Diagnosis and management of hypoaldosteronism without hypoadrenocorticism in an alpaca

Kelly A. Butterworth Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Alessandra M. Pellegrini-Masini Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Michelle H. Barton Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Abstract

Case Description—Primary hypoaldosteronism without concurrent hypoadrenocorticism was diagnosed in an 8-year-old female alpaca with acute onset of weakness progressing to recumbency within 6 hours after onset.

Clinical Findings—Hematologic testing at admission revealed profound hyponatremia, hypochloremia, and acidemia with a normal blood potassium concentration. Further diagnostic testing, including an ACTH stimulation test, led to a diagnosis of hypoaldosteronism in conjunction with normal cortisol production.

Treatment and Outcome—The hembra responded well to IV polyionic fluid therapy with sodium supplementation and was managed successfully long term with free access to saline (0.9% NaCl) solution in addition to water ad libitum.

Clinical Relevance—To our knowledge, this is the first reported case of hypoaldosteronism in an alpaca. Hypoaldosteronism should be considered in alpacas as a possible differential diagnosis for refractory hyponatremia or for hyponatremia in which an underlying etiology is not determined.

Abstract

Case Description—Primary hypoaldosteronism without concurrent hypoadrenocorticism was diagnosed in an 8-year-old female alpaca with acute onset of weakness progressing to recumbency within 6 hours after onset.

Clinical Findings—Hematologic testing at admission revealed profound hyponatremia, hypochloremia, and acidemia with a normal blood potassium concentration. Further diagnostic testing, including an ACTH stimulation test, led to a diagnosis of hypoaldosteronism in conjunction with normal cortisol production.

Treatment and Outcome—The hembra responded well to IV polyionic fluid therapy with sodium supplementation and was managed successfully long term with free access to saline (0.9% NaCl) solution in addition to water ad libitum.

Clinical Relevance—To our knowledge, this is the first reported case of hypoaldosteronism in an alpaca. Hypoaldosteronism should be considered in alpacas as a possible differential diagnosis for refractory hyponatremia or for hyponatremia in which an underlying etiology is not determined.

A 70-kg (154-lb) 8-year-old female Huacaya alpaca that was 9 months pregnant was admitted to the University of Georgia Veterinary Teaching Hospital with a history of acute onset of hypothermia (36.1°C [97.0°F]), ataxia, and weakness that progressed to recumbency within 6 hours after onset.

On initial examination at the Veterinary Teaching Hospital, the hembra was recumbent and unable to rise or hold its head erect. Bruxism and ptyalism were observed. Muscle fasciculations were present over the trunk and hind limbs. Heart rate was 48 beats/min, respiratory rate was 54 breaths/min, and rectal temperature was 38.06°C (100.5°F). The hembra's mucous membranes were pink and slightly tacky with a capillary refill time of 2 seconds. Gastrointestinal borborygmi and first compartment contractions were decreased on auscultation. Salient abnormalities on a CBC and serum biochemical profile included severe hyponatremia (111 mmol/L; reference range, 149 to 160 mmol/L) and hypochloremia (73 mmol/L; reference range, 106 to 120 mmol/L) with a normal blood potassium concentration (4.2 mmol/L; reference range, 3.7 to 5.9 mmol/L). Total protein concentration was 6.1 g/dL (reference range, 5.4 to 7.2 g/dL), and serum albumin concentration was 3.3 g/L (reference range, 3.4 to 4.5 g/dL). Venous blood gas analysis revealed metabolic acidemia with partial respiratory compensation: blood pH, 7.24 (reference range, 7.46 to 7.48); base excess, −7 mmol/L (reference range, 2 to 6 mmol/L); lactate concentration, 4.2 mmol/L (reference range, < 2 mmol/L); bicarbonate concentration, 8 mmol/L (reference range, 19.6 to 21.3 mmol/L); and Pvco2, 22.1 mm Hg (reference range, 40 to 50 mm Hg). The anion gap was 34 mmol/L (reference range, 15.6 to 25.4 mmol/L), and the independent strong ion difference was 38 mmol/L. The neurologic signs and profound weakness were presumed secondary to acute hyponatremia and acidosis, and after placement of a jugular IV catheter, fluid administration aimed at rapid correction of hyponatremia (0.5 to 1 mmol/L/h increase in serum sodium concentration) was initiated. Following a 1-L bolus of polyionic fluids,a the alpaca was administered hypertonic saline (7.2% NaCl) solution at a rate of 80 mL/h. The rate was increased to 160 mL/h in 6 hours when the alpaca's serum sodium concentration failed to increase. The bicarbonate deficit was corrected via a continuous IV infusion of isotonic sodium bicarbonate at a rate aimed at administering half of the bicarbonate deficit over a 12-hour period. Because sodium was supplied in both the hypertonic saline and isotonic sodium bicarbonate solutions, fluid rate and composition were adjusted on the basis of plasma sodium concentrations and evaluated every few hours with a blood gas whole blood analyzer.b Lactated Ringer's solution was used to meet the remaining volume of the total desired fluid volume (80 mL/kg [36.4 mL/lb], q 24 h). By 18 hours after admission, the hembra's serum sodium concentration had risen to 131 mmol/L, and the acidemia had resolved. Clinical improvement was dramatic. The patient regained the ability to stand and eat, and with the exception of very mild facial muscle fasciculations, neurologic deficits or signs of weakness were not appreciated on physical examination. Vital signs returned to normal (heart rate, 72 beats/min; respiratory rate, 24 breaths/min; rectal temperature, 38.7°C [101.6°F]). By 72 hours after admission, the serum sodium concentration increased to 148 mmol/L, and facial muscle fasciculations had resolved.

Fluid therapy was gradually discontinued. However, the alpaca's serum sodium concentration decreased to 131 mmol/L within 48 hours after fluid therapy was discontinued. During this period, the hembra became polydipsic (water intake, 80 to 120 mL/kg/d [36.4 to 54.5 mL/lb/d]; reference range, 30 to 40 mL/kg/d [13.6 to 18.2 mL/lb/d]1) and urine was hyposthenuric (specific gravity, 1.000 to 1.004). Sodium-containing IV fluid therapy (saline [0.9% NaCl] solution) was reinitiated, and the patient was offered saline solution, in addition to water ad libitum. The hembra consumed 0.5 to 4 L of saline solution/d for the duration of hospitalization. After 36 hours of fluid therapy and return to a normal serum sodium concentration, IV fluid therapy was again discontinued, without a concurrent decrease in serum sodium concentration. The alpaca remained hospitalized for 6 days, during which serum electrolyte concentrations remained within reference range and hydration was maintained without IV fluid supplementation.

Further consideration was given to the underlying cause of the alpaca's severe hyponatremia. Dietary insufficiency and primary gastrointestinal or renal disease were considered possible etiologies of the electrolyte abnormalities. Considering the alpaca's feeding regimen had not recently changed, and other alpacas on the farm were fed the same commercial feed formulated for South American camelids, dietary mismanagement was considered unlikely. Diagnostic testing aimed at investigating gastrointestinal pathological changes included transcutaneous abdominal ultrasonography, 3 consecutive Salmonella PCR assays on fecal specimens, Clostridium difficile and Clostridium perfringens ELISAs for toxins in feces, and fecal floatation. Transabdominal ultrasonographic examination did not reveal any clinically relevant abnormalities; a live fetus was visualized (fetal heart rate, 60 to 80 beats/min). Results of all fecal laboratory diagnostic tests, including the fecal egg count, were negative. Complete urinalysis of a free-catch urine sample collected 4 hours following admission revealed hyposthenuria (specific gravity, 1.004); however, its importance in the setting of fluid resuscitation was uncertain. Urine sodium fractional excretion was 3%. A normal reference range for urine sodium fractional excretion has not been established in healthy adult alpacas; however, this value was interpreted as inappropriately high on the basis of comparison with other domestic species,2 especially in light of the hyponatremia observed in this patient. Urine pH was 8, and results of urine sediment examination were normal.

Differential diagnoses for persistent hyponatremia and increased urinary sodium fractional excretion included tubular nephropathy and abnormalities in the hypothalamic-pituitary-adrenal axis and the renin-angiotensin-aldosterone system. Baseline serum cortisol (chemiluminescent immunoassay)c concentration was 2.1 μg/dL (reference interval for llamas in late gestation, 0.26 to 5.19 μg/dL),3 and serum aldosterone (radioimmunodiffusion assay)d concentration was 0 pmol/L, suggestive of hypoaldosteronism. Serum samples obtained from 3 healthy adult alpacas (2 males and 1 female) housed at a nearby farm were submitted for comparison. Aldosterone concentrations in these clinically normal animals ranged from 321 to 402 pmol/L. In addition, plasma antidiuretic hormone (vasopressin) concentrations were measured by ethanol extraction enzyme immunoassay.e Despite the lack of published reference ranges for alpacas, the sick hembra's plasma vasopressin concentration (2.96 pg/mL) was comparable to those of 2 age-matched healthy controls (3.22 and 3.28 pg/mL). Collectively, these results were considered most compatible with a diagnosis of selective hypoaldosteronism without concurrent hypoadrenocorticism.

An ACTH stimulation test, which would have more accurately diagnosed dysfunction in cortisol production, was not performed because of the risk of inducing parturition. The alpaca was discharged; the owner was instructed to offer saline solution, in addition to fresh water ad libitum. Hormone replacement therapy was discussed but not deemed necessary on the basis of the positive response to conservative medical (ie, dietary) management.

The hembra remained healthy and gave birth to a female cria 64 days after discharge. Four weeks after parturition, the dam and cria were returned to the Veterinary Teaching Hospital for additional testing. The owner reported that the hembra willingly consumed saline solution in approximately equal volume to free water. Upon evaluation, physical examination and vital parameters were within normal limits (heart rate, 72 beats/min; respiratory rate, 28 breaths/min; rectal temperature, 37°C [98.6°F]). Results of a CBC and serum biochemical analysis were normal. Baseline plasma ACTHb concentration was 4.6 pmol/L, and baseline serum cortisol concentration was 1.6 μg/dL.c These values fall within the previously reported reference intervals for clinically normal alpacas following transportation.4 After injection of 0.25 mg of ACTH (cosyntropinf), serum cortisol concentrations measured at 30, 60, 90, and 120 minutes after ACTH administration increased to 4.6, 7, 7.5, and 8.2 μg/dL, respectively.5 Baseline aldosterone concentration was 0 pmol/L; after ACTH administration, aldosterone concentrations increased to 53, 35, 55, and 29 pmol/L at 30, 60, 90, and 120 minutes after ACTH administration, respectively. This slight increase in serum aldosterone concentration was considered an insufficient response; a low serum aldosterone concentration is often seen in primary and secondary hypoaldosteronism and hypoadrenocorticism (Addison's disease) in other species.6,7 The cria's baseline aldosterone (552 pmol/L) and serum electrolyte concentrations were normal.

Discussion

Aldosterone production by the zona glomerulosa, the outermost region of the adrenal cortex, is stimulated by several factors, including increased plasma potassium concentration or decreased plasma sodium, angiotensin II, and ACTH concentrations. The stimulus for increased secretion of aldosterone is primarily via upregulation of the enzyme aldosterone synthase (cytochrome P450 11B2), responsible for the conversion of 11-deoxycorticosterone to aldosterone. Genetic mutations that render this enzymatic pathway ineffective have been identified in humans. In people affected by this condition, further classification of the genetic mutation into either type I or type II hypoaldosteronism is made on the basis of the specific defect detected in the cytochrome P450 11B2 enzymatic pathway. Human patients affected by this condition typically develop symptoms at a very young age, and extrarenal salt-conserving mechanisms that mature with age often lead to decreased or discontinued mineralocorticoid replacement treatment later8,9; however, cases of late-onset clinical disease have been reported.10 A primary genetic mutation in the aldosterone synthase enzyme is possible in the alpaca in the present report; however, the age of onset of clinical signs is inconsistent with the syndrome described in people. To our knowledge, mutations in the aldosterone synthase gene have not been described in other species.

Immune-mediated destruction of the adrenal cortex and resulting hypoadrenocorticism (Addison's disease) is a documented condition in both human and veterinary medicine, with the gold standard for diagnosis of Addison's disease in dogs being the cortisol response to exogenous ACTH administration (ie, the ACTH stimulation test).7,11 The underlying cause of the autoimmune condition resulting in Addison's disease is often elusive; however, possible genetic predisposition has been suggested in both humans and dogs.12,13 The normal basal serum cortisol concentration and expected 2- to 4-fold increase in serum cortisol concentrations following administration of ACTH in the patient in the present report were not consistent with the diagnosis of Addison's disease7; however, a similar immune-mediated process resulting in selective destruction of the outer adrenal cortex without affecting glucocorticoid production is possible. To our knowledge, this has not been previously reported in veterinary medicine.

Hypoaldosteronism with normal cortisol production has been further classified in the human literature into hyperreninemic and hyporeninemic hypoaldosteronism, referred to as primary and secondary hypoaldosteronism, respectively. Hyperreninemic hypoaldosteronism is most commonly observed with critically ill patients. The condition is related to transient adrenal insufficiency associated with the disease state; however, the dissociation of the renin-angiotensin-aldosterone system in critically ill patients is not fully understood. The condition is defined as a plasma aldosterone-to-plasma renin concentration ratio < 2.14,15 The possibility of hypoaldosteronism as a result of critical illness in the alpaca in the present report seems unlikely given the lack of identification of other disease conditions at the initial evaluation and the low serum aldosterone concentrations found on subsequent testing during periods of good health. One case of hyperreninemic hypoaldosteronism without a clear etiology has been reported in an 8-year-old German Shepherd Dog.16

Hyporeninemic hypoaldosteronism in human patients often occurs as a result of chronic renal failure in older patients, and most often, diabetes mellitus and interstitial renal pathological lesions are concurrently present. The condition has also been reported in human patients with glomerulonephritis and nephropathies associated with multiple myeloma, systemic lupus erythematosus, or chronic use of NSAIDs, presumably due to decreased prostaglandin production.17 In the patient in the present report, hyposthenuria and polydipsia were attributed to hypoaldosteronism, and the normal serial serum creatinine concentrations and normal urine sediment did not support a diagnosis of renal disease. However, chronic low-grade renal disease cannot be ruled out. A renal biopsy was considered to more conclusively diagnose or rule out primary renal disease, but the risk was deemed to outweigh the benefits, especially in consideration of the patient's positive response to dietary management. Because of the lack of a commercially available renin assay for veterinary patients, differentiation between primary or secondary hypoaldosteronism could not be determined for this hembra. In retrospect, the rate of sodium replacement used in this patient may have been overly aggressive given the fact that the duration of hyponatremia was not known and subsequent long-standing neurologic deficits have been documented in other species following an increase in serum sodium concentration > 0.5 mEq/L/h.

To our knowledge, this is the first reported case of hypoaldosteronism in an alpaca. Hypoaldosteronism should be considered in alpacas as a possible differential diagnosis for refractory hyponatremia or for hyponatremia in which an underlying etiology is not determined. Once a diagnosis is achieved, the outcome in this case would support initial treatment with ad libitum saline solution supplementation without hormone replacement therapy.

a.

Normosol R, Abbott Laboratories, Abbott Park, Ill.

b.

StatLab5, Nova Biomedical, Waltham, Mass.

c.

Clinical Pathology Laboratory, College of Veterinary Medicine, University of Georgia, Athens, Ga.

d.

Diagnostic Center for Population and Animal Health, Michigan State University, Lansing, Mich.

e.

NYS Animal Health Diagnostic Center, College of Veterinary Medicine, Cornell University, Ithaca, NY.

f.

Cortrosyn, Amphastar Pharmaceuticals Inc, Cucamonga, Calif.

References

  • 1.

    Fowler ME. Medicine and surgery of South American camelids. Ames, Iowa: Iowa State University Press, 1989.

  • 2.

    Lefebvre HP, Olivier D, Trumel C, et al. Fractional excretion tests: a critical review of methods and applications in domestic animals. Vet Clin Pathol 2008; 37:420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Leon JB, Smith BB, Timm KI, et al. Endocrine changes during pregnancy, parturition, and early post partum period in the llama (Llama glama). J Reprod Fertil 1990; 88:503511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Anderson DE, Grubb T, Fernando S. The effect of short duration transport on serum cortisol response in alpacas. Vet J 1999; 157:189191.

  • 5.

    Bonacic C, Macdonald DW, Villouta G. Adrenocorticotrophin-induced stress response in captive vicunas (Vicugna vicugna) in the Andes of Chile. Anim Welf 2003; 12:369385.

    • Search Google Scholar
    • Export Citation
  • 6.

    Norton F, Nadler JL. Hypoaldosteronism. Curr Ther Endocrinol Metab 1997; 6:164167.

  • 7.

    Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979–1993). J Am Vet Med Assoc 1996; 208:8591.

    • Search Google Scholar
    • Export Citation
  • 8.

    White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 314:250258.

  • 9.

    Kayes-Wandover KM, Tannin GM, Shulman D, et al. Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene. J Clin Endocrinol Metab 2001; 86:53795382.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kayes-Wandover KM, Lee Schindler RE, Taylor HC, et al. Type 1 aldosterone synthase deficiency presenting in a middle-aged man. J Clin Endocrinol Metab 2001; 86:10081012.

    • Search Google Scholar
    • Export Citation
  • 11.

    Schaer MS, Riley WJ, Buergelt CD, et al. Autoimmunity and Addison's disease in the dog. J Am Anim Hosp Assoc 1986; 22:789794.

  • 12.

    Oberbauer AM, Bell JS, Belanger JM, et al. Genetic evaluation of Addison's disease in the Portuguese water dog. BMC Vet Res 2006; 15:111117.

    • Search Google Scholar
    • Export Citation
  • 13.

    Maclaren NK, Riley WJ. Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigen-DR3 and/or DR4, except when associated with type 1 autoimmune poly-glandular syndrome. J Clin Endocrinol Metab 1986; 22:789794.

    • Search Google Scholar
    • Export Citation
  • 14.

    Du Cheyron D, Bouchet B, Cauquelin B, et al. Hyperreninemic hypoaldosteronism syndrome plasma concentrations of interleukin-6 and outcome in critically ill patients. Intensive Care Med 2008; 34:116124.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Raff H, Findling JW, Diaz SJ, et al. Aldosterone control in critically ill patients: ACTH, metoclopramide, and natriuretic peptide. Crit Care Med 1990; 18:915920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Lobetti RG. Hyperreninaemic hypoaldosteronism in a dog. J S Afr Vet Assoc 1998; 68:3335.

  • 17.

    Knochel JP. The syndrome of hyporeninemic hypoaldosteronism. Ann Rev Med 1979; 30:145153.

Contributor Notes

Supported by the Southeastern Alpaca Association. Crooked Pines Hollow Alpaca Farm provided healthy control alpacas for comparison testing.

Address correspondence to Dr. Butterworth (kelly.butterworth@gmail.com).
  • 1.

    Fowler ME. Medicine and surgery of South American camelids. Ames, Iowa: Iowa State University Press, 1989.

  • 2.

    Lefebvre HP, Olivier D, Trumel C, et al. Fractional excretion tests: a critical review of methods and applications in domestic animals. Vet Clin Pathol 2008; 37:420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Leon JB, Smith BB, Timm KI, et al. Endocrine changes during pregnancy, parturition, and early post partum period in the llama (Llama glama). J Reprod Fertil 1990; 88:503511.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Anderson DE, Grubb T, Fernando S. The effect of short duration transport on serum cortisol response in alpacas. Vet J 1999; 157:189191.

  • 5.

    Bonacic C, Macdonald DW, Villouta G. Adrenocorticotrophin-induced stress response in captive vicunas (Vicugna vicugna) in the Andes of Chile. Anim Welf 2003; 12:369385.

    • Search Google Scholar
    • Export Citation
  • 6.

    Norton F, Nadler JL. Hypoaldosteronism. Curr Ther Endocrinol Metab 1997; 6:164167.

  • 7.

    Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979–1993). J Am Vet Med Assoc 1996; 208:8591.

    • Search Google Scholar
    • Export Citation
  • 8.

    White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 314:250258.

  • 9.

    Kayes-Wandover KM, Tannin GM, Shulman D, et al. Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene. J Clin Endocrinol Metab 2001; 86:53795382.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kayes-Wandover KM, Lee Schindler RE, Taylor HC, et al. Type 1 aldosterone synthase deficiency presenting in a middle-aged man. J Clin Endocrinol Metab 2001; 86:10081012.

    • Search Google Scholar
    • Export Citation
  • 11.

    Schaer MS, Riley WJ, Buergelt CD, et al. Autoimmunity and Addison's disease in the dog. J Am Anim Hosp Assoc 1986; 22:789794.

  • 12.

    Oberbauer AM, Bell JS, Belanger JM, et al. Genetic evaluation of Addison's disease in the Portuguese water dog. BMC Vet Res 2006; 15:111117.

    • Search Google Scholar
    • Export Citation
  • 13.

    Maclaren NK, Riley WJ. Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigen-DR3 and/or DR4, except when associated with type 1 autoimmune poly-glandular syndrome. J Clin Endocrinol Metab 1986; 22:789794.

    • Search Google Scholar
    • Export Citation
  • 14.

    Du Cheyron D, Bouchet B, Cauquelin B, et al. Hyperreninemic hypoaldosteronism syndrome plasma concentrations of interleukin-6 and outcome in critically ill patients. Intensive Care Med 2008; 34:116124.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Raff H, Findling JW, Diaz SJ, et al. Aldosterone control in critically ill patients: ACTH, metoclopramide, and natriuretic peptide. Crit Care Med 1990; 18:915920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Lobetti RG. Hyperreninaemic hypoaldosteronism in a dog. J S Afr Vet Assoc 1998; 68:3335.

  • 17.

    Knochel JP. The syndrome of hyporeninemic hypoaldosteronism. Ann Rev Med 1979; 30:145153.

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