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1
Q

What is celiac disease?

A
  • Immunologically mediated disease in genetically susceptible individuals, driven by an environmental Ag (gluten), found in wheat, rye, barley, which results in chronic inflammation of the SI mucosa.
  • Remission on a gluten free diet is the hallmark of the disease
  • Very strong genetic association with the HLA DQ2/HLADQ8 genes
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2
Q

What is the prevalence of celiac disease?

A

1:100 (may be more prevalent)

• Most races affected rare in SE Asians, Japanese, and Indigenous Australians.

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3
Q

When does celiac present?

A

• Can present anytime from infancy (after introduction of gluten into diet) to late adulthood

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4
Q

How do we treat celiac disease?

A

Remove gluten from the diet

CD8+ disappear rapidly but mucosa may not become villous for some time

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5
Q

What is absorbed in the various parts of the small intestine?

A

a. Duodenum = protein, fat, fat soluble vitamins, glucose, iron, water soluble vitamins, terminal ileum = B12+ bile

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6
Q

How does the absorption in various parts of the SI affect celaic disease?

A

Celiac disease tends to affect the more distal regions of the SI. Thus patients may present with iron deficiency anaemia, folate deficiency and fat soluble vitamin deficiency (leading to osteoporosis and coagulopathy)
ii. Uncommon to have B12 deficiency (as this is absorbed in the terminal ileum)

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7
Q

What is a potential consequence of the failure to reabsorb bile acids?

A

It may cause osmotic diarrhoea in the colon

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8
Q

What are the three zones of the villi?

A

1) pluripotent stem cells 2) zone of proliferation 3) zone of maturation

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9
Q

How many cells are lots per day? what happens if more then usual are lost?

A

normally about 1400, if more are lost there is an expansion of the proliferative zone. However the cells replacing the surface are immature and therefore not able to perform functions of mature cell, this causes a reduction in nutrient absroption

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10
Q

What are the regions of the SI that increase its surface area?

A

a. Valves of Kerkring (3x) + villi (10x) + microvilli (20x) = amplification of the absorptive surface of small intestine (600x)

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11
Q

What do paneth cells produce?

A

They are secretory cells, in particular they produce alpha-defencins which proptect the bowel against bacteria

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12
Q

How do alpha defensins work?

A

They are positively charged particles which bind to the negatively charged lipid membranes of the bacteria

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13
Q

Where are endopeptidases, proteases and lipases located in the SI?

A

They are found on the top of the brush boarder

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14
Q

What is found in the lamina propria?

A

Contains lymphocytes, plasma cells, macrophages, mast cells, and eosinophils

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15
Q

What is the histology of the duodenal villus?

A

i. Tall columnar cells with basal nuclei + brush border (enzymes located) + goblet cells + IELS
ii. In the lamina propria (loose CT) there are CD4+ helper cells, B cells and plasma cell (adaptive)
iii. Tight junctions between enterocytes with surface microvilli; lots of mitochondria + ER

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16
Q

what is the ratio of villi to crypts (in healthy small bowel)

A

4:1

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17
Q

What is the normal ratio of intraepithelial lymphocytes to enterocytes?
What changes occur in celiac disease?

A

less than 25/100 (healthy)

2-300/100 (in celiac)

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18
Q

What are the stages in the development of villous atrophy with crypt hyperplasia?

A

i. Marsh 1 = villous to crypt length is normal (4:1), but there are more than 30 IELs per 100 enterocytes
ii. Marsh 2 = IELs + elongation and branching of crypts [increased proliferation, longer crypts]
iii. March 3 = villi are shortened and blunted and the villous to crypt ratio is less than 1:4; mucosa is FLAT

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19
Q

What happens to the remaining enterocytes in celiac disease?

A

Enterocytes are stunted, there is loss, distortion and stunting of residual microvilli as compared with normal enterocytes

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20
Q

What is the clinical presentation of celiac disease?

A

a. 1) gastrointestinal: diarrhoea, bloating, abdominal cramps, flatulence 2) anaemia (iron deficiency due to low ferritin), vitamin deficiencies 3) malabsorption of nutrients (especially of fat) -> stools become bulky/greasy
4) failure to thrive as an infant 5) osteoporosis due to reduced vitamin D and calcium absorption 6) lethargy (chronic fatigue), migraine, infertility, mouth ulcers 7) ↑ autoimmune diseases eg. T1D, autoimmune thyroiditis [autoimmune + environment] BUT can be completely asymptomatic

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21
Q

What are some other causes of intraepithelial lymphocytosis and villous atrophy with crypt hyperplasia

A

a. Tropical spruce = travel to tropics (India, Mexico, Brazil etc.) ? cause but probably bacterial as it can be treated with certain antibiotics; tends to involve the ileum as well
b. Small bowel bacterial overgrowth = stasis usually due to surgery/other disease bacteria can multiply and cause innate immune system to be activated -> increase IEL
c. Common variable immunodeficiency
d. Autoimmune enteropathy
e. Drugs – colchicine, vincristine, neomycin, mycophenolate mofetil

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22
Q

What are the four elements that corntibute to the pathogenesis of celiac disease?

A

Genetics
Enthronement
T-cells
Gluten

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23
Q

How does genetics contribute to celiac disease?

A

HLA-DQ2 or HLA-DQ8 present in 99.6% of all patients with coeliac disease

i. 20-30% of those without coeliac disease (in populations at risk) also have HLA-DQ2 or HLA-DQ8
ii. BUT do not get celiac disease so there must be another element; other unidentified genes involved

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24
Q

How do environmental factors contribute to celiac disease?

A

early infant environment plays a role in development of ceoliac disease

i. Breast feeding protective, timing/amount of diet introduced to infant diet important
ii. Possible role for gastrointestinal infections

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25
Q

How does T cells contribute to celiac disease?

A

CD4+ HLA-DQ2 or HLA-DQ8 restricted T cells, reactive to gluten specific epitopes, in small intestine

i. These cause damage by producing harmful cytokines eg. IFN-g (and TNF)
ii. CD8+ T cells accumulate in the epithelium and are involved in the innate immune response

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26
Q

How does gluten contribute to celiac disease?

A

Found in wheat germ (endosperm); protein component has gliadin and glutenins

i. Gliadins are the most toxic (also glutenin, secalins, hordeins etc. in other grains)
ii. High in the amino acids proline (P) and glutamine (Q) (35% and 20% respectively) whereas glutamate (E) is rare [glutamate is deamidated form of glutamine] -> resistant to proteases
iii. The intact peptides are deaminated by tissue transglutaminase (tTG) converting glutamaine residues to negatively charged glutamate

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27
Q

What is the pathophysioloy of celaic disease?

A

a. Certain gluten peptides pass through the intestinal epithelium intact into lamina propria (33mer + 31-39mer)
b. 33mer (ADAPTIVE) = deaminated by tTG converting glutamine residues to negatively charged glutamate
i. Deamidated gluten peptides (negatively charged glutamate at position 4, 6 or 7) can bind tightly to HLA-DQ2/8 (preferentially binds peptides with negative charges at these positions) on APCs
ii. Presentation of gluten peptides to CD4+ T cells -> CD4+ T cells recognize the deamidated peptides bound to MHC II molecules and elaborate cytokines IF-g, IL-4 and TNF-alpha -> DAMAGE to epithelium
iii. CD4 T cells produce conjugate of tTG to the surface -> antibodies against gliadin and tTG
1. NOT cytotoxic but useful for diagnosing celiac disease
c. 31-39mer (INNATE) = able to induce stress response in the enterocyte (upregulate MIC-A and MIC-B) in addition to secreting IL-15
i. IL-15 causes the IEL CD8+ T cells to express NK cell receptors (NKG2D) on the surface
ii. Now become autoreactive; able to recognize the non-classical MHC I (MIC-A and MIC-B) -> apoptosis
iii. IFN-g is also very important in damaging epithelial cells
iv. NOTE: IL-15 also causes IELs to proliferate which can lead to malignant transformation
1. Patient may be non-responsive to gluten withdrawal; become autonomous and undergo malignant transformation to a hybrid lymphoma

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28
Q

How is celiac disease diagnosed?

A

a. Tissue transglutaminase antibody (tTG) = 90% sensitivity, good specificity
b. Deamidated gliadin peptide (DGP-IgG) = 80-90% sensitivity
c. HLA-DQ haplotyping – the absence of HLA-DQ2 od DQ8 effectively rules out a diagnosis of coeliac disease

The gold standard is a small bowel biopsy during gluten exposure

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29
Q

Why is early diagnosis important?

A

Long term risks if left untreated include osteoporosis, autoimmune diseases, increased risk of cancer

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30
Q

Does the lamina propria of the stomach have inflammatory cells?

A

No, except for mast cells and a few lymphocytes

31
Q

How is acid secretion regulated?

A

i. Parietal cells have receptors for ACh (M3), histamine (H2), somatostatin + gastrin ii. Gastrin released by G cells as food arrives -> binds parietal cell directly + ECL cell iii. ECL cells secrete histamine in response to ACh and gastrin -> histamine is main stimulus for acid secretion by parietal cells iv. Negative feedback: acid produced by the body bathes the antrum -> stimulates D cells to secrete somatostatin which circulates in the blood stream then inhibits acid secretion from parietal cells

32
Q

How does the stomach prevent self-digestion?

A

1) mucous gel
200 micron layer
2) bicarbonate
binds to mucous gel thus making the pH next to the cells pH of about 7 as opposed to 2 inside the lumen
3) The surface mucous cells have tight junctions which prevent the infiltration of H ions into the lamina propria
4) phospholipids on surface
Heads of phospholipids are positively charged and bind to negatively charged bicarbonate layer and form a non-wettable surface (like wax) which is impermeable to H+ - the tails are hydrophobic which repel water

33
Q

What breaks down the mucosal barrier?

A

H. pylori, aspirin, NSAIDs, bile, alcohol, release of histamine and other mediators cause inflammation

34
Q

What prevents mucosal injury?

A

Prostaglandins prevent and reverse mucosal injury

35
Q

How do Prostaglandins prevent and reverse mucosal injury?

A

1) inhibit acid secretion
2) stimulate HCO3- production
3) increase mucosal blood flow [carry away H+]
4) modify local inflammation by releasing LTs 1. NSAIDS are CO2 inhibitors and therefore prevent the stimulating action of PG

36
Q

What is the difference between erosion, acute ulcer and chronic ulcer?

A

Erosion typically occurs due to micro circulatory changes as the result of systemic shock or blood loss.
Erosion is above the muscularis mucosae (differentiates between erosion and ulcer)
An acute ulcer goes through the muscularis mucosae bu there is no fibrosis and tend to heal.
CHronic ulcers penetrate through the muscularis mucosae through the muscularis propria and into the serosa. It either does not heal or heals by fibrosis

37
Q

Ulcers in proximal duodenum associated with severe burns/trauma?

A

Curling ulcers

38
Q

Gastric and duodenal ulcers in persons with intracranial injury (increased intracranial pressure results in vagal stimulation and increased ACh secretion)

A

Cushing’s ulcers

39
Q

What causes NSAID ulcers

A

inhibition of COX and prostaglandin synthesis which normally promotes bicarbonate secretion, mucin synthesis and vascular perfusion

40
Q

What are the three main causes of chronic gastritis?

A

Autoimmune
Bacteria (helocbacter assocaited)
Chemical

41
Q

What is B12 used in the synthesis of?

A

Myelin

42
Q

What is autoimmune gastritis?

A

Immune mediated destruction of acid secreting tubules followed by atrophy with consequent achlorhydria (no acid) and loss of intrinsic factor leading to pernicious anaemia (B12 deficiency)

43
Q

what anitbodies are present in autoimmune gastritis?

A

Circulating autoantibodies to parital cell membrane:

H+/K+ ATPase (90%), intrinsic factor (70%) and gastrin receptor (70%)

44
Q

What is a consequence of the production of intrinsic factor antibody?

A

It can complex with B12 preventing its absorbtion via receptors in the terminal ileum

45
Q

How is autoimmune gastritis characterised histologically?

A
  1. Gastric body = total atrophy of acid secreting tubules, replaced by intestinal (intestinal metalasia - goblet cells and enterocytes) and pyloric glands (called pyloric gland metaplasia) accompanied by chronic inflammation, thinner mucosa
    constant stimulation cause the formation of nodules called carcinoids
  2. Gastric antrum = Normal, preserved specialized pyloric glands + foveolar epithelium lining gastric pits
46
Q

What causes chemical gastritis?

A

i. Reflux of bile + alkaline duodenal juice due to altered antra-duodenal motility or gastro-jejunostomy
ii. Long term use of aspirin, NSAIDs, have a similar effect
iii. Direct mucosal injury – disruption of the mucous layer and gastric barrier, epithelial desquamation
iv. Gastric erosions/ulceration may result and there is compensatory foveolar hyperplasia with elongation and tortuosity of gastric pits, vasodilation of gastric pits, vasodilation and oedema and fibromuscular hyperplasia of the lamina propria but mild inflammatory cell infiltration
v. Vertically oriented SM hyperplasia, intestinal metaplasia can also result

47
Q

What are the bacteria factors enabling H. pylori to colonise the gastric mucosa?

A

1) motile [flagella] 2) microaerophilism [only require 5% O2] 3) adhesins [stick to surface foveolar epithelium] 4 urease

48
Q

What are foveolar cells?

A

Foveolar cells are mucus-producing cells which cover the inside of the stomach, protecting it from the corrosive nature of gastric acid. Foveolar cells are also known as surface mucous cells or mucous neck cells

49
Q

Epidemiology of H. Pylori?

A

low incidence in Australia, incidence increases with age, by 50 30-40% of population have had H. plori; more common in in developing countries (80-90% of adolescents infected)

50
Q

What is neutrophilic gastritis?

A

Neutrophilic gastritis = 1) acute inflammatory response (soluble antigens/chemoattractants, interleukins such as IL-8) 2) transient hypochlorhydria (up to 4 months)

51
Q

What is observed with H. pylori infection?

A

Neutrophilic gastritis

Infiltration with chronic inflammatory cells (antibodies but not curative)

52
Q

What is implied by the high infection rate worldwide?

A

Low rate of clearance

Persists for life when established

53
Q

Where are the h.pylori observed?

A

they bind to tight junctions and release ammonia which damages them and makes them more permeable to acid

54
Q

What is observed histologically in h. pylori infection?

A

acute inflammation - pit abscesses (acute foveolitis) and mixed neutrophilic and lymphoplasmacytic infiltration of lamina propria

55
Q

What happens in chronic h. pylori infection?

A

chronic antral gastritis with moderate mucosal atrophy, as well as the formation of lymphoid follicles (NOT NORMALLY FOUND IN STOMACH LP, normally found in intestine = intestinal metaplasia)

56
Q

How can chronic h. pylori infection cause adenocarcinoma?

A

chronic gastritis - atrophic gastritis - intestinal metaplasia - dysplasia - adeoncarcinoma

57
Q

How are B cell lymphomas formed with chronic h. pylori infection?

A

Constantly stimulated lymphoid molecules (by interlukens) may gain mutations and develop into marginal cell lymphomas

58
Q

What are the long term outcomes of h. pylori infection?

A

Acute gastritis -> chronic gastritis -> either antral predominant or multifocal gastritis

a. Antral predominant -> duodenal ulcer (20-40 year olds)
b. Multifocal -> gastric ulcer (40-70 yo) or gastric cancer (>70

59
Q

What happens with antral predominant gastritis?

A
  1. Inflammation -> G cells overactive -> hypergastrinaemia -> increased acid 2. ↑ acid load -> low duodenal pH -> gastric foveolar cell metaplasia of D1 mucosa 3. Colonization of duodenum (which now has gastric epithelium) by H. pylori -> active chronic duodenitis -> erosion ->duodenal ulcer
60
Q

What happens in H. plyori pangastritis?

A
  1. Gastric mucosal atrophy + intestinal metaplasia -> gastric adenocarcinoma a. Normal mucosa -> chronic gastritis -> atrophic gastritis -> intestinal metaplasia -> dysplasia -> ADENOCARCINOMA
  2. Gastric ulcer
  3. B cell lymphoma of MALT
61
Q

Diseases associated with H. pylori?

A

1) peptic ulcer disease 2) gastric adenocarcinoma 3) gastric B cell lymphoma of MALT 4) iron deficiency anaemia 5) atrophic gastritis (-> B12 def. + gastro)

62
Q

What are the sites of peptic ulcer disease?

A

i. Commonest in D1 and antrum, ratio of 4:1 (first part of duodenum cf. antrum)
ii. Oesophagus at squamocolumnar junction with gastric cardia or Barrett’s mucosa
iii. Gastro-enterostomy stoma – anastomic/stomal ulcer
iv. Meckel’s diverticulum – 25% have heterotopic gastric mucosa + peptic ulceration occurs if H. pylori

63
Q

What is peptic ulcer disease?

A

breach of the mucosa extending beyond the muscularis mucosae due to digestion of mucosa by acid and pepsin

64
Q

Chronic vs acute peptic ulcer?

A

Acute can heal (restitution)
Chronic = deep, sharply punched out, destroying all layers through muscular propria to subserosa, with scarring at the base drawing in gastric folds to its margin

65
Q

What happens as the result of scaring in chronic petic ulcer disease?

A

Scarring precludes restoration of the submuocsa and muscularis propria leaving a radial scar on healing with partial restitution of specialized gastric muocsa which is replaced by intestinal and pyloric gland metaplasia

66
Q

What does a peptic ulcer look like with an endoscope?

A

Yellow slough (of inflammatory infiltrate) covering ulcer floor. Fairly sharp margins

67
Q

What are the four zones on the peptic ulcer floor?

A

i. Exudate of fibrin, neutrophils and necrotic debris
ii. Narrow zone of fibrinoid necrosis
iii. Zone of cellular granulation tissue
iv. Zone of fibrosis including endarteritis and hypertrophied nerves

68
Q

What are the complications of peptic ulcer disease?

A

Perforation -

Haemoarrage - (erode artery) –rapid blood loss (haematemesis or malaena) + slow loss (anaemia) 1. Heat coagulation treatment eg. erosion into head of pancreas + gastroduodenal artery

Penetration into adjacent organ (erodes into adjacent organ eg. posteriorly into pancreas, anteriorly into liver or into transverse colon (gastro-colic fistula) -> peritonitis), the Omentum attempts to seal off a perforation but not successful

Stenosis

69
Q

What is antral adeoncarcinoma?

A

macroscopic view characteristically shows smooth area surrounding the carcinoma with lifted and smoothed edges (cf. radiating appearance of peptic ulcer) i. Infiltrated the mucosa and submucosa ii. In a gastric cancer the ulcer is within the outline of the stomach; peptic ulcer would have gone through the muscle coat

70
Q

What is fungating gastric aden rcinoma?

A

i. More commonly ulcerating gastric cancers usually located in the antrum; where gastric ulcers occur ii. Fungating = breaks the skin

71
Q

What is gastric adenocarcinoma of intestinal type?

A

Intestinal metaplasia dysplasia pathway leads to gastric adenocarcinomas of the intestinal type

72
Q

What is a Diffuse type gastric carcinoma (linitis plastica)?

A

i. Causes the mucosa to be diffusely thickened ii. Contrasting adenocarcinomas of intestinal type (occur where H. plyori is found) this type of cancer is genetically determined iii. More often in females than males

73
Q

What is a signet ring cell carcinoma?

A

Signet ring cells = contain a large amount of mucin which pushes the nucleus to the cell periphery forming a ring like structure

GIT (15 decks)

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