Fever (Pyrexia)

Definition

• Fever - the hypothalamus intentionally raises the set-point (controlled, regulated)
• Hyperthermia - temperature rises beyond hypothalamic control (e.g., heat stroke, malignant hyperthermia)

Pathophysiology - How Fever Develops

1. Pyrogens trigger the process

• Exogenous - from outside the body (bacteria, viruses, fungi, toxins like lipopolysaccharide [LPS] from bacterial cell walls)
• Endogenous - produced by the body's own immune cells (cytokines such as IL-1, IL-6, TNF-alpha)

2. The hypothalamic set-point rises

3. Body generates heat

• Shivering (rapid muscle contractions to generate heat)
• Vasoconstriction (reducing heat loss from skin)
• The patient feels cold and may have chills

4. New set-point is maintained

5. Resolution (defervescence)

• Vasodilation
• Sweating
• The patient feels warm and sweaty as temperature returns to normal

Why Fever is Beneficial

• Lymphocytes and macrophages are more active at elevated temperatures
• The metabolism of most pathogens (adapted to 37°C) is impaired at higher temperatures
• It accelerates immune cell activity and pathogen clearance

Common Causes

How Antipyretics Work

Key Symptoms

• Chills and rigors (during temperature rise)
• Flushed, hot skin (at fever plateau)
• Sweating (during defervescence)
• Headache, fatigue, myalgias
• Some degree of cognitive slowing or sleepiness (from both temperature change and the cytokine response)

When Fever Becomes Dangerous

• Hyperpyrexia - temperature above 41°C - risk of seizures, brain damage, multi-organ failure
• Fever in immunocompromised patients, neonates, or the elderly requires urgent evaluation
• Prolonged fever leads to dehydration, catabolism, and nutritional depletion

Jaundice (Icterus)

Definition

Bilirubin Metabolism - The Foundation

1. Production - Red blood cells are broken down in the reticuloendothelial system (liver, spleen). Haemoglobin releases heme, which is converted to biliverdin, then reduced to unconjugated (indirect) bilirubin
2. Transport - Unconjugated bilirubin is lipid-soluble and bound to albumin for transport in the blood. It cannot be excreted in urine or bile in this form
3. Conjugation - In the liver, hepatocytes take up bilirubin and conjugate it with glucuronic acid via the enzyme UGT (UDP-glucuronosyltransferase), making it water-soluble (conjugated / direct bilirubin)
4. Excretion - Conjugated bilirubin is secreted into bile via the MRP2 transporter on the hepatocyte canalicular membrane, passes into the small intestine, and is metabolised by gut bacteria into urobilinogen
5. Elimination - Most urobilinogen is excreted in faeces as stercobilin (gives stool its brown colour). A small amount is reabsorbed and excreted by the kidneys as urobilin (gives urine its yellow colour)

Classification of Jaundice

1. Pre-hepatic (Haemolytic) Jaundice

• Cause: Excess destruction of red blood cells (haemolysis) overwhelms the liver's capacity to conjugate bilirubin
• Result: Raised unconjugated (indirect) bilirubin
• Examples: Haemolytic anaemia, sickle cell disease, malaria, G6PD deficiency, ABO/Rh incompatibility (neonates), thalassaemia
• Key features: Urine is normal (no bilirubin in urine - unconjugated bilirubin cannot pass through kidneys), dark stools (more stercobilin), raised urobilinogen in urine

2. Hepatic (Hepatocellular) Jaundice

• Cause: Liver cell damage impairs uptake, conjugation, and/or excretion of bilirubin
• Result: Mixed conjugated and unconjugated hyperbilirubinaemia
• Examples: Viral hepatitis (A, B, C), alcoholic liver disease, cirrhosis, drug-induced liver injury, autoimmune hepatitis, liver failure
• Genetic causes: Gilbert syndrome (mild deficiency of UGT), Crigler-Najjar syndrome (severe UGT deficiency), Dubin-Johnson syndrome (defect in canalicular transport of conjugated bilirubin)
• Key features: Elevated ALT/AST, bilirubin in urine (bilirubinuria), variable stool colour

3. Post-hepatic (Obstructive / Cholestatic) Jaundice

• Cause: Blockage of bile flow from the liver to the duodenum - bile (containing conjugated bilirubin) backs up into the blood
• Result: Raised conjugated (direct) bilirubin
• Examples: Gallstones in the common bile duct, pancreatic cancer (head of pancreas), cholangiocarcinoma, primary sclerosing cholangitis, strictures
• Key features: Dark urine (conjugated bilirubin is water-soluble - it appears in urine), pale/clay-coloured stools (no stercobilin reaching gut), pruritus (bile salts deposited in skin), raised ALP and GGT

Key Lab Differences at a Glance

Important Clinical Points

• Delta (δ) bilirubin - A fraction of conjugated bilirubin covalently binds to albumin, giving it albumin's half-life (~3 weeks). This is why jaundice may persist for weeks after resolution of the underlying cause (e.g., after a bile duct stone is removed). (Yamada's Textbook of Gastroenterology, p.799)
• Conjugated bilirubin is essentially absent from healthy blood - any elevation is highly specific for hepatobiliary disease
• Pruritus commonly accompanies jaundice, especially obstructive jaundice - caused by bile salt deposition in skin
• Jaundiced patients undergoing surgery carry a higher risk of: wound infection, renal failure (hepatorenal syndrome), clotting abnormalities (impaired vitamin K absorption), poor wound healing, and hypoalbuminaemia (Pye's Surgical Handicraft)
• Neonatal jaundice is common because foetal erythrocytes have a shorter lifespan and the neonatal liver has low UGT activity - unconjugated bilirubin can cross the blood-brain barrier and cause kernicterus (brain damage) if untreated

Symptoms and Signs

• Yellow skin and eyes (most visible in sclera first)
• Dark (tea-coloured) urine
• Pale / clay-coloured stools (in obstructive jaundice)
• Itching (pruritus)
• Fatigue and malaise
• Right upper quadrant pain (if gallstones or hepatitis)
• Weight loss (if malignancy)