Cystic fibrosis (GIT)

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Vitebsk State Order of Peoples’ Friendship Medical
University
Department of Facultative Therapy
Head of Department:​ ​В.И. Козловский
Teacher: ​Л.В. Бабенкова
Report:
CYSTIC FIBROSIS (MUCOVISCIDOSIS) -
GASTROENTEROLOGY
Dinoosh De Livera
Group 53, 6th Course
Overseas Students Training Faculty
2018
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INTRODUCTION
Overview:
Cystic fibrosis (CF) generally is thought of as a lung disease because much of the associated morbidity and mortality
is related to pulmonary complications. However, 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, biliary sludge)
Epidemiology:
❏ 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
History & 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) was discovered.
Dorothy Andersen
(1901-1963)
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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 found in approximately 70%.
Types of mutations in CFTR:
❏ Class 1​ Mutations: (2-5%) Defective Protein Production Leads to premature termination of the mRNA and
complete absence of CFTR protein.
❏ Class 2​ Mutations: (70%) Defective Protein Processing. Includes delta F508 mutation: prevents the protein
from trafficking to the correct cellular location.
❏ Class 3​ Mutations: Defective regulation lead to diminished channel activity in response to ATP.
❏ Class 4​ Mutations: Defective conduction
❏ Class 5​ Mutations: Reduced amounts of functional CFTR protein
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DIAGNOSIS OF CYSTIC FIBROSIS
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CLINICAL PRESENTATION
A. Distal Intestinal Obstruction Syndrome (DIOS):
❏ 10-47% Of Cases
❏ Acute complete or partial obstruction of the Ileocaecal intestinal contents.
❏ DIOS can occur at any age, but it is more common in older patients and those with pancreatic insufficiency.
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
Treatment:
Incomplete Obstruction: responds 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 at a dose of 20–40ml/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 nasogastric tube,
Children <6 years : 50 ml in 200 ml of water or juice
Older patients : 100 ml diluted
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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 no response to treatment, 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
1) 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 complications.
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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Treatment:
1) 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 %.
2) 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
D.Malignancy
❏ From 1990 to 2009, 41,188 patients were followed.
❏ Increased risk of GI cancers involving the esophago-gastric junction, biliary tract, small bowel, and colon.
❏ Any adolescent CF patient with chronic GI complaints needs evaluation for cancers.
Pancreatic manifestations
A. Pancreatic Insufficiency
❏ Most common inherited cause of exocrine pancreatic insufficiency.
❏ The most common gastrointestinal complication of CF, affecting 85 % of patients.
❏ 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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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 antibiotics.
❏ Approximately 60 %of CF infants have pancreatic insufficiency at birth.
❏ 90 %have developed pancreatic insufficiency by one year of age.
Diagnosis
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 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.
Treatment:
1. 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 improved fecal fat.
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Dose:
Dosing of pancreatic enzymes is based upon the units of lipase determined depending upon patient weight or dietary
fat intake.
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.
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.
2. Approach to Failure of pancreatic enzyme therapy
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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
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.
❏ Hemoglobin A1C ≥6.5 % or fasting plasma glucose ≥126 mg/dL can be used as a confirmatory test.
Treatment:
❏ 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 hepatosplenomegaly
II. Multilobular cirrhosis
III. Neonatal cholestasis
IV. Bile duct strictures
V. Gallstones / common bile duct
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Diagnosis:
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 (jaundice, spider angiomata, palmar erythema, ascites)
Investigations:
1. Liver function tests
2. US with Doppler flow
3. Liver Biopsy: 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 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 endstage 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.
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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 porcine pancreatic duct epithelial cells.
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