Journal Club Presentation

Dept. of Internal Medicine

MAGNESIUM DISORDER

Dr. SADIA ISLAM NOWRIN

Internal Medicine (Phase-A)
MU-1 Dhaka Medical College and Hospital
electrolyte forgotten

Unravel … the mysteries of magnesium

There has been unlocking of certain Mg-specific channels,
transporters, as well as many physiological and hormonal
processes that regulate Mg homeostasis in the body.

This review focuses on recent discoveries in how Mg functions

in the body, concentrating on hypomagnesemia, the most
common clinical Mg disorder.
 Typically, magnesium exists as Mg++.

Magnesium as
Vital for Cell It is an essential cofactor for ATP, the cellular
Function and source of energy and for hundreds of enzymatic
Health reactions in every cell type.

It regulates glucose, lipid, and protein

metabolism.
Cont.
It is Involved in the --
• Control of neuromuscular function
• Regulation of cardiac rhythm
• Modulation of vascular tone
• Hormone secretion
• NMDA release in the CNS.

Magnesium is a second messenger involved in

• intracellular signaling
• regulation of circadian-clock genes, which control circadian rhythm
in biologic systems.
 Magnesium Transporters and Their Roles

Intracellular Mg level is tightly controlled for proper regulation of cell

function and signaling.

The first Mg transporters characterized in humans were the transient

receptor potential cation channel subfamily M, members 6 and 7
(TRPM6 and TRPM7).

TRPM6 is expressed primarily in the colon and DCT of the kidney and
is responsible for Mg reabsorption in the intestine and kidney. On the
other hand, TRPM7 is ubiquitously expressed.
Numerous factors influence TRPM6 and TRPM7 activity are
described as magnesiotropic (involving magnesium regulation).
They include —
 Epidermal growth factor (EGF).
 Fibroblast growth factor 23 (FGF23).
 Uromodulin.
 ADP ribosylation factor–like protein 15.
 Aldosterone.
 Angiotensin II.
 Bradykinin.
 Insulin.
Other Magnesium transporters include:
 Solute carrier family 41 members 1, 2, and 3.

 Cyclin and CBS domain divalent metal cation

transport mediators 1 through 4 (CNNM1 through
CNNM4).

 The magnesium-selective mitochondrial RNA splicing

protein 2 (MRS2).
Coordinated Control of Magnesium Balance:
 The body contains approximately 25g of magnesium, majority of
which is stored in bones and soft tissues.

 In cells, 90 to 95% of Mg is bound to ligands and Only 1 to 5% of

exists as free Mg.

 The intracellular concentration of free Mg is 1.2 to 2.9 mg/dl (0.5 to

1.2 mmol/l), which is similar to the extracellular conc.
Cont.
 In plasma, 30% of the circulating Mg is bound to proteins, mostly
through free fatty acids.

 Therefore, patients with chronically high levels of FFA generally have

a lower blood Mg concentration, and plasma Mg levels are inversely
proportional to the risk of cardiovascular and metabolic diseases.

 Changes in free fatty acids and levels of EGF, insulin, and aldosterone
contribute to variability in blood magnesium levels.
Mg is regulated by 3 organs:

INTESTINE KIDNEY

BONE
 The Intestine–Bone–Kidney Axis and Magnesium
Homeostasis

 Dietary sources rich in Mg include cereals,

beans, nuts, and green vegetables.

 Of the total dietary Mg consumed, 30 to 40%

is absorbed in the intestine.

 Intestinal Mg absorption is influenced by factors such as dietary Mg,

intestinal lumen pH, hormones (estrogen, insulin, EGF, FGF23, and PTH)
and gut microbiota.
Cont.
 In the kidney, Mg
reabsorption by nephron is
facilitated by paracellular and
transcellular pathways.

 Only a small amount (20%) of

Mg is reabsorbed in PCT.
Cont.
 Magnesium is a key component of bone — 60% of the
total magnesium in the body is stored in this
compartment.

 High Mg intake increases bone mineral content and

thus reduces the risk of bone fractures and osteoporosis.

 There’s also a role in vascular calcification.

Magnesiu
m
disorders
 HYPOMAGNESEMIA

 The normal serum magnesium concentration in adults is 1.7 to 2.4 mg

per deciliter (0.7 to 1.0 mmol per liter).

 Hypomagnesemia is defined as serum magnesium levels below 1.7 mg

per deciliter.

 Most patients with borderline hypomagnesaemia are asymptomatic.

Cont.
 Hypomagnesemia is present in 3 to 10% of the general population, but
the prevalence is increased among persons with –

 Type-2 diabetes (10 to 30%) and

 Hospitalized patients (10 - 60%), especially those in ICU (>65%).

 Data from several cohorts indicate that hypomagnesemia is

associated with an elevated risk of death from any cause and death from
cardiovascular causes.
 The Clinical Spectrum of Hypomagnesemia

Hypomagnesemia may result from—

 Inadequate dietary intake.
 Increased gastrointestinal loss.
 Reduced renal reabsorption or increased renal excretion.
 Redistribution of Mg from the extracellular to the intracellular space.

It is usually associated with other electrolyte derangements, including

hypocalcemia, hypokalemia, and metabolic alkalosis.
Cont.
Patients with hypomagnesemia often present with nonspecific symptoms,
such as --
• Lethargy
• muscle cramps or
• muscle weakness.

In severe cases of hypomagnesemia (<1.2 mg/dl [0.5 mmol/l) symptoms

become evident, such as—
 Neuromuscular irritability(carpopedal spasm, seizures, and tremors).
 Cardiovascular abnormalities (arrhythmias, vasoconstriction).
 Metabolic disorders (insulin resistance and chondrocalcinosis)
Cont.
 Low S. Mg levels are associated with an increased
hospital stay and increased mortality, especially when
associated with concurrent hypokalemia

 But intracellular stores of Mg can be depleted with a

normal S. Mg level

 Therefore, the use of blood Mg levels alone, without

consideration of dietary Mg intake and urinary loss
underestimates Mg deficiency in clinics
 Hypokalemia and Hypomagnesemia

 Hypokalemia is common in patients with hypomagnesemia.

 Refractory K+ repletion is often linked to magnesium depletion and is

corrected only after the Mg deficit has been normalized.

 Decreased intracellular magnesium levels inhibit Na+–K+– ATPase pump

activity and increase the opening of renal outer medullary potassium
(ROMK) channels leading to renal potassium loss.
Cont.
 The interplay between magnesium and potassium also involves
activation of the Na+–Cl− cotransporter (NCC), which promotes sodium
reabsorption.

 Magnesium deficiency causes NCC down-regulation and enhances distal

Na+ delivery during states of hypomagnesemia.

 Thus, Mg deficiency amplifies potassium secretion in the collecting duct

promoting kaliuresis and hypokalaemia.
 HYPOCALCEMIA AND HYPOMAGNESEMIA

 Hypocalcemia is also frequently linked to hypomagnesemia

 Mg deficiency suppresses the release of PTH and decreases renal

sensitivity to PTH. that leads to secondary hypocalcemia (HSH)
 Hypocalcemia resulting from hypomagnesemia-induced
hypoparathyroidism is refractory to correction until the Mg
concentration is normalized
 Non-drug causes of
hypomagnesaemia

 Hypomagnesemia is the most common electrolyte abnormality

associated with chronic alcohol use disorder

 Underlying mechanisms include increased gastrointestinal loss and renal

tubular damage

 The presence of hypomagnesemia in persons with alcohol use disorder

is often associated with liver dysfunction and worse prognosis of their
liver disease
In type 2 diabetes mellitus

 Renal magnesium wasting and increased albumin binding in blood are

probably the causes here

 Insulin activates TRPM6 activity in the distal convoluted tubule. So,

insulin resistance results in decreased renal magnesium reabsorption
and increased magnesuria
Autoimmunity

 Autoantibodies against claudin 16 have been identified as a novel

cause of hypomagnesemia and tubulointerstitial nephropathy. It
suggests that autoimmunity could be a novel cause of
hypomagnesemia.
 Preeclampsia and eclampsia the hypertensive diseases of
pregnancy may show reduced or normal level of Mg. Although
the causes of preeclampsia and eclampsia are unknown,
intravenous Mg treatment is beneficial here.
 Hereditary Hypomagnesemia

 Familial hypomagnesemia is attributed to pathogenic variants in genes

that encode for magnesium transport pathways and their regulators.

 Mutations in TRPM6 and TRPM7 subunits lead to HSH.

 Mutations in CLDN16 and CLDN19, which encode claudin 16 and

claudin 19, result in familial hypomagnesemia, hypercalciuria, and
nephrocalcinosis.
Cont.
 Pathogenic variants in EGF and EGFR result in hypomagnesemia and
renal magnesium wasting, because of reduced TRPM6 activity.

 Gitelman’s syndrome is primarily a sodium wasting disorder caused by

mutations in the NCC but patients present with hypomagnesemia,
hypokalemia and metabolic alkalosis.
 Evaluating Hypomagnesemia in the Clinic

 Measurement of total serum magnesium is the standard approach to

determine magnesium status in the clinic

 Magnesium measurement is influenced by-

• Endogenous factors (hypoalbuminemia)

• exogenous factors (hemolyzed specimens and sample tube
anticoagulants [e.g., EDTA])
Cont.…
 When hypomagnesemia is diagnosed, the cause is usually apparent from
the patient’s history.

 However, if there is no clear underlying cause, it is important to

distinguish between renal and gastrointestinal Mg losses with the use of
specific diagnostic approaches, such as 24-hour Mg excretion, fractional
excretion of Mg, and the Mg-loading test.
 Magnesium Replacement

 Mg replacement is the basis for managing hypomagnesemia

 Mild hypomagnesemia is managed with oral supplements

 The most effectively absorbed forms are organic salts (magnesium

citrate, aspartate, glycinate, gluconate, and lactate)
 However, a common side effect of oral magnesium supplementation is
diarrhea, which poses a challenge for oral replacement
Cont.
In resistant cases, adjuvant drug therapies may be necessary.

 Pharmacologic inhibition of the epithelial Na channel Amiloride or

triamterene increases serum magnesium.

 Inhibitors of sodium-glucose cotransporter type-2, increase serum

magnesium levels, especially in patients with diabetes.
Cont.
 Parenteral therapy is indicated in patients whose hypomagnesemia
is refractory to oral treatment.
Such as those with --
 short-bowel syndrome
 patients with tetany or seizures
 hemodynamically unstable pt. with arrhythmias
 or associated potassium and calcium imbalance.
 Magnesium as a therapeutic agent

 In severe asthma exacerbations with an inadequate response to

intensive initial treatment and in patients with life-threatening asthma,
clinical guidelines recommend I/V MgSO4
 Nebulized MgSO4 when added to inhaled β2-agonists and
ipratropiumbromide have additional benefit for lung function

 These Beneficial effects probably involve Ca channel blockade in

bronchial smooth muscle, resulting in bronchodilation
Cont.
 Patients with torsades de pointes that is refractory to beta-blockers
should be treated with magnesium

 The treatment of hypertension in pregnancy, women with eclampsia

should receive magnesium sulfate to prevent seizures

 Women with preeclampsia who have proteinuria and severe

hypertension or hypertension with neurologic signs and symptoms
should be treated with magnesium sulfate to prevent eclampsia
 Take home message
 Mg is a vital but often poorly understood electrolyte in clinical medicine

 There have been advances in the understanding of renal Mg handling

and new genes have been identified causing rare forms of inherited
hypomagnesemia
 Many drugs cause hypomagnesemia

 Hypomagnesemia is common in hospitalized patients and is a risk factor

for a prolonged ICU stay
 Hypomagnesemia should be corrected with Mg replacement after
exclusion of the spurious hypomagnesemia.
-- THANK YOU --