chronic inflammations.
- Pancreas: Blockage of the exocrine gland’s secretion outlets, fibrotic and cystic mutation, loss of exocrine function.
- Gall: Obstruction of bile drainage, development of biliary cirrhosis.
- Intestines: Obstipation.
- Perspiratory glands: CFTR-channel loses ability to reabsorb chloride ions from primary sweat, leading to high NaCI concentrations in secondary sweat.
Clinical Signs of Cystic Fibrosis
Symptoms of mucoviscidosis
Mnemonic: CF PANCREAS
C – Chronic cough
F – Failure to thrive
P – Pancreatic insufficiency (exocrine)
A – Alkalosis and hypotonic dehydration
N – Nasal polyps, neonatal dehydration
C – Clubbing of fingers (Hippocratic fingers and nails)
R – Rectal prolapse
E – Electrolyte elevation (sweat)
A – Atresia, Absence of vas deferent
S – Sputum with staph or pseudomonas
Lung and respiratory tract
Cystic Fibrosis patients suffer from chronic productive cough. The tough secretion can barely drain, which results in recurring bouts of bronchitis and pneumonias (bacterial, especially Pseudomonas aeruginosa and Staphylococcus aureus).
The increasing lung insufficiency leads to anoxia and exertional dyspnea and bronchiectasis. The oxygen deficiency manifests itself clinically in hippocratic fingers and nails.
10 – 50 % of patients develop polyposis nasi and a chronic pansinusitis in the lower respiratory tract.
First, the disease usually manifests itself in young patients as meconium ileus, and very rarely meconium plug syndrome. Other symptoms include icterus prolongatus, obstipation, abdominal cramps, flatulence and steatorrhea (fatty and pestilential stools).
Tough stool can cause a rectal prolapse. The manifestation of exocrine pancreas insufficiency leads to the malabsorption of nutrients and liposoluble vitamins.
Due to the lack of digestive enzymes, the body is deprived of the macro- and micronutrients that are absorbed with food. Malabsorption in turn leads to a failure to thrive (dystrophy), despite the patients’ showing a much increased demand for energy.
Genital organs and reproduction
Male teenagers affected by CF can experience obstructive azoospermia and infertility because of bilateral aplasia and atresia of the deferent duct.
|Exacerbation of the pulmonary disease||Severe cough, sputum production, clinical pulmonary report: rhonchus ↑, rale ↑, dyspnoea, lung function ↓, use of accessory respiratory muscles ↑, appetite ↓, weight ↓, fever, exhaustion|
|Spontaneous pneumothorax||Danger of spontaneous pneumothorax as lung destruction advances|
|Chronic germ population (Evidence of one germ in at least three sputum cultures in at least six months)||Toddlers: Staphylococcus infection, haemophilus influenzae
Children and teenagers: Pseudomonas aeruginosa (biofilm formation), stenotrophomonas maltophilia
|Allergic bronchopulmonary aspergillosis (ABPA)||Anamnesis: Poor general condition, irritation of the throat ↑, chest pain ↑, fever, subfebrile temperature|
|Biliary cirrhosis||Bile duct obstruction in adults|
|Endocrine pancreas insufficiency||Development of diabetes mellitus including the destruction of the islets of Langerhans in adulthood|
|Haemoptysis||Haemorrhage of pulmonary arteries, with potentially lethal outcome if blood loss more than 0.5 l in 24 hours|
Initial diagnostics of mucoviscidosis
Clinical symptoms usually lead to the suspected diagnosis of mucoviscidosis, which is then confirmed by more tests and procedures.
The sweat test is considered the gold standard of diagnostics (determination of the NaCl-concentration by stimulating sweat using pilocarpine iontophoresis). The chloride ion concentration in the sweat must be > 60 mmol/l in two recordings.
Genetic mutation analysis
In case of borderline values, the sweat test should be retaken as well as a genotyping performed. The genetic mutation analysis captures almost 90 % of those affected. Mucoviscidosis can already be detected in prenatal diagnostics by means of CFTR-genotype analysis prior to birth.
This procedure makes sense for siblings of index patients and mucoviscidosis patients wishing to have children.
Transepithelial potential difference
In case of a clinical suspicion with no evidence of CFTR-mutations, the transepithelial potential difference can be detected in the Using chamber (using tissue of the nasal and rectal mucosae). Pathological levels range from -100 mV to 60 mV.
Pancreas insufficiency can be detected when screening the stool for pancreas elastase, which is reduced in CF patients.
In case of suspected mucoviscidosis, a blood test for immunoreactive trypsin can be performed as part of the neonatal screening. It is, however, not standard routine procedure.
Development diagnosis of mucoviscidosis
- Chronic (> 3 Mon) cough, sputum production, whistling breath, Hippocratic fingers
- Hyperkyphosis with chicken or funnel breast due to pulmonary hyperinflation;
- Chronic rhinosinusitis with / without nasal polyps, often exacerbating during childhood and adolescence;
- Nutritional status: Dystrophy, hypoproteinemia and edemas.
- Electrolyte (Na+, K+, Ca2+)
- Liver parameter (GOT, GPT)
- Cholestasis parameter (liver-specific alkali phosphatase)
- Pancreas function reading (lipase, P-amylase)
- Breakdown of liposoluble vitamins
- Upper abdominal sonography;
- Thorax X-ray: Persistent pulmonary image findings: bronchiectasis, atelectasis, infiltrates, hyperinflation, enlarged hilar lymph nodes; late stage: pulmonary heart disease;
- Thorax-CT: Possibility of abscesses, aspergillum infection.
- Persistent detection of staphylococcus aureus, haemophilus influenzae, pseudomonas aeruginosa and burkholderia cepacia in respiratory secretion and sputum.
Similar diseases to mucoviscidosis
|Asthma||Allergy anamnesis, reversible lung obstruction with peribronchial thickening, hyperinflation, air-trapping, atelecstasis, complications due to allergic bronchopulmonary aspergillosis|
|Primary ciliary dyskinesia||Congenital dysfunction of the ciliated epithelium, recurring sinobronchial infections, more bland lung changes, recurring aspiration, Kartagener syndrome|
|Recurring aspiration||Bronchiectasis (frequently in the inferior lobe and posterior lung segments), common with neuromuscular diseases|
Therapy of Cystic Fibrosis
Once diagnosed, mucoviscidosis patients should be treated multi-modally where possible. Antibiotic therapy is crucial, since it can slow down the progression of the disease. See the following comprehensive overview for details on the particular pathogens and therapeutics.
Multimodal therapy for mucoviscidosis
|Organ / Pathophysiology||Therapy|
|Exocrine pancreas insufficiency||Dose of pancreas enzymes with defined lipase and protease concentration with every meal|
|Failure to thrive, dystrophy||High calorie normal diet (patient-specific and rich in fat), no restriction on fat, enteral nutrition via PEG|
|Vitamin deficit||Prophylactic substitution of liposoluble vitamins in supra normal doses|
|Deficit of minerals and trace elements||Substitution in case of detectable deficiency|
|CF-diabetes||Fare adjusted to energy demand, no restriction on carbohydrates, reduction of blood sugar by means of oral diabetics medication or insulin|
|Lung infections, respiratory lung insufficiency||
|Liver cirrhosis, cholestasis, portal vein pressure||
|Hypotone dehydration and hypochloremic alkalosis||In case of high outside temperature, sweating, fever, infections, throwing up, diarrhea, NaCl to be added increasingly to food|
Antibiotics therapy for mucoviscidosis
One distinguishes between two different types of antibiotics therapy: Exacerbation therapy and long-term prophylactic therapy.
Long-term prophylactic therapy
This therapy is usually aimed at the pathogen pseudomonas aeruginosa. It is administered irrespectively of symptoms and pathogenic evidence.
This type of therapy is linked to symptoms and should be adjusted to the antibiogram and the specific pathogenic evidence.
- Staphylococcus aureus: Cephalosporine of the 1st and 3rd generation, Flucloxacillin, Piperacillin with Tacobactam, Clindamycin, Fosfomycin, Imipenem, Cotrimoxazol
- Haemophilus influenza: Cephalosporine of the 2nd/3rd generation
- Pseudomonas aeruginosa: Ciprofloxacin, Ceftazidim, Cefepim, Piperacillin with Tazobactam, Meronpenem, Imipenem, Aztreonam, Tobram, Aminoglykoside
- Burkholderia cepacia: Meropenem and Piperacillin, Ceftazidim, Trimethoprim, Sulfmethoxazol, Cotrimoxazol, Doxycyclin, Minozyklin, Chloramphenicol, Ciprofloxacin and Aminoglykoside
- Stenotrophomonas maltophilia: Trimethroprim/Sulfmethoxazol, Cotrimoxazol, Doxycycline
Prognosis of Cystic Fibrosis
Cystic fibrosis patients live to be between 30 and 40 years when treated optimally. 50 % of patients die before age 18 from respiratory failure.
The prognosis depends on several factors:
- Time of diagnosis (neonatal screening)
- Population of resistant pathogens
- Lung function
- Complications (see above)
- Pregnancy: Women suffering from CF are fertile, in contrast to men. The CFTR-allele is passed on from the mother to the fetus. The child is hence at a 1 : 50 risk of falling ill with mucoviscidosis, too.
The answers are below the references.
1. Which test is diagnostically most conducive for mucoviscidosis?
- Determination of antibodies against calcium channels
- Determination of antibodies against transglutaminase
- Concentration test
- Gastroesophageal pH/monitoring
- Sweat test
2. Certain pathogens can cause complications, especially at an advanced stadium of mucoviscidosis and are particularly dreaded. Which of the following germs does this apply to most?
- Bacteroides fragilis
- Pneumocystis jiroveci
- Bartonella henselae
- Burkholderia cepacia
- Corynebacterium amycolatum
3. Besides the accumulation of problematic germs, a range of other manifestations and complications affecting different organs can occur with mucoviscidosis. Which of the following complications in the respiratory tract does not typically count among them?
- Monocellular Bronchial-CA
- Nasal polyps
- Allergic bronchopulmonary aspergillosis