diseases of the gastrointestinal system 2018 · • intraluminal digestion is affected if the...

Diseases of the

gastrointestinal system

2018 Dr H Awad

Lecture 5: diseases of the small intestine

Small intestinal villi

Small intestinal

villi -Villi are tall, finger like mucosal

projections, found in the small intestine.

-most of food absorption occurs in the

small intestine.

-the villi increase the surface area

through which absorption occurs, this

maximises food absorption.

-if the villi are lost or shortened, in certain

diseases then absorption will decrease.

Small intestinal diseases • the most important disease that affects the small intestine is malabsorption.

• Malabsorption means decreased absorption of food.

• If less food is absorbed , then there will be more food in the intestinal lumen.

• More food in the lumen results in increased concentration of nutrients and

minerals… this creates an osmotic gradient resulting in movement of water from the

epithelial lining to the lumen

• So we will have more fluid in the lumen admixed with unabsorbed food… this is

passed as diarrhoea.

• In malabsorption, the diarrhoea contains large amount of unabsorbed fat, this is

called steatorrhea

• Steatorrhea is defined as the presence of excess fat in feces. Stools may be bulky

and difficult to flush, have a pale and oily appearance and can be foul-smelling

• Malabsorption is caused by disturbance of any of the stages of absorption.

• There are four stages of food absorption:

• 1. Intraluminal digestion: inside the lumen large molecules ( carbs, lipids,

proteins) are digested into absorbable forms ( small molecules).

• 2.terminal digestion: hydrolysis of carbohydrates and peptides by

disaccharidases and peptidases in the brush border of small intestinal mucosa.

• 3.transepithelial transport: nutrients transported across the epithelium

• 4. Lymphatic transport of absorbed lipids. ( note that lipids are transported

through lymphatics whereas other nutrients are transported through blood)

• Interference with any of the four stages above causes malabsorption.

Intraluminal

Digestion

Terminal digestion

Transepithelial transport

Lymphatic transport

Types of malabsorption:

• Intraluminal digestion is affected if the enzymes

responsible for digestion are decreased like in chronic

pancreatitis or in cystic fibrosis

• Terminal digestion is affected in disaccharidase

deficiency and in other diseases celiac disease and

some infections.

• Transepithelial transport is affected in celiac and

infections.

• Lymphatic transport affected in Whipple disease.

this table aims to show you the diverse

causes of malabsorption.. I don't want you

to memorise it!

Most important diseases that

cause malabsorption

• Celiac disease

• Tropical spur ( tropical enteropathy)

• Lactase deficiency

• Whipple disease

• Infections…. you will study these in microbiology.

Celiac disease

• Celiac disease is also known as celiac sprue or

gluten sensitive enteropathy.

• It’s an immune mediated disease triggered by

ingestion of gluten-containing cereals in genetically

predisposed individuals.

• Gluten is the main protein in wheat, rye ,oat and

barley.

• the main treatment is gluten free diet.

Gluten: found in wheat, oats

,rye(ُشوفَان) and barley(الشعير)

Gluten is the storage protein in these grains: it

is digested to smaller components, including

gliadin which is responsible for celiac disease.

Oat

Wheat

note that gluten in the mentioned grains is

a large protein. the gliadin in gluten is the

peptide responsible for celiac disease

rice and corn are gluten free

Epidemiology

• 0.5-1% of white people have the disease.

• In Jordan Preliminary statistics indicate that there are

around 120,000 people diagnosed with celiac disease,

constituting 1.5 per cent of the population

• Friends of Celiac Disease Patients Charity Association,

is a charity in Jordan taking care of celiac patients.

Pathogenesis/ overview of

autoimmune diseases • Celiac is an autoimmune disease.

• Autoimmune diseases occur when our cells recognise our normal internal (self) antigens

as foreign.

• the cells that recognise antigen in our body are called antigen presenting cells, these

recognise the antigen ( by their HLA proteins on their surface) and present it to the T

helper cells.

• once T helpers recognise the antigen they are activated; they produce cytokines that can

cause tissue damage.

• Also activated helpers can stimulate B lymphocytes to produce antibodies(

immunoglobulins) and can stimulate cytotoxic T lymphocytes.

• the antibodies and cytotoxic T produce more damage to tissues.

• note that we have two types of T cells: helpers ( CD4 cells) that “help”: regulate all the

immune response. And cytotoxic T cells ( CD 8) which kill other cells.

This summarises what’s in the previous slide. APC =

antigen presenting cell. Killer T = cytotoxic.

note that also macrophages can be activated by T helpers.

Pathogenesis of celiac

disease • Celiac is caused by autoimmune reaction to gluten.

• Gluten is digested by luminal and brush border enzymes to several amino acids and peptides.

One of these peptides is gliadin.

• Gliadin resists further degradation by GI enzymes.

• Gliadin is deaminated by tissue transglutaminase

• After deamination, gliadin can interact with HLA DQ2 or HLA DQ 8 on antigen presenting cells.(

remember that APC recognises antigens by HLA= human leukocyte antigens)

• if this interaction happens, then gliadin can be presented to T helpers ( CD4 T cells)

• once activated T helpers produce cytokines.

• These cytokines cause damage of the intestinal epithelium, damaging the villi.

• When villi are damaged they become short… so we loose surface area important for absorption..

so less absorption occurs ( malabsorption)

Pathogenesis of celiac..

continuation • So: T helpers destroy villi by the cytokines.. but they also

stimulate Cytotoxic T cells and B cells.

• Stimulated cytotoxic T cells kill enterocytes ( epithelial cells

of the small intestine, which line the villi)

• Stimulated B cells produce antibodies including: anti tissue

transglutaminase, anti deaminated gliadin, antiendomysial

antibody.

• these antibodies are very helpful in diagnosing celiac but

it’s not clear if they play a role in destruction of enterocytes.

• Note: for the gliadin to cause autoimmune reaction, it’s important that it is

transferred to the lumen of the intestine.

• Gliadin is a large molecule, it cannot normally pass through the

epithelium

• That’s why not every person with genetic predisposition will have celiac.

• Environmental factors are important for disease development, which

could be viral infection that increases the permeability of the intestinal

epithelium so gliadin can move to the lumen.

• Early weaning increases risk of celiac, probably because the epithelial

cells and their junctions might not be fully developed in young babies,

which increases the probability of gliadin to one to the lumen.

Genetic factors

• autoimmune diseases occur in genetically susceptible individuals.

• in the case of celiac, all patients have HLA DQ2 or DQ 8.. you

should know why!

• However, not every person with HLA DQ2 or 8 will have the

disease.. so other factors play a role. see next slide for a brief idea

of what HLA proteins are.

• we don't know the other genetic factors yet.

• there is association with other autoimmune diseases like type 1

Diabetes and thyroiditis.(as a rule this is always correct:

autoimmune diseases occur in clusters!)

HLA • HLA = human leukocyte

antigen (HLA) is a gene

complex encoding the major

histocompatibility complex

(MHC) proteins in humans.

• they are surface proteins

responsible for the regulation

of the immune system.

• HLA genes are highly

polymorphic; they have many

different alleles allowing them

to fine-tune the immune

response.

Pathogenesis

Morphology

• Biopsy from second portion of duodenum or proximal jejunum are

needed to diagnose celiac disease.

• Why these sites? because they are exposed to the highest

concentration of gluten.

• Biopsy shows: short villi ( villous atrophy) and increased

lymphocytes in the epithelium ( increased intraepithelial

lymphocytes).

• Please note that these features are not specific for celiac. The

histological features of celiac disease can be seen in other diseases

like viral infections and tropical sprue. SO: TO DIAGNOSE CELIAC

YOU NEED CLINICOPATHOLOGICAL CORRELATION>

Clinicopathological

correlation in celiac

• Many diseases require several lines of evidence to be diagnosed.

• in many diseases, no one single test is diagnostic of the disease.

• So: medical professionals must work in a team to reach the

correct diagnosis.

• in celiac, to diagnose the patient with celiac you need: 1. clinical

symptoms related to eating gluten, improvement of symptoms

when stopping eating gluten , 2. Serological evidence; the

presence of antibodies , 3. Histopathological features of villous

atrophy and increased intraepithelial lymphocytes.

Villous atrophy

Villous atrophy

what do mean by increased

intraepithelial lymphocytes • As you know, within the GI epithelium there are

lymphocytes to protect the mucosa ( MALT )

• in the small intestine, normally there are 25

lymphocytes per 100 epithelial cells ( enterocytes).

• this is equivalent to 1 lymphocyte per 4 epithelial

cells.

• In celiac the number of lymphocytes is increased, so

you will have more than 25 lymphocytes per 100.

increased intraepithelial

lymphocytes

Clinical features • Coeliac disease can manifest in childhood or in adults.

• in children, it manifests between 6-24 months of age and affects

males and females equally.

• Symptoms in children: irritability, diarrhoea, weight loss, failure

to thrive,

• in adults most common age of onset is 30-60 years

• Main symptoms in adults are abdominal pain and steatorrhea.

• The malabsorption in Celiac patients results in anaemia and

vitamin deficiencies.

• the disease in children starts

at or after weaning; when they

start eating solid food besides

milk.

Serology

• IgA to tissue transglutaminase

• IgA or IgG to gliadin

• Antiendomysial Ab

• HLA DQ2 or 8 : high negative predictive value. but if

positive not useful. this means a person with

negative DQ2 or 8 cannot have celiac.

Complications

• increased rate of malignancy

• most common malignancy associated with celiac is

Enteropathy associated T cell lymphoma, which is

aggressive

• Adenocarcinoma risk is also increased.

• Refractory sprue: if the symptoms are not controlled

despite strict gluten free diet.. then investigate for

malignancy.