What are the implications of a total cholesterol level of 98 mg/dL in a patient?

Very Low Total Cholesterol (98 mg/dL): Clinical Implications

A total cholesterol of 98 mg/dL is unusually low and warrants investigation for underlying causes rather than celebration, as this level may signal occult disease, malnutrition, or declining health status—particularly in elderly patients—despite the cardiovascular benefits of low LDL cholesterol in those on lipid-lowering therapy.

Understanding the Context of Very Low Total Cholesterol

The interpretation of a total cholesterol of 98 mg/dL depends critically on whether this represents:

• Treated hyperlipidemia: If the patient is on intensive statin therapy (especially high-dose statins or combination therapy with ezetimibe/PCSK9 inhibitors), this may represent appropriate aggressive LDL-lowering in a very high-risk cardiovascular patient 1, 2
• Untreated baseline level: If this is a naturally occurring level without lipid-lowering therapy, this raises significant concern for underlying pathology 3, 4

Cardiovascular Risk Perspective

When Low Cholesterol is Beneficial

For patients on lipid-lowering therapy with established cardiovascular disease:

• Very low LDL-C targets (<70 mg/dL) are appropriate for very high-risk patients, including those with established CVD plus multiple major risk factors, severe and poorly controlled risk factors, metabolic syndrome with high triglycerides (≥200 mg/dL) plus non-HDL-C ≥130 mg/dL with low HDL-C (<40 mg/dL), or acute coronary syndromes 5, 1
• The Heart Protection Study and PROVE IT trial demonstrated that no threshold exists below which cardiovascular benefit ceases—even patients achieving LDL-C <25 mg/dL continue to show risk reduction without significant safety concerns 5
• Intensive LDL-lowering to median levels of 62 mg/dL reduced major cardiovascular events by 16% compared to achieving 95 mg/dL 2

Safety of Very Low LDL Cholesterol on Therapy

• Clinical trials with statin therapy have not identified significant side effects from LDL lowering per se 1
• Patients with PCSK9 loss-of-function mutations living with lifelong low LDL-C show no evidence of neurocognitive impairment, higher incidence of diabetes, cataracts, or stroke 5
• Pooled data from 14 alirocumab trials showed patients with LDL-C <25 mg/dL had no significant difference in gonadal hormones or fat-soluble vitamins A, D, and K 5

Red Flags: When Low Cholesterol Signals Danger

Untreated Low Cholesterol as a Warning Sign

In patients not on lipid-lowering therapy, total cholesterol <160 mg/dL is associated with:

• Increased in-hospital mortality in elderly hospitalized patients (5.2% mortality with cholesterol <160 mg/dL vs. 1.7% with cholesterol ≥240 mg/dL, P<0.001) 3
• Higher all-cause mortality risk in community-dwelling elderly (hazard ratio 0.53-0.57 for those with cholesterol >189 mg/dL compared to <189 mg/dL) 4
• These associations persist even after adjustment for comorbid conditions, nutritional status, inflammatory markers, and frailty indicators 3, 4

Underlying Causes to Investigate

When encountering unexplained low total cholesterol, evaluate for:

• Malnutrition or malabsorption syndromes (low serum albumin, low serum iron) 6
• Chronic liver disease (hepatic synthetic dysfunction) 3
• Hyperthyroidism (increased cholesterol catabolism)
• Malignancy (occult cancer causing cachexia) 4
• Chronic inflammatory conditions (sepsis, severe infections) 3
• Severe heart failure (cardiac cachexia)

Practical Clinical Algorithm

Step 1: Determine Treatment Status

• Is the patient on lipid-lowering therapy?
  • If YES → Proceed to Step 2
  • If NO → Proceed to Step 3

Step 2: For Patients on Lipid-Lowering Therapy

• Obtain fasting lipid panel to calculate LDL-C, HDL-C, and triglycerides 5
• If LDL-C <70 mg/dL in a very high-risk patient (established CVD with multiple risk factors, metabolic syndrome, or post-ACS), this is appropriate and should be continued 5, 1
• If LDL-C <70 mg/dL in a moderate-risk patient without established CVD, consider whether this represents overtreatment and discuss risk-benefit with the patient 5
• Monitor for adequate HDL-C levels (should be >40 mg/dL in men, >50 mg/dL in women) to ensure balanced lipid profile 2

Step 3: For Patients NOT on Lipid-Lowering Therapy

• Obtain complete metabolic panel including albumin, liver function tests, and inflammatory markers (CRP, ESR) 3, 6
• Assess nutritional status: weight loss, BMI, dietary intake, serum iron 6
• Screen for occult malignancy: age-appropriate cancer screening, review of systems for constitutional symptoms 4
• Evaluate thyroid function: TSH, free T4 4
• Consider genetic causes: family history of hypobetalipoproteinemia (though this is rare) 5

Common Pitfalls to Avoid

• Assuming all low cholesterol is protective: In untreated patients, very low cholesterol often reflects underlying disease rather than cardiovascular protection 4, 6
• Ignoring HDL-C in patients with "desirable" total cholesterol: 60% of patients with total cholesterol <200 mg/dL and CAD had HDL-C <35 mg/dL, indicating that total cholesterol alone is insufficient for risk assessment 7
• Undertreating high-risk patients with baseline low LDL-C: Even if baseline LDL-C is already <100 mg/dL in a high-risk patient with established CVD, statin therapy should still be initiated to achieve the <70 mg/dL target 5, 2
• Failing to exclude early deaths in epidemiological interpretation: The association between low cholesterol and mortality is largely explained by reverse causation (illness causing low cholesterol) when deaths within the first year are excluded 6

Key Takeaway for Total Cholesterol of 98 mg/dL

If this patient is on intensive lipid-lowering therapy for established cardiovascular disease, obtain a complete lipid panel to confirm appropriate LDL-C lowering (<70 mg/dL) with adequate HDL-C, and continue therapy 1, 2. If this patient is NOT on lipid-lowering therapy, this represents a significant red flag requiring comprehensive evaluation for malnutrition, chronic disease, malignancy, or other underlying pathology 3, 4, 6.