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Cystic Fibrosis
“Overview of Gastrointestinal Diseases”
Mahmoud Hashim
Visiting student at Upstate Medical university
Final year Medical student – Ainshams School of Medicine
Cystic fibrosis (CF)
generally is thought of as a
lung disease because
much of the associated
morbidity and mortality is
related to
pulmonary complications.
Gastrointestinal
complications have become
an increasingly important cause
of morbidity in patients with CF.
 Autosomal
Recessive
 Multisystem
Disease
Gastrointestinal tract
(meconium ileus, distal
intestinal obstruction
syndrome)
Hepatobiliary system
(neonatal cholestasis,
steatosis, biliary cirrhosis,
Carrier rate in Caucasians
of 1 in 25
 Disease prevalence
 Caucasians 1 in 2,500
 African Americans 1 in
15,000
 Asians 1 in 31,000
Background
Described in medical
texts in 1595 as infants
with salty skin and
pancreatic damage who
died because of a curse.
Cystic Fibrosis disease
was first described by
Dorothy Andersen in
1938.
In 1989 the
responsible gene (CFTR)
Dorothy Andersen
(1901-1963)
Genetics and
PathogenesisCaused by mutations in a
single large gene on
chromosome 7 that
encodes CFTR protein.
There are > 1300 different
mutations
in the CFTR gene with
potential to cause disease.
The most common mutation is
delta F508 which is
Types of mutations in
CFTRo Class 1 Mutations: (2-5%)
Defective Protein Production
Leads to premature termination of the mRNA and
complete absence of CFTR protein.
o Class 2 Mutations: (70%)
Defective Protein Processing
Includes delta F508 mutation
prevents the protein from trafficking to the correct
cellular location.
o Class 3 Mutations:
Defective regulation
lead to diminished channel activity in response to
ATP
o Class 4 Mutations:
Defective conduction
o Class 5 Mutations:
Reduced amounts of functional CFTR protein
Diagnosis of CF
A. Distal Intestinal Obstruction
Syndrome (DIOS)
 10-47% Of Cases
 Acute complete or partial obstruction of
the Ileocecum by intestinal contents.
 DIOS can occur at any age, but it is more
common in
older patients and those with pancreatic
insufficiency.
PathogenesisRisk Factors
The majority of patients with
DIOS have pancreatic
insufficiency
Severe genotype (e.g., delta
F508)
Intestinal dysmotilityPancreatic insufficiency
Abnormal mucins and water
and electrolyte composition
of the intestinal contents
Dehydration
History of meconium ileus
or prior episodes of DIOS
Clinical Presentation
Diagnosis
I. Symptoms
1) Crampy Abdominal pain
“RLQ”
2) Bilious Vomiting “
Complete Obstruction”
3) Constipation
II. Imaging
1) X-ray
2) CT scan
proximal small-bowel
dilation and inspissated
fecal material in the distal
ileum.
Air fluid level
Treatme
ntIncomplete Obstruction
respond to oral rehydration
combined with stool softeners.
I. Oral polyethylene glycol
(Mirlax),
2 gm/kg/day with max. dose 80 -
100 gm/day.
Or
II. Iso-osmotic PEG solution
(GoLYTELY )at a dose of 20–40
ml/kg/h up to a maximum of 1 L/h
over 8 hours.
Or
III. sodium meglumine diatrizoate
(Gastrografin) can be
administered orally or by naso-
gastric tube,
 Children <6 years : 50 ml in
200 ml of water or juice
Complete Obstruction
 Hospitalization with IV rehydration.
 Sodium meglumine diatrizoate
(Gastrografin) Enema, 100 mL of
Gastrografin, diluted in
400 mL water, under direct vision
until the terminal ileum is reached
.
 If not responding, surgical
laparotomy and decompression is
indicated .
Prophylaxis
I. Oral PEG, 0.5–1 g/kg/day to a
maximum of 40 g/day for 6–12
months.
II. optimize pancreatic enzyme
B. Meconium Ileus
 10-20%
 Early clinical manifestation of CF.
 characterized by partial or
complete intestinal obstruction
in the neonate.
Diagnosis
I. Symptoms
Infants generally present during
the first three days of life with
abdominal distension with or
without bilious vomiting and
failure to pass meconium.
2) MI is “complex” if it is
complicated by gastrointestinal
pathology, including intestinal
perforation, meconium
peritonitis, atresia, or volvulus.
Approximately 40 % of MI in
newborns with CF is
complex.
3) MI is “simple” if there is no
II. Imaging
1. X-ray Dilated bowel loops
with ground glass
appearance in RLQ
2. Contrast enema usually
shows microcolon with
filling defects caused by
mucous and meconium
Contrast
enema
Treatment
Diluted sodium meglumine diatrizoate,
(Gastrografin), under direct vision until the terminal
ileum is reached .
The Hyperosmolar contrast breaks up the meconium
plug.
Success rates of 30 to 60 %.
If Failed, surgical intervention is needed
Intraoperative infusions of n-acetylcysteine or
hyperosmolar contrast have been shown to decrease
the need for surgical resection.
C.GERD
 20% of CF patients report reflux-
type symptoms.
Pathogenesis
I. Increased intra-abdominal
pressure due to chronic
coughing and wheezing
II. Absence of the normal basal
tone of the LES
III. The mechanical effect of a
depressed diaphragm caused
by lung hyperinflation
IV. Medications that reduce LES
pressure, such as theophylline
Clinical Manifestation and
Treatment
D.Malignancy
o From 1990 to 2009,
41,188 patients were followed.
o Increased risk of GI cancers
involving the esophago-gastric
junction, biliary tract, small
bowel, and colon.
o Any adolescent CF patient with
chronic GI complaints needs
evaluation for cancers.
Pancreatic
manifestations
A. Pancreatic
Insufficiency
o Most common inherited cause of
exocrine pancreatic
insufficiency
o The most common
gastrointestinal
complication of CF, affecting
85 % of patients.
o CFTR genotypes are more
closely related to the severity
of pancreatic exocrine
dysfunction > to the severity
of lung disease.
Pathogenesis
Thickened secretions from the
pancreas, these secretions
block the exocrine movement of
the digestive enzymes into the
duodenum and result in
irreversible damage to the
pancreas.
Symptoms
Mainly Fat Malabsorption
1) Steatorrhea
2) Flatulence and abdominal
distention
3) Fat-soluble vitamin
deficiencies occur in up to
50% CF infants by 2 months of
age.
4) Coagulation abnormalities
due to Vit. K
because of fat malabsorption,
and also because of
disturbances in the bowel flora
caused by frequent use of
Approximately 60 % of CF
infants have pancreatic
insufficiency at birth.
 90 % have developed
pancreatic insufficiency by
one year of age.
Diagnosi
s1) 72 hour fecal fat
collection
 The gold standard indirect
measure of lipolytic enzyme
activity.
 Very accurate measure of
lipase activity, but difficult.
2) Stool
trypsin/chymotrypsin
(poor sensitivity)
3) Breath Hydrogen Test
4) Serum Immuno-reactive
trypsinogen
 Used to screen New born.
 Serum IRT is elevated
5) Secretin/
Cholecystokinin
infusion test
 The gold standard direct
measurement of pancreatic
exocrine enzyme secretion.
 Bicarbonate concentration < 80
mEq/L is consistent with
pancreatic exocrine insufficiency.
6) Fecal Elastase
 Fecal elastase < 200
micrograms/gram indicate
pancreatic insufficiency.
 High sensitivity and
specificity.
Pancreatic enzyme replacement
therapy (PERT)
Mechanism
 Extracts of porcine pancreas
containing varying amounts of
lipase, protease, and amylase.
 Most enzyme preparations are in
the form of granules or
microspheres that are coated
with a pH-sensitive material
that protects the enzyme from
destruction by acid in the
stomach.
 The coating dissolves in the
alkaline medium of the
duodenum, releasing the
enzyme.
B. The fat-based method
 useful for infants who take a
known amount of formula or
in patients who receive tube
feedings.
 The dose starts at
approximately 2000
lipase units/120 ml of
formula or per breast
feeding.
 The dose can be adjusted up
to no more than 2,500 lipase
units /kg /feeding, with a
maximum daily dose of 10,000
lipase units/kg.
A. The weight-based method
 Used at any age.
 The starting dose for children
< 4 years =1000
lipase units/kg /meal.
 For children > 4 years =
500 lipase units/kg /meal .
 Dosing is increased based
upon symptoms of pancreatic
insufficiency to a maximum of
2500 lipase units/kg per
meal to avoid fibrosing
colonopathy.
Dose
Dosing of pancreatic enzymes is based upon the
units of lipase determined depending upon patient
weight or dietary fat intake.
Approach to Failure of pancreatic
enzyme therapy
B. CF- Related Diabetes
(CFRD)
25 % of patients had developed CFRD by 20 years of age.
 Mechanism : Progressive pancreatic fibrosis with β cell loss.
Risk Factors
Advancing age
Female Gender
Pancreatic Insufficiency
Delta-508 Genotype
Diagnosis
 The CFF and American Diabetes Association
recommend annual screening for CFRD
beginning at age 10 years.
 An oral glucose tolerance test (OGTT)
should be used for screening because either
fasting plasma glucose or hemoglobin
A1C has low sensitivity in this patient group.
Impaired glucose tolerance : 140 to
200 mg/dL
Diabetes mellitus : >200 mg/dL
Abnormal results of the OGTT should
have confirmatory testing on a different
day.
o Hemoglobin A1C ≥6.5 % or fasting
plasma glucose ≥126 mg/dL can be
used as a confirmatory test.
Treatme
ntThe standard medical
therapy for CFRD is
subcutaneous insulin
The available data suggest
that oral agents are not as
effective as insulin in
CFRD.
Hepatobiliary
ManifestationsIncreasing problem as patient life
span increases.
Incidence in CF: 10% of infants,
72% of adults.
 Liver disease in CF is difficult to be
diagnosed because patients may remain
asymptomatic until late in the disease
process.
 Clinically significant cirrhosis occurs
in 1 to 2 % of patients with CF with the
highest prevalence in patients aged 18
to 24 years.
 Almost all patients with severe CF-
related liver disease are diagnosed
Hepatobiliary
disease:
I. Asymptomatic
elevation in liver
enzyme tests and
hepatosplenomega
ly
II. Multilobular
cirrhosis
III. Neonatal
cholestasis
IV. Bile duct strictures
V. Gallstones /
Diagnos
is
Symptoms
1. history of jaundice.
2. change in stool pattern.
3. abdominal pain or nausea.
4. weight loss, medication
intake.
5. history of blood transfusion.
6. family history.
Physical Examination
1. Hepatosplenomegaly
2. Other manifestations of
chronic liver disease (such
as jaundice, spider
angiomata, palmar
Investigations
1. Liver function tests
2. US with Doppler flow
3. Liver Biopsy
o can be considered in
patients in whom the
diagnosis is unclear
Treatment
I. Optimization of nutrition
including the correction of
abnormalities of fat-soluble
vitamins and essential fatty
acids.
II. Ursodeoxycholic
acid (UDCA) may delay the
progression of liver disease
related to CF.
 Given if ALT, AST > 3 times
the upper limit of normal for
at least 3 months and/or if
GGT is significantly
elevated.
 Given at a dose of 20 mg/kg
per day in 2 divided doses.
III. Treatment of cholelithiasis and
upper GI bleeding treated as
other patients.
IV. Patients with liver failure or end-
stage liver disease should be
considered for liver
transplantation.
Gene Therapy
Gene Therapy Development start in 1989 with the discovery of the
CFTR Gene
Research in this field is focusing on developing vectors for the safe
delivery of a normal CFTR gene to the airways of patients with CF.
References
I. Cystic fibrosis: gastrointestinal disease
http://www.uptodate.com
II. Guidelines for the diagnosis and management of
distal intestinal obstruction syndrome in cystic
fibrosis patients.
http://www.ncbi.nlm.nih.gov/pubmed/21658638
III. Clinical Care Guidelines for Cystic Fibrosis–
Related Diabetes
http://care.diabetesjournals.org/content/33/12/2697/
F1.expansion.html
IV. A novel gene delivery method transduces
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Cystic Fibrosis "Overview of Gastrointestinal Diseases"

  • 1. Cystic Fibrosis “Overview of Gastrointestinal Diseases” Mahmoud Hashim Visiting student at Upstate Medical university Final year Medical student – Ainshams School of Medicine
  • 2. Cystic fibrosis (CF) generally is thought of as a lung disease because much of the associated morbidity and mortality is related to pulmonary complications. Gastrointestinal complications have become an increasingly important cause of morbidity in patients with CF.
  • 3.  Autosomal Recessive  Multisystem Disease Gastrointestinal tract (meconium ileus, distal intestinal obstruction syndrome) Hepatobiliary system (neonatal cholestasis, steatosis, biliary cirrhosis, Carrier rate in Caucasians of 1 in 25  Disease prevalence  Caucasians 1 in 2,500  African Americans 1 in 15,000  Asians 1 in 31,000
  • 4. Background Described in medical texts in 1595 as infants with salty skin and pancreatic damage who died because of a curse. Cystic Fibrosis disease was first described by Dorothy Andersen in 1938. In 1989 the responsible gene (CFTR) Dorothy Andersen (1901-1963)
  • 5. Genetics and PathogenesisCaused by mutations in a single large gene on chromosome 7 that encodes CFTR protein. There are > 1300 different mutations in the CFTR gene with potential to cause disease. The most common mutation is delta F508 which is
  • 6.
  • 7. Types of mutations in CFTRo Class 1 Mutations: (2-5%) Defective Protein Production Leads to premature termination of the mRNA and complete absence of CFTR protein. o Class 2 Mutations: (70%) Defective Protein Processing Includes delta F508 mutation prevents the protein from trafficking to the correct cellular location. o Class 3 Mutations: Defective regulation lead to diminished channel activity in response to ATP o Class 4 Mutations: Defective conduction o Class 5 Mutations: Reduced amounts of functional CFTR protein
  • 9. A. Distal Intestinal Obstruction Syndrome (DIOS)  10-47% Of Cases  Acute complete or partial obstruction of the Ileocecum by intestinal contents.  DIOS can occur at any age, but it is more common in older patients and those with pancreatic insufficiency. PathogenesisRisk Factors The majority of patients with DIOS have pancreatic insufficiency Severe genotype (e.g., delta F508) Intestinal dysmotilityPancreatic insufficiency Abnormal mucins and water and electrolyte composition of the intestinal contents Dehydration History of meconium ileus or prior episodes of DIOS Clinical Presentation
  • 10. Diagnosis I. Symptoms 1) Crampy Abdominal pain “RLQ” 2) Bilious Vomiting “ Complete Obstruction” 3) Constipation II. Imaging 1) X-ray 2) CT scan proximal small-bowel dilation and inspissated fecal material in the distal ileum. Air fluid level
  • 11. Treatme ntIncomplete Obstruction respond to oral rehydration combined with stool softeners. I. Oral polyethylene glycol (Mirlax), 2 gm/kg/day with max. dose 80 - 100 gm/day. Or II. Iso-osmotic PEG solution (GoLYTELY )at a dose of 20–40 ml/kg/h up to a maximum of 1 L/h over 8 hours. Or III. sodium meglumine diatrizoate (Gastrografin) can be administered orally or by naso- gastric tube,  Children <6 years : 50 ml in 200 ml of water or juice Complete Obstruction  Hospitalization with IV rehydration.  Sodium meglumine diatrizoate (Gastrografin) Enema, 100 mL of Gastrografin, diluted in 400 mL water, under direct vision until the terminal ileum is reached .  If not responding, surgical laparotomy and decompression is indicated . Prophylaxis I. Oral PEG, 0.5–1 g/kg/day to a maximum of 40 g/day for 6–12 months. II. optimize pancreatic enzyme
  • 12. B. Meconium Ileus  10-20%  Early clinical manifestation of CF.  characterized by partial or complete intestinal obstruction in the neonate. Diagnosis I. Symptoms Infants generally present during the first three days of life with abdominal distension with or without bilious vomiting and failure to pass meconium. 2) MI is “complex” if it is complicated by gastrointestinal pathology, including intestinal perforation, meconium peritonitis, atresia, or volvulus. Approximately 40 % of MI in newborns with CF is complex. 3) MI is “simple” if there is no
  • 13. II. Imaging 1. X-ray Dilated bowel loops with ground glass appearance in RLQ 2. Contrast enema usually shows microcolon with filling defects caused by mucous and meconium Contrast enema
  • 14. Treatment Diluted sodium meglumine diatrizoate, (Gastrografin), under direct vision until the terminal ileum is reached . The Hyperosmolar contrast breaks up the meconium plug. Success rates of 30 to 60 %. If Failed, surgical intervention is needed Intraoperative infusions of n-acetylcysteine or hyperosmolar contrast have been shown to decrease the need for surgical resection.
  • 15. C.GERD  20% of CF patients report reflux- type symptoms. Pathogenesis I. Increased intra-abdominal pressure due to chronic coughing and wheezing II. Absence of the normal basal tone of the LES III. The mechanical effect of a depressed diaphragm caused by lung hyperinflation IV. Medications that reduce LES pressure, such as theophylline Clinical Manifestation and Treatment D.Malignancy o From 1990 to 2009, 41,188 patients were followed. o Increased risk of GI cancers involving the esophago-gastric junction, biliary tract, small bowel, and colon. o Any adolescent CF patient with chronic GI complaints needs evaluation for cancers.
  • 16. Pancreatic manifestations A. Pancreatic Insufficiency o Most common inherited cause of exocrine pancreatic insufficiency o The most common gastrointestinal complication of CF, affecting 85 % of patients. o CFTR genotypes are more closely related to the severity of pancreatic exocrine dysfunction > to the severity of lung disease. Pathogenesis Thickened secretions from the pancreas, these secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas.
  • 17. Symptoms Mainly Fat Malabsorption 1) Steatorrhea 2) Flatulence and abdominal distention 3) Fat-soluble vitamin deficiencies occur in up to 50% CF infants by 2 months of age. 4) Coagulation abnormalities due to Vit. K because of fat malabsorption, and also because of disturbances in the bowel flora caused by frequent use of Approximately 60 % of CF infants have pancreatic insufficiency at birth.  90 % have developed pancreatic insufficiency by one year of age.
  • 18. Diagnosi s1) 72 hour fecal fat collection  The gold standard indirect measure of lipolytic enzyme activity.  Very accurate measure of lipase activity, but difficult. 2) Stool trypsin/chymotrypsin (poor sensitivity) 3) Breath Hydrogen Test 4) Serum Immuno-reactive trypsinogen  Used to screen New born.  Serum IRT is elevated 5) Secretin/ Cholecystokinin infusion test  The gold standard direct measurement of pancreatic exocrine enzyme secretion.  Bicarbonate concentration < 80 mEq/L is consistent with pancreatic exocrine insufficiency. 6) Fecal Elastase  Fecal elastase < 200 micrograms/gram indicate pancreatic insufficiency.  High sensitivity and specificity.
  • 19. Pancreatic enzyme replacement therapy (PERT) Mechanism  Extracts of porcine pancreas containing varying amounts of lipase, protease, and amylase.  Most enzyme preparations are in the form of granules or microspheres that are coated with a pH-sensitive material that protects the enzyme from destruction by acid in the stomach.  The coating dissolves in the alkaline medium of the duodenum, releasing the enzyme.
  • 20. B. The fat-based method  useful for infants who take a known amount of formula or in patients who receive tube feedings.  The dose starts at approximately 2000 lipase units/120 ml of formula or per breast feeding.  The dose can be adjusted up to no more than 2,500 lipase units /kg /feeding, with a maximum daily dose of 10,000 lipase units/kg. A. The weight-based method  Used at any age.  The starting dose for children < 4 years =1000 lipase units/kg /meal.  For children > 4 years = 500 lipase units/kg /meal .  Dosing is increased based upon symptoms of pancreatic insufficiency to a maximum of 2500 lipase units/kg per meal to avoid fibrosing colonopathy. Dose Dosing of pancreatic enzymes is based upon the units of lipase determined depending upon patient weight or dietary fat intake.
  • 21. Approach to Failure of pancreatic enzyme therapy
  • 22. B. CF- Related Diabetes (CFRD) 25 % of patients had developed CFRD by 20 years of age.  Mechanism : Progressive pancreatic fibrosis with β cell loss. Risk Factors Advancing age Female Gender Pancreatic Insufficiency Delta-508 Genotype
  • 23. Diagnosis  The CFF and American Diabetes Association recommend annual screening for CFRD beginning at age 10 years.  An oral glucose tolerance test (OGTT) should be used for screening because either fasting plasma glucose or hemoglobin A1C has low sensitivity in this patient group. Impaired glucose tolerance : 140 to 200 mg/dL Diabetes mellitus : >200 mg/dL Abnormal results of the OGTT should have confirmatory testing on a different day. o Hemoglobin A1C ≥6.5 % or fasting plasma glucose ≥126 mg/dL can be used as a confirmatory test. Treatme ntThe standard medical therapy for CFRD is subcutaneous insulin The available data suggest that oral agents are not as effective as insulin in CFRD.
  • 24. Hepatobiliary ManifestationsIncreasing problem as patient life span increases. Incidence in CF: 10% of infants, 72% of adults.  Liver disease in CF is difficult to be diagnosed because patients may remain asymptomatic until late in the disease process.  Clinically significant cirrhosis occurs in 1 to 2 % of patients with CF with the highest prevalence in patients aged 18 to 24 years.  Almost all patients with severe CF- related liver disease are diagnosed Hepatobiliary disease: I. Asymptomatic elevation in liver enzyme tests and hepatosplenomega ly II. Multilobular cirrhosis III. Neonatal cholestasis IV. Bile duct strictures V. Gallstones /
  • 25. Diagnos is Symptoms 1. history of jaundice. 2. change in stool pattern. 3. abdominal pain or nausea. 4. weight loss, medication intake. 5. history of blood transfusion. 6. family history. Physical Examination 1. Hepatosplenomegaly 2. Other manifestations of chronic liver disease (such as jaundice, spider angiomata, palmar Investigations 1. Liver function tests 2. US with Doppler flow 3. Liver Biopsy o can be considered in patients in whom the diagnosis is unclear
  • 26. Treatment I. Optimization of nutrition including the correction of abnormalities of fat-soluble vitamins and essential fatty acids. II. Ursodeoxycholic acid (UDCA) may delay the progression of liver disease related to CF.  Given if ALT, AST > 3 times the upper limit of normal for at least 3 months and/or if GGT is significantly elevated.  Given at a dose of 20 mg/kg per day in 2 divided doses. III. Treatment of cholelithiasis and upper GI bleeding treated as other patients. IV. Patients with liver failure or end- stage liver disease should be considered for liver transplantation.
  • 27. Gene Therapy Gene Therapy Development start in 1989 with the discovery of the CFTR Gene Research in this field is focusing on developing vectors for the safe delivery of a normal CFTR gene to the airways of patients with CF.
  • 28. References I. Cystic fibrosis: gastrointestinal disease http://www.uptodate.com II. Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients. http://www.ncbi.nlm.nih.gov/pubmed/21658638 III. Clinical Care Guidelines for Cystic Fibrosis– Related Diabetes http://care.diabetesjournals.org/content/33/12/2697/ F1.expansion.html IV. A novel gene delivery method transduces