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Pulmonary > Cystic Fibrosis > Flashcards

Cystic Fibrosis Flashcards

1
Q

Epidemiology of Cystic Fibrosis

A
  • one of the most lethal autosomal recessive diseases in US
  • 30,000 people living with it in US; 70,000 world wide
  • 1,000 new cases/year in US
  • 75% diagnosed by 2yo
  • half th epop with CF 18 yo
  • median survival age 40 yo
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2
Q

CFTR

A

•Cysic Fibrosis Transmembrane Conductance Regulator

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3
Q

CF Genetics

A
  • q31.2 locus, long arm of chromosome 7
  • 230,000 bp long
  • 1480 aa long
  • Most common mutation, ΔF508 is a deletion (Δ) resulting in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein (70% of alleles)
  • Over 1,800 mutations documented with ~ 150 causing disease
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4
Q
A
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5
Q

CF Genetics - Lung

A
  • Lung disease not correlated with specific genotype, but with class of mutation
  • Gene modification likely determines 40-50% of the pulmonary phenotype
  • Highly variable phenotype within specific genotypes; e.g. siblings
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6
Q

CF Genetics - Pancreas

A
  • Pancreatic disease requires both alleles to be ‘ severe ’ for pancreatic dysfunction
  • Highly variable phenotype within specific genotypes; e.g. siblings
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7
Q

CF Impacts Many Epithelial Systems

A
  • CF Arthropathy/ CF Arthritis
  • Osteoporosis
  • Liver Cirrhosis (25%)
  • Cholethiasis (15-24%)
  • Urolithiasis
  • Vasculitis
  • Sinusitis (90%)
  • Polyposis (6-32%)
  • Allergy
  • Lung Disease

*Salt Loss Syndrome

•Pancreatic Insufficiency

  • exocrine (85-90%)
  • endocrine (10-30%)

Gastrointestinal Dysmotility

  • GER (30%)
  • DIOS (7-15%)

•Obstructive Azoospermia (98%)

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8
Q

Pathophysiology of CF Respiratory Disease

A
  • Airway surface liquid volume (depth) is tightly autoregulated
  • In CF mucociliary clearance is disrupted due to inadequate hydration of the airway surface liquid  CFTR dysfunction leads to increased activity of the apical epithelial sodium channel (ENaC)
  • Sodium enters the cell due to the electrochemical gradient and chloride follows through non-CFTR chloride channels and paracellularly
  • WATER FOLLOWS SALT and the airway surface liquid is reduced
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9
Q

Lack of mucociliary clearance…

A

…leads to infection, inflammation and airway obstruction that leads to progressive lung disease.

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10
Q

Aggressive polymorphonucleocyte inflammation causes…

A

…proteolytic and oxidative airway damage, and remodeling.

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11
Q

The most common infective organisms are…

A

…Staphylococcus aureus and Pseudomonas aeruginosa with the latter the most strongly associated with progressive lung disease.

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12
Q

[…] develops with destruction of airway walls leads to obstructive lung disease = leading cause of death

A

Bronchiectasis develops with destruction of airway walls leads to obstructive lung disease = leading cause of death.

 Sinusitis and nasal polyposis are common as well!

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13
Q

Obstructive Lung Disease = […] FEV1/FVC ratio

A

Obstructive Lung Disease = Low FEV1/FVC ratio

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14
Q

Pathophysiology of Gastrointestinal Disease - Exocrine

A
  • Exocrine pancreatic insufficiency in ~ 85% of patients at birth
  • In-utero autodigestion of the pancreas with fibrosis, cysts, and fatty replacement leads to little or no enzyme production
  • Results in maldigestion, especially of fats and protein and leads to malnutrition with steatorrhea (fatty, oily stools)
  • May cause bowel obstruction at the ileo-caecal valve at birth called meconium ileus
  • Also dehydrated intestinal surface liquid leads to bowel obstruction in older patients as well (distal intestinal obstruction syndome)
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15
Q

Pathophysiology of Gastrointestinal Disease - Endocrine

A
  • Endocrine pancreatic insufficiency = CF Diabetes Mellitus
  • Hepato-biliary disease is common in CF due to inadequate bile flow, altered bile salts, inadequate bicarbonate concentrations in bile
  • Cholelithiasis
  • Cholecystitis
  • Biliary cirrhosis with portal hypertension ~ 25% with ~ half of these needing liver transplantation

•Gastroesophageal reflux disease (GERD) is common due to lung hyperinflation and reduced GI motility

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16
Q

Pathophysiology of Genitourinary Disease

A
  • Male infertility is almost ubiquitous (>95%) due to absence of the vas deferens from birth secondary to blockage, inflammation and fibrosis
  • Females have reduced fertility due to a failure of normal thinning of cervical mucus at ovulation; however many CF women have become pregnant and done well
  • Nephrolithiasis occurs in about 5% of the CF population compared to 2% in the non-CF mostly due to calcium oxalate stones
17
Q

Pathophysiology of Salt Loss in Sweat

A
  • Sweat is an isosmolar secretion at the level of the gland and as the sweat moves up the duct to the skin sodium is avidly reabsorbed by apical sodium channels and chloride follows through CFTR
  • CFTR dysfunction leads to high sweat chloride values because chloride can’t be reabsorbed.
  • Sweat chloride testing is central to the diagnosis of CF
  • This increased loss of chloride can lead to dehydration and a metabolic alkalosis
  • In active older children and adults in hot climates, the loss of near isosmolar sweat can lead to severe dehydration and heat prostration
18
Q

Sweat Chloride Levels

A
  • Normal sweat chloride levels are not above 40 mmol/l and commonly they are 10-20 mmol/l
  • CF sweat chloride levels are commonly almost isosmolar; i.e. 80 to 95 mmol/l
19
Q

Normal Sweat Chloride Level

A

below 30mmol/l

20
Q

Indeterminate Sweat Chloride Level

A

30-59 mmol/l

21
Q

Abnormal Sweat Chloride Level

A

> 59 mmol/l and is diagnostic

22
Q

Neonatal Presentation

A
  • Meconium ileus with blockage at the ileocecal valve and microcolon on water soluble barium enema.
  • In extreme cases, the bowel may rupture in utero. This can lead to apparent intestinal atresia (non-development of the ileum)
  • Prolonged jaundice due to slow clearance of bile and increased enterohepatic circulation of bile
23
Q

Positive Newborn Screen for CF

A
  • Immunoreactive trypsinogen (IRT) is elevated in the blood of newborns with CF
  • If IRT is elevated then genetic testing is used to find newborns with at least one CF mutation and their primary care provider is notified
  • Sweat testing is then use to determine if the newborn has CF
24
Q

Presentation in Infancy

A
  • Respiratory disease with recurrent/persistent wheezing or coughing, persistent opacities on chest radiographs, and/or staphylococcus pneumonia
  • Failure to thrive due to pancreatic insufficiency and may have edema and low albumin levels due to malnutrition
  • Malabsorption/steatorrhea and abdominal bloating due to maldigestion with pancreatic insufficiency
  • Fat soluble vitamin deficiency (ADEK) again due to inability to digest fats due to pancreatic insufficiency
  • Metabolic alkalosis due to chloride loss in sweat (uncommon)
25
Q

Presentation in Childhood

A
  • Same features as infancy, but greater risk of finding bronchiectasis/chronic sputum, digital clubbing, and airway obstruction on pulmonary function testing.
  • Rectal prolapse due to malabsorption and malnutrition
  • Distal intestinal obstruction syndrome or intussusception due to thick, dry stool
  • Liver disease – biliary cirrhosis or cholelithiasis
  • Chronic or recurrent pancreatitis, especially in pancreatic sufficient patients
  • Nasal polyps and sinusitis
26
Q

Presentation in Adolescence/Adulthood

A
  • Same as infancy and childhood, but with greater risk of advanced lung disease and its complications
  • Chronic pansinusitis and/or nasal polyps
  • Bronchiectasis complications with pneumothorax and hemoptysis
  • More advanced liver disease with biliary cirrhosis and portal hypertension
  • Poor growth/delayed puberty
  • Azoospermia in males due to congenital bilateral absence of the vas deferens
  • Idiopathic recurrent pancreatitis
27
Q

Diagnosis

A

•One or more clinical features of CF PLUS

-two CF mutations

OR

-two positive sweat tests

OR

-abnormal nasal potential difference

28
Q

Treatment of CF - Lungs

A
29
Q

Treatment of CF - Respiratory Disease

A

•Chest Clearance

  • Chest physiotherapy
  • Bronchodilator inhalation (albuterol)
  • Hypertonic saline inhalation to increase the airway surface liquid
  • Dornase alfa (human recombinant dnase) to thin secretions
  • Exercise
30
Q

Anti-Infective Therapy

A
  • Inhaled antibiotics (tobramycin, aztreonam) are used to help clear new onset infection with Pseudomonas aeruginosa and to treat it when it has become chronic/longterm. b
  • Oral antibiotics including quinolones (ciprofloxacin) for Pseudomonas and antistaphylococcal antibiotics (cephalexin, cotrimoxasole, amoxicillin-clavulanate) are used during mild exacerbations c
  • Intravenous antibiotics directed at the patients current sputum microbiology are used to treat exacerbations (see below). d
  • Anti-fungal agents (itraconazole/voriconazole) are used in patients who havefungal infection (Aspergillus fumigatus) with or without allergic bronchopulmonary aspergillosis (ABPA) e
  • Anti-mycobacterial agents are used in patients who develop atypical mycobacterial infections
31
Q

CF Pulmonary Exacerbation

A
  • Increased respiratory symptoms
  • Sputum (also change in sputum color from clear->yellow->green)
  • Cough
  • Shortness of breath
  • Chest pain
  • Fever
  • Weight loss
  • Reduced pulmonary function (FEV1)
  • Admission to hospital for intravenous antibiotics and aggressive chest clearance. Sometimes treated at home
32
Q

Anti -Inflammatories

A

•Macrolide antibiotics

  • 6% improvement vs. placebo in FEV1
  • Theoretically suppress excessive inflammatory response

•Ibuprofen

-Slowed lung decline in patients 6-13 y.o.

•Systemic glucocorticoids

-Improved lung function but too many side effects

•Inhaled corticosteroids

-Useful in asthma

33
Q

Lung Transplant

A
  • 5 year survival slightly better than 50%
  • New organ allocation system
  • Controversial for pediatric patients
  • Expensive, problematic but may be the only option for some patients
34
Q

Treatment Pancratic Insuffiency

A
  • Good nutrition is essential to maintain good health in CF, particularly in growing children and adolescence
  • Pancreatic enzyme replacement is central to nutrition
  • High calorie, High fat diet is used to maximize calories using food choices and sometimes supplements
  • Enteral feedings using gastrostomy tubes
  • Early recognition and treatment of CF diabetes mellitus
35
Q

Treatment Biliary Disease

A
  • Cholecystectomy for gall bladder disease
  • Ursodeoxycholic acid for biliary cirrhosis (unclear if it is effective in preventing/slowing disease)
  • Liver transplant

Pulmonary (29 decks)

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