Q4. Give Physiological Reasons (2 × 5)

a) Rigor Mortis

• Parikh's Textbook of Medical Jurisprudence; Junqueira's Basic Histology, 17e

b) Pancreas is Resistant to Autodigestion

1. Enzymes are synthesised and stored as inactive zymogens (e.g., trypsinogen, chymotrypsinogen, proelastase) - they are only activated in the duodenal lumen by enterokinase.
2. Intracellular calcium homeostasis - low cytosolic Ca²⁺ in acinar cells promotes destruction of any spontaneously activated trypsin.
3. Serine protease inhibitor SPINK1 (pancreatic secretory trypsin inhibitor) is co-secreted and can neutralise ~20% of intracellular trypsin.
4. Chymotrypsin C can lyse and inactivate trypsin.
5. α₁- and α₂-globulin fractions in plasma also act as protease inhibitors.

• Harrison's Principles of Internal Medicine, 22e; Robbins & Cotran Pathologic Basis of Disease

c) Heart Rate Rises During Exercise

1. Initial phase - Withdrawal of vagal (parasympathetic) tone: At the onset of exercise, the parasympathetic outflow to the SA node decreases, allowing the heart rate to rise quickly.
2. Later phase - Increased sympathetic activity: As exercise intensity increases, sympathetic stimulation of the SA node via norepinephrine (acting on β₁-adrenoceptors) further accelerates heart rate. This also increases myocardial contractility.

• Murray & Nadel's Textbook of Respiratory Medicine; Braunwald's Heart Disease, 2-vol set

d) Haemophilia Does Not Usually Affect Females

• Males have only one X chromosome (XY). If their single X chromosome carries the defective gene, they express the disease (no second X to compensate).
• Females have two X chromosomes (XX). To express haemophilia, a female would need both X chromosomes to carry the defective allele - an extremely rare occurrence (would require a carrier mother AND an affected father).
• Most females are either normal (X^N X^N) or carriers (X^N X^h) - carriers have one normal X that produces enough clotting factor to prevent clinical bleeding.

• Scott-Brown's Otorhinolaryngology & Head and Neck Surgery, Vol 1

e) Surfactant is Essential for Respiration

• Reducing surface tension at the air-alveolar interface, preventing alveolar collapse on expiration.
• Importantly, surfactant lowers surface tension more in smaller alveoli than larger ones, stabilising alveoli of different sizes and preventing smaller ones from emptying into larger ones (as predicted by the Law of Laplace).

• Langman's Medical Embryology; Robbins & Cotran Pathologic Basis of Disease

Q4. Physiological Reasons (2 × 5)

a) Rigor Mortis

• After death, ATP production stops but consumption continues briefly.
• ATP is required for detachment of myosin heads from actin filaments during the cross-bridge cycle.
• Without ATP, actin-myosin cross-bridges become permanently locked.
• Myosin cannot release from actin → filaments fuse into a stiff, dehydrated gel.
• This causes stiffening and shortening of all muscles = Rigor Mortis.
• Persists until autolysis of actin and myosin during putrefaction → secondary relaxation occurs.

b) Pancreas is Resistant to Autodigestion

• Pancreas secretes powerful proteolytic enzymes (trypsin, chymotrypsin, elastase) capable of self-digestion.
• Protected by the following mechanisms:
  • Zymogens: Enzymes are stored as inactive precursors (trypsinogen, chymotrypsinogen) - activated only in the duodenum by enterokinase.
  • SPINK1 (Pancreatic Secretory Trypsin Inhibitor): Co-secreted with enzymes; neutralises ~20% of any spontaneously activated intracellular trypsin.
  • Chymotrypsin C: Lyses and inactivates trypsin if prematurely activated.
  • Low intracellular Ca²⁺: In acinar cells promotes destruction of any spontaneously activated trypsin.
  • Plasma protease inhibitors: α₁- and α₂-globulins also inactivate escaped enzymes.
• Loss of any of these mechanisms → premature enzyme activation → autodigestion → acute pancreatitis.

c) Heart Rate Rises During Exercise

• During exercise, O₂ demand and CO₂ production increase → cardiac output must rise.
• Heart rate increases in two phases:
  • Phase 1 (Early exercise): Withdrawal of parasympathetic (vagal) tone → SA node fires faster.
  • Phase 2 (Increasing intensity): Sympathetic stimulation of SA node via norepinephrine acting on β₁-adrenoceptors → further acceleration of heart rate + increased contractility.
• Heart rate rises linearly with increasing VO₂ to meet the metabolic demands of exercising muscles.

d) Haemophilia Does Not Usually Affect Females

• Haemophilia A (Factor VIII deficiency) and B (Factor IX deficiency) are X-linked recessive disorders.
• Males (XY): Have only one X chromosome → a single defective allele is sufficient to express the disease (no second X to compensate) → affected.
• Females (XX): Have two X chromosomes → need both X chromosomes to carry the defective allele to express disease → extremely rare.
• Most females are either:
  • Normal (X^N X^N) - unaffected
  • Carriers (X^N X^h) - one normal X produces sufficient clotting factor → no clinical bleeding.
• Hence, females are usually carriers only, not clinically affected.
• Rare exceptions: extreme X-chromosome lyonization (inactivation of the normal X) or inheritance from both parents.

e) Surfactant is Essential for Respiration

• Alveoli are lined with a thin fluid film → creates an air-water interface with high surface tension.
• High surface tension tends to collapse alveoli during expiration → atelectasis.
• Surfactant (dipalmitoyl phosphatidylcholine), secreted by Type II pneumocytes, prevents this by:
  • Reducing surface tension at the air-alveolar interface.
  • Stabilising alveoli of different sizes - reduces surface tension more in smaller alveoli (counters Law of Laplace), preventing small alveoli from collapsing into larger ones.
• Without surfactant → alveoli collapse on every expiration → enormous work needed to re-inflate → breathing becomes impossible.
• Clinical example: Neonatal Respiratory Distress Syndrome (NRDS) in premature infants (<34 weeks) due to insufficient surfactant production.

Fetal Hemoglobin (HbF) Has Higher Affinity for Oxygen - Why?

1. Structure of HbF vs HbA

• The γ-chains differ structurally from β-chains at several amino acid positions.
• Ganong's Review of Medical Physiology, 26e

2. The Key Mechanism - Reduced Binding of 2,3-BPG

• 2,3-Bisphosphoglycerate (2,3-BPG) is an allosteric regulator present in red blood cells.
• In HbA, 2,3-BPG binds in the central cavity between the β-chains, stabilising the T-state (tense/deoxy form) → reduces O₂ affinity → shifts the dissociation curve to the right.
• In HbF, the γ-chains have Serine (Ser) at position H21 instead of Histidine (His) found in β-chains.
• Serine cannot form a salt bridge the way histidine can.
• Therefore, 2,3-BPG binds much more weakly to HbF than to HbA.
• Without strong 2,3-BPG binding, the T-state is less stabilised in HbF.
• HbF stays preferentially in the R-state (relaxed/oxy form) → higher affinity for O₂.
• Harper's Illustrated Biochemistry, 32e

3. Effect on the Oxygen-Dissociation Curve

• HbF's oxygen-dissociation curve is shifted to the LEFT compared to HbA.
• A left shift means: at any given PO₂, HbF carries more oxygen than HbA.
• HbF's P₅₀ (PO₂ at which Hb is 50% saturated) is lower (~19 mmHg) than HbA's P₅₀ (~27 mmHg).
• Morgan & Mikhail's Clinical Anesthesiology, 7e

4. Physiological Significance - O₂ Transfer Across the Placenta

• Fetal blood at the placenta has a PaO₂ of only 30-35 mmHg - far lower than maternal levels.
• At this low PO₂, maternal HbA (lower affinity) releases O₂ → fetal HbF (higher affinity) picks it up.
• This creates a continuous O₂ gradient from mother to fetus across the placenta.
• This mechanism is essential because the fetus cannot directly breathe air - it depends entirely on placental O₂ transfer.
• Additionally, HbF concentration is ~15 g/dL in the fetus (vs ~12 g/dL in the mother), further boosting O₂-carrying capacity.
• Ganong's Review of Medical Physiology, 26e; Morgan & Mikhail's Clinical Anesthesiology, 7e

5. Summary in One Line

HbF has higher O₂ affinity because its γ-chains bind 2,3-BPG poorly (Ser instead of His at H21), leaving HbF in the R-state (oxy-state) → left-shifted dissociation curve → essential for O₂ extraction from maternal blood at the placenta.