Brudzinski Sign — Positive in Meningeal Irritation

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Conditions where Brudzinski sign is positive:

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Classic Triad of Bacterial Meningitis (context):

Fever + Nuchal rigidity + Headache — with Kernig's and Brudzinski's signs as hallmark clinical signs of meningeal irritation.

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Important caveats (from Harrison's):

• Both Kernig's and Brudzinski's signs have uncertain sensitivity and specificity
• May be absent in: very young or elderly patients, immunocompromised individuals, severely obtunded patients
• Cervical spine disease in older patients may cause false-positive nuchal rigidity

• Harrison's Principles of Internal Medicine 22E, p. 1163
• Gray's Anatomy for Students, Case 8
• Neuroanatomy through Clinical Cases, 3rd Ed., Table 5.6

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Lipoprotein Metabolism

Structure of Lipoproteins

• Hydrophobic core: TG + cholesteryl esters
• Hydrophilic shell: phospholipids + unesterified cholesterol + apolipoproteins

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Key Apolipoproteins and Their Functions

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The Three Metabolic Pathways

1. Exogenous Pathway (Dietary Lipids → Chylomicrons)

1. Dietary fat is digested and absorbed in the proximal small intestine
2. Fatty acids + cholesterol are re-esterified in enterocytes and loaded onto ApoB-48 by MTP (microsomal TG transfer protein) → forms nascent chylomicrons
3. Chylomicrons enter the lymphatics → thoracic duct → left subclavian vein → systemic circulation
4. In the blood, nascent chylomicrons receive ApoC-II and ApoE from circulating HDL
5. LPL (on capillary endothelium in adipose, cardiac, skeletal muscle), activated by ApoC-II, hydrolyzes the core TGs → releases free fatty acids (FFAs)
   • FFAs → taken up by adipocytes (storage) or myocytes (energy)
   • Glycerol → taken up by liver
6. As >90% of TG is removed, the shrunken particle becomes a chylomicron remnant (retains ApoB-48 and ApoE; loses ApoC apolipoproteins back to HDL)
7. Chylomicron remnants are rapidly cleared from blood by the liver via ApoE binding to hepatic LDL receptors (remnant receptor)
   • After a 12-hour fast, virtually no chylomicrons remain in blood

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2. Endogenous Pathway (Hepatic Lipids → VLDL → IDL → LDL)

1. VLDL is assembled in the liver: ApoB-100 + TG + phospholipids + cholesteryl esters, loaded by MTP → secreted directly into blood
2. Nascent VLDL acquires ApoC-II and ApoE from HDL
3. LPL (activated by ApoC-II) hydrolyzes VLDL-TG at capillaries → FFAs released to tissues
4. As TG is depleted, VLDL → IDL (VLDL remnant); IDL has roughly equal TG and cholesterol
   • ~40–60% of IDL is taken up by the liver via ApoE → LDL receptor (receptor-mediated endocytosis)
   • Remaining IDL is remodeled by hepatic lipase (HL) → LDL
5. During this remodeling, CETP (cholesteryl ester transfer protein) transfers cholesteryl esters from HDL → VLDL/IDL in exchange for TG
6. LDL is the major cholesterol carrier in plasma (~70% of plasma cholesterol). It contains primarily ApoB-100
7. LDL is cleared by LDL receptor-mediated endocytosis primarily in the liver:
   • ApoB-100 binds LDL receptors (clustered in clathrin-coated pits)
   • Endocytosis → endosome → lysosomal degradation → free cholesterol released
   • Receptor is recycled; free cholesterol downregulates HMG-CoA reductase and LDL receptor synthesis (feedback)
8. PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes lysosomal degradation of the LDL receptor → reduces receptor recycling → raises plasma LDL

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3. Reverse Cholesterol Transport (RCT) — HDL Pathway

1. Nascent HDL (discoidal) is secreted by the liver and intestine, primarily as ApoA-I
2. ApoA-I promotes cholesterol efflux from peripheral cells (including macrophages in arterial walls) via ABCA1 and ABCG1 transporters
3. LCAT (lecithin:cholesterol acyltransferase), activated by ApoA-I, esterifies free cholesterol → cholesteryl ester → sequestered in HDL core → particle becomes spherical (mature HDL / HDL3 → HDL2)
4. HDL delivers cholesterol to the liver via two routes:
   • Direct: SR-BI (scavenger receptor class B1) on hepatocytes selectively uptakes CE; HDL particle is recycled
   • Indirect via CETP: CETP transfers CE from HDL → apoB-containing lipoproteins (VLDL, LDL) in exchange for TG → LDL receptor clears these particles in liver
5. Cholesterol is excreted in bile (directly or as bile acids) — the only route for net cholesterol excretion from the body

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Key Enzymes Summary

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Clinically Important Disorders

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