1. Magnesium

8. Introduction
 The Earth's crust contains approximately 2% of magnesium.
 Therefore, the Dolomites consist for the most part of magnesium
carbonate.
 Magnesium also exists in sea water - at least about 0.5%
 In addition, magnesium plays a decisive part in what city
dwellers associate with "pure nature."
 The fresh greenness of woods and meadows owes its color to
chlorophyll, a complex chemical ring with magnesium as the central
atom.
 Magnesium deficiency is therefore readily visible:
the resulting chlorosis imparts a fine yellow colour to the leaves.

9. The chlorophyll molecule

10.  The pigments in leaves and blood are chemically related.
 At first sight it seems unbelievable: i.e. the pigment in leaves
and red blood corpuscles actually have something in common.
Both, chlorophyll and hemoglobin are so-called porphyrin rings.
 The only difference is that the central atom in hemoglobin is
iron, whereas in chlorophyll it is magnesium.
Magnesium Balance
Mg2+reserves in the body
Bones about 60%, Cells about 40%
Interstitial compartment and Serum About 1%

15. Magnesium Metabolism

16. Magnesium circulation within the body...
-- Begins with the intake of food - we cannot produce the valuable mineral
alone.
-- After ingestion with food, the major part of the mineral has initially a
good way to travel:
to the small intestine.
-- Only then is it absorbed:-
1. via the active carrier transport process and
2. for larger quantities, via passive diffusion.
Important! Interaction with iron when supplements are used:
-- the absorption of magnesium interferes with that of iron!
-- In replacement therapy with both minerals, they should be taken at a
2 to 3 hour interval from one another.

18.  Magnesium is the major intracellular divalent cation.
 Normal concentrations of extracellular magnesium and calcium are
crucial for normal neuromuscular activity.
 Intracellular magnesium forms a key complex with ATP and is an
important cofactor for a wide range of enzymes, transporters, and nucleic
acids required for normal cellular function, replication, and energy
metabolism.
 Concentration of magnesium in serum is closely regulated within range of
0.7–1 mmol/L (1.5–2 meq/L; 1.7–2.4 mg/dL),
--- of which 30% is protein-bound and
--- another 15% is loosely complexed to phosphate and other anions.
 More than one-half of 25 g (1000 mmol) of total body magnesium is
located in bone, only one-half of which is insoluble in the mineral phase.
 Almost all extraskeletal magnesium is present within cells, where the total
concentration is 5 mM, 95% of which is bound to proteins and other
macromolecules.
 Because only 1% of body magnesium resides in the ECF, measurements of
serum magnesium levels may not accurately reflect the level of total body
magnesium stores.

20. What does the body do with this valuable substance?
 60% of magnesium is stored in bone.
 Bone forms our most important stocks of magnesium and body can call on
two thirds of these stores (as 45% of the total reserves) if need be.
 40% migrates into soft tissue, principally muscles and organs.
 Magnesium is the second most frequently occurring intracellular cation and is
found mainly in the cells.
 Extracellular, i.e. in the interstitial fluid between the cells, and in blood ,
only 1% of magnesium is to be found.
 Major part is ionized and therefore pharmacologically active and a smaller
portion is bound to other substances, to citrate.
 Normal value for magnesium reserves within the body is approximately 24 to
28 grams.
 Magnesium is excreted via the intestines and the kidneys:-
1. Only approximately 5% of the amount filtered by the kidneys is ultimately
excreted.
2. The major part returns to the blood vessels via the ascending limb of Henle's
loop.

21. Magnesium
1. Absorption depends on concentration
Human Study
Fed Fractional Absorption
7 mg 65-75%
36 mg 11-14%
2. Absorption is saturable and non-saturable (7-10%)
3. Fully saturable in ileum but not jejunum (contrast with calcium)
4. Absorption in the colon significant
5. Vitamin D has no influence on magnesium absorption

22. Magnesium
Enterocyte
TRPM6
Mg2+
Distal jejunum and ileum
Cation channel protein
(transient receptor
protein TRP)
Mg2+
Since TRPM6 operates by
diffusion without co-transporters,
Mg2+ absorption
efficiency depends on the
amount of Mg2+ in the diet
and within the cell
ATP
ase
ATP
ADP
Mg2+
Mg2+ -bound to
phytate, fiber,
fatty acids

25.  Dietary magnesium content normally ranges from 140–360 mg/d, of which
30–40% is absorbed, mainly in the jejunum and ileum.
 Intestinal magnesium absorptive efficiency is stimulated by 1,25(OH)2D and
can reach 70% during magnesium deprivation.
 Urinary magnesium excretion normally matches net intestinal absorption
and is ∼100 mg/d.
 Regulation of serum magnesium concentrations is achieved mainly by
control of renal magnesium reabsorption.
 Only 20% of filtered magnesium is reabsorbed in the proximal tubule,
whereas 60% is reclaimed in the cTAL and another 5–10% in the DCT.
 Magnesium reabsorption in the cTAL occurs via a paracellular route that
requires both
1. a lumen-positive potential, created by NaCl reabsorption, and
2. tight-junction proteins encoded by members of the Claudin gene family.
 Magnesium reabsorption in the cTAL is increased by PTH but inhibited by
hypercalcemia or hypermagnesemia, both of which activate the CaSR (calcium-sensing
receptor) in this nephron segment.

28. Figure in above slide
Epithelial magnesium transport in intestine and kidney
A, intestinal absorption follows a curvilinear kinetic resulting from two transport
mechanisms:
1. a saturable transcellular transport (dotted line) which is of functional importance at
low intraluminal concentrations and
2. a paracellular passive transport (dashed line) linearly rising with intraluminal
magnesium concentrations.
 TRPM6 is a component of the active transcellular pathway as HSH patients are able to
compensate for their genetic defect by high oral magnesium intake.
B, in thick ascending limb magnesium is reabsorbed via the paracellular route.
 Here, a specific tight juntion protein, paracellin-1 or claudin-16, permits the selective
paracellular flux of calcium and magnesium.
 Defects in paracellin-1 lead to combined calcium and magnesium wasting.
C, distal convoluted tubule reabsorbs magnesium in a transcellular fashion, consisting
of an apical entry into DCT cell through a magnesium-selective ion channel, probably
consisting of TRPM6/TRPM7 heterotetramers, and a basolateral extrusion of unknown
molecular identity.

29. TRPM6 is a transient receptor potential ion channel associated with hypomagnesemia
with secondary hypocalcemia.
TRPM6 and TRPM7--Gatekeepers of human magnesium metabolism.
Abstract
 Human magnesium homeostasis primarily depends on the balance between intestinal
absorption and renal excretion.
 Magnesium transport processes in both organ systems - next to passive paracellular
magnesium flux - involve active transcellular magnesium transport consisting of an apical
uptake into the epithelial cell and a basolateral extrusion into the interstitium. Whereas
the mechanism of basolateral magnesium extrusion remains unknown, recent molecular
genetic studies in patients with hereditary hypomagnesemia helped gain insight into the
molecular nature of apical magnesium entry into intestinal brush border and renal tubular
epithelial cells.
 Pts with Hypomagnesemia with Secondary Hypocalcemia (HSH), a primary defect in
intestinal magnesium absorption, were found to carry mutations in TRPM6, a member of
the melastatin-related subfamily of transient receptor potential (TRP) ion channels.
 Before, a close homologue of TRPM6, TRPM7, had been characterized as a magnesium
and calcium permeable ion channel vital for cellular magnesium homeostasis. Both
proteins share the unique feature of an ion channel fused to a kinase domain with
homology to the family of atypical alpha kinases. The aim of this review is to summarize
the data emerging from clinical and molecular genetic studies as well as from
electrophysiologic and biochemical studies on these fascinating two new proteins and
their role in human magnesium metabolism.

30. Important!
 Side-effect of loop diuretics:
these exert their action precisely at
this site and in so doing, block
re-absorption of magnesium.
 Long-term diuretic treatment
therefore frequently causes magnesium
deficiency!

31. Reported Magnesium Requirements

32.  Even without diuretics, however, it is recommended that you monitor your
current intracellular mineral status with Exatest, because we must ensure a supply
of magnesium, regardless of sex and age.
 Magnesium requirements increase constantly in childhood and adolescence.
 Older teenagers need the most: youths from 15 to 19 years of age require 400
mg, adolescent girls, 350 mg per day.
 During adulthood, the value remains constant at 50 mg below these respective
figures - this remains unchanged, even in old age.
 Pregnant women are, as a rule, administered magnesium routinely from the
15th week of pregnancy onwards - at least 300 mg per day.
 On the basis of experience, cramps, premature contractions and complications
during labor are reduced in this manner.
 During lactation also, magnesium replacement therapy is recommended.
 In this case, the requirements increase to 375 mg per day.
 In foods, the magnesium content is varied in its order of magnitude from one
food to another.
 100 g of sunflower weeds for example contain 420 mg of magnesium.
 A breakfast of sunflower seed bread is therefore just what we order!

33. Magnesium Content

35. The Origins of Magnesium Deficiency

36. From acid rain to magnesium deficiency
 Acid rain not only damages forests, but also the soil.
 Fertilizers become necessary - yet fertilizer often contains too little
magnesium.
 Soils poor in magnesium are the result.
 Animals suffer:
---the tetany occurring early in the year in grazing animals is not
infrequently fatal without magnesium injections.
 Humans also suffer depletion as a result because soil products or foods
contain too little magnesium.

38. Magnesium deficiency in humans
 During all the phases of magnesium circulation within the body, there are
factors which may lead of magnesium deficiency:
1. Impoverished foodstuffs lead, in a similar manner as dieting or other
unbalanced nutrition, to a reduced magnesium intake.
2. Impaired absorption and
3. Increased excretion number among the causes of magnesium
deficiency in humans.

39. Magnesium Deficiency

42. Increased Magnesium Requirements

43.  According to age and living conditions, increased magnesium
requirements may occur in humans.
 We have the greater need during lactation and fasting diets.
 Magnesium replacement therapy may become necessary in
individuals placed under professional stress or practicing active sports.
 In addition, magnesium is also employed in cardiac patients, in order
to compensate for the increased magnesium excretion under diuretics or
digitalis treatment.

45. Hypomagnesemia

46. Causes of Hypomagnesemia
 Hypomagnesemia usually signifies substantial depletion of body magnesium stores
(0.5–1 mmol/kg).
 Hypomagnesemia can result from
1. Intestinal malabsorption;
2. Protracted vomiting, diarrhea, or intestinal drainage;
3. Defective renal tubular magnesium reabsorption; or
4. Rapid shifts of magnesium from the ECF into cells, bone, or third spaces.
 Dietary magnesium deficiency is unlikely except possibly in setting of alcoholism.
 A rare genetic disorder that causes selective intestinal magnesium malabsorption
has been described (primary infantile hypomagnesemia).
 Another rare inherited disorder (hypomagnesemia with secondary hypocalcemia) is
caused by mutations in gene encoding TRPM6, a protein that, along with TRPM7, forms
a channel important for both intestinal and distal-tubular renal magnesium transport.
 Malabsorptive states, often compounded by vitamin D deficiency, can critically limit
magnesium absorption and produce hypomagnesemia despite compensatory effects of
secondary hyperparathyroidism and of hypocalcemia and hypomagnesemia to enhance
cTAL magnesium reabsorption.
 Diarrhea or surgical drainage fluid may contain ≥5 mmol/L of magnesium.

47. Causes of Hypomagnesemia
I. Impaired intestinal absorption
A. Hypomagnesemia with secondary hypocalcemia (TRPM6
mutations)
B. Malabsorption syndromes
C. Vitamin D deficiency
II. Increased intestinal losses
A. Protracted vomiting/diarrhea
B. Intestinal drainage, fistulas

48. III. Impaired renal tubular reabsorption
A. Genetic magnesium-wasting syndromes
1. Gitelman's syndrome
2. Bartter's syndrome
3. Claudin 16 or 19 mutations
4. Na+,K+-ATPase -subunit mutations (FXYD2)
5. Autosomal dominant, with low bone mass
B. Acquired renal disease
1. Tubulointerstitial disease
2. Postobstruction, ATN (diuretic phase)
3. Renal transplantation
C. Drugs and toxins
1. Ethanol
2. Diuretics (loop, -thiazide, osmotic)
3. Cisplatin
4. Pentamidine, foscarnet
5. Cyclosporine
6. Aminoglycosides, amphotericin B
7. Cetuximab
D. Other
1. Extracellular fluid volume expansion
2. Hyperaldosteronism
3. SIADH
4. Diabetes mellitus
5. Hypercalcemia
6. Phosphate depletion
7. Metabolic acidosis
8. Hyperthyroidism

49. IV. Rapid shifts from extracellular fluid
A. Intracellular redistribution
1. Recovery from diabetic ketoacidosis
2. Refeeding syndrome
3. Correction of respiratory acidosis
4. Catecholamines
B. Accelerated bone formation
1. Post-parathyroidectomy
2. Treatment of vitamin D deficiency
3. Osteoblastic -metastases
C. Other
1. Pancreatitis, burns, excessive sweating
2. Pregnancy (third trimester) and lactation

51.  Several genetic magnesium-wasting syndromes have been described,
including inactivating mutations of :-
1. genes encoding the DCT NaCl co-transporter (Gitelman's syndrome),
2. proteins required for cTAL Na-K-2Cl transport (Bartter's syndrome),
3 paracellin-1 (autosomal recessive renal hypomagnesemia with hypercalciuria),
4. a DCT Na+,K+-ATPase γ-subunit (autosomal dominant renal hypomagnesemia
with hypocalciuria), and
5 a mitochondrial DNA gene encoding a mitochondrial tRNA.
 ECF expansion, hypercalcemia, and severe phosphate depletion may impair
magnesium reabsorption, as can various forms of renal injury, including those
caused by drugs such as cisplatin, cyclosporine, aminoglycosides, and
pentamidine as well as the EGF receptor inhibitory antibody cetuximab.
 A rising blood concentration of ethanol directly impairs tubular magnesium
reabsorption,
 Persistent glycosuria with osmotic diuresis leads to magnesium wasting and
probably contributes to the high frequency of hypomagnesemia in poorly controlled
diabetic patients.
 Magnesium depletion is aggravated by metabolic acidosis, which causes
intracellular losses as well.

57. Clinical and Laboratory Findings
 Hypomagnesemia may cause generalized alterations in neuromuscular function,
including tetany, tremor, seizures, muscle weakness, ataxia, nystagmus, vertigo, apathy,
depression, irritability, delirium, and psychosis.
 Patients are usually asymptomatic when serum magnesium concentrations are >0.5
mmol/L (1 meq/L; 1.2 mg/dL), although the severity of symptoms may not correlate with
serum magnesium levels.
 Cardiac arrhythmias may occur, including sinus tachycardia, other supraventricular
tachycardias, and ventricular arrhythmias.
 Electrocardiographic abnormalities may include prolonged PR or QT intervals, T-wave
flattening or inversion, and ST straightening.
 Sensitivity to digitalis toxicity may be enhanced.
 Other electrolyte abnormalities often seen with hypomagnesemia, including
hypocalcemia (with hypocalciuria) and hypokalemia, may not be easily corrected unless
magnesium is administered as well.
 Hypocalcemia may be a result of concurrent vitamin D deficiency, although
hypomagnesemia can cause impaired synthesis of 1,25(OH)2D, cellular resistance to PTH,
and, at very low serum magnesium [(<0.8 meq/L; <1 mg/dL)], a defect in PTH secretion;
these abnormalities are reversible with therapy.

60. RECENT MAGNESIUM NEWS
 Researchers from the University of Hertfordshire have recently found that magnesium
supplements offer clinically significant reductions in blood pressure.
 In a paper published in the European Journal of Clinical Nutrition, the researchers also
discovered that the size of the effect increased in line with increased dosage.
 In another study researchers concluded that magnesium supplementation in
overweight individuals for four weeks “led to distinct changes in gene expression and
proteomic profiling consistent with favorable effects on several metabolic pathways.”
 Four weeks of magnesium supplementation was also associated with a decrease in
C-peptide levels.
 C-peptide levels are equal to the amount of insulin being produced in the body and is
used to determine insulin production. In type 2 diabetes, insulin is produced in excessive
amounts, but not used properly in the body due to insulin resistance, so the C-peptide
levels run high.
 The decrease in C-peptide in type 2 diabetics is a positive signal that insulin resistance
is decreasing and that the load on the pancreas is lessening.
 A reduction in the concentrations of fasting insulin levels was also noted by the
researchers lead by Simin Liu, M.D., ScD and Professor of Epidemiology and Medicine at
UCLA.
 These studies add to the ever-growing body of science proving the crucial role
magnesium plays in our lives and wellbeing.

76. Two unusual cases of severe recalcitrant hypocalcemia
due to aminoglycoside-induced hypomagnesemia