Hypokalemia;

Why should I check serum magnesium level in my patient with hypokalemia in need of potassium replacement?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Short answer: Potassium and magnesium are highly intertwined in their physiological roles and magnesium is critical for renal retention of potassium.

Hypomagnesemia increases the release of renin from the kidney, leading to elevated levels of angiotensin II, which stimulates the adrenal cortex to secrete aldosterone. 1,2 The resulting secondary hyperaldosteronism contributes to refractory hypokalemia through increased sodium reabsorption via epithelial sodium channels (ENaC) in the distal nephron.  Increased sodium reabsorption in turn increases the expression and activity of the renal outer medullary potassium (ROMK) channels, which increases potassium secretion into the tubular lumen.1,3 Interestingly, magnesium also directly inhibits ROMK channels which, in the setting of hypomagnesemia, further leads to potassium loss.1,4

Parenthetically, most patients with mild to moderate hypomagnesemia are asymptomatic or have non-specific symptoms such as lethargy, muscle weakness or cramps. So don’t rely on symptoms to decide who should have their serum magnesium checked in the setting of hypokalemia. 5

Last, hypomagnesemia is not uncommon. It is found in 3-10% of general population, 10-30% of patients with type 2 diabetes, 10-60% of hospitalized patients and over 65% of those in the intensive care unit.5   What’s more concerning is that hypomagnesemia is also associated with an elevated risk of death from any cause and death from cardiovascular diseases.5

So, don’t forget to check serum magnesium level in your patient with hypokalemia in need of potassium replacement!

Bonus Pearls: Did you know that many drugs such as proton pump inhibitors (PPIs), thiazide and loop diuretics, aminoglycosides and chemotherapeutic agents are associated with magnesium wasting and hypomagnesemia, while sodium-glucose cotransporter-2 (SGLT2) inhibitors may be associated with increased renal magnesium reabsorption? 5

Contributed by Andy Wu, PhD, Medical Student, St. Louis University Medical School, St. Louis, Missouri

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References

  1. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007 Oct;18(10):2649-52. doi: 10.1681/ASN.2007070792. Epub 2007 Sep 5. PMID: 17804670. https://pubmed.ncbi.nlm.nih.gov/17804670/
  2. AlShanableh Z, Ray EC. Magnesium in hypertension: mechanisms and clinical implications. Front Physiol. 2024 Apr 10;15:1363975. doi: 10.3389/fphys.2024.1363975. PMID: 38665599; PMCID: PMC11044701. https://pubmed.ncbi.nlm.nih.gov/38665599/
  3. Valinsky WC, Touyz RM, Shrier A. Aldosterone, SGK1, and ion channels in the kidney. Clin Sci (Lond). 2018 Jan 19;132(2):173-183. doi: 10.1042/CS20171525. PMID: 29352074; PMCID: PMC5817097. https://pubmed.ncbi.nlm.nih.gov/29352074/
  4. Rodan AR, Cheng CJ, Huang CL. Recent advances in distal tubular potassium handling. Am J Physiol Renal Physiol. 2011 Apr;300(4):F821-7. doi: 10.1152/ajprenal.00742.2010. Epub 2011 Jan 26. PMID: 21270092; PMCID: PMC3074996. https://pubmed.ncbi.nlm.nih.gov/21270092/
  5. Touyz RM, de Baaij JHF, Hoenderop JGJ. Magnesium Disorders. N Engl J Med. 2024 Jun 6;390(21):1998-2009. doi: 10.1056/NEJMra1510603. PMID: 38838313. https://pubmed.ncbi.nlm.nih.gov/38838313/

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why should I check serum magnesium level in my patient with hypokalemia in need of potassium replacement?

Is there a connection between urinary tract infections (UTIs) and hypokalemia?

FA Manian MD, MPH, , , , , , Leave a comment

Although we don’t usually think of UTIs being associated with electrolyte abnormalities, there seems to be a connection between UTI—particularly pyelonephritis—and hypokalemia in adults, possibly related to the impairment of renal potassium resorption due to tubular injury.1

A 2020 study of over 80,000 hospitalized patient found a significantly higher rate of hypokalemia (10%) in patients with UTI (identified based on ICD9 codes) vs non-UTI patients (4%, O.R. 2.3, 95% C.I. 2.2-2.4). This association was independent of patients’ comorbidities and medications. Among patients with UTI, recurrent UTI was associated with hypokalemia (O.R. 1.1, 95% C.I. 1.1-1.2). Unfortunately, no attempt was made to distinguish cystitis from pyelonephritis. The authors reported that in “several patients”, the urinary potassium secretion was increased.  

The association between pyelonephritis and hypokalemia was first reported back in the 1950s and was initially referred to as “potassium losing nephropathy”. 2 It turns out that some of these cases might have had underlying primary hyperaldosteronism (Conn’s) and perhaps pyelonephritis unmasked this condition.  Later, cases of urinary potassium wasting with probable pyelonephritis in the absence of excessive aldosterone excretion were also reported, with resolution of potassium wasting with treatment of the infection in some instances.3,4  

So it looks like the association between pyelonephritis and hypokalemia may be real! Next time you see hypokalemia in a patient with pyelonephritis, don’t be surprised! The corollary: watch for hypokalemia in your patient with pyelonephritis!

Bonus Pearl: Did you know that prevention of potassium loss with spironolactone treatment in pyelonephritis has been reported, suggesting a possible role for aldosterone despite lack of hyperaldosteronism.3

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References

  1. Shen AL, Lin HL, Lin HC, et al. Urinary tract infection is associated with hypokalemia: a case control study. BMC Urology 2020;20:108. Urinary tract infection is associated with hypokalemia: a case control study | BMC Urology | Full Text (biomedcentral.com)
  2. Eastham RD, McElligott M. Potassium-losing pyelonephritis. BMJ 1956; :898-89. Potassium-losing pyelonephritis. – Abstract – Europe PMC
  3. Gerstein AR, Franklin SS, Kleeman CR, et al. Potassium losing pyelonephritis:response to spironolactone. Arch Intern Med 1969;123:55-57. Potassium Losing Pyelonephritis: Response to Spironolactone | JAMA Internal Medicine | JAMA Network
  4. Jones NF, Cantab MB, Mills IH, et al. Reversible renal potassium loss with urinary tract infection. Am J Med 1964;37:305-310. REVERSIBLE RENAL POTASSIUM LOSS WITH URINARY TRACT INFECTION – PubMed (nih.gov)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University,their affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is there a connection between urinary tract infections (UTIs) and hypokalemia?

What’s the connection between Covid-19 and hypokalemia?

FA Manian MD, MPH, , , , , , , , Leave a comment

The association of hypokalemia with hospitalized Covid-19 patients has been recognized since the early days of the pandemic, with more severe cases associated with lower concentration of serum potassium.1-4

A study involving 175 hospitalized patients with Covid-19 found low serum potassium in 54% of patients with 18% having severe hypokalemia (<3.0 mmol/L) and 37% having serum potassium 3.-3.5 mmol/L.  Compared to patients with mild to moderate Covid-19, those with severe or critical disease were more likely to have low serum potassium (3.5 mmol/L or less) (85% vs 45%).1

Another study involving 306 hospitalized patients with Covid-19, nearly a third (31%) had hypokalemia (3.5 mmol/L or less). Hypokalemia was associated with invasive mechanical ventilation, longer hospital and ICU stays.2 In contrast, a non-peer-reviewed MedRxive study found no association between hypokalemia and ICU admission or in-hospital mortality, possibly related to milder hypokalemia in the patients studied.3

Although various mechanisms may be invoked to explain hypokalemia in hospitalized Covid-19 patients (eg, poor intake, diuretics, corticosteroids, diarrhea, etc…), the most fascinating explanation may revolve around the direct impact of SARS-CoV-2 on the renin-angiotensin system.5  Because this virus uses the enzymatic receptor of ACE2 to penetrate the host cell, it can lead to downregulation of ACE2. Since ACE2 serves as a counterbalance to ACE by transforming a part of angiotensin I and II before they attach to angiotensin II type 1 receptor (AT1R), aldosterone effect is enhanced with resultant hypokalemia. High urinary excretion of potassium in many patients with Covid-19 seem to support the latter hypothesis.1,3  

Who would have predicted the versatility of this virus in causing hypokalemia in addition to all the other physiologic derangements it causes?  

Bonus Pearl: Did you know that there may be an association between lower prevalence of dry cough in patients with Covid-19 and hypokalemia, possibly related to low ACE2—therefore bradykinin— activity mediated by SARS-CoV-2? 2

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References

  1. Chen D, Li X, Song Q, et al. Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Network Open 2020;3(6):e2011122. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767008
  2. Moreno-Perez O, Leon-Ramirez JM, Fuertes-Kenneally L, et al. Hypokalemia as a sensitive biomarker of disease severity and the requirement for invasive mechanical ventilation requirement in COVID-19 pneumonia: A case series of 306 Mediterranean patients. International J Infect Dis 2020;100:449-54. https://www.ijidonline.com/article/S1201-9712(20)30749-9/pdf
  3. Gaetano A, Annachiara F, Francesco F, et al. Hypokalemia in patients with COVID-19. MedRxive preprint. Doi:https://doi.org/10.1101/2020.0614.20131169. https://www.medrxiv.org/content/10.1101/2020.06.14.20131169v2.full.pdf
  4. Lippi G, South Am, Henry BM. Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19). Ann Clin Biochem 2020;57:262-65. https://pubmed.ncbi.nlm.nih.gov/32266828/
  5. Silhol F, Sarlon G, Deharo JC, et al. Downregulation of ACE2 induces overstimulation of renin-angiotensin system in COVID-19: Should we block the renin-angiotensin system? Hypertension Research 2020;43:854-856. https://www.nature.com/articles/s41440-020-0476-3

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the connection between Covid-19 and hypokalemia?

My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

FA Manian MD, MPH, , , , , , , , , , , , Leave a comment

Although originally described in 1949 in patients with liver disease and labelled as “liver flap”, numerous other causes of asterixis exist aside from severe liver disease (1,2). As early as 1950s, asterixis was observed among some patients with heart failure and pulmonary insufficiency but without known significant liver disease (3). Azotemia has also been associated with asterixis.

Don’t forget about medication-associated asterixis . Commonly used drugs such as gabapentin, pregabalin, phenytoin, and metoclopramide have been associated with asterixis (1,4) . Even antibiotics such as ceftazidime and high dose trimethoprim-sulfamethoxazole may be culprits (1,5). There are many psychiatric drugs including lithium, carbamazepine, clozapine, and valproic acid that have been implicated (1,6) as well. Some reviews have also included hypomagnesemia and hypokalemia on the list of causes of asterixis (1).

Although asterixis is essentially a negative myoclonus with episodic loss of electrical activity of muscle and its tone, its exact pathophysiology remains unclear (7). 

 

Bonus Pearl: Did you know that the origin of the word asterixis is An (negative)-iso (equal)-sterixis (solidity) which was shortened by Foley and Adams, its original discoverers, to what we now refer to as “asterixis” (1).

 

References
1. Agarwal R, Baid R. Asterixis. J Postgrad Med 2016;62:115-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944342/

2. Pal G, Lin MM, Laureno R. Asterixis: a study of 103 patients. Metab Brain Dis; 2014:29:813-24. https://link.springer.com/article/10.1007%2Fs11011-014-9514-7
3. Conn HO. Aterixis—Its occurrence in chronic pulmonary disease, with a commentary on its general mechanism. N Engl J Med 1958;259:564-569. https://www.nejm.org/doi/full/10.1056/NEJM195809182591203
4. Kim JB, Jung JM, Park MH. Negative myoclonus induced by gabapentin and pregabalin: a case series and systemic literature review. J Neurol Sci 2017;382:36-9. https://www.sciencedirect.com/science/article/pii/S096758681830225X
5. Gray DA, Foo D. Reversible myoclonus, asterixis, and tremor associated with high dose trimethoprim-sulfamethoxazole: a case report. J Spinal Cord Med 2016; Vol. 39 (1), pp. 115-7. https://www.ncbi.nlm.nih.gov/pubmed/26111222
6. Nayak R, Pandurangi A, Bhogale G, et al. Aterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. J Neuropsychiatry Clin Neurosci 2012;24: E26-7. https://neuro.psychiatryonline.org/doi/pdf/10.1176/appi.neuropsych.101102667.

7.Ugawa Y, Shimpo T, Mannen T. Physiological analysis of asterixis: silent period locked averaging. J Neurol Neurosurg Psych 1989;52:89-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032663/pdf/jnnpsyc00523-0104.pdf

 

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My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. 1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.3

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? 7

 

References

  1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
  2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
  3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
  4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
  5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
  6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
  7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?