The Laboratory and Clinical Perspectives of Magnesium Imbalance

Abstract

Magnesium (Mg²⁺) is a predominantly intracellular cation that plays significant roles in various enzymatic, membrane, and structural body functions. As a calcium (Ca²⁺) antagonist, it is imperative for numerous neuromuscular activities. The imbalance of body Mg²⁺ concentration leads to clinical manifestations ranging from asymptomatic to severe life-threatening complications. Therefore, the contribution of Mg²⁺ measurement regarding various laboratory and clinical aspects cannot be ignored. Mg²⁺ is often described as the forgotten analyte. However, its close relationship with body potassium (K⁺), Ca^2+, and phosphate homeostasis proves that Mg²⁺ imbalance could co-exist as the root cause or the consequence of other electrolyte disorders. Meanwhile, several preanalytical, analytical, and postanalytical aspects could influence Mg²⁺ measurement. This review highlights Mg²⁺ measurement's laboratory and clinical issues and some analyte disturbances associated with its imbalance. Understanding this basis could aid clinicians and laboratory professionals in Mg²⁺ result interpretation and patient management.

Keywords: calcium; clinical standpoints; hypermagnesemia; hypomagnesemia; laboratory methodical aspects; magnesium disequilibrium; magnesium loading test; magnesium tolerance test; magnessium; post-analytical.

Figure 1. A flow chart illustrating the steps of this review paper.

Note: This figure is an original work drawn by the principal author. Image credit: Siti Nadirah Ab Rahim.

Figure 2. Magnesium distribution in the human body.

Notes: As an intracellular cation, the majority of the body's Mg²⁺ is found in the bone (60%), followed by soft tissues (38-39%). Only 1-2% of Mg²⁺ is present in the extracellular compartment; half of this is either protein-bound or complexed with anions, and the other half exists in its free form. Mg²⁺: Magnesium; Alb: Albumin; Mg³(PO⁴)²: Magnesium phosphate. Note: This figure is an original work drawn by the principal author. Image credit: Siti Nadirah Ab Rahim.

Figure 3. Schematic diagram showing functions of magnesium in the human body.

Notes: This figure was drawn using the premium version of BioRender (https://biorender.com/, accessed on 9 November 2023) with license number UX262NVRKR. Image credit: Susmita Sinha.

Figure 4. Laboratory approach to hypomagnesemia.

Notes: This diagram illustrates a 3-tier approach to diagnosing hypomagnesemia and Mg²⁺ deficiency. An average serum Mg²⁺ level does not necessarily reflect the total body Mg²⁺ level. A subsequent intermediate 24-hour urine Mg²⁺ level suggests the absence of Mg²⁺ deficiency, but a low 24-hour urine Mg²⁺ level might indicate the presence of Mg²⁺ deficiency. Following the Mg²⁺ loading test, an individual with total body Mg²⁺ deficiency will retain most of the given Mg²⁺ (about 85%). To calculate the Mg²⁺ retention rate, both pre- and post-urinary Mg²⁺ level measurements are required. This figure is an original work drawn by the principal author. Image credit: Siti Nadirah Ab Rahim.

Figure 5. Role of magnesium (Mg) in vitamin D synthesis.

Notes: D2 represents vitamin D from non-animal sources; D3 represents vitamin D from animal sources; 25(OH)D denotes calciferol (the inactive form of vitamin D); 1,25(OH)2D refers to 1,25-dihydroxy vitamin D (the biologically active state); 24,25(OH)2D is 24,25-dihydroxy vitamin D. This figure was created using the premium version of BioRender (https://biorender.com/, accessed on 9 November 2023) with license number EJ262NQ1ZQ. Image credit: Susmita Sinha.

Figure 6. Calcium, magnesium, and K+ tubular transport at the thick ascending loop of Henle.

Notes: Ca²⁺ binding to the Ca²⁺-sensing receptor (CaSR) inhibits tubular Mg²⁺ and Ca²+ paracellular entry and renal outer medullary K⁺ channel (ROMK) activity. This maintains the electrochemical gradient balance, preventing renal electrolyte wasting. In hypercalcemia, excessive inhibition of Mg²⁺ entry causes renal Mg²⁺ loss, leading to hypomagnesemia. Conversely, hypomagnesemia can interfere with CaSR-mediated parathyroid hormone (PTH) release, reducing PTH and Ca²⁺ levels, thereby causing hypocalcemia (not shown in the diagram). Intracellular Mg²⁺ also inhibits ROMK. A deficiency in intracellular Mg²⁺ results in the loss of ROMK inhibition, inactivity of the Na+-K+-2Cl- co-transporter, and inhibition of the Na+/K+-ATPase pump, leading to renal K+ wasting. CaSR: Ca2+-sensing receptor; ROMK: Renal outer medullary K+; PTH: Parathyroid hormone; Na+/K+-ATPase pump: Na-K-ATPase. This figure is an original work drawn by the principal author. Image credit: Siti Nadirah Ab Rahim.