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