lecture 11

Question 1

What systems are affected by CF?

Answer 1

• chronic pulmonary disease
• pancreas
• nutrition
• liver
• gut
• electrolyte disturbance
• ENT
• musculoskeletal
• genito-urinary
• renal

90% of morbidity/mortality due to lung problems

Question 2

What has happened as life expectancy of individuals with CF has risen?

Answer 2

• median life expectancy is late 30s/early 40s

- new complications emerging in the adult population

Question 3

How is the sweat gland involved in CF?

Answer 3

• Salty sweat was one of the first descriptions of CF in literature: “Woe to that child which when kissed on the forehead tastes salty. They are bewitched and soon will die”
• Involvement of the sweat gland in CF first recognised in 1949
• people with CF don’t sweat more than others, it is just that the sweat they produce is really salty
• Sweat test: gold standard for diagnosing CF
• • transdermal administration of pilocarpine by iontophoresis (i.e. they put pilocarpine on the skin and put a small electric current through it which stimulates the sweat gland)
• • collection and quantitation of sweat onto gauze or filter paper or into a Macroduct coil
• • normal value Cl very close to 105mmol/L in this part (isotonic secretion)
• what normally happens is that the sweat moves up the duct of the sweat gland, and as it moves Na and Cl are resorbed from the sweat leaving a hypotonic (dilute solution) to allow cooling evaporation to occur
• CFTR activates ENaC in sweat duct (opposite to lung) so in CF this reuptake doesn’t occur, >60 = CF

Question 4

What are the clinical features associated with high salt sweat?

Answer 4

• hyponatremic/hypochloremic dehydration - bad for all the cells in the body
• hypokalemic (potassium) metabolic alkalosis secondary to chronic salt loss: Pseudo-Bartter’s Syndrome
• headache or irritability
• muscle cramps
• nausea and vomiting
• fatigue
• poor concentration

Question 5

What are the two main functions of the pancreas?

Answer 5

Exocrine

• pancreatic acini
• • lipase
• • amylase
• • protease

Endocrine

• Islets of langerhans
• • insulin
• • glucagon

Question 6

How does CF affect the exocrine function of the pancreas? How is it treated?

Answer 6

• pancreatic enzyme insufficiency
• • 85% of patients
• • class I, II, III or VI mutations (IV, V tend to have pancreatic Sufficiency)
• steatorrhoea (fatty, bulky, smelly, floaty stool)
• fat malabsorption
• malnutrition
• low on fat soluble vitamins: A, D, E, K
• PERT (pancreatic enzyme replacement therapy)
• • lipase, amylase, protease
• • enteric coated: don’t want enzymes to be released in stomach - need to be released in first part of small intestine

Question 7

What is the pathophysiology of pancreatic disease in CF?

Answer 7

• CFTR in the apical membrane of the pancreatic ductal epithelial cell
• regulation of chloride secretion: reduced luminal liquid; if you have a reduction in the chloride secretion into the pancreatic duct you have an increase in the thickness and viscosity of the fluid within those ducts therefore obstructing them
• regulation of bicarbonate secretion: acidic pH of luminal liquid
• Viscous pancreatic secretions
• • pancreatic duct obstruction
• • progressive fibrosis and fatty infiltration
• premature activation of proteolytic enzymes
• • inflammation and destruction of pancreas

Question 8

What is the effect of CF on the endocrine function of the pancreas?

Answer 8

• Cystic fibrosis related diabetes mellitus (CFRDM)
• increasingly common with increasing age: rare under 10 years, 20% at 18, 50% over 30 years
• impaired and delayed insulin secretion
• insulin resistance
• higher mortality rates (6 fold) in CFRDM
• lung function decline (faster in patients with CFRDM)
• microvascular complications (as opposed to the macrovascular complications seen in non-CFRDM CF patients) (eye disease, renal, peripheral vascular)
• presents differently type I diabetes: often not aware of symptoms

Question 9

How does CF effect the liver ?

Answer 9

• 25% of patients have evidence of disease
• pathogenesis:
• • CFTR in epithelial cells lining intra-hepatic bile ducts
• • increased viscocity of bile
• • plugging of intra-hepatic bile ducts
• • cirrhosis, initially multi-focal, in minority
• most cirrhosis evident by 20 years of age
• more linked to modifier genes than to class of mutation

Question 10

What are the clinical features of liver disease in CF?

Answer 10

• prolonged neonatal jaundice (can occur for many reasons)
• cirrhosis and portal hypertension
• • 5/6-8% of patients
• • M:F = 3:1
• • hepato-splenomegaly (enlargement of spleen and liver)
• • raised liver enzymes, common in CF, may be of no significance
• • oesophageal varices in 20% (can develop if there is portal hypertension, increase in dilation/thickness –> can bleed, if so very hard to control the bleeding and that can actually lead to the death of the patient)
• hepatocellular failure is uncommon, 2-3%

Question 11

How does CF affect the GIT?

Answer 11

• CFTR abundant at luminal membrane of intestinal epithelial cells
• Dehydration of luminal contents
• Meconium ileus
• constipation
• distal intestinal obstruction syndrome
• gastro-oesophageal reflux (can lead to aspiration of gastric contents –> inflammation –> faster decline of lung function)

Question 12

What is meconium ileus?

Answer 12

• inspissated intraluminal meconium (stool produced when foetus is in utero) (yucky black tar-y sticky stuff) causing bowel obstruction
• associated with pancreatic insuffienciency
• incidence: 10 - 15% of CF neonates
• Later complications
• • Increased DIOS (distal intestinal obstruction syndrome) risk
• • Adhesive small bowel obstruction

Question 13

What is DIOS?

Answer 13

Distal Intestinal Obstruction Syndrome 
- abdominal pain; crampy, RIF 
(right iliac fossa)
- Palpable mass in RIF 
- Partial or complete bowel obstruction 
- Intussusception: there is a blockage but normal peristalsis keeps pushing food along leading to further blockage and increased pressure: can lead to necrosis etc 
- AXR: dilated small bowel with bubbly ileocaecal mass 
- Constipation also common

Question 14

How does CF affect gastro-oesophageal reflux?

Answer 14

• very common in CF
• aeitology is multifactorial
• exacerbates lung disease due to aspiration and reflex bronchospasm
• delayed gastric emptying and small bowel transit also common

Question 15

What are some further GI complications related to cystic fibrosis?

Answer 15

• rectal prolapse
• • pancreatic insufficient
• • frequent stools, diminished muscle tone, coughing
• malignancy
• coeliac disease
• fibrosing colonopathy: less so now but was associated with some of the older preparations of PERT especially if dosage was too high

Question 16

How does CF lead to osteoporosis?

Answer 16

• low bone mineral density very common
• risk factors include:
• • poor lung function
• • delayed puberty
• • nutritional failure
• • steroid use
• • CFRDM
• • Hypovitaminosis D and K
• • physical inactivity
• 2-fold increase in fracture rates in young adults

Question 17

What is the effect of CF on the genito-urinary system?

Answer 17

• pubertal delay and growth delay: less so now with corrections in diet and fat uptake (puberty often stimulated when you reach a particular body fat level)
• male infertility
• • 99%
• • absent vas deferens results in azoospermia
• • assisted reproduction; ICSI
• reduced female fertility though women with CF can have babies; often puts a significant strain on their bodies and the mothers health suffers significantly
• urinary incontinence

Question 18

How does CF affect the renal system?

Answer 18

• CFTR present in renal tubules
• • no clinical effect
• • increased renal clearance of antibiotics e.g. aminoglycosides
• aminoglycosides are nephrotoxic

Question 19

What are some further systems that can be involved in CF?

Answer 19

ENT

• nasal polyps in 10-30%: can have nutritional consequences because if you can’t smell food it doesn’t taste as good therefore reducing your appetite
• sinus involvement
• aminoglycosides are ototoxic

CVS

• cor pulmonale
• CFTR per say doesn’t lead to any cardiac abnormalities

Skin

• Acrodermatitis enteropathica like rash
• Vasculitis
• Nutritional