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📚 Biochemistry & Nutrition — Complete Study Notes

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SECTION A: SHORT NOTES / SAQs

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1. Calcium Homeostasis

Three Hormones Regulate Calcium:

Feedback Loop:

• Low Ca²⁺ → ↑ PTH → ↑ bone resorption + ↑ renal Ca²⁺ reabsorption + ↑ calcitriol synthesis → ↑ Ca²⁺
• High Ca²⁺ → ↓ PTH, ↑ calcitonin → ↓ Ca²⁺

Key Points:

• PTH acts via cAMP (Gs protein)
• 80% of filtered Ca²⁺ reabsorbed in proximal tubule (PTH-independent); 20% in DCT/TAL (PTH-dependent)
• Ca²⁺ exists in three forms: ionized (50%), protein-bound (40%), complexed (10%)
• Acidosis ↑ ionized Ca²⁺ (H⁺ displaces Ca²⁺ from albumin); alkalosis ↓ ionized Ca²⁺ → tetany

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2. Urea Cycle Diagram

Steps:

MITOCHONDRIA:
1. NH₄⁺ + HCO₃⁻ + 2ATP → Carbamoyl phosphate  (CPS-I; cofactor: N-acetylglutamate)
2. Carbamoyl phosphate + Ornithine → Citrulline  (OTC)

CYTOSOL:
3. Citrulline + Aspartate + ATP → Argininosuccinate  (ASS)
4. Argininosuccinate → Arginine + Fumarate  (ASL)
5. Arginine → Ornithine + UREA  (Arginase)
   → Ornithine re-enters mitochondria

Energy Cost: 3 ATP per urea molecule (4 high-energy bonds)

Key Points:

• Net reaction: 2NH₄⁺ + CO₂ → Urea + H₂O
• Fumarate links urea cycle to TCA cycle (Krebs cycle connection)
• N-acetylglutamate (from glutamate + acetyl-CoA) is allosteric activator of CPS-I
• Enzyme deficiencies → hyperammonemia; OTC deficiency is most common (X-linked)

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3. Iron Absorption & Mucosal Block Theory

Dietary Iron Forms:

• Heme iron (Fe²⁺ from meat) — absorbed directly by HCP-1 (heme carrier protein); more bioavailable (~25%)
• Non-heme iron (Fe³⁺) — must be reduced to Fe²⁺ by duodenal cytochrome b (DcytB) before absorption

Steps of Absorption:

Lumen (duodenum/upper jejunum):
Fe³⁺ → Fe²⁺ (DcytB, Vit C helps)
Fe²⁺ → enters mucosal cell via DMT-1 (Divalent Metal Transporter-1)

Inside mucosal cell:
Fe²⁺ → stored as FERRITIN (mucosal ferritin)
      OR → exported via FERROPORTIN → oxidized to Fe³⁺ by HEPHAESTIN
         → binds TRANSFERRIN in blood

Mucosal Block Theory (Granick, 1946):

• When body iron stores are high → mucosal cells are pre-loaded with ferritin (apoferritin already saturated)
• Incoming Fe²⁺ is trapped as mucosal ferritin inside cells
• As mucosal cells turn over (~3 days), iron is lost in feces → "mucosal block" prevents excess absorption

Modern Understanding (Hepcidin):

• High iron/inflammation → liver releases HEPCIDIN
• Hepcidin degrades FERROPORTIN → iron trapped in mucosal cells + macrophages
• Hepcidin is the master regulator (mucosal block theory is now understood at this molecular level)

Enhancers: Vitamin C (reduces Fe³⁺→Fe²⁺), acidic pH, meat/fish

Inhibitors: Phytates, oxalates, tannins, antacids, calcium

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4. Lesch-Nyhan Syndrome & Orotic Aciduria

Lesch-Nyhan Syndrome

1. Hyperuricemia + gout (uric acid stones, tophi)
2. Neurological: intellectual disability, spasticity, choreoathetosis
3. Self-mutilation (characteristic — biting fingers/lips)

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Orotic Aciduria (Hereditary)

• Megaloblastic anemia (not responsive to B12 or folate)
• Failure to thrive
• Orotic acid crystals in urine (orange)

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5. Products Obtained from Glycine

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6. Purine Catabolism

ADENINE → Hypoxanthine
              ↓ (xanthine oxidase)
           Xanthine ←── GUANINE → Xanthine
              ↓ (xanthine oxidase)
           URIC ACID
              ↓ (uricase — absent in humans)
           Allantoin (in most mammals)

• Men: 3.5–7.0 mg/dL
• Women: 2.5–6.0 mg/dL

• Salvage pathway (HGPRT) recycles hypoxanthine + guanine → reduces uric acid production
• PRPP (phosphoribosyl pyrophosphate) is substrate for both de novo synthesis and salvage

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7. Transamination & Deamination

Transamination

Amino acid₁ + α-keto acid₂  ⇌  α-keto acid₁ + Amino acid₂

Oxidative Deamination

Glutamate + NAD⁺ → α-Ketoglutarate + NH₄⁺ + NADH
(enzyme: Glutamate dehydrogenase, in liver mitochondria)

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8. Van den Bergh Reaction

Types of Jaundice:

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SECTION B: CLINICAL NUTRITION

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9. Kwashiorkor & Marasmus

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10. Phenylketonuria (PKU)

• Intellectual disability (most serious)
• Seizures (infantile spasms)
• Hypopigmentation (blonde hair, blue eyes, fair skin) — phenylalanine competes with tyrosine for melanin synthesis
• Eczema
• "Mousy" urine odor (phenylacetate)
• Microcephaly

• Low phenylalanine diet (avoid high-protein foods, aspartame)
• Tyrosine supplementation (becomes essential)
• BH₄ (sapropterin) for BH₄-responsive PKU

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11. Rickets

Biochemical Features:

• ↓ Serum Ca²⁺ and PO₄
• ↑ ALP (alkaline phosphatase) — marker of osteoblast activity
• ↑ PTH (secondary hyperparathyroidism)
• ↓ 25-OH Vit D (nutritional)

Clinical Features:

• Craniotabes — softening of skull (earliest sign)
• Frontal bossing — prominent forehead
• Rachitic rosary — beading at costochondral junctions
• Harrison's sulcus — groove at diaphragm attachment to ribs
• Pigeon chest / Pectus carinatum
• Bow legs (genu varum) or knock knees (genu valgum)
• Widened epiphyses (wrists, ankles) — "double malleolus"

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12. Scurvy (Vitamin C Deficiency)

• Water-soluble antioxidant
• Cofactor for proline hydroxylase and lysine hydroxylase (collagen cross-linking)
• Required for: collagen synthesis, norepinephrine synthesis, carnitine synthesis, iron absorption (reduces Fe³⁺→Fe²⁺), tyrosine metabolism

Clinical Features of Scurvy:

• Pseudoparalysis (pain on movement → child holds legs in "frog-leg" position)
• Tender swollen limbs
• "Corner sign" / Trümmerfeld zone on X-ray

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13. Trousseau's Sign (not "Troseas")

• Hypoparathyroidism (post-thyroidectomy most common)
• Vitamin D deficiency
• Hypomagnesemia
• Chronic renal failure
• Pancreatitis (Ca²⁺ saponification)
• Alkalosis (↓ ionized Ca²⁺)

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SECTION C: ESSAYS

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ESSAY 1: Vitamin D

Chemistry & Forms:

• Vitamin D₂ (ergocalciferol) — plant-derived
• Vitamin D₃ (cholecalciferol) — animal-derived; synthesized in skin from 7-dehydrocholesterol under UV-B (290–315 nm)

Synthesis & Activation:

7-dehydrocholesterol (skin) --UV-B--> Cholecalciferol (Vit D₃)
                                          ↓ (liver 25-hydroxylase)
                                     25-hydroxycholecalciferol [25(OH)D₃] — Storage form
                                          ↓ (kidney 1α-hydroxylase)
                                    1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] — ACTIVE FORM (Calcitriol)

Mechanism of Action:

• Calcitriol binds Vitamin D Receptor (VDR) → nuclear receptor
• VDR-RXR heterodimer → binds VDRE (Vit D response elements) → transcription
• Fat-soluble → stored in adipose and liver

Physiological Actions:

Deficiency:

• Children: Rickets (see above)
• Adults: Osteomalacia (soft bones without skeletal deformity)
• Elderly: Osteoporosis + myopathy

Toxicity (Hypervitaminosis D):

• Hypercalcemia → nausea, vomiting, polyuria, nephrocalcinosis, metastatic calcification
• Ectopic calcification (vessels, kidneys, lungs)

Daily Requirement: 400–800 IU (10–20 µg); serum 25(OH)D: optimal 30–50 ng/mL

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ESSAY 2: Vitamin C (Ascorbic Acid)

Chemistry:

• L-Ascorbic acid — C₆H₈O₆; enediol structure
• Exists as ascorbate at physiological pH
• Easily oxidized → dehydroascorbic acid (reversible); further oxidation → irreversible (2,3-diketogulonic acid)
• Water-soluble; heat-labile; destroyed by alkali

Sources:

• Citrus fruits (oranges, lemons), guava (highest), amla (Indian gooseberry — richest natural source), tomatoes, capsicum, green vegetables

Biochemical Functions:

• Hydroxylation of proline → hydroxyproline; lysine → hydroxylysine
• Enzymes: Prolyl hydroxylase & lysyl hydroxylase (require Fe²⁺ and ascorbate as cofactor)
• Hydroxyproline stabilizes triple helix; hydroxylysine forms cross-links

• Reduces Fe³⁺ → Fe²⁺ in intestinal lumen → ↑ non-heme iron absorption

• Scavenges free radicals; regenerates Vitamin E

• Dopamine β-hydroxylase (adrenal medulla) requires ascorbate → dopamine → norepinephrine

• Required for two hydroxylation steps; carnitine needed for fatty acid transport into mitochondria

• p-HPPD (p-hydroxyphenylpyruvate dioxygenase) requires Vit C

• Required in adrenal cortex (high concentration in adrenal gland)

• ↑ WBC function, interferon synthesis

Daily Requirement:

• Adults: 60–90 mg/day; Smokers: +35 mg; Pregnancy: +10 mg; Lactation: +45 mg

Deficiency — Scurvy (see above)

Toxicity (> 2 g/day):

• Diarrhea, oxalate kidney stones (metabolized to oxalate)
• Can interfere with Vit B12 absorption at high doses

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ESSAY 3: Vitamin B12 (Cobalamin)

Chemistry:

• Largest and most complex vitamin
• Contains cobalt (Co³⁺) at center of corrin ring
• Forms: Methylcobalamin (plasma), 5'-Deoxyadenosylcobalamin (mitochondria), Hydroxocobalamin, Cyanocobalamin (therapeutic)

Absorption:

Dietary B12 (protein-bound) → gastric acid + pepsin → free B12
                → binds R-protein (haptocorrin) in saliva
                → pancreatic protease degrades R-protein
                → B12 binds Intrinsic Factor (IF, secreted by parietal cells)
                → B12-IF complex → ileum (specific receptor: Cubilin)
                → transported by Transcobalamin II (TC-II) in blood

Metabolic Functions:

• Methionine synthase: Homocysteine + methyl-THF → Methionine + THF
• "Folate trap": Without B12, THF cannot be regenerated → methyl-THF accumulates useless → functional folate deficiency (explains megaloblastic anemia)
• ↑ Homocysteine (cardiovascular risk)

• Methylmalonyl-CoA mutase: Methylmalonyl-CoA → Succinyl-CoA (enters TCA)
• Deficiency → ↑ Methylmalonic acid (MMA) in blood and urine
• ↑ MMA → myelin sheath disruption → Subacute Combined Degeneration of Spinal Cord (SACD)

Clinical Features of B12 Deficiency:

• Megaloblastic (macrocytic) anemia
• Hypersegmented neutrophils (≥5 lobes)
• Pancytopenia in severe cases

• SACD — demyelination of posterior and lateral columns
• Posterior columns → loss of proprioception, vibration sense
• Lateral columns (corticospinal) → spastic paraparesis, upper motor neuron signs
• Peripheral neuropathy (paresthesias, glove-stocking)

• Glossitis (beefy red, smooth tongue)
• Hyperpigmentation of skin
• Infertility

Causes of B12 Deficiency:

Diagnosis:

• Serum B12 < 200 pg/mL
• ↑ MMA (sensitive and specific) — rises before anemia
• ↑ Homocysteine (also ↑ in folate deficiency)
• Schilling test (historical): distinguishes pernicious anemia from dietary deficiency

Treatment:

• IM hydroxocobalamin (1 mg) or cyanocobalamin
• High-dose oral B12 (1000 µg/day) works even without IF (passive absorption ~1%)

Daily Requirement: 2–3 µg/day; stores last 3–5 years

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ESSAY 4: Calcium

Distribution:

• Total body calcium: ~1,000 g (99% in bone as hydroxyapatite)
• Serum Ca²⁺: 8.5–10.5 mg/dL
  • Ionized (free, active): 50%
  • Protein-bound (mainly albumin): 40%
  • Complexed (with citrate, phosphate): 10%

Dietary Sources & Requirements:

Absorption (intestinal):

• Active transport (saturable, Vit D-dependent): Duodenum → via TRPV6, calbindin
• Passive diffusion: Jejunum/ileum (when intake is high)
• Enhanced by: Vit D, acidic pH, lactose, amino acids
• Inhibited by: Phytates, oxalates, high fat (calcium soaps), alkaline pH

Functions:

1. Bone mineralization — as hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂]
2. Muscle contraction — Ca²⁺ binds troponin C → actin-myosin interaction
3. Nerve conduction — membrane stabilization; ↓Ca²⁺ → ↑excitability
4. Blood coagulation — Factor IV; required in multiple clotting reactions
5. Enzyme activation — Calmodulin-Ca²⁺ activates phosphodiesterase, kinases
6. Exocytosis/secretion — Triggers neurotransmitter release, hormone secretion
7. Cell signaling — Second messenger (IP₃ pathway)
8. Cardiac pacemaker activity and cardiac contractility

Regulation: (see Calcium Homeostasis above — PTH, Calcitriol, Calcitonin)

Hypocalcemia:

• Causes: hypoparathyroidism, Vit D deficiency, CRF, pancreatitis, hypomagnesemia
• Features: Tetany, seizures, Trousseau's sign, Chvostek's sign, prolonged QTc, cataracts, papilledema

Hypercalcemia:

• Causes: Hyperparathyroidism, malignancy (PTHrP), Vit D toxicity, sarcoidosis, immobilization
• Features: "Bones, groans, stones, psychic moans" — bone pain, constipation, kidney stones, depression/confusion
• Treatment: IV fluids (saline), loop diuretics, bisphosphonates, calcitonin, cinacalcet

Excretion:

• Kidney: ~98% filtered Ca²⁺ reabsorbed (PTH ↑ DCT reabsorption)
• Feces: Unabsorbed dietary Ca²⁺ + secreted Ca²⁺

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Quick-Revision Summary Table

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📚 Biochemistry Master Notes — Complete Exam Preparation

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MODULE 1: MINERALS

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ESSAY: IRON

Body Iron Distribution:

Absorption (duodenum/upper jejunum):

Fe³⁺ (dietary) → Fe²⁺ by DcytB (duodenal cytochrome b; Vit C assists)
Fe²⁺ enters mucosal cell via DMT-1 (divalent metal transporter-1)
Inside cell: stored as FERRITIN or exported via FERROPORTIN → re-oxidized by HEPHAESTIN → Fe³⁺
Fe³⁺ binds TRANSFERRIN (apotransferrin + 2 Fe³⁺ = transferrin)

Mucosal Block Theory (Granick):

• Body iron replete → apoferritin already saturated → incoming Fe²⁺ trapped as mucosal ferritin → lost when enterocyte sloughs (every ~3 days)
• Modern master regulator = HEPCIDIN (liver peptide)
  • High iron/inflammation → ↑ hepcidin → degrades ferroportin → iron trapped → ↓ absorption

Transport:

• Transferrin: plasma glycoprotein; carries Fe³⁺; 2 binding sites; normally 33% saturated
• TIBC (total iron-binding capacity) = transferrin capacity; ↑ in iron deficiency
• Transferrin receptor (TfR): takes up Fe-transferrin by endocytosis; regulated by IRE-IRP system

Storage:

• Ferritin: water-soluble; 24 subunits (apoferritin shell); stores up to 4500 Fe atoms; ↑ in iron overload/inflammation (acute phase reactant)
• Hemosiderin: insoluble, degraded ferritin aggregates; seen in iron overload

Functions of Iron:

1. Oxygen transport (Hb, Mb)
2. Electron transport chain (cytochromes b, c, c1, a, a3)
3. Enzyme cofactor: catalase, peroxidase, ribonucleotide reductase, prolyl hydroxylase
4. Thyroid peroxidase (thyroid hormone synthesis)
5. Immune function

Regulation by IRE-IRP System:

• Low iron: IRP binds IRE on TfR mRNA (5' UTR) → ↑ TfR (↑ iron uptake); IRP on ferritin mRNA (5' UTR) → blocks translation (↓ storage)
• High iron: IRP dissociates → ↑ ferritin synthesis, ↓ TfR

Iron Deficiency Anemia:

• Stages: ↓ stores (↓ ferritin) → ↓ transport (↓ serum Fe, ↑ TIBC) → ↓ Hb (microcytic hypochromic anemia)
• Features: fatigue, pallor, koilonychia (spoon nails), angular stomatitis, glossitis, PICA, Plummer-Vinson syndrome

Hemochromatosis (Iron Overload):

• Hereditary: HFE gene mutation (C282Y most common); AR; ↓ hepcidin → ↑ absorption
• Features: "Bronze diabetes" — liver cirrhosis, diabetes mellitus, skin bronzing, cardiomyopathy, hypogonadism, arthropathy
• Treatment: Phlebotomy; deferoxamine (chelation)

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ESSAY: CALCIUM

• Albumin correction: For every 1 g/dL ↓ albumin, add 0.8 mg/dL to measured Ca²⁺
• Calcium × Phosphate product: Should be < 55 mg²/dL² (higher → ectopic calcification)
• Milk-alkali syndrome: Excess Ca²⁺ + antacid intake → hypercalcemia + metabolic alkalosis + nephrocalcinosis

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SHORT NOTE: FLUOROSIS

Dental Fluorosis (chronic, childhood):

• Mottled, chalky-white, brown/pitted enamel
• Fluoride displaces hydroxyl in hydroxyapatite → fluoroapatite (harder but brittle)
• Severity graded (Dean's index): questionable → very mild → mild → moderate → severe

Skeletal Fluorosis (> 8 mg/day for years):

• Osteosclerosis (↑ bone density paradoxically)
• Stages:
  1. Preclinical: ↑ bone density on X-ray, no symptoms
  2. Clinical: joint pain, stiffness, valgus deformity
  3. Crippling fluorosis: calcification of ligaments, kyphosis, neurological compression

Endemic fluorosis:

• High fluoride in groundwater (common in parts of India — Rajasthan, AP, Gujarat)
• Teeth of children born in endemic area most affected

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SHORT NOTE: MENKES SYNDROME (Kinky Hair Disease)

• Kinky (pili torti) — steely, twisted, depigmented hair (pathognomonic)
• Neurodegeneration (seizures, hypotonia, developmental regression)
• Connective tissue abnormalities (lax skin, vascular tortuosity)
• Hypothermia, failure to thrive
• Death in early childhood

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SHORT NOTE: WILSON'S DISEASE (Hepatolenticular Degeneration)

• ↓ Serum ceruloplasmin (< 20 mg/dL) — most useful screening test
• ↓ Total serum copper (copper bound to ceruloplasmin ↓)
• ↑ Free (non-ceruloplasmin) copper — toxic
• ↑ 24-hour urine copper (> 100 µg/day) — diagnostic
• ↑ Hepatic copper (> 250 µg/g dry weight) — gold standard

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SHORT NOTE: POTASSIUM HOMEOSTASIS

Regulators of K⁺ distribution (internal homeostasis):

External K⁺ balance (kidney):

• Principal cells (CCD): Na⁺ reabsorption via ENaC → lumen negative → K⁺ secreted via ROMK
• Aldosterone (main regulator): ↑ ENaC + ↑ Na⁺-K⁺-ATPase → ↑ K⁺ secretion
• High urinary flow rate → ↑ K⁺ secretion
• High dietary K⁺ → ↑ K⁺ secretion

Hypokalemia (< 3.5 mEq/L):

• Causes: Diarrhea, vomiting, diuretics, hyperaldosteronism, insulin overdose, alkalosis
• Features: Muscle weakness, cramps, U waves on ECG, paralytic ileus, polyuria (NDI)

Hyperkalemia (> 5.0 mEq/L):

• Causes: CKD, Addison's disease, ACE inhibitors, K⁺-sparing diuretics, acidosis, cell lysis (rhabdomyolysis)
• Features: Peaked T waves → wide QRS → sine wave → VF/asystole; muscle weakness, paresthesias

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SHORT NOTE: FUNCTIONS OF ZINC

Functions:

Zinc Deficiency:

• Acrodermatitis enteropathica (genetic; SLC39A4 mutation — ↓ intestinal zinc transporter)
• Features: Dermatitis (perioral, perinasal, perianal), alopecia, diarrhea, growth retardation, hypogonadism, hypogeusia/anosmia, impaired wound healing, immune deficiency, night blindness

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MODULE 2: NUCLEOTIDES

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De Novo Synthesis of Purines

10-Step Pathway (building the purine ring on PRPP):

• C2, C8 — Formate (via N¹⁰-formyl-THF) → requires folate
• N1 — Aspartate
• N3, N9 — Glutamine
• C4, C5, N7 — Glycine (entire unit)
• C6 — CO₂

• IMP → AMP (via adenylosuccinate; uses GTP)
• IMP → GMP (via IMP dehydrogenase; uses ATP)

Salvage Pathway:

• HGPRT: Hypoxanthine + PRPP → IMP; Guanine + PRPP → GMP
• APRT: Adenine + PRPP → AMP
• Deficiency of HGPRT → Lesch-Nyhan syndrome

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Catabolism of Purines

AMP → Adenosine → Inosine → Hypoxanthine ─┐
                                            ├→ Xanthine → Uric acid
GMP → Guanosine → Guanine ─────────────────┘
                  (xanthine oxidase)         (xanthine oxidase)

• Normal: Men < 7 mg/dL; Women < 6 mg/dL
• Urate solubility limit: ~6.8 mg/dL at 37°C (lower in cooler joint spaces)

• Adenosine deaminase (ADA): Adenosine → Inosine; deficiency → SCID (T & B cell loss)
• Purine nucleoside phosphorylase (PNP): Inosine → Hypoxanthine; deficiency → T-cell SCID
• Xanthine oxidase: last 2 steps; inhibited by allopurinol

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Gout & Hyperuricemia

Classification of Hyperuricemia:

Pathogenesis of Gouty Arthritis:

Crystal characteristics:

• MSU (gout): Needle-shaped, negatively birefringent (yellow parallel, blue perpendicular to slow vibration)
• CPPD (pseudogout): Rhomboid-shaped, positively birefringent

Clinical Stages:

1. Asymptomatic hyperuricemia
2. Acute gouty arthritis (podagra — 1st MTP joint most common)
3. Intercritical gout
4. Chronic tophaceous gout

Treatment:

• Acute: NSAIDs (indomethacin), colchicine (inhibits tubulin polymerization → ↓ neutrophil migration), corticosteroids
• Chronic: Allopurinol (XO inhibitor), Febuxostat (XO inhibitor, non-purine), Uricosurics (probenecid — blocks URAT1)
• Rasburicase (recombinant uricase): tumor lysis prophylaxis

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Regulation of Pyrimidine Synthesis

Steps:

Glutamine + CO₂ + 2ATP → Carbamoyl phosphate  [CPS-II: cytosol, rate-limiting]
Carbamoyl phosphate + Aspartate → Carbamoyl aspartate
→ Dihydroorotate → Orotate (by DHO dehydrogenase; mitochondrial)
→ Orotate + PRPP → OMP  [OPRT]
→ OMP → UMP  [ODC]
→ UMP → UDP → UTP → CTP (by CTP synthetase)

Regulation:

Pyrimidine salvage:

• Thymidine kinase: dThymidine → dTMP (important in cell cycle; target of antiviral/anticancer drugs)
• Uridine kinase

Orotic Aciduria: UMP synthase deficiency (OPRT + ODC); orotic acid accumulates → megaloblastic anemia, no response to B12/folate; treat with uridine

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MODULE 3: NUTRITION

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Respiratory Quotient (RQ)

• RQ < 0.7: starvation/ketosis or fat being synthesized into ketones
• RQ used to design enteral/parenteral nutrition (↓ carbohydrate in ventilated patients to ↓ CO₂ production)

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Dietary Fibres

Types:

Physiological Effects:

1. ↓ Serum LDL cholesterol (soluble fibre binds bile acids → ↓ enterohepatic recirculation → liver uses cholesterol for new bile acids)
2. ↓ Postprandial blood glucose (↓ glycaemic index; slows gastric emptying)
3. ↓ Constipation (↑ stool bulk, ↓ transit time)
4. ↓ Colorectal cancer risk (↓ transit time → ↓ carcinogen contact; ↑ butyrate from fermentation → colonocyte fuel + anti-cancer)
5. ↑ Satiety → ↓ obesity risk
6. Fermentation → Short-chain fatty acids (SCFA: butyrate, propionate, acetate) → colonocyte energy

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BMR and Affecting Factors

Factors Affecting BMR:

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Nitrogen Balance

• 6.25 g protein = 1 g nitrogen

Factors Affecting Nitrogen Balance:

• Adequate calorie intake (protein-sparing effect)
• Complete proteins (all EAAs present)
• Growth hormone, testosterone, insulin
• Convalescence

• Protein deficiency or high catabolism
• Trauma, infection, burns (↑ glucocorticoids → ↑ protein catabolism)
• Immobilization
• Glucocorticoid excess

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Protein Energy Malnutrition (PEM)

Marasmic Kwashiorkor:

• Combined features of both; most severe form
• Edema present + severe wasting

Assessment:

• Mid-upper arm circumference (MUAC): < 115 mm = severe acute malnutrition
• Weight-for-height (WHZ): < -3 SD = severe wasting
• MUAC < 125 mm + edema = SAM requiring hospitalization

Biochemical markers:

• Visceral proteins (short half-life — best for monitoring):
  • Retinol-binding protein (t½ 12h) → most sensitive
  • Prealbumin/Transthyretin (t½ 2 days) → commonly used
  • Transferrin (t½ 8 days)
  • Albumin (t½ 21 days) → least sensitive but most commonly measured

Complications: Hypoglycemia, hypothermia, infection, electrolyte imbalance (refeeding syndrome risk)

Refeeding Syndrome:

• Rapid refeeding after starvation → insulin surge → K⁺, PO₄, Mg²⁺ shift into cells → severe electrolyte deficiencies → cardiac arrhythmia, respiratory failure

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Obesity

• Overweight: BMI 25–29.9
• Obese class I: 30–34.9; class II: 35–39.9; class III (morbid): ≥ 40

• Energy intake > expenditure → excess stored as triglycerides in adipocytes
• Genetic (~40–70% heritability); FTO gene, MC4R mutations
• Leptin: adipokine that signals satiety to hypothalamus; obesity → leptin resistance (↑ leptin, but receptors desensitized)
• Ghrelin (stomach): hunger hormone; ↑ pre-meal, ↓ post-meal

• Metabolic: T2DM (insulin resistance), dyslipidemia (↑ TG, ↓ HDL)
• Cardiovascular: HTN, atherosclerosis, heart failure
• NAFLD/NASH
• Obstructive sleep apnea
• Osteoarthritis
• Malignancy (endometrial, breast, colon, kidney)
• PCOS, infertility

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Glycemic Index (GI)

• GL accounts for portion size; better predictor of glucose response

• ↓ GI: fibre, fat, protein, vinegar, intact grain structure, al dente cooking, fructose
• ↑ GI: refined/processed foods, high amylopectin content, overripe fruits, hot temperature

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Limiting Amino Acid

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MODULE 4: VITAMINS

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Vitamin A (Retinol)

Forms:

• Retinol (alcohol) — transport/storage
• Retinal (aldehyde) — visual cycle
• Retinoic acid — gene regulation
• β-carotene (provitamin A, plants) — 6 µg β-carotene = 1 µg retinol

Functions:

1. Vision: 11-cis-retinal + opsin → rhodopsin (rod cells); photoisomerization → visual signal; night vision
2. Gene expression: Retinoic acid binds RAR (retinoic acid receptor, a zinc finger protein) → transcription of differentiation genes
3. Epithelial integrity: Maintains mucus-secreting epithelia (→ prevents keratinization)
4. Immune function: T-cell maturation, antibody production
5. Reproduction: Spermatogenesis, fetal development
6. Antioxidant (β-carotene)

Visual Cycle:

β-carotene → retinol → retinal (all-trans)
all-trans retinal → 11-cis retinal (retinal isomerase, in RPE)
11-cis retinal + opsin → RHODOPSIN
Light → rhodopsin → metarhodopsin II (all-trans retinal released)
→ transducin → ↓ cGMP → closes Na⁺ channels → hyperpolarization → signal

Deficiency:

• Night blindness (nyctalopia) — earliest symptom
• Xerophthalmia: dryness of conjunctiva → Bitot's spots (foamy gray triangular patches on conjunctiva) → xerosis cornea → corneal ulceration → keratomalacia → blindness
• Follicular hyperkeratosis (skin — "phrynoderma")
• ↑ Infections (↓ mucosal defense, ↓ immune function)

Toxicity (Hypervitaminosis A):

• Acute: Headache (↑ ICP), vomiting, skin peeling
• Chronic: Hepatotoxicity, alopecia, dry skin, periosteal hyperostosis (bone pain), pseudotumor cerebri
• Teratogenic: Neural tube defects, craniofacial abnormalities (avoid high-dose Vit A in pregnancy)

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Vitamin D

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Vitamin B1 (Thiamine)

Enzymes requiring TPP:

Deficiency States:

Dry Beriberi:

• Peripheral neuropathy (symmetric, ascending)
• Demyelination of peripheral nerves
• Wrist drop, foot drop (motor > sensory)
• "Stocking-glove" paresthesias

Wet Beriberi:

• High-output cardiac failure (↑ CO due to peripheral vasodilation from ↓ ATP + ↑ lactic acid)
• Biventricular heart failure, edema, tachycardia
• Dilated cardiomyopathy
• Mechanism: ↓ ATP → myocardial dysfunction + peripheral vasodilation

Wernicke's Encephalopathy (acute):

• Classic triad: Confusion + Ophthalmoplegia (nystagmus, lateral gaze palsy) + Ataxia
• Mammillary body necrosis (Wernicke's area hemorrhage)
• Thiamine-dependent reaction (PDH, α-KG DH) failure → ↓ energy → neuronal death in high-metabolic areas

Korsakoff Psychosis (chronic):

• Anterograde amnesia (inability to form new memories) — hallmark
• Retrograde amnesia, confabulation (making up stories), personality change
• Thiamine-dependent neurons in mammillary bodies/thalamus permanently damaged

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Vitamin B12 (Cobalamin)

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Vitamin C

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Vitamin B6 (Pyridoxine)

Enzymes requiring PLP:

Deficiency:

• Peripheral neuropathy (defective myelin synthesis)
• Seborrheic dermatitis, glossitis, cheilosis
• Microcytic anemia (hypochromic) — ↓ ALA synthase → ↓ heme synthesis
• Seizures (infants — ↓ GABA synthesis → neuronal hyperexcitability)
• ↑ Homocysteine (↓ cystathionine β-synthase) → cardiovascular risk
• Sideroblastic anemia (iron-laden mitochondria in RBC precursors — ring sideroblasts)

Drug interactions:

• Isoniazid (INH): Structural analog of B6; inhibits pyridoxal kinase → drug-induced B6 deficiency → peripheral neuropathy (prevent with B6 supplementation)
• Penicillamine, hydralazine, oral contraceptives → ↓ B6

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CLINICAL: Pellagra (Niacin/B3 Deficiency)

• Active forms: NAD⁺ and NADP⁺ (coenzymes in >200 redox reactions)
• Can be synthesized from tryptophan (60 mg tryptophan = 1 mg niacin); requires B2, B6
• Sources: Meat, fish, groundnuts; maize lacks tryptophan

1. Dermatitis — symmetric, sun-exposed areas; "Casal's necklace" (necklace-like rash on neck); hyperpigmented, rough, scaly
2. Diarrhea — villous atrophy, malabsorption
3. Dementia — confusion, depression, psychosis; neuronal NAD⁺ depletion
4. Death — if untreated

• Maize (corn)-based diet (maize lacks tryptophan + has bound niacin as niacytin — not bioavailable unless alkali-treated/nixtamalization)
• Carcinoid syndrome (tryptophan → serotonin, less → niacin)
• Hartnup disease (↓ tryptophan absorption)
• Isoniazid (↓ B6 → ↓ kynurenine pathway → ↓ niacin from tryptophan)

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CLINICAL: Hypervitaminosis

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CLINICAL: Folate Trap

• Methionine synthase requires Methylcobalamin (Vit B12) as cofactor
• Reaction: 5-methyl-THF + Homocysteine → THF + Methionine
• Without B12: 5-methyl-THF cannot donate its methyl group → THF cannot be regenerated
• All cellular folate becomes "trapped" as 5-methyl-THF (useless form)
• Result: Functional folate deficiency even when folate intake is adequate

• ↓ Available THF → ↓ dTMP synthesis (↓ thymidylate synthase activity) → ↓ DNA synthesis → megaloblastic anemia
• Explains why B12 deficiency produces identical megaloblastic anemia to folate deficiency

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MODULE 5: HEME & HEMOGLOBIN

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Hemoglobin Structure

Types:

Heme Structure:

• Protoporphyrin IX + Fe²⁺ (ferrous) = Heme
• Fe²⁺ held by 4 N atoms of pyrrole rings + histidines (proximal/distal) of globin
• O₂ binds to Fe²⁺ without changing its valence state (oxygenation ≠ oxidation)
• Methemoglobin: Fe³⁺ (ferric) — cannot carry O₂; treated with methylene blue (reduces back via NADPH-methemoglobin reductase)

Cooperative Oxygen Binding (Allostery):

• Sigmoid O₂ dissociation curve (T state → R state)
• T state (tense/deoxy): Low O₂ affinity; stabilized by 2,3-BPG, H⁺, CO₂, Cl⁻
• R state (relaxed/oxy): High O₂ affinity; O₂ binding to one subunit → conformational change → other subunits bind O₂ more easily (positive cooperativity)

Factors shifting O₂ dissociation curve:

• ↑ PCO₂, ↑ H⁺ (↓ pH), ↑ temperature, ↑ 2,3-BPG

• HbF (less 2,3-BPG binding — has γ instead of β), CO poisoning, methemoglobin, ↓ temperature, ↓ PCO₂, alkalosis

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Heme Synthesis and Regulation

Pathway:

MITOCHONDRIA:
1. Glycine + Succinyl-CoA → δ-ALA (ALA synthase; requires PLP/B6; RATE-LIMITING STEP)

CYTOSOL:
2. 2× δ-ALA → Porphobilinogen (PBG) (ALA dehydrase; inhibited by lead)
3. 4× PBG → Hydroxymethylbilane
4. Hydroxymethylbilane → Uroporphyrinogen III (uroporphyrinogen III synthase)
5. Uroporphyrinogen III → Coproporphyrinogen III (decarboxylation)

MITOCHONDRIA:
6. Coproporphyrinogen III → Protoporphyrinogen IX
7. Protoporphyrinogen IX → Protoporphyrin IX (protoporphyrinogen oxidase)
8. Protoporphyrin IX + Fe²⁺ → HEME (ferrochelatase; inhibited by lead)

Regulation:

• Heme (end product) → feedback inhibits ALA synthase-1 (transcription + import into mitochondria)
• Drugs, steroids (CYP450 inducers) → deplete heme → ↑ ALA synthase-1 → ↑ heme synthesis

• Regulated by iron via IRE-IRP system (similar to ferritin/TfR)
• Iron deficiency → IRP binds IRE on ALA synthase-2 mRNA → ↓ translation (no point making heme without iron)

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Heme Degradation (Bilirubin Metabolism)

Heme → Biliverdin (green) → Bilirubin (yellow, unconjugated/indirect)
       (heme oxygenase; CO released)  (biliverdin reductase)

Unconjugated bilirubin (UCB):
- Lipid-soluble, NOT water-soluble
- Transported in blood bound to ALBUMIN
- Crosses blood-brain barrier → kernicterus
- Cannot be excreted in urine

In LIVER:
UCB → UGT1A1 (UDP-glucuronosyltransferase) → Conjugated bilirubin (CB/direct)
- Water-soluble (diglucuronide)
- Excreted into bile
- Can be excreted in urine (dark urine in obstructive jaundice)

In GUT:
CB → Urobilinogen (bacteria deconjugate + reduce)
Urobilinogen → Urobilin (oxidized; excreted in urine — yellow color)
             → Stercobilin (in feces — brown color)
Stercobilin absent in obstructive jaundice → pale/clay-colored stools

Van den Bergh Reaction: (covered in previous session)

Neonatal Jaundice:

• Physiological (2–7 days): ↑ RBC turnover + immature UGT1A1 → ↑ UCB
• Pathological: < 24h = hemolytic (Rh incompatibility, G6PD); > 2 weeks = breast milk jaundice, hypothyroidism
• Kernicterus: UCB deposits in basal ganglia → brain damage; treat with phototherapy (isomerizes UCB to water-soluble lumirubin)

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Porphyrias

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Hemoglobinopathies

Sickle Cell Anemia (HbS):

• Point mutation: β-chain codon 6 → GAG→GTG → Glutamic acid → Valine (hydrophilic → hydrophobic)
• HbS (α₂β₂S): In deoxy state → polymerizes → "tactoids" → sickling

• Chronic hemolytic anemia (Hb 6–10 g/dL), jaundice, gallstones (pigment)
• Vaso-occlusive crises: Bone pain (most common), dactylitis (hand-foot syndrome — 1st crisis in infants), avascular necrosis (femoral head), acute chest syndrome, stroke, priapism
• Functional asplenia (autosplenectomy) → ↑ risk of encapsulated bacteria (Strep. pneumoniae, H. influenzae, Salmonella osteomyelitis)
• Splenic sequestration (acute), aplastic crisis (Parvovirus B19)

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Thalassemias

α-Thalassemia:

β-Thalassemia:

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Jaundice — Classification

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MODULE 6: PROTEINS & AMINO ACIDS

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Ammonia Metabolism

1. Amino acid catabolism (transamination + GDH)
2. Intestinal bacteria (urea → NH₃ via urease)
3. Glutamine hydrolysis (kidney)
4. Purine nucleotide cycle (AMP → IMP + NH₃)

• Glutamine: Most important carrier (glutamate + NH₃ → glutamine; glutamine synthase); periphery → liver/kidney
• Alanine: Muscle NH₃ carried as alanine (glucose-alanine cycle: muscle pyruvate + NH₃ → alanine → liver → pyruvate (gluconeogenesis) + urea)

1. Urea cycle (liver — major route)
2. Glutamine synthesis (brain + muscle)
3. Renal glutaminase → NH₄⁺ excreted in urine (important in acidosis)

• Causes: Urea cycle defects (OTC most common, X-linked), liver failure, Reye's syndrome
• Features: Vomiting, lethargy, coma, cerebral edema; tremor, asterixis
• Mechanism: NH₃ + α-KG → glutamate (depletes α-KG → ↓ TCA → ↓ ATP); glutamate excess → glutamine → astrocyte swelling
• Treatment: ↓ Protein intake; sodium benzoate + sodium phenylacetate (conjugate glycine/glutamine → excrete N); arginine supplementation; dialysis

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Urea Cycle (covered in previous session — summary)

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Phenylalanine Metabolism

Phenylalanine  →[PAH + BH₄]→  Tyrosine
                    ↓ (PKU: defect here)
              Phenylpyruvate (phenylketone in urine)

Tyrosine:
├→ DOPA → Dopamine → Norepinephrine → Epinephrine (catecholamines)
├→ Melanin (tyrosinase, needs Cu²⁺)
├→ Thyroid hormones (T3, T4)
├→ Fumarate + Acetoacetate (glucogenic + ketogenic)
└→ Homogentisate → [blocked in Alkaptonuria]

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Tyrosine Metabolism & Clinical Disorders

Albinism:

• Tyrosinase deficiency (oculocutaneous type I; AR) → ↓ melanin → white skin/hair, pink eyes, nystagmus, photophobia, ↑ skin cancer risk

Alkaptonuria:

• Homogentisate 1,2-dioxygenase deficiency → homogentisic acid accumulates
• Features:
  • Urine turns black on standing/alkalinization (homogentisate oxidizes)
  • Ochronosis: Black-bluish pigmentation of cartilage (ears, nose, sclera)
  • Arthritis: Ochronotic arthropathy of large joints and spine
  • Prostate stones
• Inheritance: AR; 1:250,000
• Benign condition but progressive arthritis

Tyrosinemia:

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Tryptophan Metabolism

Tryptophan (essential AA):
├→ Serotonin (5-HT): Tryptophan → 5-OH-Tryptophan → 5-HT [requires Vit B6]
│    ↓
│  Melatonin (pineal gland; 5-HT + acetylation + methylation)
│    ↓
│  5-HIAA (urinary metabolite — ↑ in carcinoid syndrome)
│
├→ Kynurenine pathway → Niacin (60:1 ratio; requires B2, B6, Fe)
│
└→ Proteins, indole derivatives

1. Tryptophan → 5-Hydroxytryptophan (by Trp hydroxylase; requires BH₄)
2. 5-HTP → Serotonin (by aromatic amino acid decarboxylase; requires PLP/B6)

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Carcinoid Syndrome

• Carcinoid tumors: Neuroendocrine tumors (commonly appendix/ileum) that secrete serotonin, bradykinin, histamine
• Syndrome appears when tumor metastasizes to liver (bypasses first-pass hepatic metabolism)

• Diarrhea (watery; most common)
• Dermatitis (facial flushing)
• Dypsnea (bronchoconstriction)
• Dysrhythmia + right-heart valvular disease (tricuspid regurgitation, pulmonic stenosis)
• Abdominal cramping

• ↑ Urinary 5-HIAA (5-hydroxyindoleacetic acid) — diagnostic
• ↑ Tryptophan → serotonin → less tryptophan → pellagra-like niacin deficiency
• ↑ Serotonin in blood

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Hartnup Disease

• Defect: SLC6A19 (neutral amino acid transporter) mutation → ↓ intestinal and renal tubular absorption of neutral AAs (especially tryptophan)
• Inheritance: AR

• Pellagra-like rash (↓ Trp → ↓ niacin synthesis)
• Cerebellar ataxia
• Psychiatric symptoms (psychosis, depression)
• Aminoaciduria (neutral amino acids in urine)

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Transmethylation Reactions

Methionine + ATP → SAM (by methionine adenosyltransferase)
SAM → methylates substrate → SAH (S-adenosylhomocysteine)
SAH → Homocysteine + Adenosine (reversible; driven by product removal)
Homocysteine:
  → remethylated → Methionine (by methionine synthase; needs B12 + 5-methyl-THF)
  → transsulfuration → Cystathionine → Cysteine (by CBS; needs B6)

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Metabolic Disorders of Branched-Chain Amino Acids (BCAA)

Maple Syrup Urine Disease (MSUD):

• Defect: BCKDH complex (E1α/β, E2, E3 subunits)
• Accumulates: Leucine, isoleucine, valine + their keto-acids
• Features:
  • Maple syrup odor of urine (isoleucine-derived metabolite)
  • Neonatal encephalopathy (feeding problems, lethargy, seizures)
  • Leucine most neurotoxic (↓ cerebral glucose utilization)
  • Hypoglycemia
• Diagnosis: Tandem MS newborn screen; elevated BCAAs
• Treatment: Dietary restriction of BCAAs; thiamine (B1) — some responsive forms; acute: dialysis; liver transplant (provides BCKDH-competent tissue)

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One-Carbon Metabolism

• Serine → Glycine: SHMT (serine hydroxymethyltransferase; B6) → donates methylene group to THF → N⁵,N¹⁰-methylene-THF
• Methylene-THF → methyl-THF: (MTHFR — methyleneTHF reductase; irreversible) → for methionine synthesis
• Methionine synthesis: Methyl-THF + B12 → THF regenerated

• Methotrexate: Inhibits DHFR → ↓ THF → ↓ DNA synthesis; rescue with leucovorin (folinic acid = N⁵-formyl-THF)
• 5-Fluorouracil: Inhibits thymidylate synthase (TS) → ↓ dTMP → ↓ DNA
• Trimethoprim: Inhibits bacterial DHFR (selective)

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Polyamines

Ornithine → Putrescine (ornithine decarboxylase; ODC — rate-limiting; requires PLP/B6)
SAM → Decarboxylated SAM (dcSAM) [SAM decarboxylase]
Putrescine + dcSAM → Spermidine [spermidine synthase]
Spermidine + dcSAM → Spermine [spermine synthase]

1. Cell proliferation: Polyamines are essential for G1/S progression; ↑ in rapidly dividing cells
2. DNA stabilization: Positive charges neutralize DNA phosphates
3. RNA stabilization and translation
4. Membrane structure regulation
5. Ion channel modulation

• ↑ Polyamines in cancer cells → target for cancer therapy (DFMO = difluoromethylornithine — irreversible ODC inhibitor; used in African sleeping sickness)
• Putrescine → Spermidine → Spermine = important for eukaryotic translation initiation factor EIF5A (hypusine modification)

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MODULE 7: CLINICAL DISORDERS

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Phenylketonuria (covered in previous session)

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Alkaptonuria (covered above)

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Tyrosinemia (covered above)

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Carcinoid Syndrome (covered above)

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Hartnup Disease (covered above)

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Homocystinuria

Type I (Most common): CBS Deficiency

• Enzyme: Cystathionine β-synthase (CBS); requires PLP/B6
• Inheritance: AR (chromosome 21q22)
• CBS converts homocysteine + serine → cystathionine → cysteine
• Deficiency → ↑ homocysteine + ↑ methionine

1. Ocular: Ectopia lentis (downward lens dislocation — distinguish from Marfan's: upward)
2. Marfanoid habitus: Tall, thin, arachnodactyly, pectus deformity
3. Events (thromboembolism): DVT, PE, stroke, MI — homocysteine damages endothelium, promotes coagulation; leading cause of death
4. Neurological: Intellectual disability, seizures, psychiatric disorder
5. Skeletal: Osteoporosis

• B6-responsive (~50%): High-dose pyridoxine (B6) → stimulates residual CBS activity
• B6-non-responsive: Low methionine diet + cysteine supplementation + betaine (alternative remethylation donor) + folate + B12

Type II: MTHFR Deficiency

• ↓ 5-methyl-THF → ↓ methionine synthesis → ↑ homocysteine but ↓ methionine
• Neurological symptoms predominate; less cardiovascular

Type III: B12 Deficiency / Methionine Synthase Deficiency

• ↑ Homocysteine + ↓ methionine (similar to MTHFR deficiency)

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Aminoaciduria

Classification:

• Plasma AA > renal threshold → overwhelms transport
• Examples: PKU (↑ phenylalanine), alkaptonuria, homocystinuria, MSUD, tyrosinemia

• Plasma AA normal; renal tubule transport defective
• Examples:

• Cystine poorly soluble → recurrent kidney stones (hexagonal crystals on urine microscopy)
• Treatment: High fluid intake, alkalinize urine (↑ cystine solubility), D-penicillamine/tiopronin (form soluble mixed disulfides with cysteine)

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Quick Master Reference Table

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How to Use These Notes for Exam

• Menkes = ATP7A, X-linked, Cu deficiency (kinky hair, neurodegeneration)
• Wilson's = ATP7B, AR, Cu accumulation (KF rings, liver disease)
• AIP = PBG deaminase deficiency → ↑ ALA+PBG → no photosensitivity
• PCT = Uroporphyrinogen decarboxylase → photosensitivity, most common porphyria
• Sickle cell = Glu→Val at β-6 → HbS polymerizes when deoxygenated
• β-thal major = ↑ HbA₂ (> 3.5%) on electrophoresis
• Homocystinuria = lens dislocation downward (Marfan's = upward)
• Hartnup = neutral AA transporter → pellagra + ataxia; treat with nicotinamide
• Carcinoid = ↑ urinary 5-HIAA; flushing + diarrhea + right heart valve disease
• Folate trap = B12 deficiency traps folate as 5-methyl-THF → megaloblastic anemia

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PORPHYRIAS — Complete Study Notes

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Definition

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Heme Synthesis Pathway — Full Sequence

Step 1: Glycine + Succinyl-CoA → δ-ALA              [ALAS; MIT; rate-limiting; PLP cofactor]
Step 2: 2× ALA → Porphobilinogen (PBG)               [ALA dehydratase = ALAD; CYT; inhibited by LEAD]
Step 3: 4× PBG → Hydroxymethylbilane (HMB)          [HMB synthase = PBG deaminase; CYT]
Step 4: HMB → Uroporphyrinogen III                   [URO synthase; CYT]
Step 5: Uroporphyrinogen III → Coproporphyrinogen III [URO decarboxylase = UROD; CYT]
Step 6: Coproporphyrinogen III → Protoporphyrinogen IX [COPRO oxidase; MIT]
Step 7: Protoporphyrinogen IX → Protoporphyrin IX    [PROTO oxidase = PPOX; MIT]
Step 8: Protoporphyrin IX + Fe²⁺ → HEME             [Ferrochelatase = FECH; MIT; inhibited by LEAD]

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Classification

Two main axes:

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Master Classification Table

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Lab Patterns (Urine/Stool/RBC Accumulations)

• AIP: ↑↑ urine PBG (Watson-Schwartz test turns red) — most important
• PCT: ↑ urine uroporphyrin + isocoproporphyrin in stool (pathognomonic)
• VP: ↑ stool protoporphyrin IX + plasma fluorescence at 624–628 nm (distinguishes from AIP)
• EPP: ↑ RBC free protoporphyrin (metal-free); NO urine changes

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Individual Porphyrias — Detailed

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1. Acute Intermittent Porphyria (AIP)

Pathogenesis:

• ALA synthase-1 (ALAS1) induced by triggers → ↑ flux through pathway
• HMB synthase deficiency → ALA and PBG accumulate
• ALA is neurotoxic (structural analog of GABA → neuronal damage)

Precipitants ("PABCD FASTING"):

• Physical stress (infection, surgery)
• Alcohol
• Barbiturates, anticonvulsants (phenytoin, carbamazepine)
• Carbamazepine, sulfonamides, rifampicin, griseofulvin, OCP
• Diet — fasting/low carbohydrate (↑ ALAS1)
• Hormones (progesterone — explains female predominance in reproductive age)

Clinical Features (Triad):

1. Abdominal pain — most common; severe, colicky; no peritoneal signs
2. Neuropsychiatric: anxiety, psychosis, depression, confusion, seizures
3. Peripheral neuropathy: motor > sensory; ascending weakness → may → respiratory paralysis

Diagnosis:

• Spot urine PBG (during attack) — elevated ↑↑ → most rapid and specific test
• Watson-Schwartz test: urine PBG + Ehrlich reagent (p-dimethylaminobenzaldehyde) → red colour (PBG doesn't extract into butanol — distinguishes from urobilinogen)
• ↑ ALA in urine
• HMBS mutation analysis for family screening

Treatment:

1. Remove/avoid precipitants
2. IV Hemin (heme arginate) — exogenous heme → feedback inhibits ALAS1 → ↓ ALA/PBG; mainstay of treatment
3. IV Glucose (300–500 g/day) — carbohydrate loading → inhibits ALAS1 via PGC-1α
4. Pain management (opioids safe); propranolol for tachycardia/hypertension
5. Seizures → benzodiazepines (safe); avoid phenytoin

• Avoid precipitants
• Givosiran (Alnylam, 2019) — siRNA targeting ALAS1 mRNA in hepatocytes → ↓ ALAS1 → ↓ ALA/PBG; monthly SC injection; major advance for recurrent AIP

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2. Porphyria Cutanea Tarda (PCT)

Pathogenesis:

• UROD inhibited (not mutated in Type I) → uroporphyrins accumulate in liver → skin → react with UV light → reactive oxygen species → skin damage

Risk factors/triggers:

• Alcohol (↑ iron + UROD inhibition)
• Hepatitis C (most important association)
• Iron overload (HFE mutations — C282Y common co-factor)
• Estrogens (OCP, HRT)
• HIV
• Chlorinated hydrocarbons (industrial exposure)

Clinical Features:

• Skin fragility and blistering on sun-exposed areas (dorsum of hands, face)
• Milia (small white cysts) at sites of healed blisters
• Hypertrichosis (excess facial hair — especially temples)
• Hyperpigmentation (brownish)
• No acute neurovisceral attacks
• Liver disease (associated hepatitis C/cirrhosis)

Diagnosis:

• ↑ Urine uroporphyrin (predominantly) and 7-carboxylate porphyrin
• ↑ Stool isocoproporphyrin (pathognomonic for PCT)
• Urine PBG/ALA: normal (distinguishes from acute porphyrias)
• Skin biopsy: subepidermal blistering; DIF: IgG + C3 at DEJ

Treatment:

1. Avoid triggers: Stop alcohol, iron supplementation, estrogens
2. Phlebotomy (weekly; remove 450 mL blood) — depletes iron, most effective long-term
3. Low-dose hydroxychloroquine/chloroquine — chelates uroporphyrin from liver; for those who can't tolerate phlebotomy
4. Treat Hepatitis C (antiviral therapy → remission of PCT)
5. Sun protection

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3. Hereditary Coproporphyria (HCP)

• Clinical picture similar to AIP but milder
• Skin lesions (blistering) appear during/after attacks
• Distinguishing lab: ↑ stool coproporphyrin III (copro-III/I ratio elevated)
• Treatment: same as AIP (hemin + glucose)

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4. Variegate Porphyria (VP)

• "Variegate" = variable — can present with neurovisceral, skin, or both
• Distinguishing feature: Plasma fluorescence emission peak at 624–628 nm (specific for VP; AIP peaks at 615–622 nm)
• ↑ Stool protoporphyrin IX + coproporphyrin III
• Treatment: same as AIP; avoid precipitants

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5. Congenital Erythropoietic Porphyria (CEP) — Günther's Disease

Clinical Features (severe, from infancy):

• Pink/red urine in diapers (first sign — uroporphyrin I)
• Severe photosensitivity: blistering, scarring, mutilation of face/hands
• Fluorescent teeth (erythrodontia) — pinkish-red under UV (Woods lamp)
• Hypertrichosis of face/extremities
• Hemolytic anemia with splenomegaly
• No neurovisceral attacks

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6. Erythropoietic Protoporphyria (EPP)

Clinical Features:

• Acute painful photosensitivity — burning, stinging, edema within minutes of sun exposure
• No blisters (distinguishes from other cutaneous porphyrias — immediate/acute type)
• Mild chronic skin changes over time
• Liver disease (protoporphyrin is insoluble → cholestasis → biliary cirrhosis in ~5%)
• Gallstones (protoporphyrin)
• Mild hemolytic anemia
• No neurovisceral attacks

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7. ALA Dehydratase Deficiency Porphyria (ADP)

• Rarest porphyria (< 10 cases worldwide)
• ALAD deficiency (same enzyme inhibited by lead)
• AR; severe neonatal/childhood onset
• Neurovisceral only (↑ ALA, coproporphyrin III in urine)

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Comparison: Acute vs Cutaneous — Key Exam Points

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Precipitants of Acute Porphyria — Must Know

• Carbohydrate low (fasting)
• Alcohol
• Stress (infection, surgery)
• Estrogens/progestogens
• Phenytoin, Phenobarbital
• Halothane, hydantoins
• Isoniazid
• Sulfonamides
• Progesterone (explains female preponderance)
• Sexual hormones, rifampicin

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Mnemonic: PORPHYRIA in AIP

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Quick Comparison Table — All 7 Porphyrias

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Watson-Schwartz Test

• PBG (AIP) → Red colour, does NOT extract into butanol or chloroform
• Urobilinogen → Red colour, DOES extract into butanol (moves to organic layer)
• This extraction step differentiates AIP from normal urobilinogen

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