Metanephrines are breakdown products of catecholamines, the body’s primary “fight-or-flight” stress hormones, such as adrenaline (epinephrine) and noradrenaline (norepinephrine). Measuring metanephrines in urine typically screens for rare tumors that produce excess hormones, resulting in high levels. A low urinary metanephrine result is less common. It usually points toward either a genuine reduction in the body’s stress hormone production or, more frequently, an error in the testing process. Understanding the causes requires distinguishing between true physiological changes and external factors that interfere with the measurement.
Understanding Metanephrines and Their Measurement
The body relies on catecholamines for its immediate response to stress, regulating functions like heart rate, blood pressure, and energy mobilization. These hormones are synthesized primarily in the adrenal glands and in nerve cells throughout the sympathetic nervous system. Once released, catecholamines act quickly before being cleared from the bloodstream.
The body metabolizes catecholamines into inactive compounds, known as metanephrines, using the enzyme catechol-O-methyltransferase (COMT). Epinephrine is converted into metanephrine, and norepinephrine is converted into normetanephrine. Measuring metanephrines in a 24-hour urine collection assesses the body’s total catecholamine production activity over a full day. Since these breakdown products are continuously excreted by the kidneys, the 24-hour urine test is the standard method for gauging the long-term output of these stress hormones.
Physiological Causes of Low Levels
A truly low metanephrine result indicates decreased baseline production of precursor catecholamines, suggesting lower sympathetic nervous system activity. A specific cause relates to adrenal function, particularly primary adrenal insufficiency, such as Addison’s disease.
Adrenal Insufficiency
The conversion of norepinephrine to epinephrine requires high local concentrations of glucocorticoids within the adrenal gland. In adrenal insufficiency, this local glucocorticoid deficiency impairs the enzyme phenylethanolamine-N-methyltransferase (PNMT), which is necessary for the final step of epinephrine synthesis. This results in a genuine reduction in epinephrine and its metabolite, metanephrine.
Other Physiological Reductions
Genuinely reduced catecholamine output may also be observed in individuals with severe chronic illnesses or extreme malnutrition, where the body’s metabolic state is significantly depressed. Low levels of norepinephrine products have been noted in some chronic neurological conditions, such as Parkinson’s disease, reflecting a deficiency in the sympathetic nervous system. These physiological causes are far less common than external or test-related factors that result in a low reading.
External Factors Causing False Low Readings
The most common reason for a low metanephrine result is an error in the sample collection procedure, not a medical condition. The test requires a complete collection of all urine produced over a full 24-hour period to accurately capture the total daily output of metabolites. An incomplete collection, such as missing one or more voids, artificially lowers the total measured amount, leading to a false low result. Laboratories often measure urinary creatinine alongside metanephrines to check for the completeness of the collection, as creatinine excretion is relatively stable.
Specific medications can also interfere with catecholamine metabolism, leading to a measured result lower than the true physiological level. Certain non-metformin antidiabetic drugs (NMADs) and some antidepressants decrease metanephrine excretion. This effect often occurs because these drugs interfere with the activity of PNMT, reducing the production of metanephrine. While dietary changes like extreme fasting can influence baseline levels, medication interference and incomplete collection remain the most significant reasons for a false low measurement.
Clinical Significance and Follow-Up
The clinical concern for a low metanephrine result is generally low compared to the urgency of an elevated result, which suggests a hormone-secreting tumor. When a low result is returned, the first step is to rule out technical errors, given the complexity of the 24-hour urine collection process. Clinicians typically review the patient’s medication list for any drugs known to interfere with catecholamine metabolism or the laboratory assay.
If the initial low result is suspicious, the most common follow-up is to repeat the 24-hour urine collection to ensure a complete sample. The negative predictive value of the test is high, meaning a normal or low result effectively rules out a catecholamine-secreting tumor. A low reading only warrants extensive further investigation if the patient has other severe symptoms suggesting a generalized endocrine or neurological problem.