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Repurposing common endocrine tests for use in canine critical illness
At the intersection of endocrinology and critical illness, these case studies examine endocrine biomarkers that accompany severe illness and incipient recovery.
This article is sponsored by Zomedica.
The integration of endocrinology and critical illness has generated important new insights into the complex and constantly changing endocrine environment accompanying severe illness. These studies have uncovered endocrine biomarkers of disease severity and harbingers of incipient recovery. Studies performed 60 years ago on adrenalectomized dogs demonstrated that the adrenal response to shock and critical illness was essential for survival.1 Moreover, nonthyroidal illness (NTI) in dogs is a well-known cause of euthyroid sick syndrome and the effects of severe illness on lowering thyroid hormones have been well-described.2
Amber is a 2-year-old Yorkshire terrier that was referred to our hospital on the October 29, 2021 with marked anemia (HCT = 0.07 l/l) and severe icterus, with a history of weakness and recent onset vomiting. At admission, basal serum cortisol and TT4 concentrations were 436 nmol/l (RI 27-200); 16 ug/dl (RI 1-7) and <6.4 nmol/l (RI 15-45); 0.5 ug/dl (RI 1.2-3.5) respectively. Lipase DGGR concentrations were 1880 U/L (RI 24 - 108). Amber was diagnosed with acute intravascular hemolytic anemia and presumed secondary pancreatitis. A packed red blood cell transfusion was administered and she was managed symptomatically.
Now, let’s turn to the scientific studies and return to the case later.
Two different, comparatively homogenous models of acute critical illness and sepsis, virulent canine babesiosis and canine parvoviral diarrhoea, have been studied by the author. In dogs with babesiosis, median basal cortisol concentration at admission was significantly higher in nonsurvivors than survivors; 482 nmol/L (IQR 456-562); 17.5 ug/dl (16.5-20.4) vs. 115 nmol/L (IQR 64-208); 4.2 ug/dl (2.3-7.5).3 Basal plasma ACTH concentrations were also significantly higher in nonsurvivors than survivors. Moreover, basal TT4 and fT4 were significantly lower in nonsurvivors than survivors, yet TSH concentrations were similarly low in both groups.
Similarly, in dogs with parvoviral diarrhoea, median basal cortisol concentrations on days 1, 2, and 3 were significantly higher in nonsurvivors than survivors.4 This finding was confirmed in a follow-up study on a different group of dogs with parvoviral diarrhoea in which these puppies also demonstrated significantly lower TT4 and fT4 in nonsurvivors than survivors on all 3 days.5 Interestingly, endogenous TSH concentrations were higher in nonsurvivors on days 1 and 2, before decreasing to below the limit of detection in the nonsurvivors as critical illness progressed. TT4 and fT4 are thus more sensitive than TSH in predicting mortality, since they decrease earlier than TSH in canine critical illness. A study conducted in a mixed population of sick dogs also found significantly lower TT4, fT4 and T3 in dogs that died compared to dogs that made a full recovery.6
In dogs with induced pneumonia, the most severely affected dogs also demonstrated the highest cortisol concentrations and adrenal function changed over time.7 Experimental models provide the most uniform population to study, both in terms of the type and the time of onset of disease. The return of function of the pituitary-adrenal axis—basal cortisol secretion, stimulated cortisol secretion and the ability of dexamethasone to suppress cortisol secretion—was seen in the survivors. However, neither a single type of assessment of cortisol secretion nor at a single point in time will be able to determine all that is needed to be known in a patient.
Lately, there has been a plethora of studies in canine and feline patients that sought to confirm these earlier findings. In 28 parvo puppies, the negative association of TT4 and fT4 with survival was confirmed. In addition, those puppies with systemic inflammatory response syndrome (SIRS) had significantly lower TT4 and fT4 than puppies without SIRS.8 Similarly, another study showed that NTI was frequent in dogs with SIRS and was associated with sepsis and higher disease severity.9 Moreover, 210 dogs that presented with recent road traffic accidents had significantly higher adrenal activity as measured by urine cortisol-creatinine ratio (UCCR) and significantly lower TT4 and fT4 than a cohort with other less traumatic disease processes.10 Even in sick cats it was convincingly demonstrated that non-survivors had lower TT4, TT3 and TSH than survivors.11
Case study (continued)
On day 2 of hospitalization, Amber’s HCT rose to 0.17 l/l, but she was still very depressed, nauseous and anorexic. Baseline serum cortisol concentrations had reduced to 138 nmol/l (5ug/dl), whilst serum TT4 had risen to 8 nmol/l (1.4 ug/dl). Given her favorable endocrine response, among other parameters, treatment was continued and Amber’s demeanour showed gradual improvement. On day 3, Amber started eating voluntarily. On day 4, her serum cortisol concentration was still within normal range at 155 nmol/l, whilst her TT4 had also risen into the normal range to 18 nmol/l. Amber was discharged later that same day. Follow up phone call indicated that Amber made a full recovery.
Some evidence shows that critically ill dogs with the most severe acute illness have the highest concentrations of the pituitary- adrenal-axis hormones ACTH and cortisol, providing substrates for survival and protecting the host against the deleterious pro-inflammatory effects of the immune system. In contrast, the pituitary-thyroid axis hormones are markedly suppressed in very sick patients, with the putative beneficial effect of inactivating anabolic pathways. In addition, tracking of these endocrine trajectories may provide the clinician with prognostic information. At present, there is no solid pathophysiological basis for intervention with thyroid hormone in this acute phase of critical illness. In fact, both thyroxine and growth hormone supplementation in critical illness have led to unexpectedly higher mortality.12,13
Consequently, we need large prospective, longitudinal studies, containing enough cases with adverse outcomes, so that multivariate analysis and artificial intelligence can potentially be harnessed to identify the combined value of various hormone parameters in the prediction of mortality. In addition, the role of inflammatory cytokines as mediators of the processes warrants investigation. Lastly, transcriptomic data on glucocorticoid and mineralocorticoid receptor function might aid in identifying patients that would benefit from replacement therapy.
- Swingle WW et al. Effect of gluco- and mineralocorticoid adrenal steroids on fluid and electrolytes of fasted adrenalectomized dogs. Proc Soc Exp Biol Med. 1957;96(2):446-452. doi:10.3181/00379727-96-23504
- Kantrowitz LB et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyro- tropin concentrations in dogs with nonthyroidal disease. J Am Vet Med Assoc. 2001;219(6):765- 769. doi:10.2460/javma.2001.219.765
- Schoeman JP et al. Endocrine predictors of mortality in canine babesiosis caused by Babesia canis rossi. Vet Parasitol. 2007;148(2):75-82. doi:10.1016.j.vetpar.2007.06.010
- Schoeman JP et al. Serum cortisol and thyroxine concentrations as predictors of death in critically ill puppies with parvoviral diarrhea. J Am Vet Med Assoc. 2007;231(10):1534-1539. doi:10.2460/javma.231.10.1534
- Schoeman JP, Herrtage ME. Serum thyrotropin, thyroxine and free thyroxine concentrations as predictors of mortality in critically ill puppies with parvovirus infection: a model for human paediatric critical illness? Microbes & Infection. 2008;10(2):203-207. doi:10.1016/j. micinf.2007.11.002
- Mooney CT et al. Thyroid hormone abnormalities and outcome in dogs with non-thyroidal illness. J Small Anim Pract. 2008; 49(1):11-16. doi:10.1111/j.1748-5827.2007.00418
- Cortes-Puch I et al. Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia. Am J Physiol Endocrinol Metab. 2014;307(11):E994-E1008. doi:10.1152/ ajpendo.00345.2014
- Oikonomidis IL et al. Serial measurement of thyroid hormones in dogs with parvoviral enteritis: Incidence of non-thyroidal illness syndrome and its association with SIRS. Vet J. 2021;274:105715. doi:10.1016/j.tvjl.2021.105715
- Giunti M et al. Retrospective evaluation of circulating thyroid hormones in critically ill dogs with systemic inflammatory response syndrome. J Vet Sci. 2017;18(4):471-477. doi:10.4142/ jvs.2017.18.4.471
- Caldin M et al. Thyroid axis and adrenal activity in 28 day survivor and nonsurvivor dogs involved in recent road traffic accidents: A cohort study of 420 dogs. Res Vet Sci. 2020;132:243-249. doi:10.1016/j.rvsc.2020.06.021
- Peterson ME et al. Serum thyroxine and thyrotropin concentrations decrease with severity of nonthyroidal illness in cats and predict 30-day survival outcome. J Vet Int Med. 2020;34(6):2276-2286. doi:10.1111/jvim.15917
- Takala J et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Eng J Med. 1999; 341(11):785-792. doi:10.1056/NEJM199909093411102
- Acker CG et al. A trial of thyroxine in acute renal failure. Kidney Int. 2000;57(1):293-298. doi:10.1046/j.1523-1755.2000.00827.x