Tryptophan and tyrosine Vitamin c Lipid metabolism( mainly lipoprotein) Hypothyroidism
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1. Tryptophan and Tyrosine Metabolism
Tryptophan
Tryptophan is an essential aromatic amino acid. It is both glucogenic and ketogenic - its catabolism yields alanine (glucogenic) and acetoacetyl CoA (ketogenic).
Key Metabolic Products of Tryptophan
| Product | Pathway | Notes |
|---|---|---|
| Serotonin (5-HT) | Hydroxylation by tryptophan hydroxylase (requires BH4) → 5-hydroxytryptophan → decarboxylation | Rate-limiting step is tryptophan hydroxylase |
| Melatonin | From serotonin: N-acetylation → O-methylation | Synthesized in pineal gland; regulates circadian rhythm |
| NAD+/NADP+ | Kynurenine pathway (major route) | Quinolinate from tryptophan → used in NAD synthesis; requires pyridoxal phosphate (B6) |
| Alanine + Acetoacetyl CoA | Kynurenine pathway catabolism | Explains dual glucogenic/ketogenic nature |
Tryptophan Hydroxylase
- Catalyzes hydroxylation using tetrahydrobiopterin (BH4) as cofactor
- Shared cofactor with phenylalanine hydroxylase and tyrosine hydroxylase
- BH4 regeneration requires NADPH-linked dihydropteridine reductase
Hartnup Disease
- Autosomal recessive defect in neutral amino acid transporter (including tryptophan) in intestine and renal tubules
- Decreased tryptophan absorption → pellagra-like symptoms (niacin deficiency) since tryptophan is a NAD precursor
- Cerebellar ataxia, photosensitive rash
Tyrosine
Tyrosine is a conditionally essential amino acid - synthesized from the essential amino acid phenylalanine by phenylalanine hydroxylase (PAH), which also requires BH4.
Key Metabolic Products of Tyrosine
| Product | Pathway / Enzyme | Clinical Relevance |
|---|---|---|
| DOPA / Dopamine | Tyrosine hydroxylase (TH) → L-DOPA → DOPA decarboxylase (B6) | Rate-limiting step: TH; deficiency in Parkinson's |
| Norepinephrine | Dopamine β-hydroxylase (Vit C required) | Adrenal medulla and CNS |
| Epinephrine | PNMT methylates norepinephrine (SAM donor) | Adrenal medulla |
| Melanin | Tyrosinase oxidizes tyrosine → DOPA → melanin | Deficiency → albinism (tyrosinase defect) |
| Thyroid hormones (T3/T4) | Iodination and coupling of tyrosine residues in thyroglobulin | MIT + DIT coupling |
| Acetoacetate | Terminal catabolism | Ketogenic component |
Important: Shared BH4 Cofactor
BH4 is required for all three hydroxylases: PAH, TH, and neuronal tryptophan hydroxylase. BH4 deficiency causes atypical PKU with severe neurotransmitter deficits (both serotonin and catecholamines are deficient). Simply restricting dietary phenylalanine does NOT correct the neurological effects - neurotransmitter precursors (L-DOPA, 5-hydroxytryptophan) must be supplemented.
(Biochemistry, Lippincott 8th Ed; Tietz Textbook of Laboratory Medicine 7th Ed)
2. Vitamin C (Ascorbic Acid)
Vitamin C is a water-soluble vitamin not synthesized endogenously in humans. Dietary sources include citrus fruits, potatoes, tomatoes, spinach, broccoli, and liver.
Functions
| Function | Mechanism |
|---|---|
| Collagen synthesis | Activates prolyl hydroxylase and lysyl hydroxylase - hydroxylates proline and lysine residues in procollagen. Without this, collagen lacks stable triple-helix configuration and tensile strength |
| Neurotransmitter synthesis | Required for dopamine β-hydroxylase → converts dopamine to norepinephrine |
| Antioxidant | Scavenges reactive oxygen species (ROS); reduces ferric iron (Fe3+) to ferrous iron (Fe2+) to enhance non-heme iron absorption |
| Carnitine synthesis | Required for two hydroxylation steps in carnitine biosynthesis (needed for fatty acid transport into mitochondria) |
| Immune function | Immune modulation - though clinical trial results have been disappointing |
| HIF-1 regulation | Cofactor for α-ketoglutarate-dependent dioxygenases; downregulates hypoxia-inducible factor (HIF-1) via prolyl hydroxylases |
Deficiency - Scurvy
Scurvy develops after ~3 months of deficiency. At-risk groups: elderly living alone, alcohol use disorder, patients on hemodialysis/peritoneal dialysis, infants on unsupplemented evaporated milk formulas.
Manifestations:
- Perifollicular hemorrhages (earliest sign) and perifollicular hyperkeratosis
- Corkscrew hairs (swan-neck deformity of hair follicles)
- Gingival swelling, bleeding, and ulceration (gums spongy and purple)
- Subperiosteal hemorrhage (especially in children) - tender, painful bones
- Poor wound healing (collagen deficient)
- Skeletal changes in children: failure of osteoid matrix formation; "scurvy line" (Frankel's line) on X-ray
- Anemia (iron deficiency component due to impaired iron absorption)
Toxicity (Excess)
- Megadose supplementation has NOT been proven to prevent common cold in controlled trials
- High doses can cause oxalate kidney stones (ascorbate metabolized to oxalate)
- Excess Vitamin C can cause rebound scurvy when suddenly stopped (upregulates degradative enzymes)
- May enhance iron absorption excessively in hemochromatosis
(Robbins Cotran Pathologic Basis of Disease; Biochemistry Lippincott 8th Ed; Goldman-Cecil Medicine)
3. Lipid Metabolism - Lipoproteins
Lipoproteins are spherical particles with a hydrophobic core (triglycerides + cholesterol esters) and a hydrophilic shell (phospholipids, free cholesterol, apolipoproteins).
Classification by Density
| Lipoprotein | Protein (%) | TG (%) | Cholesterol Esters (%) | Major Apo | Origin |
|---|---|---|---|---|---|
| Chylomicrons (CM) | 1-2 | 80-95 | 2-4 | B-48, A-I, C-II, E | Intestine |
| VLDL | 6-10 | 45-65 | 16-22 | B-100, C-II, E | Liver |
| IDL | Between VLDL & LDL | - | - | B-100, E | VLDL remnant |
| LDL | 18-22 | 4-8 | 45-50 | B-100 | IDL |
| HDL | 45-55 | 2-7 | 15-20 | A-I, A-II | Liver + Intestine |
Note: Higher lipid content = lower density. Higher protein = higher density.
Exogenous Pathway (Dietary Fat Transport)
- Dietary fat absorbed in intestine → packaged as chylomicrons (Apo B-48)
- CMs enter lacteals → thoracic duct → bloodstream
- Lipoprotein lipase (LPL) on capillary endothelium (activated by Apo C-II) hydrolyzes TG → fatty acids taken up by muscle and adipose
- Chylomicron remnants (enriched in cholesterol, containing Apo E) taken up by liver LDL receptor-related protein (LRP) via Apo E recognition
Endogenous Pathway (Hepatic Lipid Transport)
- Liver secretes VLDL (Apo B-100) - carries endogenously synthesized TG
- LPL hydrolyzes VLDL TG → IDL (VLDL remnant)
- IDL is either taken up by liver (via LDL receptor, recognizes Apo E) or further processed by hepatic lipase → LDL (loses most TG, enriched in cholesterol esters, retains only Apo B-100)
- LDL delivers cholesterol to peripheral tissues via LDL receptor (recognizes Apo B-100)
- Receptor-mediated endocytosis → LDL internalized → cholesterol released → ↓HMG-CoA reductase (inhibits cholesterol synthesis), ↓ LDL receptor expression, ↑ ACAT (stores cholesterol as esters)
Reverse Cholesterol Transport (RCT) - HDL Pathway
- Nascent HDL (disc-shaped, Apo A-I) released by liver and intestine
- Acquires free cholesterol from peripheral tissues via ABCA1 transporter
- LCAT (lecithin-cholesterol acyltransferase, activated by Apo A-I) esterifies free cholesterol → cholesterol esters move to HDL core → HDL matures to spherical HDL2 and HDL3
- Cholesterol esters transferred to VLDL/LDL via CETP (cholesterol ester transfer protein)
- HDL delivers cholesterol to liver via SR-BI receptor (selective uptake)
Key Enzymes and Their Functions
| Enzyme | Activator | Function |
|---|---|---|
| LPL | Apo C-II | Hydrolyzes TG in CM and VLDL at endothelium |
| Hepatic lipase (HL) | - | Converts IDL → LDL; remodels HDL |
| LCAT | Apo A-I | Esterifies free cholesterol in HDL (plasma) |
| CETP | - | Transfers cholesterol esters from HDL to VLDL/LDL |
| ABCA1 | - | Efflux of cholesterol from cells to Apo A-I |
| HMG-CoA reductase | - | Rate-limiting step of cholesterol synthesis (inhibited by statins) |
Lipoprotein(a) - Lp(a)
- LDL-like particle with an additional apo(a) protein linked to Apo B-100 by a disulfide bond
- Apo(a) is structurally similar to plasminogen - can inhibit fibrinolysis
- Elevated Lp(a) is an independent risk factor for cardiovascular disease
(Henry's Clinical Diagnosis and Management; Tietz Textbook; Lippincott Biochemistry; Goodman & Gilman's)
4. Hypothyroidism
Definition
Hypothyroidism is deficient thyroid hormone production - can be primary (thyroid gland failure) or secondary/central (TSH deficiency from pituitary/hypothalamic failure).
Causes
Primary (most common):
| Cause | Mechanism |
|---|---|
| Iodine deficiency | Most common cause worldwide (~2 billion affected); impairs T3/T4 synthesis |
| Hashimoto thyroiditis | Most common cause in iodine-sufficient regions; autoimmune destruction |
| Post-surgical/radioablation | Loss of thyroid tissue |
| Drugs | Lithium, amiodarone, propylthiouracil, iodides interfere with synthesis |
| Dyshormonogenetic goiter | Rare congenital enzyme defects in thyroid hormone synthesis |
| Thyroid dysgenesis | Developmental failure of thyroid |
| Thyroid hormone resistance | Rare - mutations in thyroid hormone receptor |
Secondary/Central:
- Pituitary failure (↓TSH), hypothalamic failure (↓TRH)
Hashimoto Thyroiditis (Most Common Autoimmune Cause)
- Age: 45-65 years; F:M ratio = 10-20:1
- Mechanisms of destruction:
- CD8+ cytotoxic T cells kill thyroid epithelial cells directly
- CD4+ Th1 cells → IFN-γ → macrophage activation → follicle destruction
- Antithyroid antibodies (anti-TPO and anti-thyroglobulin) - possible complement-mediated damage
- Genetics: CTLA4 polymorphisms, ~40% concordance in monozygotic twins
Clinical Features by Age of Onset
Congenital Hypothyroidism (Cretinism)
- Impaired development of skeletal system and CNS
- Severe irreversible mental disability if untreated (especially if maternal hypothyroidism in early pregnancy - fetus depends on maternal T3/T4 before own thyroid develops)
- Short stature, coarse facies, protruding tongue, umbilical hernia, delayed bone maturation (bone age < chronological age)
- Neonatal screening (TSH) allows early treatment
Adult Hypothyroidism (Myxedema)
Metabolic/Systemic:
- Weight gain, cold intolerance, fatigue, lethargy
- Constipation, bradycardia
- Hyperlipidemia (↑LDL, ↑total cholesterol - reduced LDL receptor activity)
- ↑Serum CK, ↑AST (myopathy)
Skin/Mucosal:
- Myxedema - non-pitting edema due to accumulation of glycosaminoglycans (hyaluronic acid) in dermis; puffy face, periorbital edema
- Dry, coarse, pale skin; dry brittle hair; loss of outer third of eyebrow (Queen Anne's sign)
- Macroglossia
CNS:
- Slowed thought, memory impairment, depression
- Delayed deep tendon reflex relaxation (hung-up reflex)
Cardiovascular:
- Bradycardia, pericardial effusion, diastolic hypertension
- Increased risk of atherosclerosis
Reproductive:
- Menorrhagia in women (anovulatory cycles)
- Infertility
Myxedema Coma (Severe/Decompensated)
- Hypothermia, hypoventilation, hypotension, hyponatremia, altered consciousness
- Medical emergency - IV T4/T3 + supportive care
Diagnosis
| Test | Finding |
|---|---|
| TSH | ↑↑ in primary hypothyroidism (most sensitive test) |
| Free T4 | ↓ |
| Anti-TPO antibodies | Positive in Hashimoto's (~90% sensitivity) |
| Anti-thyroglobulin antibodies | Also positive in Hashimoto's |
| Serum cholesterol | ↑ (useful clue) |
| CK, LDH | May be ↑ (myopathy) |
Treatment
- Levothyroxine (L-T4) - oral synthetic T4; body converts to active T3 in periphery
- Dose titrated to normalize TSH
- Congenital hypothyroidism: treatment must begin within days of birth to prevent irreversible neurodevelopmental damage
(Robbins & Kumar Basic Pathology; Robbins Cotran; Harrison's Principles of Internal Medicine 22E; Costanzo Physiology; Sabiston Surgery)
Quick Summary Table
| Topic | Key Memory Hook |
|---|---|
| Tryptophan | Essential → Serotonin/Melatonin (via 5-HTP), NAD+ (via kynurenine/quinolinate), both glucogenic + ketogenic |
| Tyrosine | From Phe (PAH+BH4) → Catecholamines (TH is rate-limiting), Melanin (tyrosinase), T3/T4 |
| Vitamin C | Collagen (prolyl/lysyl hydroxylase), norepinephrine synthesis, antioxidant; Deficiency = Scurvy |
| Lipoprotein | CM (exogenous, ApoB48), VLDL→IDL→LDL (endogenous, ApoB100), HDL (reverse cholesterol, ApoA1+LCAT) |
| Hypothyroidism | Iodine deficiency (#1 worldwide), Hashimoto (#1 in iodine-sufficient areas); ↑TSH, ↓T4; myxedema, cretinism |
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