Recurrent hypomagnesemia, case report

Presentation.

A 67-year-old white male returned to the ER for vomiting, anorexia, generalized weakness. He has a history of type II diabetes and is supposed to be on glipizide. Although hospital records documents alcohol abuse, he was very reluctant to admit to it. Hospital records also revealed that for the past 4 months prior to this admission, he has had similar presentations with magnesium levels either at very low (~1.2 mg/dl) or undetectable level. To make matters worse, he stated he was under the impression he was not supposed to take magnesium tablets as outpatient despite being discharged on it each episode of admission. On physical exam, systolic BP was 90 and he had diminished turgor of the skin, positive Chvostek’s sign, hyperreflexia and muscle twitching. His initial labs revealed a potassium of 2.5, undetectable magnesium (<.62 mg/dl), glucose of 145, normal amylase, alcohol and lipase. He was kept on CIWA protocol and also received prophylactic high dose of thiamine to prevent Wernicke’s encephalopathy as well as .9%NS. For the next 4 days, despite aggressive replenishment of magnesium using 12gm/day in divided doses of mag sulfate by 4gm aliquots, his level was difficult to maintain at a steady and normal level; it might go up to 1.8 mg/dl only to drop again to 1.2 mg/dl. Potassium normalized but calcium then dropped, and he received calcium gluconate infusion to correct the level. However, beginning the day after his admission, his appetite returned, and his nausea and vomiting disappeared. His energy level went back to baseline. Eventually his magnesium normalized and remained at a steady level. When questioned again about his alcohol intake during his lucid moments, he stated that he drinks beer with his friends and didn’t consider this as alcohol consumption since this is not hard liquor. Time was taken to educate the patient about alcohol content of beer and the need to take magnesium supplement.

Discussion.

This case illustrates several issues associated with hypomagnesemia. The most vexing issue in this case is patient’s refusal to acknowledge his alcohol intake with the false premise that absent hard liquor ingestion, beer is not an alcoholic beverage. It has become a rule of thumb to double the amount of the avowed consumption as the accurate one. The patient did present with severe hypomagnesemia that was slow to correct due to paradoxical increased excretion of magnesium by the kidney in rapid correction; it’s estimated that up to half of the amount infused is excreted¹.

Function.

Magnesium plays an important role in the body’s homeostasis as it serves as  a cofactor for hundreds of enzymatic activities². It is also involved in both structural soundness of RNA and DNA just as importantly in their repairs. Magnesium is involved in the formation of ATP in the glycolytic pathway. ATP is a major source of cellular energy. Magnesium also serves as smooth muscle relaxer, and this has significant implication in the modulation of the vascular bed.

Physiology.

The serum concentration represents less than 1% of the total body storage of magnesium (see fig 1). The bulk of it is in the bones and this explains its role in osteoporosis. It’s absorbed in the small intestine, reabsorbed primarily in the thick ascending loop of Henle and stored primarily in bones. Under ordinary circumstances, 3-5% of filtered magnesium is excreted by the kidneys. Urinary excretion is proportional to load of magnesium^2,3.

 

 

 

 

 

 

Fig 1. Physiology of magnesium. Ahmed et al, Med Sci (Basel). 2019 Apr; 7(4): 56.

Hypomagnesemia can be found in any number of conditions and the common ones include:

• Decreased intake.
  • Alcoholism
  • TPN
  • Poor nutrition
• Increased renal loss.
  • Loop diuretic, tacrolimus, cyclosporine
  • Alcoholism
  • Hypercalcemia
• GI loss
  • PPI
  • Vomiting, diarrhea.
  • Malabsorption
• Shift from plasma to intracellular milieu
  • Acute pancreatitis
  • Treatment of DKA
  • Refeeding syndrome

Our patient clearly fell into the category of alcoholism, and he had several reasons to have hypomagnesemia: diminished intake, vomiting and enhanced renal excretion due to alcohol dependence. This latter mechanism is thought to be due to tubular dysfunction associated with the alcohol itself^1,2. The presence of hypomagnesemia induces other electrolyte abnormalities such as hypokalemia, hypocalcemia. The mechanism for hypokalemia in the presence of hypomagnesemia is felt to be multifold, involving impairment of potassium reabsorption at the distal tubule of the nephron as well as sodium-potassium ATPase malfunction since it’s dependent on magnesium. The relationship of magnesium and calcium is a bit more complicated. Hypomagnesemia is associated with hypocalcemia. It’s postulated that either through blunting of PTH secretion to its reduced efficacy at the cell receptor level or its increased metabolism². On the other hand, magnesium and calcium can compete at the receptor level of the distal tubule, depending on the concentration of magnesium. The Ob-Gyn literature is replete of reports of magnesium treatment of preeclampsia inducing hypocalcemia³.

 

Signs/Symptoms^1,2,4.

• Neuromuscular.
  • Weakness/fatigue, Chvostek’s or Trousseau’s sign, tetany, worsening of asthma.
•  Cardiac.
  •  Arrhythmia (torsade de pointes), PR prolongation, dig toxicity.
  • Endothelium dysfunction.
• Endocrine.
  • Worsening of diabetes, hypokalemia, hypocalcemia, osteoporosis.

 

The presence of hypomagnesemia in patients on diuretics is often overlooked. Just like hypokalemia, it should always be searched for in such a setting and among hospitalized patients for congestive heart failure on aggressive diuretic treatment, it should be tested frequently. The same can be said about the presence of hypomagnesemia in type 2 diabetes. According to Ahmed² in his excellent review on the subject, the following facts need to be kept in mind:

• Hypomagnesemia has a prevalence of up to 47% in type II diabetes.
• Hypomagnesemia alters glucose metabolism via following ways:
  • Change in cellular glucose transport.
  • Reduction of pancreatic insulin secretion.
  • Less effective post-receptor insulin signaling.

In other reviews about the mechanism of hypomagnesemia in diabetes type II, it’s noted that hypomagnesemia in diabetes is associated with vascular complications such as^4,5:

• CAD.
• Hypertension.
• Diabetic retinopathy, nephropathy.
• Diabetic foot ulceration.

Then again as we mentioned earlier, hypomagnesemia is associated with endothelial dysfunction and that sets up an inflammatory milieu that facilitates above complications.

Treatment.

The quickest route for replenishment of magnesium is via IV infusion of magnesium sulfate, slowly at a rate of 1gm/hour. One needs to be careful in patients with renal insufficiency since hypermagnesemia is a potential complication. IV magnesium is contraindicated in patients with myasthenia gravis; its use may bring on a crisis. While giving IV infusion, one needs to be careful and not draw a magnesium level too soon after the dose and allow a few hours for equilibration, otherwise one might end up with a falsely elevated level². This very likely explained the wide fluctuation in the level of this patient. Likely a level was drawn close to the last infusion.

In our patient, a peculiar development occurred: the initial serum calcium was normal and it fell a couple of days later while he was receiving magnesium infusion. The opposite was expected, i.e. low calcium initially in the presence of undetectable magnesium. It’s highly debatable that the magnesium infusion was associated with the hypocalcemia as was described earlier when there’s competition at the receptor level of the distal tubule. A more likely explanation is that the initial normal calcium was a lab error. Nonetheless this is food for thought and this type of paradoxical phenomenon never fails to arouse one’s curiosity.

Magnesium is also available as oral and topical preparations. The issue with oral salts is their poor bioavailability⁶. Among the 10 types of preparation reviewed in a report⁶, the gluconate and glycinate salts have reasonably good bioavailability. However other reports have looked at other salt preparations such L-Threonate⁷ and orotate⁸ and they have very good bioavailability L- Threonate seems to have good penetration of CSF and preliminary study shows some therapeutic efficacy in Alzheimer’s disease⁷. Magnesium oxide, very commonly used, has a poor bioavailability. Magnesium can be used as a cream, but not much data about its efficacy exists⁹.

Dietary source of magnesium¹⁰.

Nuts, spinach, beans, in decrescendo order.

Conclusion.

Hypomagnesemia is far more common than we acknowledge. It’s a simple test and it needs to be looked into in hospitalized patients since it is involved in so many enzymatic reactions and it may be playing a role in a lot of disease processes. However, in alcoholics, diabetics and patients on diuretic, it becomes even more of an urgency to check the level at regular intervals. Treatment in the outpatient setting should rely on magnesium preparations that have a good bioavailability and a diet rich in magnesium.

 

Reynald Altéma, MD.

References:

1. M.A Crook, V Hally, J.V Panteli. The importance of the refeeding syndrome. Nutrition, Volume 17, Issues 7–8, 2001. Pages 632-637.
2. Ahmed F, Mohammed A. Magnesium: The Forgotten Electrolyte-A Review on Hypomagnesemia. Med Sci (Basel). 2019;7(4):56. Published 2019 Apr 4.
3. Nassar, A.H., et al. Marked hypocalcemia after tocolytic magnesium sulphate therapy. Am. J. Perinatology. 2007. 24:481- 482.
4. Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2007 Mar;2(2):366-73.
5. e Baaij J.H., Hoenderop J.G., Bindels R.J. Magnesium in man: Implications for health and disease. Physiol. Rev. 2015;95:1–46
6. Coudray C, Rambeau M, Feillet-Coudray C, Gueux E, Tressol JC, Mazur A, Rayssiguier Y. Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg-depleted rats using a stable isotope approach. Magnes Res. 2005 Dec;18(4):215-23
7. Shen Y, Dai L, et al.Treatment Of Magnesium-L-Threonate Elevates The Magnesium Level In The Cerebrospinal Fluid And Attenuates Motor Deficits And Dopamine Neuron Loss In A Mouse Model Of Parkinson’s disease. Neuropsychiatr Dis Treat. 2019 Nov 11;15:3143-3153.
8. Verma, H., Garg, R. Biopharmaceutics classification and pharmacokinetics study of magnesium orotate. Magnesium Research. 2019; 132-142
9. Kass, L, et al. Effect of transdermal magnesium cream on serum and urinary magnesium levels in humans: A pilot study. PLoS One. 2017 Apr 12;12($):e0174817
10. USDA National Nutrient Database for Standard Reference, Release 25. U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory Home; Beltsville, MD, USA

 

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