Low levels of 3-Hydroxyisovaleric (beta-hydroxyisovalerate) may occur if there are low levels of precursors (leucine), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited. The enzyme that converts leucine into beta- hydroxyisovalerate is vitamin B6 dependent and this step in the BCAA breakdown pathway is shared by all of the BCAAs.

Either a nutritional deficiency or an inherited metabolic disorder may decrease the levels of all the BCAA-derived analytes (alpha- ketoisovalerate, alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, beta-hydroxyisovalerate).

• Consider supporting synthesis with vitamin B6.
  • If B6 is deficient then alpha-ketoglutarate, fumarate, kynurenate, para-hydroxyphenyllactate, alpha-hydroxybutyrate, para-hydroxyphenylacetate and neurotransmitters may also be lower than expected.
• BCAA supplementation may have beneficial effects in patients with muscle wasting, which can occur after acute critical illness or with chronic conditions such as cirrhosis, kidney failure, etc.

Elevated urinary beta-hydroxyisovalerate may occur with:

• Diabetes or metabolic syndrome
• Diet
  • Biotin deficiency
  • High protein diet or amino acid supplementation
  • BCAA or L-leucine supplementation

• Cardiovascular disorders or high blood pressure

• Inborn errors of metabolism

  • These disorders are usually diagnosed in infancy

• Liver disorders

• Medications (carbamazepine and/or phenytoin). Check all medications with a pharmacist.

• Obesity

• Smoking

High levels of 3-Hydroxyisovaleric (beta-hydroxyisovalerate) may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, if there are high levels of precursors (leucine, BCAAs), or if there are higher levels of its downstream products.

Higher levels of circulating BCAAs have been associated with obesity, metabolic syndrome, cardiovascular and hypertension risks. Higher circulating levels of leucine and isoleucine have been associated with cardiovascular risk. The risk appears to be associated with low-activity enzymes in the breakdown pathway. Higher levels of beta-hydroxyisovalerate may inhibit mitochondrial function. Medications may increase levels; check all medication use with a pharmacist. Inborn errors of metabolism, such as maple syrup urine disease, increase levels of alpha keto acids which act as neurotoxins in the central nervous system.

• Consider supporting the breakdown of beta-hydroxyisovalerate with biotin.
• Urinary orotate levels may increase if liver disorders, urea cycle disorders or other inherited metabolic disorders are present. Adipate and suberate may also increase if liver disorders are present.
  • Inborn errors of metabolism may increase the levels of all the keto-acids (alpha-ketoisovalerate, alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, beta-hydroxyisovalerate).
•  Evaluate risk of metabolic syndrome or type II diabetes if indicated.