Hypertriglyceridemia

from https://emedicine.medscape.com/article/126568-print

Definition & Overview

• Hypertriglyceridemia (HTG) = elevated fasting serum triglyceride (TG) levels (>150 mg/dL or >1.7 mmol/L).
• Common in developed nations; associated with obesity, diabetes, sedentary lifestyle.
• Risk factor for:
  • Atherosclerotic cardiovascular disease (ASCVD)
  • Acute pancreatitis (TG >1000 mg/dL)
  • Chylomicronemia syndrome

🔬 Pathophysiology

• TGs = 3 fatty acids + glycerol; transported via:
  • Chylomicrons (exogenous): from diet
  • VLDL (endogenous): from liver
• Clearance via lipoprotein lipase (LPL), requires apo C-II.
• Atherogenic potential primarily due to remnants (chylomicron & VLDL remnants).

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⚛️ Causes of Hypertriglyceridemia Primary (Genetic)

Fredrickson Type	Lipid Pattern	Lipoprotein Elevated	Key Features
I	↑ TG	Chylomicrons	Rare, LPL/apo C-II deficiency
IIa	↑ LDL-C	LDL	Familial hypercholesterolemia
IIb	↑ LDL + TG	LDL + VLDL	Mixed hyperlipidemia
III	↑ TG + Chol	IDL, remnant particles	Apo E2 homozygous + metabolic trigger
IV	↑ TG (<1000 mg/dL)	VLDL	Common in obesity/DM
V	↑ TG (>1000 mg/dL) + ↑ chol	VLDL + Chylomicrons	Pancreatitis risk

Secondary (Acquired)

• Endocrine: Uncontrolled diabetes (esp. DKA), hypothyroidism, Cushing’s
• Renal: Nephrotic syndrome, CKD
• Medications:
  • Thiazides
  • beta-blockers
  • OCPs
  • estrogen
  • isotretinoin
  • antipsychotics
  • steroids
  • protease inhibitors
• Others:
  • Alcohol
  • pregnancy
  • high-carb diet
  • obesity

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Key History & Risk-Factor Clues

• Cardiometabolic comorbidities
  • Diabetes mellitus (type 1 or 2)
  • Hypertension
  • Obesity (BMI > 30 kg/m²)
• Atherosclerotic disease or equivalent
  • Personal history of CHD, abdominal aortic aneurysm, carotid or peripheral arterial disease
  • 10-year CVD risk ≥ 7.5 % on validated calculator
• Family & lifestyle factors
  • Premature CVD in ♂ < 50 y / ♀ < 60 y first-degree relative
  • Current tobacco use
  • Diet rich in refined carbohydrates or high-risk alcohol intake
• Lipid profile abnormalities (AACE)
  • ↑ Total-C, ↑ non-HDL-C, ↑ LDL-C, persistently ↑ TG
• Secondary causes to ask about
  • Poorly controlled diabetes (check HbA1c)
  • Hypothyroidism, CKD, pregnancy
  • Drugs: oestrogens/OCP, β-blockers, thiazides, retinoids, atypical antipsychotics, HIV PI
  • Hormone replacement, anabolic steroids
• Family history of primary dyslipidaemia (e.g. familial chylomicronaemia, FCHL, familial dysbetalipoproteinaemia)

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📋 Clinical Features

Asymptomatic unless TG >1000–2000 mg/dL

Symptoms:

• GI: Epigastric/chest/back pain, nausea, vomiting (pancreatitis or chylomicronemia)
• Skin: Xanthomas (eruptive, tuberous, palmar)
• Eyes: Corneal arcus, xanthelasma, lipemia retinalis
• Neuro: Memory loss, depression (chylomicronemia syndrome)

Signs:

• Tender abdomen, hepatosplenomegaly
• Fundoscopy: Lipemia retinalis (TG >2000–4000 mg/dL)
• Skin: Eruptive xanthomas (TG >1000 mg/dL)

Focused Examination Checklist

• Skin – look for eruptive, tuberous or palmar xanthomas
• Eyes – corneal arcus, xanthelasma; fundus for lipaemia retinalis
• Abdomen – tenderness (pancreatitis), hepatomegaly ± splenomegaly
• Peripheral pulses & ABI – evidence of PAD
• Body habitus – central obesity, BMI documentation

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🧪 Investigations

Baseline Labs

• Fasting lipid profile (12h fast): TG, LDL, HDL, Total Chol
• Fasting BGL, HbA1c: Rule out DM
• TSH: Hypothyroidism
• LFTs, GGT (alcohol-related or NAFLD)
• UECs, urinalysis
• Visual chylomicron test: Refrigeration → creamy supernatant (chylomicrons)
• LDL calc not valid if TG >4.5 mmol/L
  • The ratio of TG:cholesterol in VLDL varies significantly when TGs are high (especially when chylomicrons or remnant particles are present).
  • Above 4.5 mmol/L:
    • Chylomicrons may appear (non-VLDL TG-rich lipoproteins)
    • VLDL estimation becomes unreliable
    • Therefore, LDL-C calculation becomes inaccurate or misleading
  • What to Do Instead
    • Use Non-HDL Cholesterol:
      • A validated alternative when TGs are elevated.
      • Non-HDL-C = Total Cholesterol – HDL-C
      • It includes LDL + VLDL + IDL + remnants = better ASCVD predictor than LDL-C when TGs high.
    • RACGP, NVDPA, and pathology labs all recommend avoiding calculated LDL-C when TG >4.5 mmol/L.

Advanced/Specialty Tests

• Screen for NAFLD/NASH if transaminases elevated (liver US).
• If primary disorder suspected
  • apoB
  • Apo E genotyping: Confirms type III if homozygous for apo E2
  • lipoprotein electrophoresis / ultracentrifugation.
  • homocysteine: Emerging vascular risk markers
• Screen first-degree relatives with fasting lipids.

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⚠️ Complications

• Pancreatitis: TG >1000–2000 mg/dL (≥5.6–11.2 mmol/L)
• Chylomicronemia syndrome: Recurrent abdominal pain, eruptive xanthomas, lipemia
• Atherosclerosis/CHD: Especially in type IIb, III, and IV
• Cognitive changes (rare): In severe chylomicronemia

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⚕️ Management

1. Non-Pharmacologic (First-line for all)

• Weight loss
• Low-fat, low-sugar, low-carbohydrate diet
• Reduce alcohol
• Regular aerobic exercise
• Treat secondary causes (e.g. DM, hypothyroid)

2. Pharmacologic

Class	Drug Examples	Effect on TG	Notes
Statins	Atorvastatin, Rosuvastatin	↓ 20–40%	Also ↓ LDL; 1st line if ASCVD risk high
Fibrates	Fenofibrate, Gemfibrozil	↓ 30–50%	1st line if TG >10 mmol/L; watch renal fxn
Omega-3 FAs	Icosapent ethyl (Vascepa), Lovaza	↓ 20–50%	Use ≥4 g/day; EPA-only (Vascepa) preferred
Niacin	Niacor, Niaspan	↓ 30–50%	Limited by flushing, hepatotoxicity
Insulin	In DKA/severe HTG	Rapid TG ↓ via LPL activation
Olezarsen (2024)	APOC3 inhibitor	↓ ~50–60%	FCS; SC injection; new targeted therapy

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🩺 Prognosis

• Elevated TG → ↑ risk of CHD, stroke (especially if low HDL)
• Pancreatitis risk ↑ if TG >10 mmol/L
• Long-term control (TG <4.5 mmol/L) essential for reducing risk

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Management Pathway

🔹 Step 1: Identify & Treat Secondary Causes

• Uncontrolled diabetes mellitus (check HbA1c)
• Hypothyroidism (TSH)
• Nephrotic syndrome
• Alcohol use
• Medications (thiazides, beta-blockers, estrogen, isotretinoin, etc.)

🔹 Step 2: Lifestyle Modification (Always)

Intervention	Evidence / targets
Weight loss 5–10 %	TG ↓ up to 20 %
Mediterranean / low-GI diet, < 10 % total energy from sat-fat	TG ↓, post-prandial TRL ↓
Aerobic activity ≥ 150 min/wk	TG ↓ ~10 %
Fish intake ≥ 2 serves/wk (if no seafood allergy)	ASCVD benefit

🔹 Step 3: Pharmacologic Focus by TG Level

TG Level (mmol/L)	Management Priority	First-line	Add-on/Second-line
<4.5	Focus on LDL-C lowering (ASCVD risk)	Statin	Ezetimibe, PCSK9i, Omega-3 (if ASCVD risk ↑)
4.5–10	Mixed focus: ASCVD + pancreatitis prevention	Statin	Fibrate ± Omega-3 ± Niacin (cautious)
>10	Priority = Prevent acute pancreatitis	Fibrate	Omega-3 + Statin ± Insulin ± Olezarsen ± Plasmapheresis

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Specific Scenarios

🧠 1. T2DM and Metabolic Syndrome

• Mechanism: Insulin resistance → ↑ VLDL production, ↓ LPL activity
• Treatment goals:
  • HbA1c <7%
  • TG <1.7 mmol/L ideally (at least <2.2 mmol/L)
• Therapy:
  • Statins: First-line if ASCVD risk
  • Add icosapent ethyl (if TG >1.7 mmol/L + high ASCVD risk)
  • Consider fibrate (esp. fenofibrate) if TG >4.5–10 mmol/L
  • Avoid niacin due to potential hyperglycaemia
• Trials: FIELD (fenofibrate in diabetes), REDUCE-IT (icosapent ethyl)

2. Pregnancy

• Risks: Oestrogen-driven ↑ TG (especially 3rd trimester) → pancreatitis risk
• Approach:
  • Dietary fat restriction (<20% of total kcal)
  • Omega-3 fatty acids (preferred: EPA/DHA from fish oil)
  • Strict glycaemic control (in GDM or pre-existing diabetes)
  • Fibrates, statins, niacin contraindicated
  • Hospitalisation + insulin infusion ± plasmapheresis if TG >20 mmol/L or pancreatitis
• Monitoring: Lipemic serum on routine bloods warrants urgent TG check

3. Paediatrics and Adolescents

• Common causes: Obesity, T2DM, familial HTG
• Approach:
  • First-line: lifestyle/diet, reduce sugary drinks, exercise
  • Fibrate use: Limited to severe HTG (specialist guidance)
  • Statins not routinely used unless LDL elevation present

4. Chronic Kidney Disease (CKD)

• Mechanism: ↓ LPL activity, ↑ TG-rich particles
• Considerations:
  • Fibrates may increase creatinine → use fenofibrate with dose adjustment or gemfibrozil (less renally cleared)
  • Statins recommended if ASCVD risk (avoid simvastatin >20 mg with gemfibrozil)
  • Omega-3 well tolerated in CKD
• eGFR thresholds:
  • Fenofibrate contraindicated if eGFR <30 mL/min
  • Dose reduction for eGFR 30–60 mL/min

5. Familial Chylomicronemia Syndrome (FCS)

• TG >10–20 mmol/L from childhood; risk of recurrent pancreatitis
• Pathophys: LPL, apoC-II, apoA5, GPIHBP1 mutations
• Treatment:
  • Very low-fat diet (<15% kcal)
  • Strict avoidance of alcohol, sugar
  • Olezarsen (2024): APOC3 inhibitor SC weekly (↓ TG by ~60%)
  • Plasmapheresis for acute pancreatitis episodes
• Statins ineffective due to lack of VLDL/LDL involvement

6. Established ASCVD

• Statins = first-line for LDL/ASCVD risk control
• If TG remains >1.7 mmol/L despite statins:
  • Icosapent ethyl if LDL 1.0–2.6 mmol/L and high CV risk (REDUCE-IT criteria)
  • Fibrates/niacin may be considered (if TG >4.5 mmol/L or HDL very low)
• LDL targets: <1.8 mmol/L (or <1.4 mmol/L for very high-risk groups)

7. Acute Pancreatitis Due to TGs

• Suspect if TG >11.2 mmol/L (especially if >20 mmol/L)
• Initial management:
  • NPO, IV fluids
  • IV insulin (± glucose) to activate LPL
  • Consider heparin (short-lived LPL mobilization)
  • Plasmapheresis: For very high TG, refractory cases, or severe pancreatitis

Drug Summary Table

Drug class (PBS status)	TG ↓	Usual adult dose	Key cautions / monitoring	ASCVD evidence
High-intensity statin (PBS)	10–30 %	Atorvastatin 40-80 mg or rosuvastatin 20-40 mg nocte	LFTs @ baseline & 8-12 wks; CK if myalgia	Strong ASCVD ↓ (independent of TG)
Fenofibrate (PBS item 13587D/9023X 145 mg od) Pharmaceutical Benefits Scheme	30–50 %	145 mg daily (48 mg if eGFR 30-60)	eGFR & LFTs q 6-12 m; avoid biliary disease	FIELD: microvascular; ASCVD neutral overall
Gemfibrozil (PBS item 1453L 600 mg bd) Pharmaceutical Benefits Scheme	35–55 %	600 mg 30 min pre-breakfast & dinner	Do NOT combine with statin (↑ myopathy)	Older ASCVD data inconsistent
Icosapent ethyl (EPA-only) – TGA-approved as Vazkepa 2 g bd (not PBS, private ~$330/m) Therapeutic Goods Administration (TGA)	20–30 %	2 g twice daily with meals	Monitor AF/flutter in high-risk; mild ↑ bleeding risk	REDUCE-IT MACE ↓ 25 %
Prescription Ω-3 ethyl esters 1 g caps (EPA + DHA) – private	20–50 % (dose-response)	2–4 g/day	May ↑ LDL-C (DHA fraction); GI taste	No ASCVD benefit in STRENGTH
Niacin (not marketed Aus; compounded)	10–30 %	ER 1–2 g nocte	Flushing, ↑ glucose/uric acid, hepatotoxic	AIM-HIGH/HPS2: no benefit
Severe or refractory	Inpatient insulin infusion (0.05–0.1 U/kg/h) ± plasmapheresis for pancreatitis; consider volanesorsen, olezarsen (ApoC-III ASO) or evinacumab (ANGPTL3 mAb) under specialist/clinical-trial access MDPISpringerLink	TG ↓ > 70 %	Thrombocytopaenia (volanesorsen), infusion reactions	Emerging data; not PBS-listed

Combination notes

• Statin + fenofibrate acceptable (use fenofibrate; avoid gemfibrozil).
• Statin + EPA (icosapent ethyl) is evidence-based for high ASCVD risk with TG ≥ 1.7 mmol/L.

Agent	Cost to patient (≤ concession)	Typical pack
Fenofibrate 145 mg	$31.60 / 30 tabs Pharmaceutical Benefits Scheme	1 tab daily
Gemfibrozil 600 mg	$28.26 / 60 tabs Pharmaceutical Benefits Scheme	1 tab bd
Icosapent ethyl (Vazkepa) 1 g	Private (~$330/m) Therapeutic Goods Administration (TGA)	2 caps bd
Prescription Ω-3 ethyl esters 1 g	Private	2–4 caps/day
Niacin ER	—	1–2 g nocte