ADH;

What is the role of measuring serum uric acid level in my patient with hyponatremia suspected of having syndrome of inappropriate antidiuretic hormone secretion (SIADH)?

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

The utility of checking serum uric acid (SUA) in hyponatremia primarily stems from the fact that it helps distinguish SIADH from volume contraction as the cause of hyponatremia.1 Whereas hyperuricemia commonly accompanies volume contraction, hypouricemia is found in the majority (70%) of patients with SIADH.2 This finding is caused by increased urinary excretion of SUA in patients with SIADH.3

There are several potential mechanisms for the association of SIADH with hypouricemia. First, the expanded vascular volume in these patients enhances UA clearance by decreasing its reabsorption, as supported by improved UA serum levels in SIADH patients on fluid restriction.4 Of note, UA normalization with fluid restriction is more pronounced in chronic SIADH patients compared to healthy individuals acutely volume overloaded via treatment with synthetic ADH (i.e. desmopressin).5 This may be due to the fact that, unlike endogenous ADH, desmopressin is a selective agonist of vasopressin 2 receptors (V2R), promoting water reabsorption in the collecting duct without binding to vasopressin 1 receptors (V1R), which promotes UA secretion and inhibits UA reabsorption in the proximal tubule.5,6  To make things worse, there is also evidence that chronic hyponatremia induced by SIADH can directly promote UA excretion!7

Last, keep in mind that salt-wasting disease, a less common cause of hyponatremia, may also be associated with hypouricemia. However, in contrast to patients with SIADH, UA excretion remains high and serum UA levels remain low in these patients even after their hyponatremia is corrected. 8

Bonus Pearl: Did you know that tolvaptan, a selective ADH (V2R) antagonist, has been shown to be effective in raising serum sodium and UA levels in SIADH patients with the caveat that its chronic use may also cause hyperuricemia? 9,10

Contributed by Stella Hoft, PhD, Medical Student, St. Louis University Medical School, St. Louis, Missouri

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References

  1. Liamis G, Christidis D, Alexandridis G, Bairaktari E, Madias NE, Elisaf M. Uric acid homeostasis in the evaluation of diuretic-induced hyponatremia. J Investig Med. 2007 Jan;55(1):36-44. doi: 10.2310/6650.2007.06027. PMID: 17441410. https://journals.sagepub.com/doi/10.2310/6650.2007.06027?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
  2. Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol. 2008 Jul;3(4):1175-84. doi: 10.2215/CJN.04431007. Epub 2008 Apr 23. PMID: 18434618. https://journals.lww.com/cjasn/abstract/2008/07000/clinical_laboratory_evaluation_of_the_syndrome_of.38.aspx
  3. Li R, Wu B, Han M, Li M, Yang X, Zhang J, Zhang Y, Liu Y. Uric Acid Metabolic Disorders in Pituitary-Target Gland Axis. Diabetes Metab Syndr Obes. 2024 Feb 7;17:661-673. doi: 10.2147/DMSO.S448547. PMID: 38343584; PMCID: PMC10859102. https://www.dovepress.com/uric-acid-metabolic-disorders-in-pituitary-target-gland-axis-peer-reviewed-fulltext-article-DMSO
  4. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1979 Sep 6;301(10):528-30. doi: 10.1056/NEJM197909063011005. PMID: 460306. https://www.nejm.org/doi/abs/10.1056/NEJM197909063011005
  5. Decaux G, Namias B, Gulbis B, Soupart A. Evidence in hyponatremia related to inappropriate secretion of ADH that V1 receptor stimulation contributes to the increase in renal uric acid clearance. J Am Soc Nephrol. 1996 May;7(5):805-10. doi: 10.1681/ASN.V75805. PMID: 8738818. https://journals.lww.com/jasn/abstract/1996/05000/evidence_in_hyponatremia_related_to_inappropriate.23.aspx
  6. Taniguchi K, Tamura Y, Kumagai T, Shibata S, Uchida S. Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH. Clin Exp Nephrol. 2016 Dec;20(6):845-852. doi: 10.1007/s10157-016-1248-x. Epub 2016 Mar 2. PMID: 26935049. https://link.springer.com/article/10.1007/s10157-016-1248-x
  7. Decaux G, Prospert F, Soupart A, Musch W. Evidence that chronicity of hyponatremia contributes to the high urate clearance observed in the syndrome of inappropriate antidiuretic hormone secretion. Am J Kidney Dis. 2000 Oct;36(4):745-51. doi: 10.1053/ajkd.2000.17623. PMID: 11007676. https://www.ajkd.org/article/S0272-6386(00)08495-X/ppt
  8. Momi J, Tang CM, Abcar AC, Kujubu DA, Sim JJ. Hyponatremia-what is cerebral salt wasting? Perm J. 2010 Summer;14(2):62-5. doi: 10.7812/TPP/08-066. PMID: 20740122; PMCID: PMC2912080. https://www.thepermanentejournal.org/doi/10.7812/TPP/08-066
  9. Nagamine T. Uric acid levels with tolvaptan treatment for syndrome of inappropriate antidiuretic hormone secretion. Endocrine. 2024 Mar;83(3):826-827. doi: 10.1007/s12020-023-03612-3. Epub 2023 Nov 20. PMID: 37982946. https://link.springer.com/article/10.1007/s12020-023-03612-3
  10. Bondanelli M, Aliberti L, Gagliardi I, Ambrosio MR, Zatelli MC. Long-term low-dose tolvaptan efficacy and safety in SIADH. Endocrine. 2023 Nov;82(2):390-398. doi: 10.1007/s12020-023-03457-w. Epub 2023 Jul 28. PMID: 37507553; PMCID: PMC10543144. https://link.springer.com/article/10.1007/s12020-023-03457-w

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!

What is the role of measuring serum uric acid level in my patient with hyponatremia suspected of having syndrome of inappropriate antidiuretic hormone secretion (SIADH)?

Can hypothyroidism be associated with hypertension?

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

Short answer: Yes! Just as hyperthyroidism, hypothyroidism is also associated with hypertension (1-5). Compared to normal subjects, patients with hypothyroidism have a 3-fold increased prevalence of hypertension, usually diastolic (2). In fact, hypothyroidism has been identified as a cause of hypertension in 3% of patients with high blood pressure and is the most common cause of secondary hypertension after renovascular hypertension (1-3).

 
High systemic vascular resistance and increased arterial stiffness are among the important mechanisms explaining hypothyroid-induced hypertension (1). High systemic vascular resistance is thought to be due to the absence of the vasodilator effects of T3 on vascular smooth muscle and decreased response to beta-adrenergic stimulation, which in turn leads to increased alpha-adrenergic responses. Increased arterial stiffness may also contribute due to the myxedema involvement of the arterial wall. Other potential factors include free water retention due to an inappropriate secretion of anti-diuretic hormone (ADH) and obesity in hypothyroid patients (1,4).

 
Similar to its prevalence in hypothyroidism, hypertension is about 3-fold higher in patients with overt hyperthyroidism compared to normal subjects (1). However, in contrast to hypothyroid patients, the hypertension in hyperthyroidism is primarily “cardiogenic”, where the increased blood pressure levels are mainly maintained by the increased cardiac output due to high stroke volume and heart rate (1).

 
Thus, both hypothyroidism and hyperthyroidism can be associated with hypertension!

 
Bonus pearl: Did you know that hypertension due to hypothyroidism is typically associated with a low-renin state, is particularly sensitive to salt intake, and may not respond as well to angiotensin -converting enzyme inhibitors (1)?

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References
1. Mazza A, Beltramello G, Armigliato M, et al. Arterial hypertension and thyroid disorders: what is important to know in clinical practice? Annales d’Endocrinologie 2011;72:296-303. https://www.sciencedirect.com/science/article/abs/pii/S0003426611000886
2. Dernellis J, Panaretou M. Effects of thyroid replacement therapy on arterial blood pressure in patients with hypertension and hypothyroidism 2002; Am Heart J 2002;143:718-24. https://www.ncbi.nlm.nih.gov/pubmed/11923811
3. Anderson GH, Blakeman N, Steeten DHP. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertension 1994;12:609-15. https://insights.ovid.com/hypertension/jhype/1994/05/000/effect-age-prevalence-secondary-forms-hypertension/15/00004872
4. Saito I, ITO K, Saruta T. Hypothyroidism as a cause of hypertension. Hypertension 1983;5:112-15. https://www.ahajournals.org/doi/10.1161/01.hyp.5.1.112
5. Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet 2017;390:1550-62. https://www.ncbi.nlm.nih.gov/pubmed/28336049

Can hypothyroidism be associated with hypertension?

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

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

Although we may expect patients with DKA to present with hypotension due to hypovolemia, many patients with DKA may actually be hypertensive. This finding is particularly intriguing because hyperinsulinemia, not insulinopenia as found in DKA, has been associated with hypertension. 1,2

Though not proven, potential explanations for hypertension in DKA include elevated serum levels of catecholamines, pro-inflammatory cytokines, renin, angiotension II and aldosterone.3-5 Hyperosmolality may also lead to the release of antidiuretic hormone (ADH) which increases blood pressure via V2 receptors.  Another possibility is that the high insulin levels associated with the treatment of DKA suppress the catecholamine-stimulated production of vasodilative eicosanoids (eg, prostaglandins) by adipose tissue. 1 It’s possible that in any given patient, 1 or more of these mechanisms may be enough to override the potential hypotensive effect of insulin deficiency in DKA.

We should note that reports of frequent hypertension in DKA have primarily involved pediatric patients. A 2011 study found that 82% of pediatric patients with DKA had hypertension during the first 6 hours of admission with no patient having hypotension.3  

On the other extreme, refractory hypotension without obvious cause (eg, sepsis, acute adrenal insufficiency, cardiogenic causes) has also been reported in DKA.5Because insulin inhibits the production of vasodilative prostaglandins (eg, PGI2 and PGE2), severe insulin deficiency in DKA can also contribute to hypotension along with volume depletion. 

Potential genetic polymorphism in the synthesis and metabolism of prostaglandins may at least partially explain the varied blood pressure response and whether a patient with DKA presents with hypertension or hypotension. 5  

The author would like to acknowledge the valuable contribution of Lloyd Axelrod MD, Massachusetts General Hospital, to this post.

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References

  1. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991;40:1223-1227. https://diabetes.diabetesjournals.org/content/40/10/1223 
  2. Chatzipantelli K, Head C, Megerman J, et al. The relationship between plasma insulin level, prostaglandin productin by adipose tissue and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis. Metabolism 1996;45:691-98. https://www.sciencedirect.com/science/article/abs/pii/S002604959690133X 
  3. Deeter KH, Roberts JS, Bradford H, et al. Hypertension despite dehydration during severe pediatric diabetic ketoacidosis. Pediatr Diabetes 2011;12:295-301. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-5448.2010.00695.x 
  4. Ferris JB, O’Hare JA, Kelleher CM, et al. Diabetic control and the renin-angiotensin system, catecholamines and blood pressure. Hypertension 1985 7(Suppl II):II-58-II-63. https://www.ahajournals.org/doi/abs/10.1161/01.HYP.7.6_Pt_2.II58  
  5. Singh D, Cantu M, Marx MHM, et al. Diabetic ketoacidosis and fluid refractory hypotension. Clin Pediatrics 2016;55:182-84. https://journals.sagepub.com/doi/abs/10.1177/0009922815584549?journalCode=cpja 

 

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?