Lipid, Lipoprotein & Bile Acid Metabolism Disorders

Lipoprotein metabolism (chylomicrons, VLDL, LDL, HDL) · Primary hyperlipidemias (familial hypercholesterolemia, familial combined, hypertriglyceridemia) · Cholesterol synthesis defects (Smith-Lemli-Opitz) · Bile acid synthesis defects · Secondary hyperlipidemia · Treatment (lifestyle, statins, ezetimibe, bile acid binders, apheresis)
🧬 Key concepts: FH (LDLR mutation, tendon xanthomas, premature CAD). Sitosterolemia (plant sterols, xanthomas). Smith-Lemli-Opitz (7-DHC, cholesterol synthesis). Bile acid defects (cholestasis, fat-soluble vitamin deficiency).

📖 Lipid & lipoprotein disorders: hyperlipidemia, cholesterol/bile acid defects

🧬 Lipoprotein metabolism
Exogenous pathway: chylomicrons (TG). Endogenous: VLDL → IDL → LDL (cholesterol). HDL (reverse transport). Key enzymes: LPL, HL, LCAT. Receptors: LDLR, LRP1.
⚠️ Primary hyperlipidemias
FH (LDLR, APOB, PCSK9): high LDL, tendon xanthomas, premature CAD. Familial hypertriglyceridemia (LPL, APOC2). Familial combined hyperlipidemia (elevated LDL + TG). Dysbetalipoproteinemia (APOE).
🧫 Cholesterol synthesis & bile acid defects
Smith-Lemli-Opitz (DHCR7 deficiency): low cholesterol, elevated 7-DHC, dysmorphism, intellectual disability. Cerebrotendinous xanthomatosis (CYP27A1): cholestanol, xanthomas, neurological decline. Bile acid synthesis defects: cholestasis, fat-soluble vitamin deficiency, liver failure.
💊 Treatment of hyperlipidemia
Lifestyle (diet, exercise). Statins (HMG-CoA reductase inhibitors) – first-line for FH. Ezetimibe (cholesterol absorption). Bile acid sequestrants. PCSK9 inhibitors (evolocumab). LDL apheresis for homozygous FH.
⚠️ Red flags for genetic hyperlipidemia: Premature CAD (male <55, female <65), tendon xanthomas (Achilles, knuckles), xanthelasma, corneal arcus <45y, family history of hyperlipidemia or early MI.

🩺 Clinical & diagnostic approach to lipid disorders

1
History & physical – Premature atherosclerosis (MI, stroke in family), xanthomas (tendon, tuberous, eruptive), xanthelasma, corneal arcus (age <45y). Obesity, acanthosis nigricans (metabolic syndrome).
2
Lipid panel (fasting) – Total cholesterol, LDL, HDL, triglycerides. Lipoprotein(a), apolipoprotein B, A-I. Non-HDL cholesterol. Secondary causes: TSH, LFT, glucose, renal function.
3
Special tests – LDL receptor functional assay, genetic testing (LDLR, APOB, PCSK9). Plant sterols (sitosterolemia). 7-DHC (Smith-Lemli-Opitz). Cholestanol (cerebrotendinous xanthomatosis).
4
Bile acid synthesis defect workup – Cholestasis, fat-soluble vitamin levels (A, D, E, K), urinary bile acids by mass spectrometry.
📌 Clinical pearl: Tendon xanthomas (Achilles, knuckles) are virtually diagnostic of familial hypercholesterolemia. Initiate statin therapy early to prevent atherosclerosis.

📋 Stepwise management of hyperlipidemia & bile acid defects

1
Lifestyle modification – Heart-healthy diet (low saturated fat, high fiber), increased physical activity, weight management. For children >2 years with FH, dietary counseling.
2
Pharmacotherapy (FH, severe hyperlipidemia) – Statins (atorvastatin, simvastatin) first-line from age 8-10 years (or earlier if homozygous). Ezetimibe add-on. Bile acid sequestrants (cholestyramine). PCSK9 inhibitors (evolocumab) for refractory.
3
Homozygous familial hypercholesterolemia (HoFH) – High-dose statin + ezetimibe + PCSK9 inhibitor. LDL apheresis (weekly). Liver transplantation in extreme cases.
4
Hypertriglyceridemia (LPL deficiency, APOC2) – Very low fat diet (<20% calories), medium-chain triglyceride oil, fibrates (gemfibrozil), omega-3 fatty acids.
5
Bile acid synthesis defects – Oral bile acid replacement (chenodeoxycholic acid, cholic acid) to suppress toxic intermediates. Fat-soluble vitamin supplementation (ADEK).
6
Smith-Lemli-Opitz syndrome – Cholesterol supplementation (dietary cholesterol). Statins not used (low baseline cholesterol). Monitor 7-DHC levels.
🚨 Emergency in hypertriglyceridemia: Severe hypertriglyceridemia (>1000 mg/dL) risks pancreatitis. Immediate fat restriction, IV fluids, fibrates.

🧠 Reflex prompts: lipid & bile acid disorders

🧬 10-year-old with LDL 220 mg/dL, Achilles tendon xanthomas, father had MI at 48. Diagnosis?
Familial hypercholesterolemia (LDLR mutation). Start statin, cascade screening.
🍟 Adolescent with eruptive xanthomas, recurrent abdominal pain, triglycerides 2500 mg/dL. Most likely?
Lipoprotein lipase deficiency (type I hyperlipoproteinemia). Very low fat diet.
🧫 5-year-old with global developmental delay, microcephaly, hypospadias, 2-3 toe syndactyly. Low cholesterol, elevated 7-DHC. Diagnosis?
Smith-Lemli-Opitz syndrome (DHCR7 deficiency). Cholesterol supplementation.
🧠 Adolescent with progressive ataxia, dementia, cataracts, tendon xanthomas, normal cholesterol but elevated cholestanol. Diagnosis?
Cerebrotendinous xanthomatosis (CYP27A1). Chenodeoxycholic acid therapy.
🩺 Child with cholestasis, bleeding (vitamin K deficiency), and neurological deterioration. Suspected bile acid synthesis defect. Treatment?
Primary bile acid therapy (cholic acid), fat-soluble vitamins.
💊 First-line medication for pediatric familial hypercholesterolemia (age ≥10)?
Statin (atorvastatin, simvastatin) with diet and exercise.
🧬 Which genetic defect causes sitosterolemia (plant sterol accumulation)?
ABCG5 or ABCG8 mutations. Xanthomas, hemolytic anemia.
🩺 What is the treatment for homozygous FH refractory to statins and ezetimibe?
PCSK9 inhibitors + LDL apheresis (weekly).
🧪 Which apolipoprotein is defective in type I hyperlipoproteinemia (chylomicronemia)?
Lipoprotein lipase (LPL) or apolipoprotein CII (APOC2) deficiency.
💊 What is the primary therapy for cerebrotendinous xanthomatosis?
Chenodeoxycholic acid (CDCA) 15 mg/kg/day.