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Cystic Fibrosis“Overview of Gastrointestinal Diseases”

Mahmoud HashimVisiting student at Upstate Medical universityFinal year Medical student – Ainshams School of Medicine

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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.

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Autosomal Recessive

Multisystem Disease

Gastrointestinal tract (meconium ileus, distal intestinal obstruction syndrome)

Hepatobiliary system (neonatal cholestasis, steatosis, biliary cirrhosis, biliary sludge)

Pancreas(exocrine dysfunction)

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

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BackgroundDescribed 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) was identified and its genetic code was sequenced.

Dorothy Andersen(1901-1963)

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Genetics and PathogenesisCaused by mutations in a

single large gene on

chromosome 7 that encodes CFTR protein.

There are > 1300 different mutationsin the CFTR gene with potential to cause disease.

The most common mutation is

delta F508 which is

found in approximately 70 % of Caucasian patients.

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Types of mutations in CFTRo Class 1 Mutations: (2-5%)

Defective Protein ProductionLeads to premature termination of the mRNA and complete absence of CFTR protein.

o Class 2 Mutations: (70%)Defective Protein ProcessingIncludes delta F508 mutationprevents the protein from trafficking to the correct cellular location.

o Class 3 Mutations: Defective regulationlead to diminished channel activity in response to ATP

o Class 4 Mutations:Defective conduction

o Class 5 Mutations:Reduced amounts of functional CFTR protein

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Diagnosis of CF

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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. 

Pathogenesis Risk Factors

The majority of patients with DIOS have pancreatic insufficiency

Severe genotype (e.g., delta F508)

Intestinal dysmotility Pancreatic insufficiency

Abnormal mucins and water and electrolyte composition of the intestinal contents

Dehydration

History of meconium ileus or prior episodes of DIOS

Clinical Presentation

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DiagnosisI. Symptoms1) Crampy Abdominal pain

“RLQ”2) Bilious Vomiting “

Complete Obstruction”3) Constipation

II. Imaging1) X-ray2) CT scan

proximal small-bowel dilation and inspissated fecal material in the distal ileum.

Air fluid level

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Incomplete 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

Older patients : 100 ml diluted in 400 ml.

half doses on subsequent days should this be required

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 .

ProphylaxisI. Oral PEG, 0.5–1 g/kg/day to a

maximum of 40 g/day for 6–12 months.

II. optimize pancreatic enzyme treatment

III. adequate hydration

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B. Meconium Ileus 10-20% Early clinical manifestation of CF. characterized by partial or

complete intestinal obstruction in the neonate.

DiagnosisI. 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 associated gastrointestinal pathology.  

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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

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TreatmentDiluted 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 neededIntraoperative infusions of n-acetylcysteine or

hyperosmolar contrast have been shown to decrease the need for surgical resection.

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C.GERD 20% of CF patients report reflux-

type symptoms.

PathogenesisI. 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 Treatmentas usual GERD

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.

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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.

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SymptomsMainly Fat

Malabsorption

1) Steatorrhea2) Flatulence and

abdominal distention3) 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 antibiotics.

5) Growth Failure

Approximately 60 % of CF infants have pancreatic insufficiency at birth.

90 % have developed pancreatic insufficiency by one year of age.

18Diagnosis

1) 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 Test4) 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.

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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.

Leading to  improves fecal fat absorption decreased stool frequency, and improved stool consistency.

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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.

DoseDosing of pancreatic enzymes is based upon the units of lipase determined depending

upon patient weight or dietary fat intake.

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Approach to Failure of pancreatic enzyme therapy

Decrease Fat

intake to

50-75 g/day

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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

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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.

o IF these tests are normal, OGTT should be repeated.

TreatmentThe standard medical

therapy for CFRD is subcutaneous insulin

The available data suggest that oral agents are not as effective as insulin in CFRD. 

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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 before age 20.

Hepatobiliary disease:

I. Asymptomatic elevation in liver enzyme tests and hepatosplenomegaly

II. Multilobular cirrhosisIII. Neonatal cholestasisIV. Bile duct stricturesV. Gallstones / common

bile duct stonesVI. Steatosis /

steatohepatitisVII. Portal hypertension

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Diagnosis

Symptoms1. 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 Examination7. Hepatosplenomegaly 8. Other manifestations of

chronic liver disease (such as jaundice, spider angiomata, palmar erythema, and ascites) are uncommon.

Investigations1. Liver function tests2. US with Doppler flow3. Liver Biopsyo can be considered in

patients in whom the diagnosis is unclear 

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TreatmentI. 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.

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Gene TherapyGene Therapy Development start in 1989 with the discovery

of the CFTR GeneResearch in this field is focusing on developing vectors for the

safe delivery of a normal CFTR gene to the airways of patients with CF.

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ReferencesI. 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 Diabeteshttp://care.diabetesjournals.org/content/33/12/2697/F1.expansion.html

IV. A novel gene delivery method transduces porcine pancreatic duct epithelial cells.http://www.ncbi.nlm.nih.gov/pubmed/24257348

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