Aetiology and Pathophysiology

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on the long arm of chromosome 7 at 7q31.2.

 

CFTR is a cyclic-AMP (cAMP) regulated chloride channel which also regulates...

  • Other ion channels including sodium (and therefore water movement across the membrane)
  • Composition of cell surface glycoproteins
  • Anti-bacterial defences

Epidemiology

1/25 people are carriers in the UK, and the prevalence of CF is 1/2500 people. The majority of those affected are Caucasian. The only risk factor is a positive family history.

The CFTR comprises two membrane spanning domains (MSD), two nucleotide binding domains (NBD) and a regulatory domain (R). Normally, NBD1 interacts with R in response to cAMP to open and close the channel for intracellular Cl- to flow out.

 

Mutations result in retention of intracellular Cl- and Na+ and the cell makes thick and sticky, salty secretions which reduce mucociliary clearance, favouring bacterial colonisation. Salt also impairs local bacterial defences and a change in glycoproteins increases their adherence. Over 1000 different mutations have been described, the most common being ΔF508 (the deletion of phenylalanine).

 

Presentation

The CFTR mutation has systemic consequences resulting in a complex presentation of symptoms. The age of presentation varies depending on functional decline, as normal function may be preserved despite 95% pancreatic insufficiency. Common problems are summarised in the table below.

CF Presentation

i) Respiratory -

Patients may describe a picture of recurrent chest infections that are hard to clear, a chronic cough and shortness of breath. The cough tends to be dry early on but later, patients can bring up mucous and pus. They may have a chronic wheeze and recurrent sinus pain and nasal congestion.

Common pathogens of the recurrent LRTIs in CF patients include:

  • Staph aureus
  • Haemophilus influenzae
  • Psuedomonas aeruginosa - dangerous!
  • Burkholderia cepacia - dangerous!
  • E. Coli
  • Klebsiella pneumoniae

 

They also get an inflammatory lung reaction by neutrophils and related mediators. Pulmonary fibrosis may lead to cor pulmonale or ventricular failure. CF patients commonly get nasal polyps.

  

ii) Pancreatic -

Stagnated secretions in pancreatic ducts cause localised autolysis causing an initial exocrine malabsorptive disorder (vitamins A, D, E and K are a particular problem) which leads to endocrine dysfunction causing secondary diabetes mellitus.As an infant, they may have 'failure to thrive.' This is a presentation whereby an infant starts to fall off of their growth and weight charts despite eating adequately. This presentation has a wide differential list (including other malabsorptive conditions and neglect). Patients may be shorter and/or thinner than their siblings, or struggle to put on weight. They may experience recurring bouts of abdominal pain and distension.

They may have unexplained bruising or bone deformities such as bowed legs. A patient with secondary diabetes would present with a triad of polyuria, polydipsia and fatigue.

 

iii) Hepatobiliary -

Defective ion transfer across the bile duct lessens water concentration in bile. 

This leads to primary biliary cirrhosis and hepatic damage, which could lead to portal hypertension and varices that could bleed (haematemesis). Infants may appear jaundiced.

 

iv) GI

The gut is affected by a low intraluminal water concentration.

The main GI presentation in neonates is meconium ileus, which can cause a small bowel obstruction. CF accounts for 7-10% of cases of meconium ileus, so this should be an alarm bell for CF if you see this. These patients will present with an obstructive picture (bilious vomiting, abdominal distension and constipation). Neonates may also suffer from volvulus (where the bowel twists and kinks on itself), intestinal atresia, perforation or peritonitis.

Infants may suffer from intussusception, where the bowel ‘telescopes’ and they present with severe abdominal pain (often drawing their knees up to their chest) and pass ‘jelly red’ stools.

Patients experience diarrhoea and steatorrhoea (fatty, loose, floating stools).

 

v) Urogenital (& fertility) -

This is more a problem for men, whose vas deferens and epididymis may be absent, or present but obstructed. Boys are also more likely to suffer undescended testicles or hydroceles in CF.

Women may be subfertile, having more cervical mucus for sperm to penetrate. They may also report delayed sexual development and in more severe illness may suffer amenorrhoea.

O/E

Respiratory

Inspection - 

  • Signs of respiratory distress – tachypnoea, intercostal or sternal recession, tracheal tug, cyanosis
  • Clubbing (a sign with relatively few differentials, so is an important clue!)

 

Percussion -

  • May be normal or hyperresonant

 

Auscultation - 

  • Crackles
  • Rhonchi
  • Wheeze

 

ENT

  • Nasal congestion
  • Nasal polyps (may erode sinus wall) - see image below from Dermatology Images, of a 7 year old girl with CF, with a left sided nasal polyp
7 year old girl with CF and left sided nasal polyp

GI

Inspection –

  • Distension
  • Jaundice (look at skin, sclera and check under the tongue)
  • Dry skin
  • Rectal prolapse
  • Bloody nappy (intussusception)

 

Palpation –

  • Hepatosplenomegaly

 

Urological

  • Absent vas deferens (may be present)

 

Musculoskeletal

  • Bowed legs
  • Kyphosis
  • Scoliosis

Differential Diagnosis

Respiratory -

  • Asthma
  • Bronchiolitis
  • Bronchiectasis
  • Aspergillosis
  • Sinusitis

 

GI/Pancreatic -

  • Malabsorptive - coeliac disease, inflammatory bowel disease
  • Neglect
  • Constitutional delay in growth

 

Some complications may be assumed to be an isolated problem rather than part of a bigger picture e.g. rickets, intussusception, undescended testes.

Investigations

Sweat test – passes electric current through skin using macroduct band system. Positive result = Cl- >60mmol/l (40-60 borderline, 10-20 normal) and Cl- > Na+. Accurate in children, less so in adults. Can give false positives in anorexia, hypothyroid, adrenal insufficiency, atopic dermatitis, coeliac disease.

 

Guthrie heelprick test - for 1-2 week neonates (ineffective if >8 weeks old). Positive if immunoreactive trypsin level >80mcg/l. False positives can occur if encephalopathic or in haemorrhagic shock.

 

To identify carriers - Mouthwash test – genotyping of buccal cavity’s epithelial cells.

To monitor - Spirometry - FEV1 shows obstructive picture. Unreliable if <6 yrs old.

Other -

  • LRTIs e.g. CXR, sinus XR, sputum microbiology, etc.
  • Fertility – semen analysis may show obstructive azoospermia

Diagnostic Criteria

1. ≥1 of phenotypic features (chronic sinopulmonary disease/GI and nutritional abnormalities/salt loss syndromes/obstructive azoospermia) OR Hx of CF in sibling OR Positive newborn screening test

AND

2. CFTR abnormality demonstrated e.g. by sweat test

Management

This is complex and will depend on the stage of the clinical course and disease severity. Patients with CF require a multiple disciplinary approach to their care and management. This will involve respiratory physicians, specialist nurses, physiotherapists and occupational therapists.There are no current DoH, SIGN or NICE guidelines, though the Cystic Fibrosis Society provides some brilliant documents about specific management areas:  http://www.cftrust.org.uk/aboutcf/publications/consensusdoc/

1. Respiratory

  • Chest physio x2 day. Moreso in LRTIs and increased exercise
  • Bronchodilators
  • Inhaled steroids
  • Mucolytics e.g. pulmozyme, hypertonic saline (4.5-7%) - drawing water into airway
  • Steroids for nasal polyps (polypectomy if fails)
  • Treatment of LRTIs depending on organism, with nebulised antibiotics

 

In end stages -

  • Bronchial artery embolisation to prevent bleeding
  • Pneumothoraces drained
  • Non-invasive ventilatory support
  • Lung and heart/lung transplants (70% 1yr survival)

 

2. Pancreatic

  • High calorie intake (130% normal)
  • Pancreatic supplements
  • Vitamins A, D and E and calcium supplements
  • Insulin for diabetes and suitable lifestyle advice

 

3. Hepatobiliary

  • Ursodeoxycholic acid improves bile flow
  • Some may need liver transplant - 80% 1yr survival.

 

4. Gastrointestinal

  • Laxatives for some
  • High fluid intake

 

5. Fertility

  • Counselling
  • IVF has been successful

 

6. Psychological – not to be forgotten!

  • Advice and support
  • Charitable groups and organisations
  • Counselling for patient, partner and family, possibly for children

Prognosis

CF is an incurable lifelong condition. This is likely to have a significant psychological impact on the patient and their loved ones.

Mean survival time for a CF patient will depend on the level of CFTR activity and disease severity, the age of diagnosis and the treatment package. Thanks to research, earlier detection and advancing interventions, has increased over the years and now, the mean survival time for a patient with CF is now 40-50 years.

Summary Points

  • Cystic fibrosis (CF) is a relatively common autosomal recessive disease
  • They suffer from a multi-system dysfunction with thick, sticky secretions and a predisposition to recurrent lower respiratory tract infections (LRTIs)
  • Diagnosis is made by the sweat test
  • They require lifelong multi-disciplinary management

References

Patient UK - Cystic Fibrosis

Cystic Fibrosis Trust

Oxford Handbook of Clinical Specialities, 8th Edition

Cystic Fibrosis Foundation Consensus Panel - the diagnosis of CF: a consensus statement 1998

Clinical Knowledge Summaries - Cystic Fibrosis

GP Notebook - Cystic Fibrosis

Dermatology Image Atlas: Dermatology Images - http://dermatlas.med.jhmi.edu/derm/indexDisplay.cfm?ImageID=1902261790

Medscape - Cystic Fibrosis

Advertisement

Fastbleep © 2019.