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ABSTRACT:

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Hypoadrenocorticism is an uncommon but potentially life-threatening condition in dogs. It most commonly arises due to primary failure of all three layers of the adrenal cortex, resulting in reduced cortisol and aldosterone secretion. Clinical findings are non-specific and common to other conditions. Diagnosis can therefore be challenging, since hypoadrenocorticism can mimic other common diseases. A presumptive diagnosis is based on history, clinical signs and laboratory findings. Definitive diagnosis, however, requires an adrenocorticotropic hormone (ACTH) stimulation test. This should be performed especially in patients with a history of vague, waxing and waning gastrointestinal signs, acute collapse or hyponatremia and hyperkalemia.


INTRODUCTION

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Commonly known as Addison's disease, hypoadrenocorticism describes a condition in which there is at least 85–90% destruction of the adrenocortical tissue, leading to glucocorticoid (cortisol) and mineralocorticoid (aldosterone) deficiencies. This is an uncommon disease in dogs, with an estimated incidence that ranges from 0.36–0.5%, and young females tend to be overrepresented. Rare cases are reported in cats. This article will highlight some of the main aspects of the pathophysiology of this condition in dogs, as well as its clinical features and definitive diagnosis.

PATHOPHYSIOLOGY

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

The adrenal gland is comprised of an inner medulla and outer cortex, and is surrounded by a capsule. The medulla produces catecholamines that are not vital for life, but the hormones secreted by the cortex are essential.

The cortex is composed of three zones with different physiological functions:

  • • 
    the zona glomerulosa is the outer layer, producing mineralocorticoids (aldosterone)
  • • 
    the zona fasciculata is the middle layer, producing glucocorticoids (cortisol)
  • • 
    the inner layer is the zona reticularis, producing sex hormones (androgens and oestrogens), and, to a lesser extent, glucocorticoids (cortisol).

Aldosterone and cortisol are the two most important hormones involved in the pathogenesis of hypoadrenocorticism. Knowledge of their major functions, and the regulation of their secretion, is therefore critical in order to understand hypoadrenocorticism and its diagnosis.

Aldosterone

Aldosterone is vital for life, due to its involvement in the homeostasis of sodium, potassium and water in the body. It acts primarily on the kidney, where it is involved in regulation of potassium excretion. The hormone specifically affects the sodium and potassium channels of renal collecting-duct cells, resulting in a net reabsorption of sodium and chloride ions, with excretion of potassium and hydrogen ions into the renal tubular fluid. The sodium retention subsequently leads to secondary water absorption with increased extracellular fluid volume.

The primary trigger for secretion of aldosterone is angiotensin II, part of the renin-angiotensin system (RAS). The main role of the RAS is to control fluid balance and blood pressure. It is regulated by various factors, including those listed in Table 1.

Table 1.  Factors involved in regulation of the renin-angiotensin system
Blood pressure
Renal tubular fluid sodium concentration
ACTH
Blood sodium concentration
Extracellular fluid volume
Extracellular pH
Extracellular fluid potassium concentration

Cortisol

Since all body tissues require cortisol to function, its roles are wide-ranging, and include those listed in Table 2. Cortisol release is primarily regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Within the HPA axis, the hypothalamus acts as the integrating centre. Its paraventricular nuclei produce corticotropin releasing factor (CRF) which binds to anterior pituitary gland receptors, triggering ACTH release. Following transport to the adrenal glands, ACTH stimulates cortisol production by the zona fasciculata and zona reticularis. Control of CRF and ACTH release occurs as a result of negative feedback by cortisol at the levels of both the hypothalamus and pituitary gland.

Table 2.  Some of the functions of cortisol
Regulation of blood pressure
Regulation of fluid balance
Regulation of vascular volume
Maintenance of blood sugar levels
Immune-system suppression
tSimulation of erythropoiesis
Catabolism of bone, muscle and connective tissue

AETIOLOGY

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Hypoadrenocorticism can be naturally occurring or iatrogenic. When presented with an affected patient, it is therefore important to determine its underlying cause, since this will ultimately influence the treatment regime. There are four main mechanisms by which adrenal insufficiency can arise:

  • • 
    natural primary hypoadrenocorticism
  • • 
    natural secondary hypoadrenocorticism
  • • 
    iatrogenic primary hypoadrenocorticism
  • • 
    iatrogenic secondary hypoadrenocorticism

Natural primary hypoadrenocorticism

Natural cases of adrenal insufficiency arise most commonly as a result of primary failure of all three layers of the adrenal cortex, due to their destruction or atrophy. Immune-mediated destruction seems to represent the most common mechanism of natural primary hypoadrenocorticism. Rarely, cases have been reported due to adrenocortical infiltration by neoplasia or fungal organisms, as well as in association with amyloidosis, trauma and coagulopathy.

Natural secondary hypoadrenocorticism

Natural cases of adrenal insufficiency can also rarely arise as a result of secondary failure of the adrenal cortex, caused by cranial trauma or pituitary disease. Secondary hypoadrenocorticism is thus associated with adrenal gland atrophy rather than destruction. In these patients, the zona fasciculata and zona reticularis undergo atrophy as a result of a lack of stimulation due to reduced ACTH release by the pituitary gland. Cortisol secretion by these zones is consequently reduced. Since ACTH only minimally affects mineralocorticoid production, the zona glomerulosa is spared in this condition, and the ability to secrete aldosterone is preserved. Clinical signs of secondary hypoadrenocorticism are therefore associated only with cortisol deficiency, and electrolyte abnormalities are rare.

Iatrogenic primary hypoadrenocorticism

Adrenolytic drugs

Iatrogenic cases occur in patients treated with adrenolytic drugs such as mitotane. Mitotane is used to control pituitary-dependent hyperadrenocorticism, and, when dosed according to standard published protocol, it is cytotoxic to the adrenal cortex. Dose-dependent, progressive necrosis and atrophy of the zona fasciculata and zona reticularis result, with relative sparing of the zona glomerulosa. However, in a small proportion of patients (<6%) undergoing mitotane treatment, non-selective destruction of the adrenal cortex occurs, and the concomitant damage to the zona glomerulosa leads to hypoadrenocorticism.

Adrenal hormone inhibitors

Treatment with adrenal hormone inhibitors such as trilostane can also result in iatrogenic hypoadrenocorticism. Trilostane competitively inhibits the enzyme 3 -hydroxysteroid dehydrogenase, an enzyme integral to the biosynthesis of all adrenocortical steroids. Therapy therefore results in reduced production of both cortisol and aldosterone. Although originally thought to be a safer alternative to mitotane for treatment of pituitary-dependent hyperadrenocorticism, trilostane use in some dogs has been associated with adrenal necrosis and hypoadrenocorticism. In one study of dogs undergoing trilostane therapy, 25% of the patients experienced at least one episode of hypoadrenocorticism.

Iatrogenic secondary hypoadrenocorticism

Iatrogenic secondary hypoadrenocorticism can occur upon abrupt cessation of chronic glucocorticoid administration, and is more common than the naturally occurring form of the condition. Feedback inhibition from exogenous glucocorticoids leads to suppression of ACTH from the anterior pituitary gland and subsequent atrophy of the zona fasciculata and zona reticularis. Sudden withdrawal of chronic glucocorticoid treatment therefore leads to cortisol deficiency.

CLINICAL PRESENTATION AND LABORATORY FINDINGS

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Since cortisol and aldosterone affect the function of many body systems, the signs of hypoadrenocorticism are varied. Insufficient concentrations of free plasma cortisol and aldosterone lead to various biochemical and physical changes, and these give rise to the characteristic features of the disease; however, in order for clinical signs to be present, greater than 85–90% of the adrenocortical tissue must be lost.

Clinical presentation

Signalment

Hypoadrenocorticism occurs predominantly in young to middle-aged female dogs, and the mean age at presentation is 4–5 years. Cases have, however, been reported in dogs of both sexes, ranging from 4 weeks to 16 years of age. Although all breeds can be affected, there is a higher incidence in certain breeds, including the West Highland White Terrier, Great Dane, Portuguese Water Dogs, Bearded Collies and Poodles of all sizes. A familial predisposition is suspected in some breeds, including Standard Poodles, Bearded Collies and Portuguese Water Dogs.

Clinical signs

Clinical signs arise due to the reduced secretion of cortisol and aldosterone, and are often nonspecific and vague. They may be waxing and waning in up to 43% of cases, although the clinical course of the condition can be progressive in many patients. Whilst signs can be attributed to various body systems, those consistent with gastrointestinal, neurological and renal disease are often seen. Some of the most common presenting problems include lethargy, anorexia, weakness, weight loss, vomiting and diarrhoea. Polyuria, polydipsia, shaking and collapse have also been reported

Disease progression tends to be chronic, although, typically, an acute-on-chronic episode leads to presentation and diagnostic evaluation. Often some ‘stressful’ event (such as being boarded or a trip to the veterinary surgery) precipitates the acute episode. Even when cases appear to represent a sudden, acute onset of disease, prior subtle chronic signs are likely to have been present, and the difference between clinical signs when the dog is mildly sick compared with extremely sick tends to lie in their severity rather than their type.

Physical abnormalities

Physical abnormalities of hypoadrenocorticism are variable, depending on the severity of disease, but can include dehydration, weakness, poor body condition, recumbency, prolonged capillary refill time, bradycardia and hypothermia.

Laboratory findings

Biochemistry

The classic serum biochemistry abnormalities in dogs with hypoadrenocorticism are hyponatremia and hyperkalemia. Patients typically have a sodium to potassium ratio of less than 27:1 (the normal range is between 27:1 and 40:1), and a ratio of less than 15:1 increases the likelihood of hypoadrenocorticism over other conditions that are also associated with a reduced ratio (Table 3).

Table 3.  Conditions associated with reduced sodium:potassium ratio
Hypoadrenocorticism
Renal disease
Severe metabolic acidosis
Severe respiratory acidosis
Illness during late pregnancy
Large volume pleuritis and peritonitis
Severe gastrointestinal disease
Gastroenteritis treated with low sodium ion-
containing fluids
Diarrhoea due to whipworm infection
Repeated drainage of chylothorax

Other biochemical changes can also be seen in hypoadrenocorticism, including those listed in Table 4, and a serum chemistry profile may reveal one or more of these abnormalities.

Table 4.  Possible serum chemistry changes in hypoadrenocorticism
Hyperkalemia
Hyponatremia
Reduced sodium:potassium ratio (<27:1)
Increased blood urea nitrogen
Increased creatinine
Hypochloremia
Hypoglycemia
Hyperphosphataemia
Hypercalcaemia
Increased alanine aminotransferase (ALT)
Increased aspartate aminotransferase (AST)
Haematology

Normocytic, normochromic anaemia has been reported in dogs with hypoadrenocorticism, along with eosinophilia and lymphocytosis. Since lymphopenia usually arises as a result of hypercortisolaemia in sick patients, an inappropriately normal-to-high lymphocyte count in a sick patient should be cause for suspicion of hypoadrenocorticism.

Urinalysis

Inadequate urine concentrating ability (specific gravity <1.030) is frequently reported.

Atypical hypoadrenocorticism

Atypical hypoadrenocorticism can occur in some dogs, and is associated with reduced cortisol concentrations but normal electrolyte values. Its clinical signs, however, are similar to those seen in dogs with both cortisol and electrolyte abnormalities.

Addisonian crisis

Although many cases of hypoadrenocorticism involve only a few mild, intermittent clinical signs, the Addisonian crisis represents a medical emergency. Typically, in this situation, the dog is collapsed, although still conscious, and dehydrated, with bradycardia and a weak pulse. Vomiting and diarrhoea are also common.

DIAGNOSTIC EVALUATION

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

If the history, clinical signs and laboratory findings are suggestive of hypoadrenocorticism, subsequent diagnostic evaluation is necessary. The gold-standard test for definitive diagnosis of hypoadrenocorticism is the ACTH stimulation test.

ACTH stimulation test

Since the ACTH stimulation test evaluates the reserve capacity of the zona fasciculata and zona reticularis of the adrenal cortex to produce glucocorticoids, its primary use is to diagnose hypoadrenocorticism. Additionally, it is the only test that can distinguish between iatrogenic and spontaneous hyperadrenocorticism.

The test measures and compares cortisol levels in the bloodstream, before and after injection of ACTH. In healthy dogs, baseline cortisol levels are normal, and ACTH stimulates a three- to five-fold increase in cortisol following administration.

Dogs with typical hypoadrenocorticism have lowered baseline cortisol concentration. Post-injection, plasma cortisol levels are also below normal. This represents a reduced response to ACTH administration, indicative of adrenocortical atrophy, as also occurs in iatrogenic hyperadrenocorticism. On the other hand, concentrations that are higher than in normal dogs represent an exaggerated response to ACTH administration, indicative of spontaneous hyperadrenocorticism.

Dogs with pituitary ACTH deficiency (natural secondary hypoadrenocorticism) have low to normal baseline cortisol levels that may rise only slightly in response to ACTH administration, but the response is relatively blunted.

Of all the screening tests used to evaluate adrenocortical function, this has the highest specificity and a relatively high sensitivity. The test does not assess the ability of the adrenal cortex to produce mineralocorticoids, however, so once a diagnosis of hypoadrenocorticism is made, measurement of plasma ACTH levels is required to differentiate between primary and secondary cases of natural hypoadrenocorticism. Plasma ACTH concentrations are increased in patients with primary hypoadrenocorticism, and decreased in those with secondary hypoadrenocorticism.

ADDITIONAL DIAGNOSTIC TECHNIQUES

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Thoracic and abdominal radiography, abdominal ultrasonography and electrocardiography can also be used as part of the diagnostic evaluation.

Radiography and ultrasonography

Thoracic radiography of patients with hypoadrenocorticism can show microcardia, decreased caudal vena cava size or reduced pulmonary vessel size as a consequence of hypovolemia and hypoperfusion. Megaoesophagus is sometimes also seen. Microhepatica may additionally be evident on abdominal radiography, also as a consequence of the hypovolemia.

Abdominal ultrasonography can reveal a reduced adrenal gland size, as well as microhepatica.

Electrocardiography

Electrocardiographic changes can be variable in patients with hypoadrenocorticism, and the electrocardiogram (ECG) may even be normal in some patients. An early change associated with mild hyperkalaemia is increased T-wave amplitude, along with bradycardia. As hyperkalaemia progresses, there is an increased P-R interval, widening of the QRS complex, decreased R-wave amplitude and S-T segment depression. Further elevation leads to: progressive lengthening of QRS and P-R intervals; P-wave amplitude decreases, and its duration increases; Q-T levels also lengthen. Severe hyperkalemia can produce atrial standstill and loss of P waves, resulting in a sinoventricular rhythm. Terminally, there may be ventricular flutter, ventricular fibrillation and ventricular asystole.

It is therefore especially important to be able to recognize changes associated with severe hyperkalemia that will allow initiation of lifesaving medical treatment.

SUMMARY

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

Hypoadrenocorticism is an uncommon disease in dogs, and, whilst a definitive diagnosis can be made using the ACTH stimulation test, this condition still represents a diagnostic challenge. It can present in a variety of ways, often mimicking other conditions, but should especially be considered in patients with hyponatremia and hyperkalemia, chronic gastrointestinal signs or acute collapse. Consequently, the importance of using history, clinical signs and other laboratory findings in reaching a diagnosis of hypoadrenocorticism cannot be underestimated. It should also be remembered, however, that the absence of electrolyte abnormalities does not rule out the possibility of hypoadrenocorticism.

CONTINUING PROFESSIONAL DEVELOPMENT

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

In order to test your understanding of this article, answer these multiple choice questions, or if you are a subscriber, go online at http://www.ukvet.co.uk, and find many more multiple choice questions to test your understanding.

  • 1
    What is the gold-standard test for definitive diagnosis of hypoadrenocorticism:
    a. Low-dose dexamethasone suppression test
    b. High-dose dexamethasone suppression test
    c. Urinary cortisol:creatinine ratio
    d. ACTH stimulation test
  • 2
    What haematological finding can be associated with hypoadrenocorticism:
    a. Normocytic, normochromic anaemia
    b. Macrocytic, hypochromic anaemia
    c. Rouleaux formation
    d. Heinz body formation
  • 3
    In dogs, which most commonly destroys the adrenal gland to cause natural primary hypoadrenocorticism:
    a. Neoplasia
    b. Fungal infection
    c. Immune-mediated disease
    d. Trauma

Answers to the above questions appear on page 47 of the print version, and as supporting information in the online version of this article at: http://www.wileyonlinelibrary.com/journal/coan

FURTHER READING

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information
  • ALENZA, D. P., ARENAS, C., LOPEZ, M. L. and MELIAN, C. (2006) Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. Journal of the American Animal Hospital Association 42:269276.
  • BRADDOCK, J. A., CHURCH, D. B., ROBERTSON, I. D. and WATSON, A. D. (2003) Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Australian Veterinary Journal 81:600607.
  • CHAPMAN, P. S., KELLY, D. F., ARCHER, J., BROCKMAN, D. J. and NEIGER, R. (2004) Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. Journal of Small Animal Practice 45:307310.
  • DUESBERG, C. and PETERSON, M. E. (1997) Adrenal disorders in cats. Veterinary Clinics of North America Small Animal Practice 27:321347.
  • GUNN-MOORE, D. (2005) Feline endocrinopathies. Veterinary Clinics of North America Small Animal Practice 35:171210.
  • KLEIN, S. C. and PETERSON, M. E. (2010) Canine hypoadrenocorticism: Part I. Canine Veterinary Journal 51:6369.
  • KLEIN, S. C. and PETERSON, M. E. (2010) Canine hypoadrenocorticism: Part II. Canine Veterinary Journal 51:179184.
  • LATHAN, P. and TYLER, J. (2005) Canine hypoadrenocorticism: Pathogenesis and clinical features. Compendium on Continuing Education for the Practicing Veterinarian 27:110120.
  • LATHAN, P. and TYLER, J. (2005) Canine hypoadrenocorticism: Diagnosis and treatment. Compendium on Continuing Education for the Practicing Veterinarian 27:121132.
  • NEIGER, R., RAMSEY, I., O'CONNOR, J., HURLEY, K. J. and MOONEY, C. T. (2002) Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 150:799804.
  • RAMSEY, I. (2003) Diagnosis and treatment of canine hypoadrenocorticism. Compendium on Continuing Education for the Practicing Veterinarian 27:17.
  • REUSCH, C. E., SIEBER-RUCKSTUHL, N., WENGER, M., LUTZ H., PERREN, A. and POSPISCHIL, A. (2007) Histological evaluation of the adrenal glands in seven dogs with hyperadrenocorticism treated with trilostane. Veterinary Record 160: 219224.
  • SHARAM, J., GALAC, S., BOER, J., ROBBEN, J. H., TESKE, E. and KOOISTRA, H. S. (2006) Aldosterone-to-renin and cortisol-to-adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. Journal of Veterinary Internal Medicine 20: 556561.
  • THOMPSON, A. L., SCOTT-MONCRIEF, J. C. and ANDERSON, J. D. (2007) Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985–2005). Journal of the American Veterinary Medical Association 230: 11901194.

Supporting Information

  1. Top of page
  2. ABSTRACT:
  3. INTRODUCTION
  4. PATHOPHYSIOLOGY
  5. AETIOLOGY
  6. CLINICAL PRESENTATION AND LABORATORY FINDINGS
  7. DIAGNOSTIC EVALUATION
  8. ADDITIONAL DIAGNOSTIC TECHNIQUES
  9. SUMMARY
  10. CONTINUING PROFESSIONAL DEVELOPMENT
  11. Supporting Information
  12. FURTHER READING
  13. Supporting Information

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