GIT

Lec. 4

GSE
Celiac disease (Gluten Sensitive Enteropathy ) is an immune-mediated enteropathy caused by permanent sensitivity to gluten in genetically susceptible individuals

PATHOGENESIS

Celiac disease develops only after dietary exposure to the protein gluten, which is found in wheat, rye, and barley. The activity of gluten resides in the gliadin fraction, that lead to sensitization of lamina propria lymphocytes.

The inflammatory response results in villus atrophy, crypt hyperplasia, and damage to the surface epithelium in the small bowel. The injury is greatest in the proximal small bowel and extends distally for a variable distance. Celiac disease results in a decrease in the absorptive and digestive capacity of the small intestinal surface area and a relative increase in immature epithelial cells.

Genetic predisposition 

Concordance in monozygotic twins approaching 100%. Two to 5% of first-degree relatives have symptomatic gluten-sensitive enteropathy, and as many as 10% of first-degree relatives have asymptomatic damage to small bowel mucosa consistent with this disorder. Celiac disease is associated with (HLA) types (DQ8 and DQ2) Down syndrome Type 1 diabetes Viruses

CLINICAL PRESENTATION

The typical presentation of celiac disease (diarrhea, abdominal distention, & FTT) appear in toddler (6-24 mo.) after introduction of gliadin containing diet. The stools are characteristically pale, loose, and offensive. Neurologic symptoms do occur; many children are emotionally withdrawn, irritable, and fretful. Other Manifestations: smooth tongue , oral ulcers, excessive bruising, finger clubbing, peripheral edema

Non-Intestinal Manifestations and Association of Celiac Disease

DIFFERENTIAL DIAGNOSIS
GIARDIASIS MALNUTRITION COWS MILK PROTEIN ALLERGY

LABORATORY INVEST

Anaemia usually IDA but dimorphic anaemia may occur. Hypoproteinaemia, hypoprothrombinaemia, ↑fecal fat estimation.

SCREENING AND DIAGNOSIS

The anti-endomysium IgA antibody and anti-tissue transglutaminase IgA antibody tests are highly sensitive and specific in identifying individuals with celiac disease.
Serological Test

A problem with serology is represented by the association of celiac disease with IgA deficiency (10-fold increase compared to the general population). Serum IgA should always be checked, and in the case of IgA deficiency, D-AGA, IgG anti-endomysium, or TG2 should be sought.

Negative serology should not preclude a biopsy examination when the clinical suspicion is strong


Genetic tests have an increasing role in the diagnosis. Less than 2% of celiac patients lack both HLA specificities; at the same time, approximately one third of the “normal” population has one or the other marker; that means that the measurement of HLA DQ2 and/or DQ8 has a strong negative predictive value but a very weak positive predictive value for the diagnosis of celiac disease. Genetic tests



Small Intestinal Biopsy
Definitive diagnosis of celiac disease requires small intestinal biopsy, as none of the available serologic tests are 100% reliable.

The characteristic histologic changes include partial or total villous atrophy, crypt elongation and decreased villous/crypt ratio, increased number of intraepithelial lymphocytes . The mucosal involvement can be patchy, so multiple biopsies must be obtained.

ESPGHAN current criteria, The 2 requirements mandatory for the diagnosis of celiac disease are: characteristic histologic features + full clinical remission after withdrawal of gluten from the diet Reversal of positive serologic tests after gluten withdrawal is considered supportive evidence.

In children <2 yr of age, milk protein–sensitive enteropathy can produce changes similar to celiac disease; confirmation of diagnosis after a gluten challenge is sometimes required. This necessitates three biopsies: an initial biopsy at presentation, the 2nd to document healing with gluten withdrawal, and the 3rd to show recurrent damage with reintroduction of gluten. Gluten challenge is not considered mandatory except in situations where there is doubt about the initial diagnosis

TREATMENT

The only treatment for celiac disease is lifelong exclusion of gluten. This requires a wheat-, barley-, and rye-free diet. After gluten withdrawal, there is rapid remission of symptoms, improved bone mineralization, and reversal of growth failure and nutritional deficiencies.

It is recommended that children with celiac disease be monitored with periodic visits for assessment of symptoms, growth, physical examination, and adherence to the gluten-free diet.

PROGNOSIS

The clinical response to a gluten-free diet usually results in improvement of mood, appetite, and lessening of the diarrhea within a week. Reduced bone mineral density also improves with gluten exclusion. No long-term complications from a gluten-free diet have been recognized.

Celiac disease is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, and of the esophagus. Several follow-up studies suggest that a gluten-free diet protects from cancer development, especially if started in the 1st years of life. Therefore, early diagnosis and strict dietary restrictions appear to be the only possibility of preventing risk for rare but very aggressive forms of cancer associated with celiac disease.

CYSTIC FIBOSIS

A multisystem disease Autosomal recessive inheritance Commonest lethal genetic condition affecting Caucasian people. DEFECT IN CHLORIDE TRANSPORT IN EPITHELIAL TISSUE. This result in relative dehydration of airway secretions.


GENETICS
CF is inherited as an autosomal recessive trait.
Let C= normal CFTR Let c= mutant CFTR If mom and dad are both carriers then:
C
c
c
C
With mom and dad carriers, then: 50% chance of having child who is a carrier 25% chance of child being affected 25% of child with no mutant copies of CFTR

GENETICS

The CF gene codes for a protein of 1,480 amino acids called the CF transmembrane regulator (CFTR). CFTR is expressed largely in epithelial cells of airways, the gastrointestinal tract (including the pancreas and biliary system), the sweat glands, and the genitourinary system.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene

The most comm CFTR gene is located on the long arm of chromosome 7. There are >1500 mutations in CFTR. Commonest mutation is Δ F508---70% CF alleles in caucasians (deletion of a single phenylalanine residue at amino acid 508 )

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

A Cl- channel2 sets of 6 transmembrane domains2 “ATP-binding cassettes” (thus “ABC transport protein”) ATP
ATP


What’s wrong with DF508? The most common mutation (70% of mutants): A phenylalanine (F) is deleted at position 508 in ATP-binding cassette #1

PATHOGENESIS

Four long-standing observations are of fundamental pathophysiologic importance: failure to clear mucous secretions a paucity of water in mucous secretions an elevated salt content of sweat and other serous secretions chronic infection limited to the respiratory tract.

CFTR helps to control bulk water flow across epithelia

1. Na+ channels are usually open, but extensive Na+ flux requires a counterion. 2. If CFTR is open, Cl- becomes the counterion. Therefore NaCl flows across the membrane. 3. Water then flows around the cells to maintain osmotic pressure. 4. Result: isotonic NaCl solution flows from the blood to the lumen (or vice-versa)

CFTR and Airway Surface Liquid

Clinical features of Cystic Fibrosis
Chronic Sino-Pulmonary Disease Nutritional deficiency/GI abnormality Obstructive Azoospermia Electrolyte abnormality CF in a first degree relative

Bronchiectasis

Bronchiectasis



Mucous in the airways cannot be easily cleared from the lungs

Nasal Polyps

Digital Clubbing
Schamroth sign +v

Colon

Sticky mucus secretion

Pancreas

Ducts are filled with sticky mucus. Scaring of tissue.

Meconium ileus

Diagnostic Methods

Sweat chloride

Chemical that stimulates sweating placed under electrode pad; saline under other electrode pad on arm Mild electric current is passed between electrodes Sweat collected Positive Sweat chloride: > 60 meq/L

Genetic testing

DNA Testing for most common CFTR mutations

Other Diagnostic Tests

increased potential differences across nasal epithelium Prenatal diagnosis is possible by Amniotic fluid or Chorionic villous sampling Newborn Screening for CF: Immunoreactive trypsinogen usually first followed by either sweat or DNA testing

Diagnostic Criteria for Cystic Fibrosis

TREATMENT Multidisciplinary
Pulmonary Therapy. Infection Nutrition Gastrointestinal Infertility Social Issues

Nutrition

High calorie supplemental Vitamin supplementation Pancreatic enzymes