Elevated urinary citrate levels when:
1. Diet
- High alkaline diet
- High carbohydrate intake
- High citrate/citrus intake
- High (4-5 servings/day) dairy intake (May decrease hippurate)
- High-dose vitamin D
2. Endocrine disorders
- High estrogen levels (birth control or estrogen replacement therapies)
- Parathyroid extract or hyperparathyroidism
3. Renal function
- Renal tubular reabsorption defects
- Alkalosis, dietary alkali loads
- Hypercalcuria
4. Toxic exposures
- Lead
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High levels of citrate may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, if there are high levels of its precursor (pyruvate, malate) or if there are higher levels of its downstream products (cis-aconitate). High levels of citrate may be damaging, and can increase oxidative stress, nitric oxide (nitrosative stress), and pro-inflammatory prostaglandins. Endocrine or kidney disorders may increase citrate levels, as may dietary citrate intakes (citrus, dairy) or highly alkaline diets. Toxic metals such as lead may also increase levels.
Aconitase converts citrate into cis-aconitate and isocitrate; if inhibited then citrate will be high, but cis-aconitate and isocitrate will be low. Aconitase is the CAC enzyme most vulnerable to oxidative stress. It requires iron-sulfur clusters as co-factors. The synthesis of the iron- sulfur clusters can be supported with B2, B3, B6, zinc, and glutathione.
- Increased levels of methylmalonate, quinolinate and pyroglutamate, with decreased levels of cis-aconitate and isocitrate, may indicate poor antioxidant status. Antioxidant supports may include CoQ10, alpha-lipoic acid, vitamins C and E, curcumin, resveratrol, etc. Fresh fruits and vegetables are rich in antioxidant compounds.
If citrate, cis-aconitate and isocitrate appear imbalanced, also consider iron deficiency or anemia because the rate of conversion is related to iron status.
Citrate levels may also increase if citrate cannot be broken down outside the mitochondria in the cytoplasm. This cellular breakdown may be supported with magnesium and the use of a plant-based, low-fat diet.
Lead exposure increases oxidative stress and can inhibit aconitase. Lead can leach out of bones during and after andropause or menopause. Lead solder was not banned in housing construction until about 1990 and may still be found in drinking water.
Low leverls of citrate may occur if there are nutritional enzyme inhibitions or inherited low-activity enzyme variants on the synthesis pathway, or if there are low levels of precursor (pyruvate) available. Low-calorie diets or problems with the precursor pathways may decrease citrate levels. Lower levels of citrate may also occur if there are problems with the liver’s fatty acid beta-oxidation pathway. Low levels of citrate have been associated with chronic fatigue syndrome. Urinary tract infections may decrease urinary citrate and increase lactate and succinate excretion.
If citrate levels are low, but pyruvate and lactate levels are higher, there may be an inherited low-activity enzyme of the rate-limiting enzyme citrate synthase or inhibition due to toxic exposures.
- Arsenic or other toxic metals may prevent the conversion of pyruvate into citrate. Arsenic may be found in well water, in factory-farmed poultry, alcoholic beverages and as a pesticide contaminant in conventionally-farmed fruits and vegetables. Arsenic exposure can increase alpha-ketoglutarate and pyruvate, while citrate, succinate, and pyroglutamate levels decrease.
- Inherited low-activity citrate synthase variants may require more dietary citrate (lemonade, citrus fruits, etc.).
The beta-oxidation pathway in the liver is the primary fatty acid breakdown pathway. Inhibition of the pathway can increase adipate and suberate, and may also increase ethylmalonate and ethylsuccinate levels.
Chronic fatigue may increase pyruvate and decrease citrate, cis-aconitate, isocitrate, malate.
Citrate
