Apolipoprotein C-II (Apo-CII)
ApoC-II is the ESSENTIAL ACTIVATOR of lipoprotein lipase (LPL) — without it, LPL cannot clear triglycerides from blood. ApoC-II deficiency is a RARE genetic disorder causing SEVERE hypertriglyceridemia (TG often >1,000-2,000+) and recurrent pancreatitis. Not routine testing — ordered when investigating genetic causes of extreme triglyceride elevation. Treatment: very strict low-fat diet (10-15% fat), MCT oil supplementation, avoid alcohol. Gene therapy emerging.
Apolipoprotein C-II, or ApoC-II, is a small but essential protein that plays a critical role in triglyceride metabolism. It serves as the required activator for lipoprotein lipase (LPL), the enzyme that breaks down triglycerides in the bloodstream. Without functional ApoC-II, LPL cannot work, and triglycerides accumulate to dangerously high levels.
Why does this matter? ApoC-II deficiency, while rare, causes severe hypertriglyceridemia — triglyceride levels that can reach thousands, far above normal. This extreme elevation carries a high risk of acute pancreatitis, a potentially life-threatening condition. Identifying ApoC-II deficiency is crucial because it explains the underlying cause of severe triglyceride elevation and guides specific treatment strategies.
ApoC-II testing is not routine but becomes essential when evaluating severe hypertriglyceridemia that doesn’t respond to standard treatments or when a genetic cause is suspected, particularly in young patients with recurrent pancreatitis.
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Key Benefits of Testing
ApoC-II testing identifies a specific, treatable cause of severe hypertriglyceridemia. When triglycerides are extremely elevated without obvious cause, ApoC-II deficiency must be considered — it changes management from general triglyceride-lowering approaches to targeted strategies.
Diagnosis of ApoC-II deficiency has implications for family members, as the condition is inherited. Identifying the genetic basis allows screening and early intervention in relatives.
What Does This Test Measure?
ApoC-II testing measures the concentration or functional activity of apolipoprotein C-II protein in blood. The test may be performed as a protein level measurement or as a functional assay assessing LPL activation capacity.
The Role of ApoC-II in Triglyceride Metabolism
The key enzyme — Lipoprotein Lipase (LPL):
- LPL sits on blood vessel walls, especially in muscle and fat tissue
- It breaks down triglycerides in circulating lipoproteins (chylomicrons, VLDL)
- Released fatty acids are taken up by tissues for energy or storage
ApoC-II’s essential role:
- ApoC-II is an absolute requirement for LPL activity
- It binds to LPL and activates its triglyceride-hydrolyzing function
- Without ApoC-II, LPL cannot break down triglycerides
- Triglyceride-rich particles (chylomicrons, VLDL) accumulate in blood
Where ApoC-II Is Found
ApoC-II is synthesized primarily in the liver and circulates on various lipoprotein particles:
- VLDL (very low-density lipoprotein)
- Chylomicrons
- HDL (serves as a reservoir, transferring ApoC-II to triglyceride-rich particles when needed)
ApoC-II Deficiency
Familial ApoC-II deficiency is a rare autosomal recessive genetic disorder:
- Mutations in the APOC2 gene prevent production of functional ApoC-II
- LPL cannot be activated
- Triglycerides accumulate to extreme levels
- Typically presents in childhood or young adulthood
- Characterized by recurrent pancreatitis, eruptive xanthomas, lipemia retinalis
Why This Test Matters
Diagnoses a Specific Cause of Severe Hypertriglyceridemia
When triglycerides are severely elevated, identifying the cause is essential. ApoC-II deficiency is a specific, diagnosable cause that requires different management than other forms of hypertriglyceridemia.
Prevents Recurrent Pancreatitis
Patients with ApoC-II deficiency face repeated episodes of acute pancreatitis unless properly diagnosed and managed. Identification allows implementation of preventive strategies.
Guides Treatment Selection
ApoC-II deficiency doesn’t respond to standard triglyceride-lowering medications the way other hypertriglyceridemia does. Knowing the diagnosis prevents futile treatment attempts and directs care toward effective strategies:
- Very strict low-fat diet
- Medium-chain triglyceride (MCT) supplementation
- Emerging gene therapies and ApoC-II replacement approaches
Identifies Family Members at Risk
As an autosomal recessive condition, siblings of affected individuals have a 25% chance of being affected. Parents and other relatives may be carriers. Testing identifies who needs monitoring and dietary intervention.
Distinguishes from Other LPL Pathway Defects
Severe hypertriglyceridemia can result from LPL deficiency itself, ApoC-II deficiency, ApoA-V deficiency, or other genetic causes. ApoC-II testing helps pinpoint the specific defect.
What Can Affect Your ApoC-II?
Causes of Low or Absent ApoC-II
Genetic ApoC-II deficiency:
- Autosomal recessive inheritance
- Mutations in APOC2 gene
- Complete or near-complete absence of functional ApoC-II
- Presents with severe hypertriglyceridemia from young age
Secondary causes of low ApoC-II:
- Severe liver disease (reduced synthesis)
- Malnutrition
- Some inflammatory conditions
Factors That Don’t Significantly Affect ApoC-II
Unlike triglycerides themselves, ApoC-II levels are relatively stable and not dramatically affected by:
- Recent meals (though fasting is still recommended for consistency)
- Standard lipid-lowering medications
- Moderate dietary changes
Testing Considerations
Fasting recommended: For consistency in interpretation, fasting is typically recommended.
Timing with triglyceride levels: Testing is most informative when triglycerides are elevated — during a “flare” if the condition is episodic.
Specialized testing: ApoC-II is not part of standard lipid panels. It requires specific ordering, often at specialized laboratories.
Functional vs. quantitative: Both protein level and functional activity may be measured. Some mutations produce ApoC-II protein that doesn’t function.
When Should You Get Tested?
Severe Hypertriglyceridemia
When triglycerides are extremely elevated (especially over 1,000 or certainly over 2,000), consider ApoC-II testing as part of the evaluation for genetic causes.
Recurrent Pancreatitis with High Triglycerides
Multiple episodes of pancreatitis in the setting of severe hypertriglyceridemia strongly suggest a genetic defect in triglyceride metabolism.
Young Patients with Severe Hypertriglyceridemia
When severe triglyceride elevation presents in childhood, adolescence, or young adulthood without obvious secondary cause, genetic testing including ApoC-II is indicated.
Family History of Severe Hypertriglyceridemia or ApoC-II Deficiency
First-degree relatives of affected individuals should be evaluated.
Poor Response to Standard Treatment
When severe hypertriglyceridemia doesn’t respond to fibrates, omega-3s, and lifestyle changes, consider genetic causes including ApoC-II deficiency.
Clinical Signs Suggesting Genetic Cause
- Eruptive xanthomas (yellow skin bumps from lipid deposits)
- Lipemia retinalis (milky appearance of retinal vessels)
- Hepatosplenomegaly
- Milky (lipemic) plasma on blood draw
Understanding Your Results
ApoC-II interpretation focuses on identifying deficiency states:
Normal ApoC-II
Normal ApoC-II levels or activity indicate that ApoC-II deficiency is not the cause of hypertriglyceridemia. Other causes should be investigated — LPL deficiency, ApoA-V deficiency, secondary causes, or other genetic disorders.
Low or Absent ApoC-II
Very low or undetectable ApoC-II in a patient with severe hypertriglyceridemia confirms ApoC-II deficiency as the cause. This diagnosis:
- Explains the metabolic defect
- Guides specific dietary management
- Indicates need for genetic counseling
- May qualify patient for specialized treatments or clinical trials
Borderline Results
Some mutations cause partially functional ApoC-II. Functional assays may help clarify if borderline protein levels are clinically significant.
Heterozygous Carriers
Carriers of one defective APOC2 gene copy typically have reduced but adequate ApoC-II function. They usually don’t have severe hypertriglyceridemia but may have mildly elevated triglycerides, especially with secondary factors.
What to Do About Abnormal Results
For Confirmed ApoC-II Deficiency
Very strict low-fat diet (cornerstone of treatment):
- Fat intake often limited to 10-15% of calories (compared to typical 30-35%)
- Avoid all high-fat foods
- Requires careful meal planning and dietary counseling
- Lifetime dietary restriction needed
Medium-chain triglycerides (MCTs):
- MCTs are absorbed differently — they don’t require LPL for clearance
- Can provide dietary fat calories without raising triglycerides
- MCT oil can be used for cooking and supplementation
Avoid triggers:
- Alcohol — dramatically worsens hypertriglyceridemia
- Excess carbohydrates — converted to triglycerides
- Medications that raise triglycerides
Manage pancreatitis risk:
- Strict adherence to diet prevents most episodes
- Know warning signs of pancreatitis
- Prompt medical attention for abdominal pain
Emerging and specialized treatments:
- Gene therapy approaches under investigation
- ApoC-II replacement strategies in development
- Volanesorsen and other antisense therapies (for related conditions)
- Consider referral to specialized lipid center
Screen Family Members
Siblings and children of affected individuals should be tested. Early identification allows dietary intervention before pancreatitis occurs.
Genetic Counseling
Families benefit from genetic counseling to understand inheritance patterns and implications for family planning.
Related Health Conditions
Familial Chylomicronemia Syndrome
Broader Category: ApoC-II deficiency is one cause of familial chylomicronemia syndrome (FCS), a group of genetic disorders causing severe hypertriglyceridemia from impaired chylomicron and VLDL clearance.
Acute Pancreatitis
Major Complication: Severe hypertriglyceridemia from ApoC-II deficiency causes recurrent acute pancreatitis — the most dangerous complication and often the presenting symptom.
Lipoprotein Lipase Deficiency
Related Condition: LPL deficiency causes a similar syndrome to ApoC-II deficiency — both result in inability to clear triglyceride-rich particles. ApoC-II testing distinguishes between them.
Severe Hypertriglyceridemia
The Clinical Manifestation: ApoC-II deficiency presents as severe hypertriglyceridemia. Understanding the specific cause guides treatment and prognosis.
Why Testing Matters
ApoC-II testing transforms unexplained severe hypertriglyceridemia into a specific, manageable diagnosis. Identifying ApoC-II deficiency prevents futile treatment attempts, guides effective dietary management, and protects patients from recurrent life-threatening pancreatitis. For affected families, diagnosis enables screening and prevention in relatives.
Related Biomarkers Often Tested Together
Triglycerides — Severely elevated in ApoC-II deficiency. The clinical indicator prompting evaluation.
Lipoprotein Lipase Activity — Tests LPL function directly. Low in LPL deficiency, normal in ApoC-II deficiency (but LPL can’t work without ApoC-II).
Apolipoprotein C-III — Another apolipoprotein affecting triglyceride metabolism (inhibits LPL, unlike ApoC-II which activates it).
Total Cholesterol — Part of complete lipid assessment.
Lipase — Pancreatic enzyme elevated during pancreatitis episodes.
Note: Information provided in this article is for educational purposes and doesn’t replace personalized medical advice.
Frequently Asked Questions
Apolipoprotein C-II (ApoC-II) is a small protein that activates lipoprotein lipase (LPL), the enzyme that clears triglycerides from blood. Without ApoC-II, LPL cannot function, and triglycerides accumulate to dangerously high levels.
ApoC-II deficiency is a rare genetic disorder where mutations prevent production of functional ApoC-II. Without this activator, LPL cannot clear triglycerides, resulting in severe hypertriglyceridemia and high risk of pancreatitis.
ApoC-II deficiency is very rare — estimated at fewer than 1 in 1 million people. However, it should be considered in anyone with unexplained severe hypertriglyceridemia, especially presenting at a young age.
The main manifestations include severe hypertriglyceridemia, recurrent acute pancreatitis (often the presenting symptom), eruptive xanthomas (yellow skin bumps), lipemia retinalis, and hepatosplenomegaly.
Yes — the cornerstone is a very strict low-fat diet (often 10-15% of calories from fat). Medium-chain triglycerides (MCTs) can provide fat calories safely. Emerging therapies including gene therapy are under development.
Yes — it’s autosomal recessive, meaning both parents must carry a defective gene copy. Each sibling has a 25% chance of being affected. Genetic counseling is recommended for affected families.
Consider testing for severe hypertriglyceridemia (especially triglycerides over 1,000), recurrent pancreatitis with high triglycerides, young age of onset, poor response to standard treatments, or family history of the condition.
No — ApoC-II is a specialized test ordered when genetic hypertriglyceridemia is suspected. It requires specific ordering, often performed at specialized laboratories.
References
Key Sources:
- Brahm AJ, Hegele RA. Chylomicronaemia — current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362.
- Burnett JR, Hooper AJ. Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev. 2008;29(1):11-26.
- Gaudet D, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200-2206.
