In the case of an emergency, you are always urged to seek medical assistance as soon as possible.
A: Taking extra fluid and salt is reasonable under conditions of heat and excessive perspiration, but should not be any more necessary in people with Addison’s than in people without Addison’s, as long as the doses of cortisone and fludrocortisone are sufficient. Hence, crises sufficient to need extra cortisone or Florinef should not develop if the usual treatment is optimal. The situation with your crises needs to be reviewed in more detail by your treating doctor.
AADAI newsletter Issue 53 April 2005
A: Hot weather should not affect the body's metabolism of Cortate but can lead to fluid loss/dehydration and an increased need for a salt supplementation although most people do not notice this with air conditioning and adequate fluid intake.
AADAI newsletter Issue 65 April 2007
A: Your question raises the possibility of a lack of aldosterone (mineralocorticoid) rather than Cortate (cortisone acetate, glucocorticoid). Generally, Cortate would not need to increased. Some Addison's patients need to take extra salt/fluid in the heat but this should be to a fairly normal degree if the aldosterone is replaced with fludrocortisone.
AADAI newsletter Issue 70 February 2008
A: Addisonians are at risk of salt depletion if exposed to prolonged heat stress, due to salt losses from high volumes of sweat. Practically, some Addisonians find extra salt (and water) intake can control salt hunger and the dehydration that may develop in these conditions. A small minority of Addisonians take extra Florinef in prolonged heat conditions but this should only be done if it has been found necessary on past experience or recommended by your physician. Altered cortisone doses should not be needed except in the unusual situation of heat stroke. For many people, exposure to heat conditions sufficient to induce severe salt and water loss from sweating is mitigated by air-conditioning to the point where no dietary alterations are needed.
AADAI newsletter Issue 81 December, 2009
A: When ill with significant infections causing fever and general malaise, it is advisable to increase the glucocorticoid medication, such as cortisone acetate, for approximately 2 days usually doubling the dose. In normal physiology aldosterone production does not increase under these circumstances and hence it is not necessary to increase the Florinef dosage during illness.
AADAI newsletter Issue 53 April 2005
A: It is not generally necessary to take extra glucocorticoid medication for a head cold. If a temperature develops it would be reasonable to increase the glucocorticoid dose three fold for 3 days ("3x3 rule").
AADAI newsletter Issue 62 October 2006
A: Yes, cortisone replacement does depend on body size. It has been recommended that body surface area, calculated using height and weight, be used to determine initial cortisone replacement doses.
AADAI newsletter Issue 53 April 2005
A: Florinef (Fludrocortisone) has a biological half-life of 18-36 hours so it is not necessary for most people to take the drug more often than once daily. It is also possible to have adequate effects with less frequent dosing in some people but this requires individual assessment. Overall, once daily Florinef is suitable for most people, unless there are special circumstances such as drugs that may accelerate Florinef's metabolism. Less frequent or more frequent than once daily Florinef is unusual and usually relates to a special individual circumstance.
AADAI newsletter Issue 59 April 2006
A: Cortisone acetate (Cortate) is converted to hydrocortisone by an enzyme found in the liver and other organs. Historically it was widely used due to availability. The body is also capable of converting cortate to hydrocortisone. I favour the use of hydrocortisone, as it is the glucocorticoid secreted by the adrenals in humans. However, I would concede that cortate is also effective, as are longer acting synthetic (non natural) glucocorticoids.
AADAI newsletter Issue 65 April 2007
A: Cortate (cortisone acetate) is converted by the liver to hydrocortisone (Hysone). The dose of Cortate is about 20% higher than Hysone for an equivalent effect. Both Cortate and Hysone can be expected to produce similar effects, allowing for this dose difference. Since Hysone or hydrocortisone is the same as natural cortisol it is preferred by some doctors.
AADAI newsletter Issue 75 December 2008
A: Adjusting the Florinef dose, with observation of sodium, potassium, BP and renin levels is generally the best way to achieve a healthy salt balance. It is not generally necessary to increase salt intake on a chronic basis to achieve this as most of us take more than sufficient salt with food. Some people need to take extra salt at times of increased heat stress due to salt losses with sweating.
AADAI newsletter Issue 85 August 2010
A: Hydrocortisone is cortisol so in that sense it is more natural. Cortisone however is also produced by the body naturally, but it is the inactive metabolite of hydrocortisone. Cortisone is useful because the body can convert cortisone to hydrocortisone, predominantly in the liver. Cortisone acetate was used as initially because it was readily available in the years before hydrocortisone was manufactured. In general, the hydrocortisone dose is 20% lower than that of cortisone since it does not need to be activated by the body for normal activity. Both hydrocortisone and cortisone boost the body’s cortisol levels for a few hours, depending on dose, and have longer effects in the body’s tissues. Both hydrocortisone and cortisone acetate are effective and they have never been compared closely, so that it is not known if one is in fact better for treating Addison’s than the other.
AADAI newsletter Issue 84 June 2010
A: Hydrocortisone and Cortisone (natural steroids) have half-lives (time taken for the blood concentration to reduce by half from peak) of about 90 mins, whereas the synthetic steroids prednisolone and prednisone have a half-life of around 2-4 hours and dexamethasone around 4 hours. Typically, it takes around several half-lives before all the steroid has left the body. In addition, the effects of the steroids in the tissues last for some time after the steroid concentrations fall to very low levels.
Very high doses of steroid lead to a prolongation of the duration of effect of steroids hence a single emergency high dose hydrocortisone (usually injected) dose lasts many hours, allowing time for help to arrive and/or evacuation.
Practically, the duration of action of each of these steroids varies as does their potency, so the more potent prednisolone or dexamethasone must be given in lower doses than hydrocortisone to avoid side effects of excess dose. Mostly maintenance doses of hydrocortisone and cortisone need to be given twice or even three times daily for best effect, whereas prednisolone and dexamethasone are generally once daily steroids.
As long as the dose and dosing interval of these steroids is adjusted for steroid type and individualised, any of the steroids listed can be used to replace the cortisol (hydrocortisone) deficiency in Addison’s disease.
Most of the work in this area has involved hydrocortisone and this is used, along with cortisone most often, however prednisolone works well in many patients. Dexamethasone has a limitation in that the smallest available tablets (0.5mg) are an excessive dose for many patients. Hydrocortisone is identical to natural cortisol, thereby minimizing the possibility of small immeasurable differences between natural and synthetic steroids.
Overall, the choice of steroid and the dosing schedule need to be individualised and patient preference is a key determinant along with knowledge of the usual dose range and necessary dose intervals for the available steroids.
AADAI newsletter Issue 93 December 2011
A: The effects of taking a second dose late at night vary between people. Some people find that a late night dose makes it difficult to sleep as hydrocortisone often increases arousal. However, if the dose is low this effect may not be noted and an evening dose is reasonable. In addition, some people are taking a similar dose of hydrocortisone later in the day as in the morning; missing the dose entirely may halve their hydrocortisone dose for the day and they would be rather deficient the next morning compared to usual. If the afternoon dose is in fact much lower than the morning dose, missing the dose altogether may make relatively little difference. Hence the decision to take a dose later in the day such as the evening when an afternoon dose is missed would need to be individualised. If many afternoon doses are missed, it may be better to consider using a longer acting glucocorticoid such as prednisolone.
The background to this, of course, is that some studies have suggested that more frequent
hydrocortisone dosing twice a day or even three times a day does produce improved wellbeing
but this effect may not be appreciated in all people and the inconvenience of frequent dosing may
overwhelm the benefit particularly if doses are often missed. Despite more frequent hydrocortisone dosing the current hydrocortisone tablets do not produce the natural diurnal rhythm of cortisone which rises from very early in the morning and peaks at around the time of wakening.
AADAI newsletter Issue 79 August 2009
A: People with Addison’s prior to mineralocorticoid treatment (Florinef) have high serum potassium, low serum sodium and dehydration. Although various strategies may be used to increase sodium and lower potassium only Florinef does both and restores hydration, all in the right ratio, since Florinef acts on the same receptor in the kidneys (and bowel, and sweat glands) to retain sodium and excrete potassium, as natural aldosterone. People with low potassium while taking Florinef may be taking an excessive dose.
AADAI newsletter Issue 81 December 2009
A: The optimum dosing frequency for hydrocortisone in Addison’s disease is still subject to question. However, there is some data to suggest that more frequent hydrocortisone dosing is associated with better wellbeing. In general, an attempt is made to at least partly mimic the circadian rhythm of cortisol by giving a higher dose in the morning and lower doses through the day. As cortisol levels are usually very low at night, hydrocortisone is not usually given at this time and some people report disturbance of sleep if it is taken before bed. Generally the first dose, a higher dose, is given soon after waking with a further dose in the early afternoon and in some cases, a three times a day dosing schedule is required with doses in relation to meals for convenience. Meals have a small (around 10%) affect on hydrocortisone absorption. Single doses above 10mg generally produce cortisol levels well above those transiently produced cortisol levels seen in people
without Addison’s disease. Hydrocortisone has a half life in blood of around 90 minutes but its effect in the tissues is longer than this. Other synthetic glucocorticoids which can be substituted for hydrocortisone, such as prednisolone or dexamethasone, have much longer affects on the body’s tissues and hence can be given once daily. The hydrocortisone dose should be adjusted on the basis of body surface area which most closely approximates studies of normal cortisol secretion by the adrenals. Thyroxine has a much longer half life of around six days and can be given at any time of the day but is usually given in the morning. The effects of food are quite minor but maximum absorption would occur with an empty stomach but I do not generally recommend this as it is often inconvenient. Iron tablets and to a lesser degree calcium tablets may reduce
thyroxine absorption. Fludrocortisone has a longer action than hydrocortisone so it is generally given once daily.
AADAI newsletter Issue 82 February 2010
A: Calcium carbonate may reduce thyroxine absorption. These tablets can be taken separately and TSH and/or Thyroxine levels can be readily checked to ensure that the interaction is not affecting your thyroid treatment significantly.
AADAI newsletter Issue 56 October, 2005
A: The average daily dose of Thyroxine (Oroxine) is 1.6 mcg per kg. However using the TSH level in people who have thyroid destruction we are able to individualise the thyroxine dose very accurately. Typically, we aim for a TSH level in the normal range and this is thought to represent an accurate Thyroxine replacement dose for the individual person taking this treatment. 200 mcg of Thyroxine daily would be an excessive dose for many people, but the dose needs to be individualised. Unlike hydrocortisone, it is not necessary to increase the dose of Thyroxine in times of stress. The reason for this is that thyroid hormone levels do not normally increase during stress, and in fact during severe illness thyroid hormone levels often gradually fall.
AADAI newsletter Issue 64 February 2007
A: There have been studies of treated Addison’s disease patients where bone density has been reported to be relatively low, but these studies are small and it is unclear if this translates to an increase risk of fractures. In addition, the mechanism of reduced bone density in Addison’s disease is also unclear. In the past, excessive doses of glucocorticoids have been used and these can clearly reduce bone density. There has also been speculation on the possibility that the lack of adrenal androgens could contribute to low bone density. It is also possible that other diseases related to Addison’s disease such as coeliac disease could contribute to the findings. This has led to bone density monitoring in patients with Addison’s disease. A fall in bone density should prompt consideration of other causes of falls in bone density as well as a review of the glucocorticoid dose. Patients with Addison’s disease, assuming that the cause of their Addison’s disease is autoimmune as is often the case, could have an increase of other autoimmune diseases such as type 1 diabetes, coeliac disease and pernicious anaemia. In addition, people with Addison’s disease may be at risk of the side effects of excessive glucocorticoid dose producing features similar to mild Cushing’s syndrome. Finally, there is an increased risk of an Addisonian crisis if the steroids are not managed well at the time of trauma or infection, or the medication is interrupted for any reason. For this reason, the Medic-Alert bracelet is a necessity as has been mentioned in this column on many occasions. A proportion of people with Addison’s disease report reduced well being. Overall, however, studies of patients with Addison’s disease have suggested an excellent life expectancy comparable to the general population.
AADAI newsletter Issue 71 April 2008
A: Patients with Addison’s disease should have medical follow-up 6–12 monthly. There are a number of issues that need to be assessed at each visit. These issues can be discussion generally but often need to be individualised. There is no blood test that can tell us whether a Glucocortoid dose is a little too high or a little too low for a particular patient. Glucocortoid dose is based on clinical assessment, for example, low blood pressure or blood pressure that drops excessively with standing or the presence of excessive fatigue suggests inadequate glucocortoid dose. Excessive glucocortoid dose on the other hand may be manifest by weight gain and/or a redistribution of fat away from the arms and legs towards the abdomen as well as facial rounding. In addition, there may be evidence of muscle weakness or osteoporosis on bone density scanning or fracture, if glucocortoid dose is excessive. The adequacy of a mineralacortoid dose can be assessed quite readily with a blood test, namely the plasma renin activity. A high plasma renin activity suggests inadequate fludrocortisone dose whereas a low plasma rennin activity would suggest excessive fludrocortisone dose. More severe excursions of fludrocortisone dosage could result in a change in plasma potassium levels or blood pressure. Once the plasma renin activity is stable, it should be perhaps checked every 12 months, although there is not definite consensus on this matter. An additional important issue in Addison's disease is to review the patient’s general health looking for evidence of associated immune-endocrine disease in the larger group of patients who have Addison’s disease on an autoimmune basis. The monitoring of plasma lipid levels should be performed on the same basis as that in the non-Addison’s population.
AADAI newsletter Issue 53 April 2005
A: You are correct in your explanation, one would expect the cortisol level to be zero so many hours
after hydrocortisone tablets. Such a measurement does confirm the diagnosis of complete cortisol
deficiency, but can not be used to fine tune hydrocortisone dosing. Theoretically, testing after the medication could be done and would reflect absorption and metabolism of hydrocortisone and used to adjust dose. However, many other factors are likely to influence optimum hydrocortisone dosage, especially glucocorticoid sensitivity where marked variability between individuals has been described. Hence, measuring cortisol levels is not routinely required in the management of Addison’s, and can be misleading as you have found. Similarly measurement of ACTH is also not useful as ACTH levels are high in appropriately replaced Addison’s patients – attempts to normalise ACTH will lead to hydrocortisone overdosage. Overall, there is no blood test that can tell us whether the hydrocortisone dose an individual is taking is appropriate. Hydrocortisone dosing is initially based on dose per body surface area and then adjusted on
clinical judgement, preferably by a clinician with experience in glucocorticoid replacement.
AADAI newsletter Issue 77 April 2009
A: Renin is a peptide produced by the kidney that acts to catalyse the production of the hormone
angiotensin II. Angotensin II acts as a constrictor of blood vessels to increase blood pressure and also to increase levels of aldosterone from the adrenal glands. Renin levels are increased when blood pressure (BP) is low and the kidneys are not getting enough blood flow. When aldosterone levels are low, as in Addison’s disease, renin levels are very high as the lack of salt and water in the body is sensed by a particular part of the kidney (the macula densa) and renin levels are increased. When we replace aldosterone with its synthetic analogue drug, fludrocortisone (Florinef), salt and water levels increase in the body and renin levels fall. If the Florinef dose is too high, renin levels are below normal. If the Florinef dose is too low, renin levels are too high. So, we aim for normal renin levels by adjusting the Florinef dose. In addition to renin, Florinef dose can be monitored by observing BP and potassium levels, since excessive Florinef can increase BP and reduce serum potassium. Sodium levels also change with Florinef, increasing with higher Florinef doses. However, potassium tends to be a more sensitive guide to Florinef dose. Renin levels can be affected by salt intake and posture. Some diseases and medications can affect renin levels and may make its measurement invalid for Florinef dose adjustment. Salt intake is not a problem if reasonably stable, but posture should be standardised for the measurement range – hence a person needs to be sitting (e.g., for 10 mins) for a sitting renin range to be applied. Recently, renin levels are being measured directly in blood whereas previously they were measured by the activity of a patient’s blood to stimulate angiotensin II levels. The latter measure is actually a “plasma renin activity” whereas the newer assay is known as a “direct renin concentration.” For monitoring in Addison’s there is no clear consensus on which measurement is preferable and either one is currently considered satisfactory. Actual levels will vary
between manufacturers testing systems and sometimes between laboratories. It is not necessary or useful to measure aldosterone in established Addison’s disease. Overall, measuring renin allows fine tuning of Florinef dose as long as BP, potassium and the possibility of factors that may confound the renin measurement are taken into account.
AADAI newsletter Issue 77 April 2009
A: If a full panel of adrenal tests is performed, including tests of mineralocorticoid function and
appropriate testing of cortisol, the tests can and have been shown to be positive even before
symptoms. However, if only partial or less sensitive adrenal tests are performed, the situation you describe is possible, but still quite unlikely.
AADAI newsletter Issue 76 February 2009
A: Although untreated Addison’s makes an adrenal crisis, often triggered by an intercurrent illness, a strong possibility it is possible to survive for prolonged periods without adrenal function. Such survival is usually accompanied by fatigue, nausea, postural dizziness and sometimes more severe symptoms which can diminish the quality of life considerably. Preserved aldosterone with low cortisol is more often seen in non-autoimmune Addison’s. The effects of cortisol and aldosterone on blood pressure are synergistic, so the presence of aldosterone would help to alleviate low BP which accounts for some of the symptoms, so aldosterone was probably helping to keep you as well as possible without cortisol.
AADAI newsletter Issue 85 August 2010
A: Plasma renin falls with Florinef replacement and reliably reaches the normal range if the Florinef dose, generally 0.05-0.3mg daily, is taken.
AADAI newsletter Issue 85 August 2010
A: Your travel plans invoke the risks of visiting parts of the world with less accessible medical facilities as well as risks from local environmental factors especially infections and altitude illness. You should make enquiries to ensure that good quality medical assistance is available promptly should you become unwell. It will be necessary to visit your local general practitioner or a travel clinic to have any relevant immunisations. Travel advice in this regard is continually updated. You should be well versed in the use of stress doses of cortisone for use during mild illness. This has been covered in other questions in this series. It would be preferable if you could take parental hydrocortisone for injection, ideally by your partner if you develop vomiting and were unable to take your usual hydrocortisone tablets. This would be an interim measure and you would then require immediate vacation for medical attention. Altitudes above 2500 metres put you at risk of altitude sickness. Normally breathing rates are increased to allow sufficient oxygen intake to the blood as one ascends to high altitudes. Prevention of altitude sickness allows for acclimatization by gradual ascent. In addition, there is increased urination (diuresis) as part of the acclimatization process. It is not specifically known if patients with Addison’s disease are at higher risk of acute altitude sickness. It is however, very important that you are able to recognise the acute symptoms such as headache, loss of appetite, nausea, vomiting, fatigue, dizziness, difficulty sleeping, drowsiness, confusion and unsteadiness. Such symptoms, particularly in your circumstances, would require immediate descent. Diuretics such as acetazolamide are sometimes used to increase the rate of the acclimatization process but the risks and benefits specifically in Addison’s patients taking fludrocortisone are not known. Your plans need to be considered carefully with your personal physicians in the light of your proposed travel.
AADAI newsletter Issue 57 December, 2005
A: I understand that you are taking cortisone acetate in divided doses three times over 24 hours. I would suggest that you take your cortisone acetate on your normal schedule up until the time of departure and then continue to take the cortisone acetate at the meal times on the flight. Just prior to arrival in Heathrow, you could take the usual one tablet in the morning and convert to your usual schedule adjusted for the night/day cycle for the UK. You should try to be sure that even if you miss a tablet because of sleep on the plane that you take your normal total dose over 24 hours even if the timing somewhat altered on the plane.
AADAI newsletter Issue 69 December, 2007
A: Both cortisol and melatonin, in common with many other biological processes, are subject to a circadian rhythm. In both cases the circadian rhythm is entrained by light with the highest levels of hormone at night and in the early morning. However, deficiency of adrenal hormones does not directly alter melatonin production.
The taking of melatonin is known to reduce body temperature and act as a mild sleep inducing agent. Melatonin has been used to modest effect in some individuals for treatment of jetlag symptoms. Melatonin is available as an over-the-counter product in some countries, but in Australia homeopathic preparations are generally all that is available, which implies that there is no actual melatonin in the product. There is no good evidence that the use of melatonin in people with Addison’s disease is advantageous.
AADAI newsletter Issue 67 August 2007
A: Influenza vaccine contains killed influenza virus, so that it cannot cause influenza, cultivated in hens’ eggs. The vaccine is especially recommended for people at increased risk of adverse consequences from infections of the lower respiratory tract. This applies most strongly to people with chronic lung or heart disease. Elderly and indigenous people are also likely to benefit due to an increased risk of complications of influenza. A favourable cost-benefit for influenza vaccine has been shown in the work place and many people are now being immunized to reduce the sick leave burden.
Influenza vaccine may also benefit people with other chronic diseases, as the consequences of infection may be greater than the general population. This includes people with metabolic diseases such as diabetes and also Addison's disease and people receiving immune suppressants. Cortisone medication in replacement doses is not an immunosuppressant. However people with Addison's may be expected to be at an increased risk in terms of the effect of inflammatory stress with influenza, particularly if severe pneumonia develops.
Hence, it lies within the range of current recommendations to include people with Addison's disease in an influenza vaccination program, provided they are not allergic to egg proteins or have reacted adversely to influenza vaccine in the past.
AADAI newsletter Issue 68 October 2007
A: Addison’s disease patients are not immunosuppressed if on appropriate replacement so immunisations can be embarked on safely.
AADAI newsletter Issue 76 February 2009
A: Vitamin B12 is not generally necessary for wellbeing in patients with Addison’s disease. There is an association between Addison’s disease and pernicious anaemia, which is another autoimmune disease, affecting the parietal cells of the stomach. Parietal cells are involved in the process of vitamin B12 absorption. Hence there are occasional patients with both Addison’s disease and pernicious anaemia who will require vitamin B12 as well as adrenal hormone replacement. Testing for vitamin B12 levels as well as other evidence of autoimmune disease is important particularly where there is a family history of other autoimmune disorders. Such testing is also important in people with symptoms or routine blood tests suggestive of additional autoimmune disorders.
AADAI newsletter Issue 82 February 2010
A: Weight gain (or elevations in blood pressure) when on hydrocortisone replacement should always arouse suspicion that the dose may be excessive. This is especially the case when the weight gain is principally in the abdomen and facial/neck regions. There are variations in dose between individuals, probably on the basis of altered cortisol absorption and metabolism. Hydrocortisone dosing can be predicted to some extent on a dose per body size basis but then requires monitoring and adjustment when required.
Of course, many people gain weight due to excessive dietary intake/limited exercise or both and this needs to be considered.
AADAI newsletter Issue 59 April 2006