# Fatigue
URL: https://genohealth.app/symptoms/fatigue
Type: Symptom
Evidence: Strong evidence
Last reviewed: 2025-06-30

## Intro
Most chronic fatigue has a biological cause that shows up on basic labs. Before assuming stress or sleep is the problem, it's worth ruling out iron deficiency, vitamin D and B12 status, thyroid function and methylation issues — particularly if the fatigue persists despite normal sleep.

## Summary
Persistent low energy has dozens of causes — but a small set of biomarkers and genetic variants explain most chronic cases.

## Key facts
- Top biomarker: Ferritin < 50 ng/mL
- Other key labs: 25(OH)D, B12, TSH, free T3
- Common genetic links: MTHFR, HFE, COMT

## Most common biomarker drivers
- Iron deficiency — ferritin below 50 ng/mL often causes symptoms before anemia develops
- Vitamin D below 30 ng/mL — fatigue and muscle weakness are early signs
- B12 deficiency — pair B12 with MMA for true status
- Subclinical hypothyroidism — TSH > 2.5 with low-normal free T3
- High homocysteine — flags methylation inefficiency, often MTHFR-related

## Genetic context
- MTHFR C677T/A1298C — impaired methylation, often with high homocysteine
- HFE C282Y/H63D — iron overload in some, but heterozygotes occasionally run lower iron
- COMT Met/Met — slower catecholamine clearance, fatigue under stress is common
- VDR variants — same blood 25(OH)D can feel insufficient to tissues

## Practical next steps
- Run a complete blood count, ferritin, 25(OH)D, B12, TSH, free T3 and homocysteine
- Address sleep quality (apnea screen if snoring or AM headache)
- Investigate gut absorption if multiple nutrients run low
- Discuss results with a clinician — fatigue with weight change, night sweats or red-flag symptoms deserves prompt evaluation

## Related (knowledge graph)

### Biomarkers
- Ferritin (/biomarkers/ferritin): Iron deficiency (ferritin < 50) is one of the most common reversible causes of chronic fatigue. [Strong evidence]
- 25(OH)D (/biomarkers/25-oh-vitamin-d): Low vitamin D commonly presents with fatigue and muscle weakness. [Moderate evidence]

## FAQ
**Q: Can low ferritin cause fatigue without anemia?**
A: Yes. Many people feel symptomatic when ferritin drops below 50 ng/mL even with normal hemoglobin. Repleting iron stores typically resolves it.

**Q: Does MTHFR cause fatigue?**
A: Indirectly — by impairing methylation when B-vitamin intake is suboptimal. Correcting folate and B12 status often improves energy in MTHFR carriers with high homocysteine.

## Citations
- Camaschella, NEJM 2015 (PMID 25946282): Iron deficiency without anemia is a common cause of fatigue and is corrected by iron repletion.

Disclaimer: Informational only — not medical advice.