VetCpd Adrenal Disease Notes

Christopher Scudder BVSc (dist) MVetMed (dist) PhD DipACVIM MRCVS

Christopher.scudder@southfields.co.uk

Hypoadrenocorticism in dogs

Summary
• Hypoadrenocorticism is the deficiency of corticosteroid production from the
adrenal glands, either glucocorticoids and mineralocorticoids or glucocorticoids
alone.
• The condition is typically due to primary adrenal disease, although secondary
(pituitary) and tertiary (hypothalamic) causes can occur.
• Affected patients can present with a wide range of clinical symptoms:
o from waxing and waning lethargy and gastrointestinal upset,
o to neuromuscular disease
o to life threatening refractory hypotension.
• Serum basal cortisol >60nmol/L almost excludes hypoadrenocorticism
• An ACTH stimulation is the diagnostic test of choice.
• Most patients require life-long glucocorticoid and mineralocorticoid therapy,
although patients with secondary and tertiary causes require glucocorticoids alone.
• Always consider serum sodium and potassium concentrations separately when
attempting to correct electrolyte disturbances. The sodium:potassium ratio is a
diagnostic tool not a tool to monitor treatment.
• Patients treated with Zycortal require additional glucocorticoid supplement, while
less than half of patients treated using fludrocortisone require additional
glucocorticoids.
• Patients have an increased requirement for glucocorticoids on ‘sick’ days.
• The prognosis is good if patients are treated effectively
• Iatrogenic hyperadrenocorticism occurs commonly and should be avoided.

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Historical Aspects

Thomas Addison identified adrenal pathology (known as supra-renal capsules at the time) in

patients who had died with skin pigmentation and chronic anaemia. Later adrenalectomy

studies confirmed the adrenals were vital to life, and that only 10 to 20 % of normal adrenal

mass was needed to maintain life. Spontaneous adrenal atrophy was first reported in three

dogs in 1953, but is now considered to have a prevalence of ~ 1 in 90 to 333 dogs (Bellumori

et al., 2013).

Regulation of mineralocorticoids and glucocorticoids

Mineralocorticoids and glucocorticoids are primarily synthesised and secreted from the

adrenal glands. The adrenal gland has outer capsule, cortex and inner medulla (Figure 1). The

cortex has three distinct zones which contain slightly different steroidogenic enzymes from

one another, so each zone produces one or more specific hormones. The initial and rate-

limiting step of mineralocorticoid or glucocorticoid synthesis is the conversion of cholesterol

to pregnenolone by the side chain cleavage enzyme (P450scc). The remaining steps and

enzymes required are described in Figure 2. The outermost layer is the zona glomerulosa

which is the only layer to synthesise aldosterone and is primarily under the control of the

renin-angiotensin system (RAS) (Figure 3). The middle layer is the zona fasciculata which

synthesises and secretes cortisol under the control of adrenocorticotrophic hormone (ACTH)

from the anterior pituitary gland (Figure 4). The innermost zone is the zona reticularis where

sex steroid hormone precursors are produced.

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Figure 1 Zonation of the adrenal gland

C
G

F
R

C, capsule; G, zona glomerulosa; F, zona fasiculata; R, zona

reticularis

Figure 2 Adrenal cortex hormone synthesis per zonation

G F R

G, zona glomerulosa; F, zona fasciculata; R, zona reticularis

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 Figure 3 Regulation of the renin-angiotensin-aldosterone system

Figure 4 Hypothalamic-Pituitary-Adrenal regulation of cortisol

Aetiology

Hypoadrenocorticism (HA) is the “deficiency of corticosteroid production from the adrenal

glands”. This can be described as primary when the condition is caused by adrenal disease, or

secondary when the condition is caused by pituitary disease.

• Primary HA can be ‘typical’ if there if concurrent glucocorticoid and

mineralocorticoid deficiency

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 • Atypical HA is when there is glucocorticoid deficiency only.

This terminology has at times led to some confusion as there are atypical presentations of the

‘typical’ HA when patients lack glucocorticoids and mineralocorticoids but present with

electrolytes within reference interval. Possible explanations for this phenomenon are

hyperkalaemia itself increases potassium excretion and a high renal tubular flow rate can

increase potassium excretion, with an end result of normokalaemia.

Immune-mediated adrenal destruction of the adrenal cortex is the most common cause of HA.

This can be identified histopathologically by CD4+ T cell lymphocyte infiltration which

results in adrenal atrophy in the long-term. Adrenal auto-antibodies, either against 21

hydroxylase or p450scc, have been measured in up to 25% of patients with HA. HA may also

present as part of a multiple autoimmune syndrome when patients have concurrent

hypothyroidism, diabetes mellitus and/or hypoparathyroidism. Other causes of primary HA

include:

• metastatic neoplasia
• drug-induced
o permanent destruction by mitotane
o one case report of temporary HA induced by Delmadinone acetate
• adrenalectomy
o temporary HA induced by unilateral adrenalectomy of adrenal-dependent HA
o permanent by bilateral adrenalectomy to treat pituitary-dependent HA
• amyloidosis
• infectious disease
o fungal disease
• bilateral adrenal infarction

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Secondary HA is caused by pituitary disease, and these patients do not present with

electrolyte abnormalities but glucocorticoid deficiency only. Causes of secondary HA

include:

• Hypophysectomy
• Intra-cranial trauma
• Infarction / haemorrhage
• Pituitary neoplasia / Rathke’s pouch cysts

Who’s at risk and why?

Typically young to middle aged dogs, with a female predisposition in some breeds. Breeds at

risk for HA include:

Some breeds of dogs are more likely to have measurable auto-antibodies than others i.e. 50%

of Border Collie’s with HA had measurable auto-antibodies to p450scc while only 5% of

West Highland White Terrier (WHWT) had measurable auto-antibodies to p450scc. Some

breeds of dog might be genetically susceptible to HA. Certain Dog Leucocyte Antigen (DLA)

types are common within a breed, and some DLA types have been associated with risk of HA

(Boag et al., 2015).

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Clinical Presentation

Dogs with HA will present with varying clinical signs, hence why this disease has been

considered ‘the great pretender’. Roughly 30% of patients will present as an emergency

patient in a crisis, between 4 to 5% of dogs with chronic gastrointestinal signs without

electrolyte abnormalities had HA in one referral institute, many dogs may be present with

clinical signs and biochemical changes consistent with chronic kidney disease or

neuromuscular disease.

Dogs that present in crisis will likely have had a history of waxing and waning

gastrointestinal disease or lethargy, and have acutely decompensated. These patients may

present collapsed and hypovolaemic and have one or more of the following clinical signs:

• Haemorrhagic vomiting and diarrhoea

• Bradycardia or tachycardia
• Abdominal pain
• Physical examination may reveal hypothermia

Patients with HA but not in crisis are likely to present with lethargy (between 66% to 94%),

anorexia (54% to 92%), vomiting (50% to 85%), diarrhoea (13% to 50%), weight loss (17% to

48%), weakness (21% to 66%), and polyuria/polydipsia (17% to 28%). Some patients will also

have fine muscle tremors. Unusual presentations include epistaxis and peripheral oedema.

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Diagnosis

HA can be suspected in many patients. Additional clues can be obtained from routine CBC,

biochemistry and electrolyte analysis.

CBC

• Non-regenerative anaemia (~25%)

• Lymphocytosis (~14%)
• Eosinophilia (~20%)
• Lack of stress leukogram in an ill patient (i.e. mature neutrophilia / lymphopaenia)

Biochemistry

• Azotaemia without maximally concentrated urine (up to 85%)

• Hypoalbuminaemia (~40%)
• Hypocholesterolaemia and increased liver enzymes (up to 50%)
• Increased CK activity (~25%)
• Hypoglycaemia (~15%)

Electrolytes

• Hyperkalaemia (75 to 95%)

• Hyponatraemia (~80%)
• Hypercalcaemia (~30%)

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Sodium:potassium Ratio
Na:K ratios < 20 highly suggestive of HA (Figure 5) (Boretti et al., 2015). Data from one

study suggested sensitivity and specificity of Na:K ratio of 28 was 93% and 96%

respectively, while sensitivity and specificity of a Na:K ratio of 24 were 79% and 100%,

respectively (Adler, Drobatz and Hess, 2007). To put this another way, the authors of one

paper produced a table for the sensitivity and specificity of the Na:K ratio for different values

(Table 1)

Figure 5 Na:K Ratio in HA and other conditions

J Vet Intern Med 2015;29:1335–1341

Evaluation

Table 1 Na:K Ratio Sensitivity and Specificity

J Vet Intern Med 2011;25:1351–1356

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The utility of the Na:K ratio increased when the lymphocyte count is taken into account. In

fact, a lymphocyte count >2.4x109/L had a sensitivity of 49% and specificity of 92% in one

study (M. Seth, K.J. Drobatz, D.B. Church, 2011).

Also, a recent study considered the use of urine sodium excretion in patients with suspected

HA (Lennon, Hummel and Vaden, 2017). The rationale behind this study was dogs with

normal RAS system should retain sodium when hypovolaemic and hyponatraemic, while

those with HA would have sodium wasting. The study showed that all dogs with HA had

urine sodium concentrations > 30 mmol/L while only one non-HA dog had urine sodium > 30

mmol/L (Figure 6). Therefore, if for some reason synthetic ACTH was unavailable, then

urine sodium concentration could be a component of a diagnostic panel to diagnose HA.

Figure 6 Urine sodium concentration in dogs with HA

J Small Anim Pract. 2017 Dec 20. doi: 10.1111/jsap.12792. [Epub ahead of print]

Basal cortisol
One of the most widely used screening tests is the use of basal cortisol. There are two large

studies, one performed in the USA and one in the UK which both provided very similar

results (Lennon et al., 2007; Bovens et al., 2014; Gold, Langlois and Refsal, 2016). Almost

all dogs had undetectable basal cortisol, while a small number had cortisol concentrations

between 27 to 55 nmol/L and no dog with HA had a basal cortisol > 55 nmol/L. The data

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from these studies suggests a basal cortisol > 55 nmol/L excludes a diagnosis of HA in

almost all dogs with a specificity of 99 – 100 %. One note of caution however should be

taken. The European Society of Veterinary Endocrinology External Quality Assessment

Scheme has found that when the same blood sample is sent to different laboratories, a wide

range of cortisol concentrations are reported, and these are the laboratories who are enrolled

in the scheme and not from in-house machines (Figure 7). Therefore, when using basal

cortisol as a screening test, we would strongly recommend using a laboratory who are

enrolled in the scheme and undergo rigorous assay quality assurance. Studies reporting the

reliability of the SNAP® cortisol test performed by groups outside of IDEXX have not been

reported to the best of the author’s knowledge.

Figure 7 ESVE Quality Assurance Scheme results for cortisol concentration

Results of cortisol concentration obtained using the same sample from different
laboratories

ACTH stimulation test

This is the test of choice when other diagnostic tests are suggestive of HA. A dose of

synthetic ACTH (i.e. tetracosactride in Synacthn or cosyntropin in Cortrosyn) is given to

stimulate the adrenal glands sufficiently to overcome any potential suppressive factor, and

therefore document the ability of the adrenal glands to secrete ACTH (± aldosterone if

electrolytes are within normal limits). The author would recommend the minimum dose is

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5µg/kg given im or sc, and then blood is collected for cortisol measurement one hour later

(Lathan et al., 2008). It is worth noting that both prednisolone and hydrocortisone will cross

react with the measurement of cortisol and so should not be given prior to the ACTH

stimulation test. One dose of dexamethasone can be given if needed prior to performing the

ACTH stimulation test as dexamethasone does not cross react with the cortisol assay and it

does not suppress the adrenal response to 5µg/kg synthetic ACTH enough as to prevent a

response. A positive response is a post-ACTH cortisol of > 60nmol/L. There are some

patients who have post-ACTH cortisol concentrations between 60 to the lower laboratory

reference limit (typically ~150 nmol/L), which led some to believe a spectrum of HA disease

exists with some patients becoming ill if they were unable to achieve a normal physiological

cortisol response. However, to-date this is yet to be proven, and patients within the ‘grey-

zone’ may have inflammatory disease suppressing a normal cortisol response i.e.

inflammatory bowel disease (Wakayama et al., 2017).

Other tests
When the availability of synthetic ACTH became sparse, a whole number of diagnostic tools

were investigated to aid the diagnosis of HA. A particularly interesting study was the use of

basal cortisol and endogenous ACTH (Lathan, Scott-Moncrieff and Wills, 2014). Practically

this test is more challenging than performing an ACTH stimulation test because EDTA-

plasma must be frozen immediately after collection and sent frozen to the laboratory who

may only run the assay once weekly. Nonetheless, this proved to be a useful tool in the

diagnosis of HA, with no dog with HA having a cortisol:eACTH ratio >0.1, and no overlap

between dogs with HA and dogs with non-adrenal illness (NAI) (Figure 8).

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 Figure 8 Cortisol to endogenous ACTH ratios in dogs
with HA

J Vet Intern Med 2014;28:1546–1550

Another reason to measure eACTH is for the differentiation between primary and secondary

HA. In primary HA, eACTH should be above the reference interval but in secondary HA the

eACTH is undetectable to low (Peterson, Kintzer and Kass, 1996; Thompson, Scott-

Moncrieff and Anderson, 2007). The Thompson et al, 2007 study reported patients with

secondary HA having eACTH within reference interval, however in that study they separated

out patients into primary and secondary HA based on serum electrolytes, which we now

know is not a specific test for the differentiation of these two conditions. It is also worth

noting that eACTH should not be measured within 12 hours of administration of synthetic

ACTH or dexamethasone (Bugbee, Smith and Ward, 2013).

Abdominal ultrasound examination can be performed while pending the results of the ACTH

stimulation test (if performed). One would expect small adrenals in primary HA, and one

study reported that an adrenal thickness <3 mm was highly suggestive of HA. However,

some dogs without HA will present with adrenal glands <3 mm, and therefore this test can

only be use as part of a diagnosis and not as sole diagnostic test (Figure 9) (Wenger et al.,

2010).

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 Figure 9 Adrenal size measured using ultrasound in dogs with HA

Group 1: HA group, Group 2, health dogs, Group 3, dogs with disease mimicking HA
Veterinary Record (2010) 167, 207-210

Treatment

Acute HA crisis

The initial aims of treatment are as follows:

• Resolve hypotension
• Restore normovolaemia
• Normalise life-threatening hyperkalaemia (if present)

When these goals have been achieved then resolution of additional presenting clinical signs

and normalisation of electrolytes should be considered.

Fluid therapy is the key to triage for the patient with HA. A comparison of the different fluid

types available is presented in Table 1. A multitude of conditions can be fixed or improved

using Hartman’s solution for intravenous fluid therapy. This is my fluid of choice because it

is less acidifying than 0.9% NaCl despite it being slightly less effective at reducing

hyperkalaemia. It also has a lower sodium concentration, so the change in plasma [Na+]

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caused by Hartman’s is less than that of 0.9% NaCl, and therefore the risk of brain injury due

to rapid changes of [Na+] will be less. Regardless of which fluid (either Hartman’s or 0.9%

NaCl), both will improve hypovolaemia, and therefore improve perfusion and hypotension.

Give up to four boluses of 10 – 20 ml/kg over 10 – 15 min until cardiovascular improvement

is observed. This will also dilute the potassium and aid potassium urinary excretion. When

normovolaemia is achieved, the fluid therapy can be directed at restoring hydration.

Table 2 Comparison of the components of different types of intravenous fluids

Fluid, electrolyte and acid-base disorders in small animal practice, fourth edition, Edt. S.P.
DiBartola

If life-threatening hyperkalaemia persists despite the initial fluid therapy, then treatment
directed at further reducing [K+] can be initiated:

• 1 gram/kg iv glucose diluted 50:50 in water for injection

• 0.2 units/kg iv neutral insulin
• 0.5 mL/kg up to 10 mLs of 10 % calcium gluconate iv over 15 mins
• NB: arrhythmias; bradycardia; hypotension, severe tissue damage with extravasation
• Monitor ECG (particularly if calcium gluconate administration given) / NIBP / K+
and glucose

Steroid hormone supplementation can be started after the initial three goals of treatment have
been achieved. There are two different approaches which are commonly used:

- The simpler approach of give dexamethasone iv (0.3 – 0.4 mg/kg) followed by q12h
0.1 mg/kg dexamethasone iv until the patient is eating. Fluid therapy for rehydration
is continued, and when patients begin to eat then hydrocortisone / prednisolone and
DOCP can be administered for longer term steroid control. Some advocate early

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 administration of DOCP in the treatment of acute HA using this protocol, although to-
date there is no evidence this reduced time to recovery.
- The alternative approach is to replace glucocorticoids and mineralocorticoids at same
time using hydrocortisone CRI using a dose of 0.5mg/kg/hr until the patient is eating.
The hydrocortisone dose can be weaned as the patient transitions onto oral
glucocorticoid therapy. Some argue this is more physiologically appropriate and
might be associated with reduced time to recovery. DOCP and hydrocortisone /
prednisolone is used for longer term steroid hormone replacement.

Additional therapies such as glucose supplementation / ant-acids / anti-emetics / analgesics /

blood transfusions might be required depending on the severity of patients presenting clinical.
Antibiotics are uncommonly needed but should be considered in the pyrexic patient.

Chronic HA management

The goals of this phase of management are to normalise quality of life. This is achieved by

preventing recurrence of crisis while preventing side effects of the treatment. One of my

supervisors during my residency would say there are two arms to the treatment of HA; the

science of managing electrolytes and the art of managing the glucocorticoids.

• Mineralocorticoid replacement
The mainstay and only currently licensed mineralocorticoid replacement therapy is DOCP /

Zycortal®. DOCP does not appear to have much glucocorticoid action in most patients, and

therefore is it safe to assume all patients receiving DOCP will need supplemental

glucocorticoid therapy.

• Zycortal® a suspension and should be mixed thoroughly prior to being drawn up and

administered.

• The initial licensed dose is 2.2 mg/kg sc and patients should initially be re-examined

at day 10 and 25 after first administration.

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The datasheet provides recommendations how to adjust the dose depending on electrolyte

measurements. However, the recommendations are based on Na:K ratios, and my hope would

be to look at the electrolytes independently of one another and see if they are within reference

intervals. If not, then dose adjustments should be made. I would also suggest initially

increasing the time interval between injection if electrolytes are within normal limits at day

25, and aim to transition patients onto once monthly injections rather than once every 25 day

injections. When patients are receiving one monthly injection, the dose could then be titrated

to effect if electrolytes are within normal limits one month. The length of effect of Percorten-

V (a DOCP preparation available in USA) in dogs naïve to treatment was 32 to 94 days, and

in dogs who had received treatment long-term was 41 to 124 days (Jaffey et al., 2017).

However, it has been reported that some dogs require treatment as frequently as every 21

days, so always be prepared to titrate the dose frequency to effect. However, the typical

patient will receive once monthly treatments at a dose of 1.4 to 1.8 mg/kg DOCP q monthly,

which has led some clinicians to start DOCP at a lower dose than 2.2 mg/kg (Kintzer and

Peterson, 1997; Bates, Shott and Schall, 2013). Nonetheless, we would suggest starting with

the datasheet recommended dose and titrate to effect.

DOCP treatment will result in clinical and biochemical control of 85 to 90 % of those treated.

In fact, DOCP is typically more effective than fludrocortisone at achieving normalisation of

the RAS system (Baumstark et al., 2014). Even so, some patients will not achieve

normalisation of electrolytes and the addition of table salt to a diet does not seem to aid

control either. Therefore, there remains a small subset of patients who will benefit from

fludrocortisone therapy. The commercially available product is Florinef™ 0.1 mg tablets

which should be kept refrigerated. The starting dose is 0.02 mg/kg/day. Patients should

receive glucocorticoid supplementation during the initial transition phase onto

fludrocortisone which can then be weaned over time. Around 50% of fludrocortisone treated

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HA patients do not require long-term glucocorticoid supplementation because of the

glucocorticoid actions of this drug (Table 3). However, we would recommend giving

glucocorticoids on ‘sick days’ when the dog’s requirement will be greater.

Table 3 Different replacement steroid hormone glucocorticoid and mineralocorticoid

potencies

• Glucocorticoid replacement
Getting the glucocorticoid dose right can be very challenging. Too much or too little can

result in lethargy and weakness. Too little glucocorticoid can cause gastrointestinal upset, but

it is the breeds of dog which are prone to GI or pancreatic upset that also commonly affected

by HA which can limit how useful this is as a clinical sign. Too much glucocorticoid can

result is a multitude of clinical signs (Figure 10), including PU/PD, but too much

mineralocorticoid can also result in PU/PD. Therefore, getting it right is an art, and you will

need to take into account to whole clinical picture and examination features of the dog to

determine if you are prescribing an appropriate dose.

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 Figure 10 Glucocorticoid side effects

Immuno-
suppression

Vascular Visceral
fragility Adiposity

Glucocorticoid
Overdose

Skin thinning Muscle

/ pyoderma weakness /
/ comedones myopathy

Dystrophic
calcification

• Prednisolone is the most commonly used glucocorticoid replacement therapy.

• The daily dose is typically between ~ 0.1 – 0.2 mg/kg/day i.e. 1 - 2mg for a 10kg dog.

A 10kg dose can easily be dose using 1mg prednisolone tablets, however getting the

correct dose in small patients is more difficult.

• Some advocate the use of oral hydrocortisone because it has ¼ of the glucocorticoid

potency of prednisolone, which makes dosing dogs <10kg easier.

• Hydrocortisone is prescribed at a dose of 0.4 – 0.6 mg/kg q8 or q12h. It is sold as a

10mg tablet, which means a 5kg dog would need roughly half a tablet twice daily.

• The main disadvantage of using hydrocortisone is its cost, which is roughly £3/tablet

at the time of writing.

Whichever mineralocorticoid and glucocorticoid combination is used, newly diagnosed dogs

should be re-examined 7 – 10 days and three to four weeks after initial discharge. The time of

each examination the patient should be weighed, owner questioned regarding how their dog

has been and are there any signs of deficient or excessive glucocorticoid doses, physical

examination to particularly check hydration, and measure PCV/TP and serum electrolytes.

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• Medication doses should be changed to effect, and when the patient is stable, they

should be re-examined every three months for the same purposes in addition to

checking if the owner aware of glucocorticoid increase around ‘sick days’ and they

have glucocorticoids at home for this purpose?

• Re-examination appointments are good opportunities to check for concurrent disease

if a patient isn’t doing well. Multiple endocrinopathies are possible with concurrent

hypothyroidism being the most common (Melendez et al., 1996; Blois et al., 2011).

However, patients should probably receive treatment for HA for four months prior to

investigations for hypothyroidism as HA itself can lead to biochemical changes which

would be consistent with hypothyroidism, but which improve with treatment (Reusch

et al., 2017).

• Chronic pancreatitis might also be a common concurrent clinical condition, and will

make interpreting whether the patient is receiving an appropriate glucocorticoid dose

challenging. Therefore, we would recommend institution of a low-fat diet and

analgesia in patients suspected to have this condition. It would also be prudent to

include faecal parasite examination, measurement of serum B12 and consideration of

measurement of cTLI in any patient who fails to gain weight after starting treatment.

It is particularly interesting that Addison’s disease in humans is associated with an

increased risk of coeliac disease, and whether inflammatory gastrointestinal disease

risk is increased in dogs is unknown (O’leary et al., 2002).

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Prognosis
The prognosis for patients with this condition is generally believed to be good, particularly if

patients are diagnosed before a crisis event (Kintzer and Peterson, 1997). Owner education

regarding the clinical sign of a crisis is vital, and that glucocorticoid dose should be increased

on sick days or days of psychological stress. However, as veterinarians we should not accept

prescription of unnecessarily high doses long-term just to avoid the risk of a crisis. There is a

real risk of these patients receiving chronically high doses of glucocorticoids which might

overtime reduce the quality of life of the affected dog, and titrating medication to effect will

take time and good owner-veterinary team communication.

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