Syndrome of inappropriate antidiuretic hormone classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Overview

SIADH may be classified into several sub-types based on the pattern of arginine vasopressin (AVP) secretion in response to a range of plasma osmolalities into type A, type B, type C, and type D.

Classification

SIADH may be classified into several sub-types based on the pattern of arginine vasopressin (AVP) secretion across a range of plasma osmolalities:^[1]^[2]^[3]

This classification scheme includes Fenske’s^[4] observation on copeptin levels, which is “secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay.”^[5] Normal observations for copeptin are:

Level during euvolemia: 2 and 38 pmol/L“^[4]. Another view is “Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l”^[6] and levels are modulated by gender (higher in males), eGFR higher when eGFR lower), left atrial size (higher when LA larger), and longer echocardiographic deceleration times (prolonged ventricular filling)^[6].
Slope of change during hypertonic saline infusion: “slope of 0.74 pmol/L and mOsM/kg H₂O … (95% confidence interval [95% CI], 0.66 to 0.83)”^[4]


Classification	Features

Type A	Accounts for about 60-70% of SIADH Excessive secretion of arginine vasopressin (AVP) is noted “Plasma copeptin consistently >38 pmol/L with a copeptin slope <95% CI for that of healthy persons (i.e., <0.66 pmol/L/mOsM/kg H2O)”^[4] Associated with lung cancer and nasopharyngeal tumors Patients are more susceptible to development of severe hyponatremia
Type B	Accounts for (20–40%) of the cases “Any plasma copeptin concentration with a positive copeptin slope >0.25 pmol/L/mOsM/kg H2O, but a low osmotic threshold <95% CI for that of healthy persons (i.e., <281 mOsM/kg H2O)”^[4] Type B may include reset osmostat, “characterized by a decline in plasma copeptin levels with increasing saline-stimulated serum osmolality…baseline hypovolemia could not be identified [in these patient]”^[4] Secretion of AVP occurs at lower than normal plasma osmolalities
Type C	Failure to suppress AVP secretion at plasma osmolalities below the osmotic threshold “Plasma copeptin concentration between 2 and 38 pmol/L with a copeptin slope between −0.25 and 0.25 pmol/L/mOsM/kg H2O”^[4] Reset osmostat may be a Type C rather than Type b, “reset osmostat may in part be considered as a less severe variant of the type C defect…, where responsivity to osmotic challenges is completely lost. Copeptin release in this subtype was stable at levels within the normal physiologic range but was not suppressed by hypotonicity or stimulated in response to osmotic stimulation; thus, it deviates from the previously described type C”^[4] Occurs due to dysfunction of inhibitory neurons in the hypothalamus, leading to persistent low-grade basal AVP secretion
Type D	Low or undetectable AVP levels and circulating AVP response is not defective “Plasma copeptin concentration consistently <2 pmol/L regardless of the copeptin slope”^[4] Nephrogenic SIADH (NSIAD) may be attributed to this condition Associated with gain-of-function mutations in the vasopressin-2 (V2) receptor leading to a clinical picture of SIADH, with undetectable AVP levels The condition is inherited in an X-linked manner, although heterozygous females may have inappropriate anti-diuresis of varying degrees.
Type E	“Any plasma copeptin concentration with a copeptin slope <−0.25 pmol/L/mOsM/kg H₂O…Theoretically, an alternative explanation of type E could be a reversed osmotic response from stimulation to inhibition”^[4]

References

↑ Hannon MJ, Thompson CJ (2010). “The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences”. Eur. J. Endocrinol. 162 Suppl 1: S5–12. doi:10.1530/EJE-09-1063. PMID 20164214.
↑ Yamauchi T, Makinodan M, Nagashima T, Kiuchi K, Noriyama Y, Kishimoto T (2009). “Type d syndrome of inappropriate antidiuretic hormone secretion in a schizophrenia patient with polydipsia”. J Brain Dis. 1: 25–7. PMC 3676320. PMID 23818806.
↑ Gross P (2012). “Clinical management of SIADH”. Ther Adv Endocrinol Metab. 3 (2): 61–73. doi:10.1177/2042018812437561. PMC 3474650. PMID 23148195.
↑ ^4.00 ^4.01 ^4.02 ^4.03 ^4.04 ^4.05 ^4.06 ^4.07 ^4.08 ^4.09 Fenske WK, Christ-Crain M, Hörning A, Simet J, Szinnai G, Fassnacht M; et al. (2014). “A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis”. J Am Soc Nephrol. 25 (10): 2376–83. doi:10.1681/ASN.2013080895. PMC 4178436. PMID 24722436.
↑ Refardt J, Winzeler B, Christ-Crain M (2019). “Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis”. Clin Endocrinol (Oxf). 91 (1): 22–32. doi:10.1111/cen.13991. PMC 6850413 Check |pmc= value (help). PMID 31004513.
↑ ^6.0 ^6.1 Bhandari SS, Loke I, Davies JE, Squire IB, Struck J, Ng LL (2009). “Gender and renal function influence plasma levels of copeptin in healthy individuals”. Clin Sci (Lond). 116 (3): 257–63. doi:10.1042/CS20080140. PMID 18647134.

[pmid20164214-1] Hannon MJ, Thompson CJ (2010). “The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences”. Eur. J. Endocrinol. 162 Suppl 1: S5–12. doi:10.1530/EJE-09-1063. PMID 20164214.

[pmid23818806-2] Yamauchi T, Makinodan M, Nagashima T, Kiuchi K, Noriyama Y, Kishimoto T (2009). “Type d syndrome of inappropriate antidiuretic hormone secretion in a schizophrenia patient with polydipsia”. J Brain Dis. 1: 25–7. PMC 3676320. PMID 23818806.

[pmid23148195-3] Gross P (2012). “Clinical management of SIADH”. Ther Adv Endocrinol Metab. 3 (2): 61–73. doi:10.1177/2042018812437561. PMC 3474650. PMID 23148195.

[pmid24722436-4] 4.00 ^4.01 ^4.02 ^4.03 ^4.04 ^4.05 ^4.06 ^4.07 ^4.08 ^4.09 Fenske WK, Christ-Crain M, Hörning A, Simet J, Szinnai G, Fassnacht M; et al. (2014). “A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis”. J Am Soc Nephrol. 25 (10): 2376–83. doi:10.1681/ASN.2013080895. PMC 4178436. PMID 24722436.

[pmid31004513-5] Refardt J, Winzeler B, Christ-Crain M (2019). “Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis”. Clin Endocrinol (Oxf). 91 (1): 22–32. doi:10.1111/cen.13991. PMC 6850413 Check |pmc= value (help). PMID 31004513.

[pmid18647134-6] 6.0 ^6.1 Bhandari SS, Loke I, Davies JE, Squire IB, Struck J, Ng LL (2009). “Gender and renal function influence plasma levels of copeptin in healthy individuals”. Clin Sci (Lond). 116 (3): 257–63. doi:10.1042/CS20080140. PMID 18647134.

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