PAthophysiology Flashcards
1
Q
Layers of the GIT
A
Lumen Mucosa: epithelium, lamina propria, muscularis mucosae Submucosa Muscularis Externa Serosa, continuous w peritoneum
2
Q
What type of epithelium lines the GIT?
A
Esophagus and rectum: stratified squamous (hardy for protection)
Everywhere else: Simple columnar (secretes and absorbs; invaginated)
3
Q
What is the lamina propria?
A
Thin layer of connective tissue under the epithelium of the GIT (part of the mucosa). Rich in nerves and vessels
4
Q
What is the muscularis mucosa?
A
Thin layer of smooth muscle forming boundary between lamina propria and submucosa in the GIT
5
Q
What is the submucosa?
A
Dense, fibrous connective tissue (elastin and collagen)
Protects gut tube against rupturing from pressure of the contents within it.
6
Q
What is the muscularis externae?
A
Inner circular (contraction narrows lumen) and outer longitudinal (contraction shortens gut tube) smooth muscle layers Coordinated contraction -> peristalsis
7
Q
What is the serosa of the gut?
A
-> friction free glide/non-stick layer
Simple squamous epithelium, outer surface of gut tube
8
Q
What neural plexuses lie in the gut, and where?
A
Myenteric plexus: between circular and longitudinal muscle layers of muscularis external
Submucus plexus: within submucosa
9
Q
What glands (and where) exist in the oesophagus?
A
Submucosal glands produce mucus to lubricate bolus of food
10
Q
What is the muscular composition of the muscularis externae in the esophagus?
A
Top 1/3: skeletal muscle
middle 1/3: skeletal and smooth
bottom 1/3: smooth muscle
11
Q
How are the layers of the stomach specialised towards its function?
A
Muscularis externae: third outer layer, oblique oriented with respect to the circular and longitudinal layers. Additional strength of churning to produce chyme.
Mucosa: largely flat except for rugae (folds) that allow expansion.
Dotted with gastric pits (holes in mucosa) that lead to several gastric glands within the lamina propria
12
Q
What are the cells (and their order) that line gastric pits?
A
Most proximal: Foveolar cells: secrete mucous Regenerative cells: stem cells Mucous neck cells: mucous secretion Parietal cells: acid Chief cells: pepsinogen (inert) Enteroendocrine cells: Most distal
13
Q
Pepsinogen
A
Secreted by chief cells in stomach, is inactive. Is activated at low pH (2, in stomach) to cleave proteins into smaller polypeptides.
14
Q
Absorptive surface of the SI- modifications to increase SA
A
PLica circulares (transverse folds lunging across gut allowing expansion): 2-3x
Villi: finger-like projections out of plica circulares, x10
Microvilli: brush border of enterocytes, 20x
15
Q
What glands reside in the SI?
Structure, purpose
A
Crypts of Leiberkuhn
Lined by continuous sheet of columnar epithelium and penetrate into LP (invagination of the mucosa)
Contain goblet cells: mucus
Contain secretory cells that secrete watery fluid
Stem cells at the base
16
Q
Structure of villi in SI
A
Villus lined by columnar epithelium on outside.
Core of villus contains connective tissue, vessels from LP, and some muscle and muscularis mucosa for mixing (prevent unstirred layers).
Core also contains lymphocytes
17
Q
How does the duodenum deal with acidic chyme from the SI?
A
Brunner’s glands secrete bicarbonate to neutralise the acid from the stomach and turn off pepsin (only active at low pH)
18
Q
How do you distinguish between the jejunum and ileum?
A
Jejunum: More plica, longer villi than ileum
Ileum: also has peyer’s patches, smallest villi
More goblet cells distally -> produce more mucous
19
Q
Function of SI
Function of LI
A
SI: completes digestion using pancreatic enzymes
Absorption of nutrients, vitamins, electrolytes, WATER
LI: recovering last bit of water and electrolytes; compacting faeces
20
Q
Structure of a hepatocyte
A
Polyhedral (6 surfaces)
1-2 nuclei
Polyploid (multiple copies of DNA)
RER, SER, golgi, secretory vesicles, many mitochondria
21
Q
How does the liver regenerate?
A
Mature hepatocytes are able to dividing to replace damaged cells. No stem cells in the liver!
22
Q
Describe vessels supply and drain the liver? (Note: it is unusual!)
A
Hepatic arteries carry oxy blood in
Portal vein carries deoxy blood from gut in
Hepatic vein empties deoxy blood from liver into IVC
23
Q
What type of connective tissue makes up basement membranes?
A
Collagen type IV
24
Q
To what extent is there connective tissue in the liver?
A
- Liver is surrounded by a thin capsule (Glisson’s capsule)
- Hepatocytes are surrounded by reticular fibres (collagen TIII): loose cobweb-like scaffold that gives the cells 3D organisation
25
What is the structural organisation of the liver? In terms of hepatocytes and vessels.
Liver is organised into LOBULES: stacks of hepatocytes piled on top of one another like plates to form a polygonal shape 2mm long x 0.7mm wide.
LOBULES pack on top of and next to one another, separated by thin layer of connective tissue.
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CENTRAL VEIN runs through the centre of a lobule, down its length, and drains blood from that hepatocyte into hepatic vein.
PORTAL TRIADS (branch of PV, HA and bile duct) sit on the outside of the lobule and supplies blood inwards to surrounding lobules (outside->in)
Note: there may be several surrounding a lobule.
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26
What is the "hepatic acinus"?
Set of 2 adjacent lobules, in which the portal triad is "the centre" of focus, emphasising metabolic organisation.
Means that zone 1 (outer edge of lobule) of the hepatocyte will be highest in O2, nutrients but also toxins and metabolites. Whereas Zone 3 (inner, near central vein) will be lowest in O2, nutrients, but also in toxins and metabolites.
27
What is the "hepatic acinus"?
Set of 2 adjacent lobules, in which the portal triad is "the centre" of focus, emphasising metabolic organisation.
Means that zone 1 (outer edge of lobule) of the hepatocyte will be highest in O2, nutrients but also toxins and metabolites. Whereas Zone 3 (inner, near central vein) will be lowest in O2, nutrients, but also in toxins and metabolites.
28
What makes bile green?
Bile pigment, which is a breakdown product of Hb
29
What is bile made from and where?
Bile is made by hepatocytes; it is made from old RBCs, in which Hb is broken down to bilirubin, and bile is a breakdown product of bilirubin.
30
What is the drainage pattern of bile?
Drains from inside to out (into bile ducts in portal triad on outside of lobule). Bile ducts come together to form major R and L hepatic ducts which join to form common hepatic duct, which then receives the cystic duct to form the common bile duct, which empties into the 2nd part of the duodenum at the major duodenal papilla.
31
What is the function of the gall bladder?
Stores bile produced in liver.
Concentrates the bile (pulls water out of it)
Contracts to push bile into duodenum
32
What epithelium lines the gall bladder?
Columnar epithelium, absorptive
33
What epithelium lines the gall bladder?
Columnar epithelium, absorptive
34
Hormonal control of bile secretion
Fatty bolus enters duodenum, duodenal epithelium (I cells) is triggered to release CCK which enters blood and circulates to gall bladder where it signals contraction of gall-bladder and relaxation of major duodenal papilla (sphincter of Oddi) -> bile pumped into duodenum
35
Function of pancreas
Secretory organ
Endocrine: enzymes necessary for digestions (proteases, lipases, amylases, nucleases, bicarbonate)
Exocrine: insulin secretion
36
Structural organisation of pancreas
Secretory cells are organised into a foot-ball shape (ACINUS) which open onto a duct.
Nuclei are on the outer edge and the granules containing the inactive digestive enzymes (=zymogens) on the inner apical aspect, closest to the duct.
Ducts join together to eventually form the pancreatic duct
(like a bunch of grapes with each grape=acinus)
37
Zymogen
A pro-enzyme (inactive precursor)
38
Why doesn't the pancreas self-digest?
In what cases might this occur?
The enzymes it secretes are produced as zymogens (in inactive form) which require activation by bile and other enzymes, IN THE DUODENUM.
It may start to self-digest if bile finds it's way into the pancreas, which might occur if a gall stone obstructs the sphincter of Oddi, causing bile to back up into pancreas and activates the zymogens.
39
What is the pathophysiology of acute gastritis?
Irritation to mucosa (direct injury OR ischaemia) leads to migration of neutrophils and release of inflammatory mediators -> vasodilation, oedema -> more severe cases: erosions, purulent exudate in lumen -> deep erosions can progress to ulcers (acute and chronic) -> haemmhorage when you erode through vasculature
40
What is the progression of ulcer formation in gastritis?
Start with erosion of gastric mucosa -> becomes an acute ulcer when it erodes into the muscularis mucosae (reversible damage, no fibrosis -> result of severe acute gastritis) -> becomes chronic ulcer when it erodes into muscularis propria and underlying serosa, and is accompanied by fibrosis/scar formation
41
How do the symptoms of chronic gastritis differ from acute gastritis?
Symptoms of chronic gastritis less severe but more persistent - Nausea, upper abdominal pain, sometimes vomiting but hematemesis uncommon
42
What is the most common cause of chronic gastritis that is not due to H pylori infection?
Autoimmune gastritis
43
What type of gastritis does autoimmune gastritis cause?
Atrophic/diffuse gastritis
44
What is autoimmune gastritis characterised by? (Can aid w diagnosis)
```
Antibodies to IF, gastrin R and parietal cells
Decreased serum [pepsinogen]
ECL cell hyperplasia
Vitamin B12 deficiency
Decreased gastric acid secretion
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45
What is the pathogenesis of autoimmune gastritis?
Patients possess CD4 T cells directed against their parietal cell components (including H/K ATPase, IF) within gastric glands -> gastric gland destroyed (except stem cells at bottom) -> destruction of parietal cells -> decr gastric acid and IF secretion AND destruction of chief cells -> decr pepsinogen secretion
Decr IF -> inability to absorb Vitamin B12-> VB12 deficiency -> pernicious anaemia
46
What is the word for "acid-producing" in reference to gastric mucosa? Where in the stomach is it found?
Oxyntic mucosa
| Body and fundus (antrum doesn't contain gastric glands)
47
Symptoms of autoimmune gastritis
```
Mostly caused by vitamin B12 deficiency
Pernicious anaemia (Symptoms of anaemia)
Malabsorptive diarrhoea
neuropathic changes
atrophic glossitis
Cerebral dysfunction
*Anaemia can be reversed by VB12 replacement therapy, but neurological changes are not.
```
48
Morphology of autoimmune gastritis (changes to gastric mucosa)
Auto-Abs cause diffuse mucosal damage to oxyntic mucosa, progressing to diffuse atrophy over 20-30 years = mucosal thinning, loss of rugae
Inflammatory infiltrate: Lots of lymphocytes, plasma cells, macrophages (few neutrophils)
Incomplete atrophy can leave residual islands of oxyntic mucosa which can look like polyps
Intestinal metaplasia which is risk factor for gastric adenocarcinoma
49
What is the most common cause overall of chronic gastritis?
H Pylori infection
50
What are duodenal ulcers most likely caused by?
H Pylori infection
51
What are ulcers in the gastric antrum most likely caused by?
H pylori (90%)
52
What are the virulence factors of H pylori?
Flagella - motility
Urease: converts urea to ammonia (basic) which surrounds H pylori and protects it from stomach acid
Adhesins: so bacteria can attach to surface foveolar cells
Toxins
53
Epidemiology of H pylori infections:
1. Transmission route
2. Associated with?
1. Faecal oral route
2. Poverty, crowding, low education levels, ethnicity, immigrants, rural living (improved sanitation decreases infection rates)
54
Antrum dominant H pylori gastritis pathology
Acute infection
Colonisation of gastric antrum -> increased gastrin -> incr acid production -> incr risk of duodenal peptic ulcers
H pylori can move in to colonise duodenum -> acute chronic duodenitis +/- erosion -> duodenal peptic ulcers
55
Where does H pylori like to reside in the gut?
Gastric epithelium - superficial mucous overlying epithelial cells (adheres to foveolar cells at the top of gastric pits)
56
Pathology of H pylori pangastritis
Usually has progressed from acute antrum-dominant gastritis to now involve stomach body and fundus = chronic/multifocal atrophic gastritis
-> Gastric mucosal atrophy -> destruction of parietal cells and chief cells in gastric glands -> decr acid and pepsinogen -> incr stomach pH (decr risk of ulceration)
Intestinal metaplasia of stomach -> risk of gastric adenocarcinoma
Neutrophils accumulate in LP, epithelial cells and gastric pits -> pit abscesses and inflammatory exudate
Lymphocytes, plasma cells, macrophages accumulate in LP -> germinal centres form = induced form of MALT -> risk of B cell lymphoma of MALT (MALToma)
57
Methods of diagnosing H pylori infection
Breath test (detect conversion of urea to ammonia)
Faeces - detect H Pylori
Serology - Ab to H pylori
Biopsy (PCR, culture, urease test)
58
Treatment of H pylori infection
Proton pump inhibitors
| Antibiotics
59
What are the possible causes of chemical gastritis?
REflux of bile and alkaline duodenal juice into stomach antrum
Long term use of NSAIDs and aspirin
Radiation
60
What are the NT/hormonal controls leading to acid secretion in the BODY/FUNDUS of stomach
1. Vagus releases Ach -> Acts on parietal cells M3R to directly release acid (H+/K+ ATPase) AND
2. Vagus stimulates ECL to release histamine which binds H2R on parietal cells -> acid release
3. Vagus inhibits D cells -> no somatostatin release -> decr inhibition of ECL -> incr histamine release -> incr acid secretion from parietal cell (+ feedback)
61
What are the NT/hormonal controls leading to acid secretion in the ANTRUM of stomach
1. Vagus releases GRP -> binds G cells -> gastrin release -> gastrin binds ECL -> histamine release -> binds H2R on parietal cell -> acid release (H+/K+ ATPase)
2. Products of protein digestion directly stimulate release of gastrin from G cells
3. Vagus releases Ach -> binds M3R on D cells -> somatostatin release -> acts on ECL cells to inhibit histamine release -> decr acid secretion
4. Acid (H+) directly stimulates release of somatostatin from D cells (- feedback)
62
What mechanisms protect acid/peptic enzyme digestion of mucosa?
Phospholipids (prevent large food particles directly touching epithelium)
Mucin produced by foveolar cells to line epithelium
Bicarb pumped into mucin layer from surface epithelial cells
"Alkaline tide": as parietal cells pump acid into lumen, they pump bicarb into mucosal vasculature as buffer
PGE and PGI
63
What is the protective role of prostaglandins in the stomach?
Incr mucin, bicarb and PL secretion
Increase mucosal blood flow
Decr acid secretion
64
Possible causes of acute gastritis
```
H Pylori (can progress to chronic over 3-4 weeks)
NSAIDs
Alcohol, tobacco
Bile
Stress/trauma
Septicaemia
Staph food poisoning
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65
Symptoms of acute gastritis
```
Variable degrees of:
Epigastric pain
Nausea
Vomiting
Hematemesis, melena (due to mucosal erosion and haemmhorage in more severe forms) -> massive blood loss -> shock
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66
What is acute gastritis?
Inflammation of stomach w neutrophils present (few lymphocytes or plasma cells)
67
Consequences of chemical gastritis - what happens to the gastric mucosa?
Epithelial desquamination
Compensatory foveolar hyperplasia - gastric pits become longer and more torturous
Mild inflammatory infiltration; vasodilation, oedema and fibromuscular hyperplasia of LP
Erosions, ulceration and intestinal metaplasia of stomach possible
68
What are common causes of peptic ulcer disease?
Chronic mucosal irritation due to H pylori infection, smoking, NSAIDs
69
What is peptic ulcer disease in antrum/duodenum generally caused by?
Chronic H pylori antral gastritis associated w incr gastric acid secretion or decr duodenal bicarb secretion
70
What is PUD in gastric fundus or body generally caused by?
How common is this compared to PUD in atrum?
H pylori OR autoimmune gastritis
Assoc w lesser acid secretion (although still more than usual) due to destruction of oxyntic mucosa -> less common because acid isn't usually strong enough to erode deep enough through mucosa
71
PUD generally is a progression from chronic gastritis. What are potential complications of PUD?
Collagen and fibrin deposition (Granulation tissue -> Scarring) at base of ulcer (chronic ulcer, descends into muscularis externa/serosa)
Thickened, fibrosed vessel walls in scarred region
Scarring can result in puckering of mucosa radiating outwards from ulcer
Haemmhorage (bleeding from damaged vessels)
Perforation (hole through entire thickness of wall) into peritoneal cavity
Obstruction of pyloric or lower esophageal sphincter due to retraction of scar tissue
72
How is gastric cancer related to gastritis?
Progression
Pathophysiology
Long standing Chronic gastritis of body/fundus eventually leads to oxyntic atrophy
- > may lead to intestinal metaplasia of stomach
- > dysplasia
- > Increased risk of gastric adenocarcinoma
Chronic gastritis -> inflammation -> free radical damage + stressors -> genetic alterations
73
Which type of gastritis puts you at most risk for gastric cancer?
Chronic autoimmune gastritis of body/fundus
74
Genetic association with coeliac disease
HLADQ2 and HLADQ8 alleles (present in 99.6% of people w coeliac's, but also present in 20-30% of people without it)
75
What portion of the gut does coeliac disease affect?
SI (duodenum and jejunum primarily; ileum only in very extreme cases)
76
What gets absorbed where in the SI?
| Break up according to duodenum and jejunum prox/distal and ileum
Proximal duodenum and jejunum: glucose, iron, water soluble vitamins (B, C, folic acid)
Distal duodenum and jejunum: fats, fat soluble vitamins (A, D, E, K), protein
Ileum: bile acids and Vitamin B12
77
What happens to the mucosal surface with Coeliac's disease (how is the architecture and cell type presences altered)?
```
Villi atrophy (they shorten and dissappear all tgthr) -> surface flattens -> loss of absorptive SA
Crypt hyperplasia (regeneration zone lengthens to provide more proliferating cells)
Increased numbers of IELs, CD4+ and CD8+ lymphocytes, plasma cells
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78
What cell types would you expect to see in the epithelium (including crypts) of the small intestinal mucosa?
Columnar enterocytes with brush border (microvilli) on apical surface carrying peptidases and absorptive enzymes
Goblet cells -> mucous
Intraepithelial lymphocytes between enterocytes
Intercellular tight junctions
Lymphocytes, plasma cells, mast cells, macrophages in lamina propria underneath enterocytes
79
Give the 3 stages of villous atrophy that occurs with coeliac disease, and the relative ratios of villus:crypt length
At what stage do symptoms start to show?
1. Infiltrative: incr numbers IELs but no destruction (4:1)
2. Hyperplasmic: crypt hyperplasia (lengthening), incr IELs (1:1)
* Symptoms starting to show
3. Destructive: cells being destroyed faster than crypts can regenerate them -> surface flat and crypts lengthened (1:4)
80
Clinical presentations of coeliac disease
```
Diarrhoea (osmotic), bloating, flatulence, abdominal cramps
Anaemia (iron deficiency)
Vitamin deficiency
Lethargy/chronic fatigue, migraines
Mouth ulcers
Incr prevalence autoimmune diseas
```
Women: Infertility
Infants: failure to thrive
Elderly: osteoperosis
81
What are the innate and adaptive CELLULAR components of the immune response to gluten that causes coeliac's disease?
Innate: CD8+ IELs accumulate
Adaptive: CD4+ in LP produce inflammatory cytokines (IFNgamma and TNF) that damages the mucosa
82
Describe the mechanism of the adaptive immune response that occurs in response to gluten with coeliac's disease?
Gluten contains gliadin which contains proline that is resistant to digestion and can cross the epithelium -> gliadin crosses epithelium intact -> tTG converts glutamine (+) in gliadin to glutamate (-) -> glutamate (-) binds Ag-binding groove on HLA-DQ2 MHCII molecule on APC cells -> APC presents to naive CD4+ cell (primed)
APC induces B cells to become plasma cells -> secrete anti-tTG and anti-gliadin antibodies (diagnostic not pathologic)
Next time primed APC sees gliadin it secretes IFN gamma and TNF that cause damage to enterocytes
83
Describe the mechanism of the innate immune response that occurs in response to gluten with coeliac's disease?
Gliadins stress enterocytes -> enterocyte signals up regulation of atypical MHCI molecules MICA and MICB AND they secrete IL15
IL15 signals to IELs (CD8+) to lower activation threshold, auto activate and proliferate, AND upregulate NK receptor NKG2D
IELs with NKG2D bind the MICA and MICB on the stressed enterocytes -> NK induces apoptosis of enterocyte
IELs secrete IFNgamma to further incr expression of MICA and MICB in enterocytes
84
What is the gold standard for diagnosis of coeliac disease?
What are a couple of other options?
Small bowel biopsy (only when patient is still eating gluten)
Serology: test for tTg and gliadin antibody
HLA-DQ2/8 typing
85
What cancers does coeliac disease predispose you to?
Small bowel lymphoma (CD4+ lymphoma)
Small bowel adenocarcinoma
Oesophageal cancer
86
What is the breakdown of fluid balance (in/out) in the GIT in 24 hours for an adult?
10L enters the gut (only 2L) by mouth; the rest are secretions
9.5L absorbed: 8.5L in SI and 1.4L in colon
100ml excreted in faeces
87
What sort of stool is characteristic of diarrhoea of the small bowel?
What is likely organism to cause this?
Associated symptoms?
Large volume, watery
(SI unable to absorb fluids and food -> large volume (5-6L) passes into LI which exceeds the ability of the LI to absorb it all -> large amounts of liquid excreted with faeces)
S. aureus food poisoning
Vomiting and abdominal pain
88
What sort of stool is characteristic of diarrhoea of the large bowel?
What likely organisms could cause this?
Frequent evacuation, small volume with blood or pus (dysentery)
(LI inflamed and unable to absorb the last little bit of food and fluid (about 2L worth))
89
What agents (bacteria/virus/parasites) mainly cause disease in developing countries?
What about in developed countries?
Developing -> bacteria (viruses and parasites)
Developed -> viruses (bacteria but NOT parasites)
90
What is haemmhorage in the brain usually due to?
Hyaline arteriolosclerosis or arterioles in basal ganglia region -> vessels thickened but weakened and high intravascular pressures can rupture them
91
What is a berry aneurism?
Congenital defect in walls of medium vessels in brain
| High BP causes them to balloon out into subarachnoid space and they can rupture and bleed into SA space/
92
What is a key feature of malignant hypertension vs benign hypertension?
Malignant: steeper, quicker rise in BP that is rare but a medical emergency!
DBP incr to around 120.
Features necrosis of wall+ Hyperplastic arteriolosclerosis = incr number of cells (more layers) in media = "onion skin"
Benign hypertension: gradual rise in BP characterised by hyaline arteriolosclerosis (deposition of plasma proteins in walls + smooth muscle atrophy)
93
Where in the kidney are the renal corpuscles located?
Cortex ONLY!
94
Where in the kidney are the loops of henle located?
Mainly in medulla, with prox portion in cortex
95
What structures of nephrons are in medulla?
Loops of henle only
96
2 types of nephrons and relative proportions
Juxtamedullary nephrons: 15%; RC is close to CM boundary (deepest) and LOH travels deepest into medulla. IT DOES THE []ing!!
Cortical nephrons: 85%, more superficially located RCs, loop travels short distance into medulla before turning back up. DOES NOT [] urine!!!
97
Poles of the renal corpuscle
Urinary pole (where prox tubule exits the BC) is at opposite side to vascular pole (where affe and efferent arteries are located)
98
What epithelium makes up each part of the nephron?
BC: squamous
PT: cuboidal, microvilli, heaps of mitochondria
LOH: squamous, not much mitoch bc passive work only
DT: cuboidal, no microvilli, even more mitochondria (working against large [] gradients- everything is harder!)
CD: cuboidal
99
Barriers to filtration in RC
Endothelium
**Basal lamina
**Filtration slit diaphragm between podocyte foot processes
podocyte foot processes/epithelium of BC
100
What type of epithelium lines the bladder?
stratified Transitional epithelium (squamous (apical) -> columnar at base)
It is urine proof! Specially protective because urine can be damaging to epithelium!
101
What type of epithelium lines the ureters?
stratified Transitional epithelium (squamous (apical) -> columnar at base)
102
What type of epithelium lines the urethra?
Proximally stratified Transitional epithelium
| Distally squamous epithelium (protective)
