chloride metabolism and its disorders

Dr. Rohini C Sane

Functions of Chloride❖Chloride is the major extracellular anion.

❖Functions of Chloride :

1.maintenance osmotic pressure ,acid base balance and electrical neutrality

2. formation of HCl (provides optimum pH for action of pepsin ,activation of pepsinogen, kills bacteria )

3. Maintains Homeostasis of Na⁺ ,K ⁺, Cl⁻

4. Activation of Salivary Amylase by Chloride

5. CSF protein content low , high chloride content in CSF is to keep “ Donan membrane equilibrium )

6.Involved in chloride shift

Functions of Chloride

Chloride Metabolism❖Plasma chloride concentration 96-106 mequ /L (mmols/L )

❖CSF chloride concentration 120- 130mequ /L (mmols/L )

❖urinary chloride concentration 110-250 mequ /L (mmols/L )

❖Renal threshold 110 mequ /L (mmols/L ) ( parallel relationship with sodium excretion )

❖Recommended Daily Allowance (RDA) 5-10 gm

❖Dietary sourcescommon salt ,eggs, leaf vegetables ,fish, whole grains

❖Daily excretion of Chloride 5-8 gm /day

Chloride ion and anion gap• Sum of bicarbonate ion + chloride ion +10 = sodium ion concentration

• If Sum of bicarbonate ion + chloride ion is far less than sodium ion concentration ,it may be inferred that possibly there has been addition of substantial amounts of another anion (anion gap)

• anion gap is seen in lactic acidosis or diabetes ketoacidosis where lactate or ketone bodies ( acetoacetate and – hydroxy butyrate ) anions fill the anion gap respectively.

Chloride Metabolism

Role of Chloride in gastric acid

Functions of Chloride as HCl

Chloride in activation of pepsinogen

Secretion of chloride by parietal cells

Chloride shift in systemic capillaries In systemic capillaries• Carbon dioxide is generated by cellular metabolism.• Carbon dioxide diffuses from tissue to plasma and RBC.• In RBC ,water and Carbon dioxide combine to form carbonic acid.

• carbonic acid dissociates to give hydrogen (H+ and bicarbonate ions (HCO3-.• reduced Hb buffers (H+ and (HCO3-.• Concentration of (HCO3- builds inside RBC.

• (HCO3- diffuses from tissue into plasma and chloride shifts into RBC.

• In pulmonary capillaries the process is reversed. • Maintenance of electric balance : phenomenon is called Chloride shift ( catalysis by carbonic anhydrase

Chloride shift in systemic capillaries

In systemic capillariesCarbon dioxide is generated by cellular metabolism

Carbon dioxide diffuses from tissue to plasma and RBC

In RBC ,water and Carbon dioxide combine to form carbonic acid

Carbonic acid dissociates to give hydrogen (H+ and bicarbonate ions (HCO3-

Reduced Hb buffers (H+ and (HCO3-

Concentration of (HCO3- builds inside RBC

(HCO3- diffuses from tissue into plasma and chloride shifts into RBC

In pulmonary capillaries the process is reversed. *

Maintenance of electric balance : phenomenon is called Chloride shift

Chloride shift in pulmonary capillaries* In pulmonary capillaries

• (HCO3- diffuses into RBC and chloride shifts into plasma.

• In RBC , bicarbonate ions (HCO3- combine with hydrogen (H+

released from reduced Hb to form carbonic acid.

• carbonic acid dissociates to give hydrogen (H+ and Carbon dioxide.

• Carbon dioxide diffuses from RBC to plasma to be exhaled by alveoli of lung.

• ( catalysis by carbonic anhydrase

Chloride shift in pulmonary capillaries*In pulmonary capillaries

(HCO3- diffuses into RBC and chloride shifts into plasma

In RBC , bicarbonate ions (HCO3- combine with hydrogen (H+ released from reduced Hbto form carbonic acid.

Carbonic acid dissociates to give hydrogen (H+ and carbon dioxide

Carbon dioxide diffuses from RBC to plasma to be exhaled by alveoli of lung

Chloride shift

Absorption and excretion of Chloride

• Dietary Chloride : absorbed completely by the intestinal tract

• It is filtered out by glomerulus and passively absorbed in conjunction with sodium by proximal tubules.

• Excess Chloride ions are excreted in urine and through sweating .

• Excess sweating stimulates Aldosterone secretion ,which acts on sweat glands to conserve sodium and Chloride ions.

Absorption and excretion of Chloride

Disorders of Chloride Metabolism

1. Hyperchloremia and Hypochloremia ((high and low serum Chloride ions concentration respectively

2. Cystic fibrosis

3. Achlorhydria

4. Hyperchlorhydria

5. Hypochlorhydria

6. Achylia Gastrica

Comparison of Hyperchloremia and Hypochloremia

Hyperchloremiadehydration

Cushing syndrome minerocorticoidincreased reabsorption of Chloride at

renal tubule decreases

Severe diarrhea loss of bicarbonatecompensatory retention of chloride

Respiratory acidosis shallow breathing CO₂ conc increases H₂CO₃ conc increases HCO₃⁻decreases Cl⁻ conc increases

Renal tubular acidosis

Hypochloremia Excessive vomiting HCl lostincrease plasma bicarbonate “

Hyperchloremia alkalosis ”

Addison’s disease (Aldosterone decreases ,renal reabsorption of chloride ion

decreases ,excretion of chloride ions increases ) Chloride ion concentration

decreases

Respiratory alkalosis Hyperventilation elimination of CO₂ increases increase in concentration of blood

bicarbonate Chloride ion concentration decreases

Disorders of Chloride Metabolism

Cystic Fibrosis❖Cystic Fibrosis (CF is a multisystem disease that presents

• in neonates ,with failure to pass the first feces containing bile, intestinal debris and mucus ( meconium ileus

• in early childhood with respiratory infections

• in the adults

❖Inheritance of Cystic Fibrosis (CF : autosomal recessive disorder

Pathogenesis of Cystic Fibrosis❖Cystic Fibrosis arises due to mutations in gene located on

chromosome 7 encoding the Cystic Fibrosis transmembrane regulator (CFTR protein that regulates transmembrane chloride transport .

❖ The most common mutation is F 508 mutation which refers to deletion of three base pairs , resulting in the absence of Phenylalanine at position 508 in amino acid sequence of CFTR .

Clinical Consequences of Cystic FibrosisAbsence of Cystic Fibrosis transmembrane regulator (CFTR /chloride

channel leads to following Consequences :

• Exocrine pancreatic insufficiency with impaired secretion of sodium, bicarbonates and water resulting in increased viscosity (mucoviscoidosis,obstruction of pancreatic duct , pancreatic fibrosis and obstruction of pancreatic tissue.

• Chronic airways infection that affects mucus secretion in the bronchi with recurrent respiratory infections ,bronchiectasis and chronic lung disease

• Malabsorption ,cirrhosis of liver and cholelithiasis due to defective secretion of chloride and water

• abnormal sweat gland function due to excessive excretion of sodium and chloride in sweat

• Abnormal urogenital functions

Cystic Fibrosis

Disorders of Chloride Metabolism

Diagnosis of Cystic Fibrosis❖Diagnosis of Cystic Fibrosis is based on

• Clinical symptoms

• Measurement of pilocarpine induced sweat electrolyte concentration:

Na ⁺ and Cl⁻ in sweat ( 70 mmols /L or mequ /L )

• Neonatal screening test : increased plasma immunoreactive trypsin

• prenatal screening test : for F 508 mutation

Diagnosis of Cystic Fibrosis

Sweat test for Diagnosis of Cystic Fibrosis

Silver nitrate Test for qualitative analysis of chloride ions

Management of Cystic Fibrosis

Management of Cystic Fibrosis involves

• Prevention of respiratory infection by antibiotics and physiotherapy

• Maintenance of proper nutrition and pancreatic enzymes in diet

Quantitative analysis of chloride ions

Average Serum chloride ion concentration : 150 mequ/L

Achlorhydria

• Achlorhydria refers to absence of HCL in gastric secretion.

• Physiological Achlorhydria :Aging

• Pathological Achlorhydria

1. Tuberculosis

2. Gastritis

3. Gastric carcinoma

4. Terminal stages of malignancy

Hyperchlorhydria

❖ Hyperchlorhydria refers to increase in concentration free acid . The combined acidity may be normal.

• Hyperchlorhydria is common in

a) Duodenal ulcers

b) Zollinger Ellison syndrome

Hypochlorhydria

Hypochlorhydria refers to decrease in concentration of free acid.

• Hypochlorhydria is common in

a) Duodenal ulcers

b) Zollinger Ellison syndrome

Achylia Gastrica

• Achylia Gastrica refers to the absence of both acids and pepsin and is associated with pernicious anemia.

CTFR and Cholera❖Cholera is due to trapping of G –protein in the active confirmation by

Cholera toxin - Choleragen, secreted by the intestinal bacteria Vibrio Cholera .

Cholera : acute diarrhea disease that can be life threatening .

It causes the secretion of electrolytes and fluids in large amounts from intestine of the infected person.

Mechanism of action of Cholera toxin - Choleragen

• Cholera toxin – Choleragen has two functional subunits :

B- subunit that bind to GM -1 gangliosides of intestinal epithelial cells

A- subunit that has catalytic activity and enters the cell.

After entering cell it catalyzes the covalent modification of a Gs protein.

G s protein is a subunit of G-protein , s in subscript indicates stimulatory role of subunit of G-protein.

This modification traps the G-protein in the active conformation, which activates adenylate cyclase and formation of c-AMP, which in turn activates protein kinase A (PKA).

Protein kinase A (PKA) opens chloride channel, which are called CTFR Cystic Fibrosis transmembrane regulator (CFTR .

Mechanism of action of Cholera toxin - Choleragen

CTFR and Cholera:

CTFR acts as an ATP regulated chloride channel in the plasma membrane of epithelial cells.

Opening of chloride channel leads to inhibition Na+ –H + exchanger by phosphorylation.

This ultimately leads to an excessive loss of Na+ in the form of NaCl along with loss of large amount of water into the intestine.

❖Management of cholera : rehydration with glucose electrolyte solution

Mechanism of action of Cholera toxin – Choleragen:1

Cholera toxin – Choleragen has two functional subunits :

B- subunit that bind to GM -1 gangliosides of intestinal epithelial cells

A- subunit that has catalytic activity and enters the cell.

After entering cell it catalyzes the covalent modification of a Gs protein.

G s protein is a subunit of G-protein , s in subscript indicates stimulatory role of subunit of G-protein.

Mechanism of action of Cholera toxin – Choleragen-2

Covalent modification of a Gs protein traps the G-protein in the active conformation.

Activation of adenylate cyclase by active G-protein and formation of c-AMP

Activation protein kinase A (PKA) by c-AMP

Opening of chloride channel (are called CTFR Cystic Fibrosis transmembrane regulator -CFTR by active Protein kinase A (PKA)

Mechanism of action of Cholera toxin – Choleragen:3

CTFR acts as an ATP regulated chloride channel in the plasma membrane of epithelial cells.

Opening of chloride channel leads to inhibition Na+ –H +

exchanger by phosphorylation.

This ultimately leads to an excessive loss of Na+ in the form of NaCl along with loss of large amount of water into the intestine.

Management of cholera : rehydration with glucose electrolyte solution

Mechanism of action of Cholera toxin – Choleragen

Mechanism of action of Cholera toxin – Choleragen