Parietal cells IN HEALTH & DISEASES

RITASMAN BAISYASHINJAN PATRAANANNYA GHOSHCHIRANTAN MANDAL

2nd PROF MBBS

FUNCTIONAL ANATOMY

RITASMAN BAISYA

FUNCTIONAL ANATOMY

stomach histology • gastric glands• Blood supply• nerve supply• electrical activity of GI smooth muscle

Stomach

• Stomach is a sac like dilated part of the gut between OESOPHAGAS and DUODENUM.

• Capacity _ 50 ml to 5 l average 2 to 2.5l

• Stomach Parts _CARDIA, CORPUS ANTRUM

The concavity of right inner curvature is called lesser curvature. The covexity of left,outer

curvature is called greater curvature.

An angle along lesser curvature is called Incisura angularis marks the approximate point at which stomach narrows into duodenum. Entirely covered by peritonium the greater omentum extends from greater curvature to transverse colon.

Anatomy contd….

The normal gastric mucosa has 2 compartment –superficial foveolar compartment Deep glandular compartment .

The foveolar compartment is relatively uniform,The glandular compartment shows major differences in different regions .

Gastric pits are the openings of the mucosal glands .

The foveolar compartment consits of surface epithelial cells lining entire mucosa including gastric pits

HISTOLOGY

• 6 LAYERS –• 1MUCOSA-Columnar epithelium, it is thrown into

folds called Gastric Rugae,seen in empty stomach

• 2SUBMUCOSA• 3OBLIQUE MUSCLE LAYERS• 4 CIRCULAR MUSCLE LAYER• 5 LONGITUDINAL MUSCLE LAYER 6 SEROSA

Facts

These cells divide & differentiate to produce both surface epithelium & glands proper .it takes 2 to 3 days to mature ,function & desquamated this is a continuous process with desquamation of half a million cells per hour & all cells of the mucous membrane are regulared properly.

Parietal cell

Blood supply

• Arterial blood supply-left gastric,a branch of coeliac artery.right gastric artery,branch of common hepatic,right gastroepiploic,branch of gastroduodenal ,left gastroepiploic,branch of splenic 5-7 short gastric arteries.

• Veins-portal vein,splenic veins.superior mesentric,

Nerve supply

Extrinsic nerve supply -sympathetic T6-T10 of spinal cord ,via greater splanchnic plexus ,coeliac & hepatic plexus .parasympathetic –via vagi oesophageal plexus ,gastric nerves.

Intrinsic nerve supply – meissener’s plexus ,myenteric plexus

ELECTRICAL ACTIVITIES

Fluctuating of RMP

Electrogenic Na + pumps

Basal electrical rhythm

Gastric Glands

Types 1. Cardiac2.fundic & body3.pyloric

Cells – 1.isthmus 2. Neck3.oxyntic4.chief cells5.enterochromaffin cells6. D cells 7 G cells

CELLS & THEIR SECRETION

CELLS SECRETION

ISTHMUS HCL

NECK MUCIN

PARIETAL HCL,IF

PEPTIC PEPSINOGEN

ENTEROCHROMAFFIN LIKE CELLS HISTAMIN

ARGENTAFFIN CELLS SEROTONIN

D CELLS SOMATOSTATIN

G CELLS GASTRIN

Secretions of stomach

Region Luminal secretion Motility

LES& Cardiac Mucous

HCO3

Prevention of reflux

Entry of food

Regulation of belching

Fundus & body H+

IF

HCO3,Mucin ,pepsinogen

Reservoir tonic force during emptying

Antrum & pylorus Mucous,HCO3 Mixing ,seiving regulation of emptying

PARIETAL CELLS IN HEALTH

SHINJAN PATRA

Topics • Parietal cells• Gastric mucosal physiology• Mechanism of HCL secretion • Regulation of HCL secretion

parietal cells

parietal cells are the acid secreting cells

They also secrete intrinsic factor

HISTOLOGY OF PARIETAL CELLS

triangular in shape.• Situated mainly towards the of neck of the

glands and secrete HCL add Intrinsic factor.• Predominant in the gastric glands of fundus

&body.

Parietal cell

This cells have an extensive micro canalicular system with microvilli .It communicates with lumenof the glands by canaliculus

In the resting state part of this microcanalicular system is converted into tubulo vesicular structure formed of smooth membranes.These vesicles contain the proton-pump[H+-K+ ATPase] these vesicles are fused with microcanalicular system when the cell is stimulated for secretion.

Parietal cells contd….

They are bright eosinophilic in H&E staining due to several mitochondria.

Gastric mucosal phiosiology

Stages –

1.Cephalic phase ,initiated by sight taste,smell,chewing, smelling the food mediated by vagal activity.

2. Gastric phase-stimulation of strech receptors by gastric distention,mediated by vagal impulses.also involves gastrin released from endocrine cells G cells,its release promoted by luminal amino acids & peptides & vagal stimulation.

3. Intestinal phase-initiated when digested protein containing food enters proximal small intestine involving many poly peptides besides gastrin.

Signals converging on the parietal cells to activate the proton pump.

Acetyl choline released from cephalic –vagal or gastric vagal afferents stimulates the parietal cells via MUSCARINE 3 CHOLINERGIC RECEPTORS resulting in increase in cytosolic Ca+& subsequent activation of proton pump

Gastrin activates gastrin receptors & increase cytosolic Ca+ within parietal cells.

Histamine secreted by ECL cells plays a central role ;gastrin & vagal affarents induce the release of histamine stimulating H2 receptors.Inhibition of acid secretion is done by Somatostatin ,PGE via ep3 receptors ,epidermal growth factor.

Mechanism of HCL Secretion

• When stimulated the parietal cells secrete an acid solution that contains about 160 millimoles of HCL which is almost isotonic to the body .

• The pH is 0.8 the H+ ion conc. Is 3 million times that of the arterial blood .to concentrate H+ ions requires 1500 calories energy.

The HCL is formed at the villus like projections & then conducted through the canaliculi to the secretory end of the cell.

The final secretion contains H20& HCl in ratio of 150 to 160 [mEq /l].

Contd…..

CL- actively transported from the cytoplasm to the lumen of canaliculus Na + actively transported to the cytoplasm from canaliculus ,The two creating a negatjve potential of –40 to –70 mV causing diffusion k+ & a small no Na+ ions enter the canaliculus from cytoplasm.

H2O dissociates into H+ & OH- .H+ secreted in exchange of K+ via H+ - K+ ATPase pump.Na+ are also absorbed by separate Na+ pump.

CO2 formed during metabolism or entering the cell from blood combines with OH- ions in presence of carbonic anhydrase to form HCO3- . These diffuse out into extracellular fluid in exchange of CL- ions that enter the cell from extracellular fluid & later secreted into canaliculus.

ILLUSRATION OF HCL SECRETION REGULATION

Parietal cells in diseases

Anannya Ghosh

GASTRIC MUCOSAL BARRIER

Gastric mucosal protection

Acid peptic digesion- H. pylori , peptic ulcer syndrome

Therapy

Gastric mucosal protection

The mucosal barrier protects the gastric mucosa from autodigestion.

Mucous secretion -the thin layer of mucos exhibits a diffusion coefficient for H+ that is one quarter of water .

Acid & pepsin containg fluid exit the gastric glands as “jets” passing through the surface mucous layer without coming in contact with surface epithelium.

It consits of –

Bicarbonate secretion-surface epithelial cells of both stomach & duodenum secrete HCO3- into the boundary zone of adherent mucus creating an essentially p H neutral micro environment

The epithelial barrier. intercellullar tight junctions provide a barrier to prevent back diffution of H+. Epithelial disruption is followed rapidly restitution in which existing cells migrate along basement membrane to restore epithelial barrier.

Mucosal blood flow

• Rich supply of oxygen .

• Nutrients

• Removes back -diffused acid

Prostaglandin synthesis- Promotes production of mucus& HCO3- Inhibit acid secretion by parietal cells. PGE & PGI by their vasodilatory action improve

mucosal blood flow. drugs blocking PGs promote mucosal

ulceration & injury.

Superficial damage heal 1-2 days Injury extends upto submucosa weaks are required for complete healing .

• Mucosal endocrine cells affect growth regulation . GHRELIN .a recently identified growth hormone regulate body growth and appetite via a possible effect on GASTROINTESTINAL –HYPOTHALAMIC –PITUTARY AXIS.

Helicobactor pylori

• Priviously called Campyloacter pylori.• Observed by Warren &Marshall in Australia in 1983.• however being different in many aspects from

campylobacter they are redesignated as Helicobacter pylori.

The only animal it affects is monkey.Gram –ve organism, motile ,by lophotrichous flagella.nonsporing rods ,may be spheroid & Coccoid in long cultures.Microaerophilic,5-10% CO2 & high humidity is req for its growth.colonies - circular convex transluscent,diameter 2mm in diameter. contd…..

H. pylori

• Biochemical activity-produces oxidase ,• urease,• catalase,• DNAse,• alkaline phosphatase,• glutamyl aminopeptidase .

• Virulence factor-

• UREASE• UREASE BY PRODUCTS • MUCINASE• CYTOTOXIN• LIPOPOLYSACCHARIDASE-leading

to inflammatory response.

Urease activity producing NH3 neutralises gastric acidity facilitating initial colonisation.

• Motility-once colonised the bacteria can penetrate gastric mucosa & adhere to the epithelial cells.

Bacterial antigens cross react with antral gastric antigens stimulatng autoimmune response.Protease produced degrade gastric mucosa.

H . Pylori contd…..

Gastric antrum is the most favoured site.

The infecton is transmited from person – person .

• In duodenum- the most favoured site -areas of gastric metaplasia.

• Superficial infiltration of polymorphonuclear neutrophils a character of chronic gastritis .

PEPTIC ULCER SYNDROME

• ULCERS-a breach in the mucosa of the alimentary tract that extends through muscularis mucosa into deeper .

Peptic ulcer

•Chronic , often solitary leisions in any part of Gi tract exposed to acid- peptic digestion.

EPIDEMIOLOGY

• In US• 4 million have duodenal ulcer • 350,000 are diagnosed • 180,000 are admitted • 5000 die

D A N G E R

causes

• H. pylori.• NSAIDS induced mucosal injury • Acid peptic secretions • Local irritants – smoking ,alcohol• Psychological factors –stress,

anxiety ,fatigue.

H . PYLORI GENETIC FACTORS.

• CAG –A GENE

• VACUOLATING TOXIN -VAC A GENE

Contd….

• Genetic factors- biood group O• Hormonal factors – ZE

Syndrome • Miscellenious – alcoholic

cirrhosis ,chronic renal failure ,hyperparathyroidism .

Features

• Morphology –Necrotic zone Superficial exudative zone Granulation tissue zone Zone of cicatrisation

Clinical feature

PainVommitingHemetemasis & malenaWeight lossDeep tenderness

Therapy

• Approaches for the treatment of peptic ulcer syndrome :

H2 blockers[antihistaminics]: cimetidine , ranitidine , famotidine ,roxatidine

Anticholinergics :pirenzepine, oxyphenonium

Proton pump inhibitors : omeprazole,lansoprazole,pantoprazole

Prostaglandin analogue : misoprostol

1. Reduction in gastric acid secretion

systemic- Sod. Bicarbonate ,Sod. Citrate .

non systemic –mag . Hydroxide, mag trisilicate,.aluminium hydroxide , Magaldrate , calcium carbonate .

neutralisation of acids(Antacids) :

Ulcer protective drugs-

Sucralfate Colloidal Bismuth sulfate

Contd…..

• H .pylori kit- 1. Amoxicillin + tinidazole + omeprazole .

• 2. Clarithromycin + amoxicillin +lansoprazole

• 3. Clarithromycin + tinidazole + lansoprazole .

SURGERY

• NO SMOKING

• NO ALCOHOL

• STRESS FREE LIFE STYLE

INTRINSIC FACTOR

CHIRANTAN MANDAL

IIntrinsic factor; entrapment of vitamin B12 & related ntrinsic factor; entrapment of vitamin B12 & related pathology.pathology.

• Intrinsic factor is secreted by the parietal cells along with HCL.

• Properties –It is a glycoprotein .Mol .wt 45000 [.Donaldson 1987] Release of Vit B12 from injested food is by intragastric peptic digestion .

Structure of intrinsic factor

The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).

The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl.

Cyanocobalamin structure depicted in 3D-sticks form

• Secretion occurs by membrane translocation & stimulated by gastric acid secretagogues .

Contd…….

Functions –*general cell metabolism * normal heamatopoiesis. *nervous system integrity

maintainance. Methylcobalamin converts homocysteine to methionine

. S –adenocyl cobalamin converts propionyl CoA To

Succinyl CoA , Via Methyl malonyl coA .

• Deoxyadenosyl B12 or as it is sometimes referred to Ado B12: Ado B12 is essential for acid-base maintenance of the blood, simply because Ado B12 is the catalyst that assists the conversion of, Methylmalonyl CoA, into Succinyl CoA. In absence of vitamin B12, levels of Methylmalonyl CoA increase, and this is in fact a great way to distinguish folate deficiency macrocytic anemia, from vitamin B12 anemia. The following is the reaction in which Ado B12, plays a pivotal role:

• Propionyl CoA → Methylmalonyl CoA → Succinyl CoA

Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).

• Methyl B12: This form of vitamin B12 is essential for conversion of Methy-THF (Methyl Tetrahydrofolate) into THF, and methyl (CH3). The methyl group, is then used to add a carbon, to homocysteine, converting it into Methionine. Methionine is further converted to S-adenosyl methionine, which in turn gives of the extra carbon it received from THF, now to a DNA nucleotide, becoming S-adenosyl homcysteine. S-adenosyl Homocysteine, further loses its "S-adenosyl" attachment, to become homocysteine, and the cycle repeats yet again!

• Oral cavity: Vitamin B12 containing food is ingested. Salivary glands produce haptocorrin which binds vitamin B12, creating a "Vitamin B12-Haptocorrin complex". This complex is then ingested via esophageal peristalsis into the stomach.

Absorption –*vit B12 released forms a stable complex with a gastric R binder . R binder is a form of glycoprotein found in secretions & phagocytes & plasma

• Stomach: Vitamin B12-Haptocorrin, survives the low pH, highly osmotic environment of the stomach. Parietal cells produce hydrochloric acid (the effect of which Haptocorrin protects vitamin B12 from), and also intrinsic factor (IF). Intrinsic factor also has a high binding affinity for vitamin B12, but because that position is already filled by Haptocorrin, free intrinsic factor, and "Haptocorrin-vitamin B12" complex, empty from the stomach into the duodenum.

• . * on reaching the duodenum the vit B12 R binder is released & then vit B12 is complexed with intrinsic factor

– duodenum: Pancreatic juice, produced by the pancreas, contains pancreatic proteases that break the haptocorrin, degrading it and freeing the vitamin B12. Once free, vitamin B12, binds with intrinsic factor (IF), to produce an "IF-Vitamin B12" complex.

• Intrinsic factor & Vit B 12 reaches distal ileum

• Binds to specific receptor on the mucosal brush border , where after the IF is destroyed

• .vit B12 released binds to Transcobalamin II

• This complex is secreted into portal circulation & transported to liver , bone marrow .& other cells .

• Ileum: Located in the terminal portion of the ileum is a specialized receptor complex called the cubam (or sometimed called "CUBN"). Cubam is composed of two molecules, one of which is amnionless (AMN), and the other cubilin[3][4]. Cubilin specializes in recognition of the "vitamin B12-IF" complex and attaches it, while amnionless (AMN), is responsible for initiation of the endocytosis of complex, result of which is absorption of vitamin B12. It is at this point, where the IGS syndrome causes its pathology, by preventing absorption of vitamin B12 due to a defective cubam receptor, due to mutation in either the amnionless (AMN) portion, or the cubilin portion.[1] Mutation at either cubilin, or AMN, can cause this syndrome.

Pernicious anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.

Contd…..

• Pathology – vitB12 deficiency though many other causes are there the cause related to parietal cells are

• 1.Gastrectomy [idiopathic atrophic gastritis .]

• 2.congenital lack of intrinsic factor

the disease is called Pernicious anemia.

Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.

Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.

• Defiency of if subacute leads to megaloblastic anemia .

• GLOSSITIS,GI disturbance ,epithelial damage may occuur

Megaloblastic anemia (bone marrow aspirate). A to C, Megaloblasts in various stages of differentiation. Note that the orthochromatic megaloblast (B) is hemoglobinized (as revealed by cytoplasmic color)

Megaloblastic anemia

Due to deficiency of Vit B12.also called Addisonian pernicious anemia

Sub-acute degeneration of spinal cord with defective myelin formation .

Autoimmune disease antibodies are produced against components of gastric mucosa also against intrinsic factor.

Diagonostic algorithim of Vitamin B12 deficiency

Therapy

• Preparations given – methyl cobalamine in neural defects in diabetec , alcoholic ,& other peripheral neuropathy .

• Hydroxocobalamine – parenteral I.v .or I.m .or deep subcutaneous in lack of intrinsic factor

• Cyanocobalamine

Recapitulation