Magnesium is an essential ion in the human body, playing an important role in
practically every major metabolic and biochemical process, supporting and
maintaining cellular processes critical for human life. Magnesium plays an
important physiological role, particularly in the brain, heart, and skeletal
muscles. As the second most abundant intracellular cation after potassium, it
is involved in over 600 enzymatic reactions including energy metabolism and
protein synthesis. Intracellular magnesium stores are found in high
concentration in mitochondria, where this element plays a pivotal role in the
synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and
inorganic phosphate.1

Measurement of magnesium levels is used as an index to (1) metabolic activity
in the body such as, carbohydrate metabolism, protein synthesis, nucleic acid
synthesis, contraction of muscular tissue and (2) renal function, because 95%
of magnesium is filtered through the glomerulus is reabsorbed in the tubules.2

**Covered Indications**

Magnesium testing is considered reasonable and necessary under the following
conditions:

1\. Hypomagnesemia which can be induced by 2 major mechanisms:
gastrointestinal or renal losses. Symptoms of low magnesium include: weakness,
muscle cramps, confusion, irregular heartbeat, seizures.

Conditions which can produce hypomagnesemia include but are not limited to the
following2:

  *     *       * cardiac arrhythmias
      * proton pump inhibitors
      * alcohol
      * uncontrolled diabetes mellitus
      * hypercalcemia
      * posttransplant patients
      * other acquired tubular dysfunction
      * malabsorption syndromes
      * familial renal magnesium wasting
      * volume expansion
      * aminoglycoside antibiotics nephrotoxicity
      * amphotericin B nephrotoxicity
      * cisplatin
      * pentamidine
      * calcineurin inhibitors
      * digoxin
      * malabsorption syndromes
      * parenteral alimentation with inadequate magnesium content
      * diarrhea
      * diabetic ketoacidosis
      * diuretic therapy
      * hyperaldosteronism
      * hypoparathyroidism
      * hyperthyroidism
      * prolonged intravenous (IV) therapy
      * prolonged nasogastric suction
      * antibodies targeting the epidermal growth factor (EGF) receptor

2\. Hypermagnesemia which can be induced in 2 settings: when kidney function
is impaired and /or when a large magnesium load is given, whether
intravenously, orally, or as an enema. Symptoms of high magnesium include:
muscle weakness, fatigue, nausea and vomiting, trouble breathing, cardiac
arrest.

Conditions which can produce hypermagnesemia include but are not limited to
the following2:

  *     *       * kidney impairment
      * magnesium infusion
      * oral magnesium ingestion
      * magnesium enemas
      * familial hypocalciuric hypercalcemia
      * hypercatabolic states, such as tumor lysis syndrome
      * diabetic ketoacidosis
      * lithium ingestion
      * milk alkali syndrome
      * adrenal insufficiency
      * rhabdomyolysis

**Limitations**

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Services that are not reasonable and necessary cannot be covered by Medicare
as published in CMS Internet-Only Manual, Pub. 100-08, Medicare Program
Integrity Manual, Chapter 13, 13.5.4 Reasonable and Necessary Provision in an
LCD and under Title XVIII of the Social Security Act 1862(a)(1)(A).

Schelling JR (1999) reported a case study of severe symptomatic
hypermagnesemia that resulted from excess exogenous magnesium intake in a
patient with renal failure. In conclusion, this report highlights that
symptomatic hypermagnesemia is often iatrogenic, and caution should be used
before prescribing magnesium containing medications in the context of acute
renal failure.4

Tong GM (2005) reviewed magnesium deficiency in critical illness by discussing
its causes and its clinical implications based on the available clinical
trials. The use of magnesium therapy is supported by clinical trials in the
treatment of symptomatic hypomagnesemia and preeclampsia and is recommended
for torsades de pointes.5

Khan (2013) studied 3530 participants from the Framingham Offspring Study and
were free of atrial fibrillation (AF) and cardiovascular disease (CVD). They
used Cox proportional hazard regression analysis to examine the association
between serum magnesium at baseline and risk of incident AF. They concluded
that low serum magnesium was associated with the development of AF in a
longitudinal, community-based cohort over 20 years of follow up. They found
that those in the lowest quartile of serum magnesium were approximately 30%
more likely to develop AF than those in the upper 3 quartiles. Although
previous studies have reported an association between low serum magnesium and
AF in the context of cardiac surgery, the present study was the first to
demonstrate this association in the broader community.6

Kieboom (2016) studied the association of serum magnesium levels with both
coronary heart disease (CHD) and sudden cardiac death (SCD) within the
Rotterdam Study, a prospective population-based cohort study among middle-aged
and elderly persons with adjudicated end points and long term follow up. In
this prospective population-based cohort study among 9820 participants with a
median follow-up of 8.7 years, they found that low serum magnesium was
associated with an increased risk of CHD mortality and SCD. When they excluded
SCD from the CHD mortality end point, they found that higher serum magnesium
levels were associated with a lower risk of non-sudden CHD mortality.7

Rooney (2020) using data from over 2000 older adult participants of the
Atherosclerosis Risk in Communities (ARIC) Study, characterized cross-
sectional associations of serum magnesium concentrations across the spectrum
of AF burden and other arrhythmias based on up to 2 weeks of continuous
electrocardiogram (ECG/EKG) recording. The multi-center prospective ARIC Study
began in 1987-1989. Visit 6 occurred in 2016-2017. They concluded that low
serum magnesium was associated with greater premature ventricular contractions
(PVCs) burden as measured over 2 weeks of ECG/EKG monitoring. The limitations
to the study are, as this analysis was cross sectional, the temporality of the
association cannot be established particularly considering the complexity of
magnesium homeostasis and cardiac electrophysiology. Residual confounding is
another possibility given the observational nature of the study. It is
plausible that those with arrhythmias are sicker and have other confounding
characteristics shared by those with low circulating magnesium. The major
strengths of this study were the community-based population and rigorous
characterization of arrhythmia burden using a novel ECG/EKG monitor worn for
up to 2 weeks.8

Del Gobbo (2013) performed a systemic review and meta-analysis examining the
association of circulating and dietary magnesium with incidence of CVD,
ischemic heart disease (IHD) and fatal IHD. They concluded that circulating
magnesium was significantly associated with a lower risk of CVD, with trends
toward a lower risk of IHD and fatal IHD. Dietary management was associated
with a significantly lower risk of IHD and showed a nonlinear association with
fatal IHD. Their findings support the importance of dietary recommendations to
increase magnesium rich foods. The strengths were their data derived from a
systematic search and meta-analysis of prospective studies which provided the
best available evidence of how circulating and dietary magnesium may influence
CVD risk. The limitation of their findings was constrained availability of
published or unpublished data on magnesium-CVD associations.9

The analysis of evidence reviewed for magnesium included a systemic review and
meta-analysis, multi-center prospective study, prospective population-based
cohort study, longitudinal community-based cohort and a case study. The
literature supports that low serum magnesium levels is associated with an
increased risk of CHD mortality and SCD.

The literature reviewed concluded that low serum magnesium was associated with
the development of AF. The literature supports that low serum magnesium was
associated with greater PVC burden. The literature reviewed reported on a case
study that highlighted symptomatic hypermagnesemia resulting from excess
exogenous magnesium intake in the context of renal failure.