Cystic Fibrosis: A Multisystem Disorder

Question 1

Clinical features of cystic fibrosis

Multi-system disorder that affects:

Answer 1

• Lungs (COPD)
• Pancreas
• nutrition
• liver
• gut
• electrolyte disturbance
• ENT
• musculoskeletal
• genito-urinary
• renal

Question 2

Sweat test is the gold standard for diagnosing CF

How is the sweat test conducted? (2 points)

Answer 2

• Transdermal administration of pilocarpine by iontophoresis (taken up into sweat gland via low voltage current)
• Collection and quantitation of sweat onto gauze or filter paper or into a macroduct coil

Question 3

Sweat test is the gold standard for diagnosing CF

What are the diagnostic Cl- values? (2 points)

Answer 3

Normal value: Cl <40mmol/L (<30 in infant)

• in between 40-60, could either repeat the CF test again or look for other clinical features
• usually its babies who are well at this point and dont present any clinical featuers but if its low 40s it could be that they’re a carrier

CF diagnosis: Cl>60mmol/L*

Question 4

Sweat Gland

CFTR _____ _____ in the sweat gland?

*hint: opposite that in lung epithelium

Answer 4

CFTR activates ENaC in sweat glands

Cl- ions cannot move through CFTR channel in CF

Question 5

High salt sweat - clinical features

• ___natremic/___chloremic ______
• Hypokalemic ____ ____, secondary to chronic salt loss (stimulates exchange of __+ for _+ and _+)
  
  • Pseudo-Bartter’s Syndrome
• ____ or irritability
• Muscle cramps
• Nausea and vomiting
• Fatigue
• Poor concentration

Answer 5

• Hyponatremic/hypochloremic dehydration
• Hypokalemic metaboic alkalosis, secondary to chronic salt loss (stimulates exchange of Na+ for H+ and K+)
  
  • Pseudo-Bartter’s Syndrome
• Headache or irritability
• Muscle cramps
• Nausea and vomiting
• Fatigue
• Poor concentration

Question 6

Pancreas has 2 functions

Exocrine

Endocrine

Define both

Answer 6

Exocrine

• Pancrearic acini (produce pancreatic enzymes)
  
  • lipase
  • amylase
  • protease

Endocrine

• Islets of Langerhans (indicated in diabetes)
  
  • Insulin
  • Glucagon

Question 7

Pancreas is one of the earliest organs to be affected in CF (exocrine function)

• Pancreatic enzyme insufficiency (PI)
  
  • __% of patients
  • Class _, _, _, _ mutations
• *

Answer 7

• Pancreatic enzyme insufficiency (PI)
  
  • 85% of patients
  • Class I, II, III or VI mutations
• PI is the only feature of CF with correlation between variant and phenotype
• Can predict if PT is going to be PI or not
• Only 60% at birth are PI, the rest are PS, but a lot lose function and become PI by 12 months

Question 8

Pancreas is one of the earliest organs to be affected in CF (exocrine function)

• • Clinical presentation
    
    • Fat ___ and streatorrhoea
    • Malnutrition
    • Fat soluble ____
      
      • A,E,D,K
        *

Answer 8

• • Clinical presentation
    
    • Fat malabsorption and streatorrhoea (stools high in fat)
    • Malnutrition
    • Fat soluble vitamins
      
      • A,E,D,K
        *

Question 9

Pancreas is one of the earliest organs to be affected in CF (exocrine function)

• • • Treatment: ____
    • Lipase, amylase, protease
    • ____ coated

Answer 9

• • • Treatment: PERT
    • Lipase, amylase, protease
    • Enteric coated
• Pancreatic enzyme replacement therapy
• Enteric coated = dont release enzymes in stomach where pH is high, only release in small intestine

Question 10

Pancreas is one of the earliest organs to be affected in CF (exocrine function)

Summary

Answer 10

• Pancreatic enzyme insufficiency (PI)
  
  • 85% of patients
  • Class I, II, III or VI mutations
• Clinical presentation
  
  • Fat malabsorption and streatorrhoea
  • Malnutrition
  • Fat soluble vitamins
    
    • A,E,D,K
• Treatment: PERT
  
  • Lipase, amylase, protease
  • Enteric coated

Question 11

Pathophysiology of Pancreatic Disease

CFTR in the apical membrane of the pancreatic ductal epithelial cell is involved in regulation of ___ (2 points)

Answer 11

• Regulation of chloride secretion
  
  • Reduced luminal liquid
  • Thicker pancreatic secretions
• Regulation of bicarbonate secretion
  
  • Acidic pH of luminal liquid
  • key buffer for pancreatic fluid
    
    • Neutralises gastric acid
    • Optimal pH for digestive enzymefunction

Question 12

Pathophysiology of Pancreatic Disease

2 other effects of pancreatic disease are: (2 points)

• V_____ pancreatic secretions
• P_____ activation of _______ enzymes

Answer 12

• Viscous pancreatic secretions
  
  • Pancreatic duct obstruction
  • Progressive fibrosis and fatty infiltration
• Premature activation of proteolytic enzymes
  
  • Inflammation and destruction of pancreas
  • Because the enzymes cannot get down the duct, so might get activated inside the pancreas

Question 13

Pancreatitis

• 15% of CF patients are pancreatic sufficient (PS)
• *

Answer 13

• 15% of CF patients are pancreatic sufficient (PS)
  
  • Enough passage of pancreatic enzymes down the pancreatic duct
  • Generally class IV or V mutations
    
    • Allow fluid secretions, but pH still affected
      *

Question 14

Pancreatitis

• • More prone to recurrent pancreatitis
    *

Answer 14

• • More prone to recurrent pancreatitis
    
    • Inflammation of pancreas
    • Doesnt mean that PS patients do not get pancreatitis as well, they just have sufficient enzyme secretion
      *

Question 15

Pancreatitis

• • • Impaired HCO3- secretion important in development of pancreatitis

Answer 15

• • • Impaired HCO3- secretion important in development of pancreatitis
    • Impaired control of luminal pH contributes to tissue damage
    • decrease in luminal pH promotes premature zymogen (i.e. pancreatic enzymes) activation > pancreatitis

Question 16

Pancreatitis

• 15% of CF patients are pancreatic sufficient (PS)
• More prone to recurrent pancreatitis
• Impaired HCO3- secretion important in development of pancreatitis

Answer 16

• 15% of CF patients are pancreatic sufficient (PS)
  
  • Enough passage of pancreatic enzymes down the pancreatic duct
  • Generally class IV or V mutations
    
    • Allow fluid secretions, but pH still affected
• More prone to recurrent pancreatitis
  
  • Inflammation of pancreas
  • Doesnt mean that PS patients do not get pancreatitis as well, they just have sufficient enzyme secretion
• Impaired HCO3- secretion important in development of pancreatitis
  
  • Impaired control of luminal pH contributes to tissue damage
  • decrease in luminal pH promotes premature zymogen (i.e. pancreatic enzymes) activation > pancreatitis

Question 17

Pancreatitis - Genetics

• Increased ____ ____ in non-CF patients with chronic pancreatits
• ___ score predicts risk of pancreatitis
• Despite higher risk associated with milder genotypes, there remains ________ - pancreatic modifiers

Answer 17

• Increased CFTR mutations in non-CF patients with chronic pancreatits
• PIP score predicts risk of pancreatitis
  
  • Categorises CFTR mutations by predicted severity of mutations
    
    • Severity of CFTR genotype strongly associated with risk of pancreatitis
• Despite higher risk associated with milder genotypes, there remains phenotypic variation - pancreatic modifiers
  
  • Other genes that influence your risk of pancreatitis
• **There are adults who dont have CF but also have recurrent pancreatitis = alcoholics

Question 18

Pancreatitis - Clinical Presentation

• Similar to ____ ____
• May be ___ or ___ clinical manifestation of CF
• Affects 20% of PS patients of which
  
  • only 18% have single episode
  • >>
  • >>

Answer 18

• Similar to general population
• May be initial or only clinical manifestation of CF
• Affects 20% of PS patients of which
  
  • only 18% have single episode
    
    • I.e. high recurrance rate
    • Can lead to damage exocrine function enough to cause PI

Question 19

Acute vs Acute Recurrent vs Chronic Pancreatitis

Acute - 3 points

Acute recurrent - 1 point

Chronic - 2 points

Answer 19

• Acute pancreatitis (2 of 3)
  
  • Upper abdominal pain +/- emesis
  • Amylase or lipase ≥3 x uln (upper limit of normal)
  • Consistent abdominal imaging (CT/MRI, u/s)
• Acute recurrent pancreatitis
  
  • ≥ 2 episodes of AP with return to baseline between
• Chronic pancreatitis
  
  • Chronic abdominal pain or exocrine or endocrine insufficiency
  • Plus characteristic imaging

Question 20

Management of Pancreatitis

Guidelines exist for adults but not children

Acute: Supportive care
- elaborate (3 points)

• Correction of:
• Medications:
• ___ rest:

Chronic
- elaborate (4 points)

• Environmental factors:
• Medications:
• Surgery:
• Monitoring:

Answer 20

Acute: supportive care

• Correction of fluids and electrolyte imbalance (due to vomiting)
• Analgesia
• Gut rest for 24-72 hours

Chronic

• Environmental factors: smoking, alcohol, hypertriglycerdemia
• Medications: antacids, PERT, analgesia
• Surgery: TPIAT - total pancreactomy with autp-transplant of islet cells so PT is not diabetic
• Monitoring for pancreatic cancer

Question 21

Pancreas - Endocrine Function

• _______ (CFRDM)
  
  • Elaborate (how is it like both T1/T2D?)
• Increasingly common with ____ age
  
  • Elaborate
• _____ and _____ insulin secretion
• Insulin _____
• Higher ____ rates (__ fold) in CFRDM
• Lung function _____
• ______ complications (___ and ___ disease)

Answer 21

• Cystic fibrosis related diabetes mellitus (CFRDM)
  
  • Destruction of insulin producing cells
  • Unlike T1D
    
    • Still lower baseline level of insulin production
  • But also like T2D
    
    • Bit of insulin resistance
• Increasingly common with increasing age
  
  • Rare under 10 years, 50% over 30 years
• Impaired and delayed insulin secretion
• Insulin resistance
• Higher mortality rates (6 fold) in CFRDM
• Lung function decline
• Microvascular complications (eye and renal disease)

Question 22

Cystic Fibrosis Liver Disease (CFLD)

25% of PTs have evidence of disease

Pathogenesis: (just like pancreas and lungs)

• CFTR in ____ cells lining intra-hepatic ____ ____
• Increase ____ of bile
• _____ of intra-hepatic ____ _____
  
  • Elaborate
• Cirrhosis, initially multi-focal, in minority
  
  • Elaborate
• Increased risk in PTs with alpha-1 _______ allele
  
  • Elaborate
• Most cirrhosis evident by 20 years of age

Answer 22

Pathogenesis: (just like pancreas and lungs)

• CFTR in epithelial cells linign intra-hepatic bile ducts
• Increase viscosity of bile
• Plugging of intra-hepatic bile ducts
  
  • Results in inflammation of liver cells (hepatocytes)
• Cirrhosis, initially multi-focal, in minority
  
  • Can progress over time
• Increased risk in PTs with alpha-1 antitrypsin Z-allele
  
  • There are genetic modifiers that increase likelihood of developing CF liver disease
• Most cirrhosis evident by 20 years of age

Question 23

CFLD - Clinical Features

• Prolonged n____ j______
• Raised l_____ e_____, common in CF
  
  • Elaborate
• Hepatic s____ (f___ liver)
• C_____ and portal h______
  
  • 6-8% of PTs
  • M:F = 3:1
  • Hepato-splenomegaly
  • Oesophageal varices in 20%
    
    • Elaborate
• H_____ failure is uncommon, 2-3%
  
  • Elaborate
    ​

Answer 23

CFLD - Clinical Features

• Prolonged neonatal jaundice
• Raised liver enzymes, common in CF
  
  • May be of no significance, could be due to virus, medication, or CF
• Hepatic steatosis (fatty liver)
• Cirrhosis and portal hypertension (severe end of liver disease)
  
  • 6-8% of PTs
  • M:F = 3:1
  • Hepato-splenomegaly (enlarged liver and spleen)
  • Oesophageal varices in 20%
    
    • BV in oesophagus become large and weak, can exsanguinate
• Hepatocellular failure is uncommon, 2-3%
  
  • Failure to release liver enzymes uncommon,
  • Thus not prioritised for liver transplant

Question 24

CFLD - Clinical Significance

Mortality: 2.5%

• Low mortality rate, ___ a ___ ____ of death

Increased morbidity (complications)

• Poorer n____ s____
• Poorer g____
• Worse p___ o____
• CF-related d___

Answer 24

CFLD - Clinical Significance

Mortality: 2.5%

• Low mortality rate, not a major cause of death

Increased morbidity (complications)

• Poorer nutritional status
• Poorer growth
• Worse pulmonary outcomes
• CF-related diabetes

Question 25

Diagnosis of CFLD Requires two of: 1. Abnormal p\_\_\_\_ e\_\_\_\_ * H\_\_\_megaly/S\_\_\_\_megaly * S\_\_\_\_ of chronic liver disease 2. Abnormal serum transaminases * elaborate 3. Ultrasound findings of CF related LD 4. Biopsy consistent with CF related LD

Answer 25

Diagnosis of CFLD Requires two of: 1. Abnormal physical examination * hepatomegaly/splenomegaly (enlarged liver/spleen) * Stigmata of chronic liver disease (manifestation) 2. Abnormal serum transaminases * 3 consecutive occasions over a 12 month period 3. Ultrasound findings of CF related LD 4. Biopsy consistent with CF related LD

Question 26

There is no cure for CFLD, it has to be treated symptomatically * E\_\_\_ other causes of liver disease * Optimise n\_\_\_\_ status and p\_\_\_\_ function * elaborate * Monitor for CF r\_\_\_ d\_\_\_\_ * Immunisations: H\_\_\_ A & B * Ursodeoxycholic acid * Elaborate * Monitor for c\_\_\_of p\_\_\_ h\_\_\_\_ * Monitor for development of s\_\_\_ l\_\_\_ f\_\_\_ * Consideration of liver t\_\_\_\_

Answer 26

There is no cure for CFLD, it has to be treated symptomatically * Excude other causes of liver disease * Optimise nutritional status and pulmonary function * Pulmonary function has major influences on mortality * Monitor for CF related diabetes * Immunisations: Hepatitis A & B * Ursodeoxycholic acid * Stimulates Ca2+ dependent Cl- channels * Less viscous bile * Improves duct dependent bile flow * Monitor for complications of portal hypertension * Monitor for development of synthetic liver failure * Consideration of liver transplant * Possible bridging options

Question 27

GIT CFTR is abundant at luminal membrane of intestinal epithelial cells * D\_\_\_\_ of luminal contents * M\_\_\_\_ ileus * Con\_\_\_\_ * D\_\_\_ I\_\_\_\_ O\_\_\_\_ Syndrome * More severe form of c\_\_\_\_ * Gastro-Oesophageal R\_\_\_ * GOR/R\_\_\_\_ * Can be significant because you can \_\_\_\_

Answer 27

* Dehydration of luminal contents * Meconium ileus * Constipation * Distal Intestinal Obstruction Syndrome * DIO, more severe form of constipation * Gastro-Oesophageal Reflux * GOR/Reflux * Can be significant because you can aspirate and affect lungs

Question 28

Meconium Ileus * Inspis\_\_\_\_ intral\_\_\_\_ meconium causing bowel obstruction * Elaborate * Associated with p\_\_\_\_ i\_\_\_\_ * Incidence: 10-15% of CF neonates * Elaborate * Late complications * ____ DIOS risk * Ad\_\_\_\_ s\_\_\_\_ b\_\_\_ o\_\_\_

Answer 28

Meconium Ileus * Inspissated intraluminal meconium causing bowel obstruction * Thick and pluggy meconium, hard to get out * result in telescoping bowels * Associated with pancreatic insufficiency * Incidence: 10-15% of CF neonates * Present even before newborn screening * Bowel can perforate if left untreated * Requires surgery to flush bowel * Late complications * Increased DIOS risk * Adhesive small bowel obstruction

Question 29

Distal Intestinal Obstruction Syndrome * A\_\_\_\_ pain; crampy, R\_\_\_ i\_\_\_ f\_\_ (RIF) * P\_\_\_\_ mass in RIF * P\_\_\_ or c\_\_\_ bowel obstruction * Intussusception * what is this? * A\_\_\_ X-R\_\_\_: d\_\_\_ small bowel with b\_\_\_ ileocaecal mass * C\_\_\_ also common * a lot of PTs dont get full-on DIO, c\_\_\_\_ is common

Answer 29

Distal Intestinal Obstruction Syndrome * Abdominal pain; crampy, Right iliac fossa (RIF) * Palpable mass in RIF * Partial or complete bowel obstruction * Intussusception * Telescoping bowels * Abdominal X-Ray: dilated small bowel with bubbly ileocaecal mass * Constipation also common * a lot of PTs dont get full-on DIO, constipation is common

Question 30

Gastro-oesophageal Reflux * Very common in CF * A\_\_\_ (cause of disease) is m\_\_-f\_\_\_\_\_ * Exacerbates lung disease due to a\_\_\_\_ (can cause progressive lung damage in itself) and reflex b\_\_\_\_\_ * Delayed g\_\_\_ e\_\_\_\_ and small bowel t\_\_\_ also common * Elaborate

Answer 30

Gastro-oesophageal Reflux * Very common in CF * Aetiology (cause of disease) is multifactorial * Exacerbates lung disease due to aspiration (can cause progressive lung damage in itself) and reflex bronchospasm * Delayed gastric emptying and small bowel transit also common * Contents last around longer so more likely to reflux * Can cause quite significant lung disease * PTs who are referred to undergo lung transplantation also have to undergo surgical management of GE-reflux because it is known to be such a risk factor

Question 31

Other GI complications * Rectal prolapse * P\_\_\_ i\_\_\_\_ * Result in s\_\_\_\_ s\_\_\_ * Frequent stools, d\_\_\_ m\_\_\_\_ t\_\_\_, coughing * Malignancy * Increased risk of b\_\_\_ c\_\_\_ * Coeliac disease * Increased r\_\_\_ in CF * Fib\_\_\_\_ co\_\_\_\_ * Condition no longer exists * Why?

Answer 31

Other GI complications * Rectal prolapse * Pancreatic insufficient * Result in steareatic stools * Frequent stools, diminished muscle tone, coughing * Malignancy * Increased risk of bone cancer * Coeliac disease * Increased risk in CF * Fibrosing colonopathy * Condition no longer exists * Probably related to previous PERT combination of enzymes, and too high doses

Question 32

Osteoporosis Low bone mineral density is very common 2-fold increase in fracture rates in young adults Risk factors include: * P\_\_\_ l\_\_\_ f\_\_\_ * N\_\_\_ failure * C\_\_\_ F\_\_\_ R\_\_\_ D\_\_\_ M\_\_\_ * Hypov\_\_\_\_\_ D and K * why?

Answer 32

Osteoporosis Low bone mineral density is very common 2-fold increase in fracture rates in young adults Risk factors include: * Poor lung function * Nutritional failure * CFRDM * Hypovitaminosis D and K * Fat soluble vitamins

Question 33

Genito-urinary complications in CF * P\_\_\_ delay and g\_\_\_\_ delay * Becoming less common with improved n\_\_\_\_ and improved \_\_\_ * Male infertility * 98% * Absent v\_\_\_ d\_\_\_ results in azoospermia * elaborate * Assisted reproduction, ICSI * Reduced female fertility * Probably relates to: * Urinary stress i\_\_\_\_ * Associated with f\_\_\_ c\_\_\_

Answer 33

Genito-urinary complications in CF * Puberty delay and growth delay * Becoming less common with improved nutrition and improved PERT * Male infertility * 98% * Absent vas deferens results in azoospermia * obstructed because of CFTR in utero, fails to form, can produce sperm but sperm cannot exit testes * Assisted reproduction, ICSI * Reduced female fertility * Probably relates to increased mucus viscosity around the female cervix, and no ovulation * Urinary stress incontinence * Associated with frequent coughing

Question 34

Renal complications in CF Through childhood, dont often see renal complications in PTs with CF Q) Still need to be considered because?? * CFTR present in r\_\_\_ tu\_\_\_\_ * No cl\_\_\_ ef\_\_\_ * I\_\_\_\_ renal cl\_\_\_ of a\_\_\_b\_\_\_ e.g. a\_\_\_gly\_\_\_des * so what? * A\_\_\_\_\_ are n\_\_\_\_\_ * Toxic to kidney * so what?

Answer 34

Renal complications in CF Through childhood, dont often see renal complications in PTs with CF Q) Still need to be considered because?? A) need to think about pharmacokinetics and dosage of drugs for CF PTs * CFTR present in renal tubules * No clinical effect * Increased renal clearance of antibiotics e.g. aminoglycosides * so what? * Aminoglycosides are nephrotoxic * Toxic to kidney * gentamycin, tobramycin are nephorotixic, with cumulative doses can develop quite significant renal disease

Question 35

Other systems affected by CF ENT * Nasal p\_\_\_ in 10-30% * S\_\_\_ involvement * A\_\_\_\_ are ototoxic * Ear damage CVS * Cor pul\_\_\_\_ * Secondary heart failure Skin * Aquagenic wri\_\_\_\_ of palms, get oedamatus papules due to i\_\_\_\_ s\_\_\_ l\_\_ in pateints with CF * Rash * Vascu\_\_ * Nu\_\_\_\_

Answer 35

Other systems affected by CF ENT * Nasal polyps in 10-30% * Sinus involvement * Aminoglycosides are ototoxic * Ear damage CVS * Cor pulmonale * Secondary heart failure Skin * Aquagenic wrinkling of palms, get oedamatus papules due to increased salt loss in pateints with CF * Rash * Vasculitis * Nutritional