Path

Question 1

What is celiac disease?

Answer 1

• 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

Question 2

What is the prevalence of celiac disease?

Answer 2

1:100 (may be more prevalent)

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

Question 3

When does celiac present?

Answer 3

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

Question 4

How do we treat celiac disease?

Answer 4

Remove gluten from the diet

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

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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)

Question 7

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

Answer 7

It may cause osmotic diarrhoea in the colon

Question 8

What are the three zones of the villi?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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

Question 11

What do paneth cells produce?

Answer 11

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

Question 12

How do alpha defensins work?

Answer 12

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

Question 13

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

Answer 13

They are found on the top of the brush boarder

Question 14

What is found in the lamina propria?

Answer 14

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

Question 15

What is the histology of the duodenal villus?

Answer 15

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

Question 16

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

Answer 16

4:1

Question 17

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

Answer 17

less than 25/100 (healthy)

2-300/100 (in celiac)

Question 18

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

Answer 18

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

Question 19

What happens to the remaining enterocytes in celiac disease?

Answer 19

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

Question 20

What is the clinical presentation of celiac disease?

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Genetics
Enthronement
T-cells
Gluten

Question 23

How does genetics contribute to celiac disease?

Answer 23

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

Question 24

How do environmental factors contribute to celiac disease?

Answer 24

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

Question 25

How does T cells contribute to celiac disease?

Answer 25

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

Question 26

How does gluten contribute to celiac disease?

Answer 26

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

Question 27

What is the pathophysioloy of celaic disease?

Answer 27

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

Question 28

How is celiac disease diagnosed?

Answer 28

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

Question 29

Why is early diagnosis important?

Answer 29

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

Question 30

Does the lamina propria of the stomach have inflammatory cells?

Answer 30

No, except for mast cells and a few lymphocytes

Question 31

How is acid secretion regulated?

Answer 31

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

Question 32

How does the stomach prevent self-digestion?

Answer 32

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

Question 33

What breaks down the mucosal barrier?

Answer 33

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

Question 34

What prevents mucosal injury?

Answer 34

Prostaglandins prevent and reverse mucosal injury

Question 35

How do Prostaglandins prevent and reverse mucosal injury?

Answer 35

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

Question 36

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

Answer 36

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

Question 37

Ulcers in proximal duodenum associated with severe burns/trauma?

Answer 37

Curling ulcers

Question 38

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

Answer 38

Cushing’s ulcers

Question 39

What causes NSAID ulcers

Answer 39

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

Question 40

What are the three main causes of chronic gastritis?

Answer 40

Autoimmune Bacteria (helocbacter assocaited) Chemical

Question 41

What is B12 used in the synthesis of?

Answer 41

Myelin

Question 42

What is autoimmune gastritis?

Answer 42

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)

Question 43

what anitbodies are present in autoimmune gastritis?

Answer 43

Circulating autoantibodies to parital cell membrane: | H+/K+ ATPase (90%), intrinsic factor (70%) and gastrin receptor (70%)

Question 44

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

Answer 44

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

Question 45

How is autoimmune gastritis characterised histologically?

Answer 45

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

Question 46

What causes chemical gastritis?

Answer 46

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

Question 47

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

Answer 47

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

Question 48

What are foveolar cells?

Answer 48

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

Question 49

Epidemiology of H. Pylori?

Answer 49

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)

Question 50

What is neutrophilic gastritis?

Answer 50

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

Question 51

What is observed with H. pylori infection?

Answer 51

Neutrophilic gastritis | Infiltration with chronic inflammatory cells (antibodies but not curative)

Question 52

What is implied by the high infection rate worldwide?

Answer 52

Low rate of clearance | Persists for life when established

Question 53

Where are the h.pylori observed?

Answer 53

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

Question 54

What is observed histologically in h. pylori infection?

Answer 54

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

Question 55

What happens in chronic h. pylori infection?

Answer 55

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)

Question 56

How can chronic h. pylori infection cause adenocarcinoma?

Answer 56

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

Question 57

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

Answer 57

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

Question 58

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

Answer 58

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

Question 59

What happens with antral predominant gastritis?

Answer 59

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

Question 60

What happens in H. plyori pangastritis?

Answer 60

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

Question 61

Diseases associated with H. pylori?

Answer 61

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

Question 62

What are the sites of peptic ulcer disease?

Answer 62

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

Question 63

What is peptic ulcer disease?

Answer 63

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

Question 64

Chronic vs acute peptic ulcer?

Answer 64

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

Question 65

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

Answer 65

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

Question 66

What does a peptic ulcer look like with an endoscope?

Answer 66

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

Question 67

What are the four zones on the peptic ulcer floor?

Answer 67

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

Question 68

What are the complications of peptic ulcer disease?

Answer 68

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

Question 69

What is antral adeoncarcinoma?

Answer 69

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

Question 70

What is fungating gastric aden rcinoma?

Answer 70

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

Question 71

What is gastric adenocarcinoma of intestinal type?

Answer 71

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

Question 72

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

Answer 72

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

Question 73

What is a signet ring cell carcinoma?

Answer 73

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