Cystic fibrosis (cf, mucoviscidosis) — symptoms and diagnosis brain anoxia

Image: “cystic fibrosis has an autosomal recessive pattern of inheritance” by en:user:cburnett. License: CC BY-SA 3.0 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.Brain anoxia


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.Brain anoxia 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.Brain anoxia

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

Image: “lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation ” by puzik A, morris-rosendahl DJ, rückauer KD, otto C, gessler P, saueressig U, hentschel R. License: CC BY 2.0

First, the disease usually manifests itself in young patients as meconium ileus, and very rarely meconium plug syndrome.Brain anoxia 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.Brain anoxia

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

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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

Diagnostics of cystic fibrosis initial diagnostics of mucoviscidosis

Clinical symptoms usually lead to the suspected diagnosis of mucoviscidosis, which is then confirmed by more tests and procedures.

Sweat test

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.Brain anoxia

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.

Pancreatic elastase

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Pancreas insufficiency can be detected when screening the stool for pancreas elastase, which is reduced in CF patients.

Neonatal screening

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

Clinical

• 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.

Lab

• electrolyte (na+, K+, ca2+)

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• liver parameter (GOT, GPT)

• cholestasis parameter (liver-specific alkali phosphatase)

• pancreas function reading (lipase, P-amylase)

• breakdown of liposoluble vitamins

• CRP

Medical imaging

• 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.

Microbiology

• persistent detection of staphylococcus aureus, haemophilus influenzae, pseudomonas aeruginosa and burkholderia cepacia in respiratory secretion and sputum.

Differential diagnoses of of cystic fibrosis similar diseases to mucoviscidosis

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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

• respiratory physiotherapy

• autogene drainage (supporting bronchial clearance)

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• endurance sports (jogging, swimming, bicycling)

• inhalation of bronchodilators (β-sympathomimetics), antibiotics, mucolytics (recombinant rdna) for secretolytics treatment

• antimycotics and immunosuppressors in case of bronchopulmonary aspergillosis

• schematized antibiotic therapy strategies

• external administration of oxygen, ventilatory support

• vaccination against all lung germs: pertussis, pneumococci, influenza, haemophilus influenzae

• pneumectomy: indicated in case of recurring inflammation of pulmonary lobes that has a negative impact on the general condition

• lung transplantation: after exploitation of all therapeutic measures, insufficiency of both lungs, remaining life expectancy 2 years

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Liver cirrhosis, cholestasis, portal vein pressure

• treatment with ursodeoxycholic acid, possibly combined with taurine

• portosystemic shunts

• sclerotization of esophageal varices

• operative gallstone removal

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.Brain anoxia

Exacerbation therapy

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

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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.

Review questions

The answers are below the references.

1. Which test is diagnostically most conducive for mucoviscidosis?

• determination of antibodies against calcium channels

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• 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

• pneumothorax

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• nasal polyps

• allergic bronchopulmonary aspergillosis

• haemoptysis