Vibrio Cholerae: Infection, Pathophysiology & Treatment

• The tutorial covers several key topics, including cholera, kidney functions, fluid balance, nephrons, liver function, GFR and urine output, tetracycline, HSE notifiable diseases, and confidence intervals.

Cholera

• Vibrio cholerae is a gram-negative, oxidase-positive, comma-shaped bacterium with a single polar flagellum.
• This bacterium produces cholera toxin.
• It is sensitive to stomach acid, requiring a large amount of bacteria to cause infection.
• V. cholerae is non-invasive, staying within the intestinal lumen, specifically the small intestine.
• It is transmitted via the fecal-oral route or through contaminated water.
• V. cholerae is killed at 100°C in seconds but can survive in ice for up to 6 weeks.
• Recurrent outbreaks occur in parts of Africa, South Asia, and Latin America.
• Common in areas with poor sanitation, overcrowding, and limited clean water.
• The WHO estimates around 1.3-4 million cases annually, with 21,000-143,000 deaths.
• Clinical features include profuse rice water diarrhea, abdominal discomfort, and vomiting.
• Severe fluid and electrolyte loss can lead to hypovolemia, indicated by dry oral mucosa, cool skin, decreased skin turgor, and low blood pressure.
• Aetiology is the ingestion of contaminated water or uncooked food, such as shellfish.
• Following ingestion, V. cholerae uses flagella to colonize the intestinal wall.
• Cholera toxin (5B+1A subunits) binds to the GM1 ganglioside receptor on the surface of intestinal epithelial cells.
• The A subunit is endocytosed and carried to the endoplasmic reticulum, then to the cytoplasm.
• The A subunit activates Gs proteins, increasing cAMP levels, activating protein kinase A, and opening the cystic fibrosis transmembrane regulator (CFTR).
• This leads to an efflux of chloride ions into the intestinal lumen, drawing water in and causing massive diarrhea.
• A urine dipstick is a rapid initial test but has lower sensitivity and specificity.
• Stool culture is confirmatory and includes antibiotic sensitivity testing.
• Management includes IV infusion with Ringer's lactate, oral rehydration solutions, and antibiotics like doxycycline or tetracycline.
• A new therapy involves CFTR inhibitors to block chloride secretion.
• With prompt rehydration, the fatality rate is less than 1%.
• Without treatment, cholera can be fatal in hours due to hypovolemic shock.

Kidney Functions

• Renal physiology includes glomerular filtration, tubular reabsorption, and tubular secretion.
• Glomerular filtration is the first step in urine production, where water and solutes filter into the glomerular capsule.
• Tubular reabsorption involves tubule cells reabsorbing 99% of filtered water and useful solutes.
• Tubular secretion involves renal tubule and duct cells secreting waste, drugs, and excess ions into the fluid for excretion.

Glomerular Filtration

• Glomerular fenestrated capillary endothelium allows all solutes in blood plasma to exit but prevents filtration of blood cells and platelets due to pores.
• The glomerular basement membrane contains type IV collagen and heparan sulfate, providing a negative charge to prevent filtration of plasma proteins and organic anions.
• The slit membrane across each filtration slit permits the passage of water, glucose, vitamins, urea, and ions.
• The process uses capillary pressures to force fluid and solutes out: large surface area, thin and porous filtration membrane, and high glomerular capillary pressure due to the efferent arteriole being smaller than the afferent.
• Glomerular filtration rate (GFR) is the amount of filtrate formed in all renal corpuscles of both kidneys each minute.
• Glomerular blood hydrostatic pressure promotes filtration.
• Capsular hydrostatic pressure opposes filtration.
• Blood colloid osmotic pressure opposes filtration due to the presence of proteins in blood plasma.

Reabsorption and Secretion

• The proximal convoluted tubule (PCT) reabsorbs the largest amount of solute and water (65%), including glucose.
• Sodium reabsorption occurs via the sodium-glucose symporter and the sodium-hydrogen antiporter.
• Water osmosis is aided by aquaporin 1.
• In the second half of the PCT, increased solute concentration allows for the reabsorption of chloride, potassium, calcium, and magnesium down their concentration gradients.
• Secretion in the PCT includes hydrogen, urea, ammonium, and ammonia.
• Reabsorption in the PCT includes sodium, glucose, chloride, potassium, calcium, magnesium, amino acids, and bicarbonate.

Loop of Henle

• The thin descending limb is highly permeable to water (20%) via osmosis but impermeable to sodium and chloride.
• The thin ascending limb is impermeable to water.
• The thick ascending limb uses sodium-potassium-2 chloride symporters.
• Sodium and chloride are reabsorbed, and potassium is secreted into the lumen.
• Passive reabsorption of positive ions occurs.
• The loop of Henle is impermeable to water

Distal Convoluted Tubule and Collecting Duct

• Principal cells reabsorb sodium and secrete potassium.
• Most potassium is returned to the blood in the PCT and loop of Henle and excreted in variable amounts to maintain stable levels.
• Intercalated cells secrete hydrogen and reabsorb bicarbonate and potassium.
• Type A intercalated cells secrete hydrogen and reabsorb bicarbonate during acidosis.
• Type B intercalated cells secrete bicarbonate and reabsorb hydrogen during alkalosis.

Fluid Balance and Kidney

• A decrease in blood volume/BP causes the kidney to release renin.
• Renin converts angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE).
• Angiotensin II causes vasoconstriction and stimulates aldosterone secretion.
• Aldosterone stimulates principal cells in the collecting duct to reabsorb sodium and water.

Antidiuretic Hormone (ADH)

• A decrease in plasma volume or an increase in osmolarity stimulates baroreceptors and osmoreceptors.
• This causes the hypothalamus to release ADH from the posterior pituitary.
• ADH inserts aquaporin 2 into the collecting tubule and duct, promoting water reabsorption.

Atrial Natriuretic Peptide (ANP)

• Increased blood volume increases atrial stretch, promoting the release of ANP.
• ANP promotes sodium excretion, reducing water reabsorption, and inhibits renin release, also reducing sodium and water reabsorption.

Nephron

• A single layer of epithelial cells forms the entire walls of the glomerular capsule, renal tubule, and ducts.

Glomerular Capsule

• The visceral layer is made of podocytes around endothelial cells.
• The parietal layer is simple squamous epithelium.
• Mesangial cells make up the space between blood vessels and are either intraglomerular or extraglomerular.
• Intraglomerular cells provide structural support and regulate GFR.
• Extraglomerular cells produce erythropoietin.

Filtration Barrier

• The endothelium has fenestrations allowing solutes, proteins, and plasma to pass.
• The basement membrane is gel-like with a negative charge, preventing plasma proteins from passing.
• Podocytes have filtration slits.

Proximal Convoluted Tubule

• Simple cuboidal epithelial cells with a brush border of microvilli.
• Reabsorbs 60-65% of water and almost all nutrients, ions, vitamins, and small plasma proteins.

Loop of Henle

• The thin descending loop (permeable to water) and thin ascending loop (permeable to sodium chloride) are simple squamous epithelium.
• The thick ascending loop is simple cuboidal epithelium and reabsorbs sodium chloride against the concentration gradient.

Distal Convoluted Tubule

• Simple cuboidal epithelium without a brush border.
• In contact with afferent and efferent arterioles, forming the juxtaglomerular apparatus.
• The early DCT is permeable to water, sodium, and chloride via symporters and calcium via PTH.
• The distal part contains principal cells (ADH and aldosterone receptors) and intercalated cells (blood pH homeostasis).

Collecting Tubule and Duct

• Simple cuboidal epithelium.
• Aquaporins 2 are inserted via ADH for water reabsorption.

Functional Zones of Liver

• The liver is divided into functional zones based on oxygen and nutrient supply, described in the hepatic acinus model. Each zone has a varying susceptibility to damage based on the type of insult.

Zone 1 (Periportal Zone)

• Closest to the portal triad
• Highest oxygen
• Functions include oxidative metabolism, the urea cycle, and cholesterol synthesis.
• Susceptible to toxins from the bloodstream and is ischemia-resistant due to high oxygen.

Zone 2 (Intermediate Zone)

• Located between zones 1 and 3
• Intermediate oxygen
• Functions include transitional metabolic processes.
• Rarely affected but can be involved in conditions like yellow fever.

Zone 3 (Centrilobular Zone)

• Closest to the central vein, farthest from the portal triad.
• Lowest oxygen
• Functions include glycolysis, lipogenesis, and detoxification.
• Susceptible to hypoxic injury, drug-induced injury, and fatty liver disease.

Clinical Significance of Liver Zones

• Acetaminophen toxicity primarily affects Zone 3 due to CYP450-mediated metabolism.
• Hypoxia-related damage mainly occurs in Zone 3 due to poor oxygenation.
• Viral hepatitis typically affects Zone 1.

GFR and Urine Output

• Normal GFR ranges from 90 to 120 mL/min/1.73 m².
• GFR decreases with age.
• Normal 24-hour urine volume is 800 to 2,000mL with a normal fluid intake of about 2 liters per day.

Tetracycline

• Bacteriostatic antibiotic inhibiting bacterial protein synthesis.
• Binds to the 30s ribosomal subunit, blocking tRNA binding to the A-site on the mRNA ribosome complex, inhibiting translation and bacterial growth.
• Indications include atypical pneumonia, cholera, STIs, and Helicobacter pylori in penicillin-allergic patients.
• Side effects include GI issues, teeth discoloration, bone growth effects, headache, blurred vision, and thrush.
• Contraindications include pregnancy, age under 8, and severe renal impairment.
• Interactions include decreased tetracycline absorption with antacids, increased anticoagulant effect, decreased contraceptive effectiveness, and antagonism with penicillin.
• First-generation tetracyclines are not metabolized and undergo renal excretion, with some biliary excretion.

HSE Notifiable Diseases

• Meningitis, chickenpox (if hospitalized), chlamydia, cholera, COVID-19, E. coli, gonorrhea, hepatitis A/B/C/E, HIV, HPV, Legionellosis, malaria, measles, mumps, syphilis, TB, and trichomoniasis.

Confidence Interval

• Calculated with sample data, size, and a confidence level.
• If a 95% confidence interval is calculated for a population mean as (10, 15), it means that we are 95% confident that the true population mean lies between 10 and 15
• It does not mean there is a 95% probability that the true mean is in this range.

Explore Vibrio cholerae: why a large amount is needed for infection in healthy individuals and its mechanism. Learn appropriate treatments, including alternatives for those allergic to common antibiotics, and effective public health interventions for cholera outbreaks.