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Pancreatic Secretion

Overview

1. Aqueous (HCO3- rich) component - secreted by centroacinar and ductal cells
2. Enzymatic component - secreted by acinar cells

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Enzymatic Component (Acinar Cells)

Proteolytic Enzymes

• Trypsinogen is activated by enterokinase (enteropeptidase) secreted by intestinal mucosa, and also by autocatalysis (trypsin activating more trypsinogen)
• Trypsin then activates chymotrypsinogen and procarboxypeptidase

Carbohydrate-Digesting Enzyme

• Pancreatic amylase - hydrolyzes starch, glycogen (not cellulose) into disaccharides and trisaccharides

Fat-Digesting Enzymes

• Pancreatic lipase - hydrolyzes neutral fats into fatty acids and monoglycerides
• Cholesterol esterase - hydrolyzes cholesterol esters
• Phospholipase - splits fatty acids from phospholipids

Trypsin Inhibitor - Self-Protection Mechanism

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Aqueous (HCO3-) Component (Ductal Cells)

• Centroacinar and ductal cells secrete a Na+/HCO3--rich, isosmotic solution
• Function: Neutralizes the acidic chyme arriving from the stomach, bringing duodenal pH to ~7, which is optimal for pancreatic enzyme activity (especially lipase, which is inactivated at low pH)
• HCO3- secretion is directly proportional to flow rate - at high flow rates, HCO3- is ~150 mEq/L; at low flow rates, Cl- predominates

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Regulation of Pancreatic Secretion

• CCK and ACh act via IP3 / Ca2+ pathway on acinar cells
• Secretin acts via cAMP pathway on ductal cells

Triggers for Hormone Release:

• CCK release is stimulated by: amino acids (especially phenylalanine, methionine, tryptophan), small peptides, and fatty acids in the duodenum
• Secretin release is stimulated by: HCl (acidic chyme, pH < 4.5-5.0) in the duodenum; it is present as inactive prosecretin in S cells

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Phases of Pancreatic Secretion

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Inhibition of Pancreatic Secretion

• Peptide YY (from ileal endocrine cells) - inhibits secretion when fat reaches the distal small intestine (the "ileal brake")
• Somatostatin - inhibits secretion
• Sympathetic activity - inhibits pancreatic secretion (contrast: parasympathetic stimulates)

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1. Overview of Pancreatic Secretion

PANCREAS (Exocrine)
        │
        ├─────────────────────────────────────────┐
        │                                         │
   ACINAR CELLS                    CENTROACINAR + DUCTAL CELLS
        │                                         │
   ENZYMATIC COMPONENT                   AQUEOUS COMPONENT
   (Digestive enzymes)                   (HCO₃⁻ + Na⁺ + H₂O)
        │                                         │
        └──────────────┬──────────────────────────┘
                       │
              PANCREATIC DUCT
                       │
              COMMON BILE DUCT
                       │
             PAPILLA OF VATER
                       │
              DUODENUM (via Sphincter of Oddi)

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2. Enzymatic Component - Activation of Zymogens

ACINAR CELLS secrete INACTIVE ZYMOGENS
                │
    ┌───────────┼────────────────┐
    │           │                │
Trypsinogen  Chymotrypsinogen  Procarboxypeptidase
    │
    ▼
Reaches DUODENUM
    │
    ├──── Enterokinase (from intestinal mucosa) ──► TRYPSIN
    │
    └──── Autocatalysis (Trypsin activates itself)
                │
         TRYPSIN activates
                │
    ┌───────────┴───────────────┐
    │                           │
Chymotrypsinogen          Procarboxypeptidase
    │                           │
Chymotrypsin            Carboxypeptidase
    │                           │
(splits proteins           (releases free
 into peptides)             amino acids)

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
TRYPSIN INHIBITOR (secreted by acinar cells)
→ Inactivates any accidental trypsin inside the pancreas
→ Failure → ACUTE PANCREATITIS
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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3. Enzymes by Substrate

CARBOHYDRATES          PROTEINS               FATS
     │                    │                    │
Pancreatic Amylase     Trypsin             Pancreatic Lipase
     │                 Chymotrypsin        Cholesterol Esterase
     ▼                 Carboxypeptidase    Phospholipase
Disaccharides +            │                    │
Trisaccharides             ▼                    ▼
                      Peptides +          Fatty Acids +
                      Amino acids         Monoglycerides +
                                          Cholesterol

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4. Regulation - Stimuli & Second Messengers

FOOD IN DUODENUM
        │
   ┌────┴────────────────────────────────┐
   │                                     │
Amino acids / Peptides /            Acidic Chyme (pH < 4.5)
Fatty acids                               │
   │                                      │
   ▼                                      ▼
I cells (duodenum/jejunum)         S cells (duodenum/jejunum)
   │                                      │
  CCK released                      SECRETIN released
  into blood                          into blood
   │                                      │
   ▼                                      ▼
ACINAR CELLS                        DUCTAL CELLS
(CCK-A receptors)                  (Secretin receptors)
   │                                      │
IP₃ / Ca²⁺ pathway                   cAMP pathway
   │                                      │
   ▼                                      ▼
ENZYME SECRETION                  HCO₃⁻ + H₂O SECRETION
(Proteases, Lipase, Amylase)      (Neutralizes gastric acid)

        ↑ POTENTIATED BY ↑
        Acetylcholine (ACh)
        (Vagus nerve)
        Acts on BOTH acinar & ductal cells

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5. Phases of Pancreatic Secretion

MEAL INGESTION
      │
      ▼
CEPHALIC PHASE (~20% of enzyme output)
  Trigger: Sight / Smell / Taste / Thought of food
  Mediator: Vagus nerve → ACh
  Product: Mainly ENZYMES (little fluid)
      │
      ▼
GASTRIC PHASE (~5–10% of enzyme output)
  Trigger: Gastric distension
  Mediator: Vagal reflex → ACh
  Product: Mainly ENZYMES (little fluid)
      │
      ▼
INTESTINAL PHASE (~70–80% of total secretion) ← MOST IMPORTANT
  Trigger: Chyme enters duodenum
      │
      ├── H⁺ (acid) → Secretin → DUCTAL CELLS → HCO₃⁻ secretion
      │
      └── Amino acids / Fatty acids → CCK → ACINAR CELLS → ENZYME secretion
                                        + ACh (vagovagal reflex) potentiates both

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6. Inhibition of Pancreatic Secretion

Fat in DISTAL small intestine (ileum)
              │
              ▼
        Peptide YY (from ileal cells)
              │
              ▼
     INHIBITS pancreatic secretion
              │
        (also: Somatostatin)
              │
        (also: Sympathetic NS activity)

→ Signals end of intestinal phase of digestion
→ "ILEAL BRAKE" mechanism

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7. Summary - One Glance

STIMULUS → HORMONE/NERVE → CELL TYPE → SECOND MESSENGER → PRODUCT

 H⁺ in duodenum → SECRETIN (S cells) → Ductal cells → cAMP → HCO₃⁻ + H₂O

 AA/FA in duodenum → CCK (I cells) → Acinar cells → IP₃/Ca²⁺ → ENZYMES

 Sight/smell/distension → ACh (Vagus) → Both cells → IP₃/Ca²⁺/cAMP → ENZYMES + HCO₃⁻

 Fat in ileum → Peptide YY → ↓ Secretion (inhibition)

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Calcium Metabolism - Physiology (Flowcharts)

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1. Distribution of Calcium in the Body

TOTAL BODY CALCIUM (~1000 g)
           │
    ┌──────┴───────────────────────────┐
    │                                  │
  BONE (~99%)                  SOFT TISSUES (~1%)
  (Reservoir)                  Cells + ECF
    │                                  │
    ├─ Structural (99.6%)              ├─ Intracellular (~1%)
    │  (Hydroxyapatite)                └─ Extracellular fluid (~0.1%)
    └─ Exchangeable (0.4-1%)               ↓
       (CaHPO₄, amorphous salts)    Normal ECF = 9.4 mg/dL
       ← Rapid buffer pool               (2.4 mmol/L)

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2. Forms of Calcium in Plasma

TOTAL PLASMA CALCIUM (9.4 mg/dL)
              │
    ┌─────────┼──────────────────────┐
    │         │                      │
Protein-    Complexed            IONIZED Ca²⁺
bound       with anions          (50%) ← PHYSIOLOGICALLY ACTIVE
(41%)       (PO₄, citrate)
            (9%)

  ↑ Alkalosis → ↑ protein binding → ↓ free Ca²⁺ → Tetany
  ↓ Albumin → ↓ total Ca²⁺ (but ionized Ca²⁺ may be normal)

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3. Vitamin D Activation Pathway

SUNLIGHT (UV-B)
     │
     ▼
SKIN: 7-Dehydrocholesterol
     │
     ▼
Vitamin D₃ (Cholecalciferol) ← also from diet
     │
     ▼ (25-hydroxylase)
LIVER
     │
     ▼
25-Hydroxycholecalciferol (calcidiol) ← storage form; serum marker of Vit D status
     │
     ▼ (1α-hydroxylase) ← KEY REGULATORY STEP
KIDNEY
     │
     ├── STIMULATED by: ↓Ca²⁺, ↓PO₄, ↑PTH
     └── INHIBITED by: ↑Ca²⁺, ↑PO₄, ↑1,25-(OH)₂D₃ (feedback)
     │
     ▼
1,25-Dihydroxycholecalciferol (Calcitriol) ← ACTIVE FORM
     │
     ├── Intestine: ↑Ca²⁺ + PO₄ absorption (via calbindin)
     ├── Bone: ↑Ca²⁺ + PO₄ mobilization (with PTH)
     └── Kidney: ↑Ca²⁺ reabsorption (minor)

When Ca²⁺ is HIGH → 25-OH-D → 24,25-(OH)₂D (inactive form)

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4. PTH - Synthesis, Stimulus & Actions

↓ Plasma Ca²⁺ (< 9 mg/dL)
         │
         ▼
PARATHYROID GLANDS
(detect via CaSR - Calcium-Sensing Receptor)
         │
CaSR (G protein-coupled) senses ↓Ca²⁺
         │
         ▼
↑ PTH SECRETED (84 amino acid peptide)
Second messenger: cAMP
         │
    ┌────┴─────────────────────────────────────────┐
    │                 │                             │
  BONE              KIDNEY                    INTESTINE
    │                 │                             │
↑ Bone resorption   ↑ Ca²⁺ reabsorption      ↑ Ca²⁺ absorption
(Osteoclast         (distal tubule)           (INDIRECT - via
 activation via                               ↑1,25-(OH)₂D₃)
 RANKL/RANK)        ↓ PO₄ reabsorption
    │               (proximal tubule)
↑ Ca²⁺ + PO₄        ↑1α-hydroxylase
into blood           → ↑ Calcitriol
    │                 │
    └──────┬───────────┘
           ▼
     ↑ Plasma Ca²⁺
           │
     NEGATIVE FEEDBACK
           │
           ▼
     ↓ PTH secretion

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5. PTH Effects on Bone - Two Phases

PTH ACTS ON BONE
       │
  ┌────┴─────────────────────────────────────────────┐
  │                                                   │
RAPID PHASE (minutes-hours)          SLOW PHASE (days-weeks)
       │                                              │
Activates existing osteocytes              Proliferation of osteoclasts
+ osteoblasts (osteolysis)                        │
       │                              RANKL (from osteoblasts) + M-CSF
       ▼                                            │
Calcium pumped out of bone fluid                    ▼
into extracellular fluid              Osteoclast-mediated bone
                                      resorption (true resorption)
                                              │
                                      ↑↑ Ca²⁺ + PO₄ into blood

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6. Calcitonin - Counter-Regulatory Hormone

↑ Plasma Ca²⁺ (> 9-10 mg/dL)
         │
         ▼
THYROID GLAND (Parafollicular / C cells)
         │
         ▼
↑ CALCITONIN SECRETED (32 amino acid peptide)
         │
    ┌────┴────────────────────┐
    │                         │
  BONE                     KIDNEY
    │                         │
↓ Osteoclast activity     ↓ Ca²⁺ & PO₄
↓ Bone resorption         reabsorption (minor)
↑ Ca²⁺ deposition
    │
    ▼
↓ Plasma Ca²⁺

Note: Calcitonin effect is TRANSIENT and WEAK in adult humans
(PTH overrides with compensatory ↑)

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7. Calcium Balance - Daily Flux

DIETARY INTAKE: ~1000 mg/day
         │
         ▼
   INTESTINAL ABSORPTION (~350 mg absorbed, ~150 mg secreted back)
   Net absorption = 200 mg/day (regulated by Vit D)
         │
         ▼
EXTRACELLULAR FLUID POOL (~1300 mg)
         │
    ┌────┴───────────────────────┐
    │                            │
  BONE exchange               KIDNEY
  (500 mg/day in & out)   ~10,000 mg filtered/day
  (rapid buffer)          98% reabsorbed
    │                        ↓
    │                   ~200 mg excreted in urine
    │
    └── FECAL loss ~800 mg/day (unabsorbed + secreted)

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8. Renal Handling of Calcium

GLOMERULAR FILTRATION: ~59% of plasma Ca²⁺ filtered
(ionized 50% + complexed 9%)
         │
         ▼
PROXIMAL TUBULE (60-70% reabsorbed) ← passive, paracellular
         │
         ▼
LOOP OF HENLE (20% reabsorbed)
         │
         ▼
EARLY DISTAL TUBULE (10% reabsorbed)
         │
         ▼
LATE DISTAL TUBULE / COLLECTING DUCT (variable ~5-10%)
  ← THIS IS THE REGULATED STEP ←
  PTH → ↑ Ca²⁺ reabsorption
  ↑ Ca²⁺ → ↓ Ca²⁺ reabsorption
         │
         ▼
URINE: ~200 mg/day excreted

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9. Integrated Feedback Loop - Summary

         ↓ Ca²⁺ (hypocalcemia)
               │
        ┌──────┴──────────────────────────────┐
        │                                      │
  ↑ PTH secretion                    ↑ Calcitriol (1,25-OH₂D₃)
  (parathyroid)                      (kidney, stimulated by PTH)
        │                                      │
   ┌────┴──────────────┐               ┌───────┴────────────┐
   │                   │               │                    │
BONE               KIDNEY         INTESTINE              BONE
↑ Resorption    ↑ Ca²⁺ reabsorp  ↑ Ca²⁺ absorp       ↑ Ca²⁺ mob.
↑ Ca²⁺ into ECF ↓ PO₄ reabsorp
                                         │
                                         ▼
                                   ↑ PLASMA Ca²⁺ ← RESTORED
                                         │
                                   Negative feedback:
                                   CaSR on parathyroid →
                                   ↓ PTH → equilibrium restored

         ↑ Ca²⁺ (hypercalcemia)
               │
        ↑ Calcitonin (C cells of thyroid)
               │
        ↓ Osteoclast activity
        ↑ Ca²⁺ deposition in bone
               │
               ▼
        ↓ Plasma Ca²⁺ ← restored

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10. Key Hormones at a Glance

HORMONE     │ SOURCE          │ Trigger        │ Effect on Ca²⁺ │ Effect on PO₄
────────────────────────────────────────────────────────────────────────────────
PTH         │ Parathyroid     │ ↓ Ca²⁺         │ ↑ (raise)      │ ↓ (lower)
Calcitriol  │ Kidney (Vit D)  │ ↑ PTH / ↓Ca²⁺ │ ↑ (raise)      │ ↑ (raise)
Calcitonin  │ C cells/Thyroid │ ↑ Ca²⁺         │ ↓ (lower)      │ ↓ (lower)

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Calcium Metabolism - Physiology

1. Normal Values

• Total plasma calcium: 9.4 mg/dL (2.4 mmol/L)
• Only ionized Ca²⁺ (50%) is physiologically active
• The rest: protein-bound (41%) + complexed with anions (9%)
• Total body calcium: ~1000 g; 99% in bone, <1% in ECF

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2. Forms of Calcium in Plasma

Key point: Alkalosis → ↑ protein binding → ↓ free Ca²⁺ → tetany despite normal total Ca²⁺

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3. Vitamin D Activation

• ↓ Plasma Ca²⁺
• ↓ Plasma PO₄
• ↑ PTH

• Intestine → ↑ Ca²⁺ + PO₄ absorption (via calbindin synthesis)
• Bone → ↑ Ca²⁺ mobilization (with PTH)
• Kidney → ↑ Ca²⁺ reabsorption (minor)

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4. Parathyroid Hormone (PTH)

Actions of PTH:

PTH Bone Effects - Two Phases:

• Rapid (minutes-hours): Activates osteocytes → osteolysis (Ca²⁺ pumped out of bone fluid)
• Slow (days-weeks): Osteoclast proliferation via RANKL/RANK → true bone resorption

Feedback Control of PTH:

• ↓ Ca²⁺ → ↑ PTH → restores Ca²⁺ (negative feedback loop)
• Even a few % drop in Ca²⁺ can cause 100% increase in PTH
• Chronic low Ca²⁺ → parathyroid gland hypertrophy

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5. Calcitonin

Actions:

• Bone: ↓ osteoclast activity → ↓ bone resorption → ↑ Ca²⁺ deposition → ↓ plasma Ca²⁺
• Kidney: ↓ Ca²⁺ + PO₄ reabsorption (minor effect)

Important: Calcitonin effect is transient and weak in adult humans. PTH is the dominant regulator. Calcitonin is more significant in children and young animals.

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6. Daily Calcium Balance

• Kidneys filter ~10,000 mg/day; 98% reabsorbed
• The late distal tubule is the regulated step - controlled by PTH

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7. Bone as a Calcium Buffer

• Exchangeable calcium in bone = 0.4-1% of total bone calcium
• In the form of amorphous salts (CaHPO₄)
• Rapidly equilibrates with ECF Ca²⁺
• Acts as rapid buffer - restores Ca²⁺ within 30-60 minutes of sudden change

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8. Summary Table - Three Hormones

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9. Clinical Correlates (Exam Points)

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Brown-Séquard Syndrome

Definition

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Anatomy Basis - Why the Deficits Cross Sides

This explains why motor and proprioception loss are ipsilateral, but pain/temperature loss is contralateral.

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Classic Clinical Features

A. IPSILATERAL (same side as lesion) - BELOW the lesion:

B. CONTRALATERAL (opposite side) - 1-2 segments BELOW lesion:

The contralateral pain/temperature loss starts 1-2 dermatomes below the lesion because the spinothalamic fibers cross obliquely over 2-3 segments before ascending.

C. AT THE LEVEL of the lesion (ipsilateral):

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Summary Diagram (Lesion on RIGHT side)

        RIGHT-SIDED HEMISECTION
                │
    ┌───────────┴─────────────────────────┐
    │ IPSILATERAL (Right)                 │ CONTRALATERAL (Left)
    │                                     │
    │ ↓ Motor (UMN) - spastic paralysis   │ ↓ Pain sensation
    │ ↓ Proprioception                    │ ↓ Temperature sensation
    │ ↓ Vibration sense                   │ (1-2 levels below lesion)
    │ ↓ Fine touch / 2-point disc.        │
    │                                     │
    │ AT LEVEL: LMN signs + anesthesia    │
    └─────────────────────────────────────┘

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Causes / Etiology

• Most common spinal level: cervical spine
• Accounts for 1-4% of all traumatic spinal cord injuries

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BSS vs BSS-Plus

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Prognosis

• Best prognosis among all incomplete spinal cord injury syndromes
• Most patients regain bowel and bladder continence
• Good ambulation recovery, especially if upper extremity weakness predominates over lower extremity
• Recovery may occur instantaneously or in delayed fashion

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Comparison with Other Spinal Cord Syndromes

Memory aid: In Brown-Séquard - "Motor and Proprioception stay home (ipsilateral); Pain crosses the road (contralateral)"

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Treatment of Brown-Séquard Syndrome

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1. Immediate / Pre-hospital Management

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2. Pharmacological Treatment

Methylprednisolone (Controversial)

• NASCIS II & III trials: High-dose methylprednisolone within 8 hours of injury showed modest neurological benefit in post-hoc analysis
• Dose: 30 mg/kg IV bolus → followed by 5.4 mg/kg/hr infusion for 23 hours (if given within 3 hrs) or 48 hours (if given 3-8 hrs after injury)
• Complications: Pneumonia, sepsis, poor wound healing, GI bleeding
• Current guideline (Level I recommendation): Most recent guidelines recommend AGAINST routine corticosteroid use in acute SCI
• Note: Excluded in - gunshot wounds, cauda equina injury, pregnancy, age <14, patients on chronic steroids

Other

• Analgesics - for neuropathic pain (gabapentin, pregabalin, amitriptyline)
• Baclofen / Tizanidine - for spasticity
• Anticoagulation - DVT prophylaxis (heparin, LMWH) once bleeding risk is controlled
• Bladder medications - oxybutynin for neurogenic bladder

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3. Spinal Stabilization (Orthotic)

---

4. Surgical Treatment

1. Decompression of the spinal cord and nerve roots
2. Stabilization of the spine

Indications for Surgery:

• Incomplete SCI with neurological deterioration
• Compressive lesion (herniated disc, epidural hematoma, tumor, bone fragment)
• Unstable spine fracture / fracture-dislocation
• BSS due to non-traumatic compressible cause (disc, tumor)

Timing:

• Early surgery (<24 hours) is now preferred - the STASCIS trial showed significantly better ASIA grade improvement at 6 months with early decompression (<24 hrs) vs late (>24 hrs)
• Emergent surgery if neurological deterioration is ongoing
• Prior guideline of "wait for medically stable" is being replaced by early operative approach in incomplete injuries like BSS

Types of Surgery (depending on cause):

• Anterior cervical discectomy & fusion (ACDF) - for disc herniation causing BSS
• Laminectomy ± fusion - for posterior compressive pathology
• Tumor resection - if cause is spinal cord tumor
• Hematoma evacuation - for epidural/subdural hematoma

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5. Treatment of Cause-Specific BSS

---

6. Complication Management

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7. Rehabilitation (Most Important for BSS)

Rehabilitation Goals:

• Restore ambulatory function (majority of BSS patients walk independently)
• Bladder and bowel continence
• Upper limb dexterity recovery
• Sensory re-training for the contralateral side (pain/temp loss)
• Psychological support and vocational rehabilitation

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8. Prognosis After Treatment

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Summary Flow

BROWN-SÉQUARD SYNDROME DIAGNOSED
              │
    ┌─────────┴──────────────────────────┐
    │                                    │
IMMEDIATE                          DEFINITIVE
    │                                    │
Immobilize spine                 Identify CAUSE (MRI)
ABC management                          │
Prevent 2° injury               ┌───────┴─────────────┐
    │                           │                      │
Corticosteroids?           SURGICAL                NON-SURGICAL
(controversial,         Decompression +         (MS → steroids,
 within 8hrs            Stabilization           Infection → Abx,
 if used)               (<24hrs preferred)      Vascular → support)
              │
    COMPLICATION MANAGEMENT
              │
    REHABILITATION (Physio + OT + Psychology)
              │
    RECOVERY (Best prognosis of all SCI syndromes)

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