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News, Articles & Research
North American Survey
of Individuals with Addison's Disease (1997)
The original survey text and
cover are available in PDF format.
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The National Adrenal Diseases Foundation North American Survey
was supervised by
Paul L.
Margulies, MD, FACP, FACE, NADF Medical Director, and
Joyce Mullen, NADF Executive Director (1994-1999)
In 1997, the National Adrenal Diseases Foundation (NADF) conducted the
first survey of individuals with Addison's disease residing in North
America. This survey was initiated as a service to addisonians in an effort
to bring about greater understanding of life with this rare adrenal
disorder. What is a typical daily dose of replacement therapy? What can the
newly diagnosed expect in terms of quality of life over the long term? Which
symptoms and stresses are "common" with this disease? In an attempt to find
answers to these questions, NADF conducted the North American Survey. This
survey consisted of twenty-four multi-part questions covering diagnosis,
symptoms, medication, family history, quality of life issues and factors
affecting mental and physical well-being. The survey was distributed to NADF
members via the newsletter and to the general public via the NADF Web site.
NADF modeled its survey after the report from the Dutch Addison Society
entitled, "Addison Patients in the Netherlands." That study, begun in 1990,
was based on 155 questionnaires, with 143 responding. Of those, 133 were
reported to have Addison's disease. The Dutch attempted to have personal
examinations of all the respondents: 93 were examined, and 91 were found to
have definite Addison's disease. Their statistics were based on the answers
and findings of these 91 individuals, and the report was published in two
parts in 1993 and 1994.
The NADF Survey received 700 responses; 665 of these individuals had
Addison's disease. The responses were collected over several months.
September 1, 1997 was used as a baseline for calculating the age of
respondents and their age at diagnosis. Extensive statistical analysis of
the survey results was performed. Some of the questions and answers proved
to be unusable because some questions may have been too vague, or the
answers (such as dosage of Florinef) too difficult for many of the
respondents to answer precisely. Personal interviews and physical
examinations were not feasible in this national survey, so all answers were
presumed to be correct without direct confirmation. Some of the respondents
left questions unanswered, so the denominator for the percentages for each
question varies. Despite these limitations, we believe the results of this
survey provide a useful and fairly accurate view of the addisonian
population in North America.
 General Statistics
- Sex Distribution: Of 699 respondents, 23.7% were male and 76.3% were
female. After excluding other adrenal diseases in the survey, leaving only
the people identified as having Addison's disease, 23.4% were male and
76.6% were female
- Race Distribution: Of 695 respondents, 98.3% were Caucasian, 0.6%
Black, 0.6% Hispanic and 0.6% other. The Addison's respondents were
virtually the same, with 98.6% Caucasian, 0.6% Black, 0.6% Hispanic and
0.2% other.
- Age of Addison's Disease Respondents: There was a very even
bell-shaped distribution of age of the respondents, with a peak in the
40-60- year age range
- Age at Diagnosis for Addison's Disease Respondents: The age at
diagnosis shifted toward the earlier years, with a peak in the 20-50-year
age range.
- Cause of Adrenal Disease: All 700 respondents answered this question.
89.7% indicated that they had Addison's disease (primary adrenal
insufficiency), or 628 individuals.
- Cause of Addison's Disease: The cause of Addison's disease was 63.0%
autoimmune, 7.2% surgical, 1.7% hemorrhage, 0.6% infection, and 27.5% did
not know the cause [Figure 6]. 665 individuals answered this question,
even though only 628 indicated that they had Addison's in the previous
question. Using the larger figure, 418 individuals indicated that they had
autoimmune Addison's disease. This denominator was used in calculating the
associated autoimmune disease statistics and family history information.
Autoimmune
Addison's Disease - Associated Conditions
Autoimmune Addison's disease is
usually a manifestation of a process that can affect other endocrine glands.
In adults, the autoimmune polyglandular syndrome-2 (APS-2) is most common,
with the other possible endocrine glands affected including the thyroid,
pancreatic beta cells (producing juvenile or Type 1 diabetes mellitus),
stomach cells that allow absorption of vitamin B12 (producing pernicious
anemia), vitiligo from a loss of pigmented cells in the skin, and premature
gonadal failure. Autoimmune Addison's disease can also be part of APS-1, a
much less common syndrome presenting almost always in childhood, and
including fungal infections of the tongue, skin and nails,
hypoparathyroidism (causing low calcium levels), and failure of sexual
maturation (primary hypogonadism).
In the survey, we did not attempt to
identify APS-1 or APS-2 individuals. Those with autoimmune Addison's disease
were asked if they also had hypothyroidism, hyperthyroidism, Type-1
diabetes, pernicious anemia, hypoparathyroidism, primary gonadal failure
(presenting as early menopause in our mostly female adult population) or
vitiligo.
The results indicate a very large percentage with autoimmune
thyroid disease. Those with hypothyroidism can be assumed to have
Hashimoto's thyroiditis (autoimmune thyroid failure) and those with
hyperthyroidism to have Graves' disease (autoimmune hyperthyroidism). The
total with thyroid disease was 76.7%, 69.6% having hypothyroidism and 7.1%
with hyperthyroidism. The other autoimmune disorders were much less common:
6.6% with Type-1 diabetes, 9.6% with pernicious anemia, 6.9% with
hypoparathyroidism, 17.2% with primary gonadal failure, and 16.7% with
vitiligo [Figure 7].
These figures suggest a very high incidence of APS-2 in
the Addison's population. They also indicate a much higher incidence of
autoimmune thyroid disease associated with Addison's disease than seen in
the Dutch Addison Society study, where the incidence of hyperthyroidism was
only 6.0% and hypothyroidism only 20.5%. Since the North American survey did
not include a question on childhood fungal infections, it is difficult to
estimate the number of individuals with APS-1.
Family History
Respondents who had autoimmune Addison's disease were asked to list
family members who had autoimmune endocrine diseases. The first-degree
relatives were separated out and grouped by sex. Many of the relatives had
more than one endocrine disease and are listed more than once in the totals.
Percent incidence could not be calculated.
Female first-degree relatives had more associated endocrine diseases than
male relatives, with thyroid diseases predominating. From the high numbers
listed with diabetes, we suspect that many respondents included relatives
who actually had insulin-requiring Type-2 diabetes (adult onset) with those
who had insulin-dependent Type-1 diabetes (juvenile onset).
Difficulty with Diagnosis
- Time to Diagnosis:
All Addison's disease respondents were asked how long it took to arrive at
the diagnosis: 1-4 weeks for 18.7%, 1-6 months for 28.7%, 6-12 months for
14.9%, 1-2 years for 13.9%, 2-5 years for 13.0% and over 5 years for 10.7%.
When asked whether is was difficult to get the diagnosis of
Addison's disease, only 20.1% replied yes, 79.8% no.
All Addison's disease respondents were asked how many doctors they had to
see before the diagnosis was made, and what type of doctor made the correct
diagnosis. For 19.4% it was one doctor, for 22.4% it was two, for 23.6% it
was three, and for 34.5% it was four [Figure 11]. The type of doctor was a
general practitioner for 21.6%, an internist for 30.6%, a pediatrician for
2.5%, an endocrinologist for 34.8%, and 10.5% other.
- Initial Presenting Complaints:
All Addison's disease respondents were asked to check off which symptoms
were present at the time of diagnosis from the following list:
hyperpigmentation of skin and/or gums, severe fatigue, weakness, weight
loss, salt craving, dizziness upon standing, loss of appetite, nausea,
vomiting, stomach pains, muscle/joint pains, reduced blood pressure,
headache, and difficulty concentrating. The totals were then ranked by
incidence from 1 to 14.
The vague complaints of severe fatigue,
weakness and weight loss were the most common, all above 90%. The more
specific symptoms that might lead to the suspicion of the diagnosis of
Addison's disease were slightly less universal, but still very common: hyperpigmentation, reduced blood pressure, dizziness upon standing, nausea,
loss of appetite, and salt craving all appeared more than 80% of the time.
When asked if they were ever told that their symptoms were all
psychological, 43.3 % replied yes, 56.7% no.
Current Treatment
Current Medication
All Addison's disease respondents were asked to check off the medications
they currently take from the following list: hydrocortisone, cortisone
acetate, prednisone, dexamethasone (the glucocorticoids), and Florinef. They
were then asked to indicate the dosage in milligrams of each medication
taken as the first dose, second dose and third dose, with the time of day of
each dose, plus the dose of Florinef, if used. The overwhelming majority,
64.6%, take hydrocortisone as their glucocorticoid. 15.0% use cortisone
acetate, 19.6% use prednisone, and only 1.3% use dexamethasone.
The results on
dosages were difficult to calculate by time of day because of the
variability in the way the answers were written. However, the total dosage
for each glucocorticoid per day indicates that most people with Addison's
disease take a daily dosage near the textbook physiologic replacement
dosage.
For hydrocortisone, that replacement dosage is near 30 mg. For cortisone
acetate, that is near 37.5 mg. For prednisone it is about 7.5 mg. Only 8 individuals indicated that they use dexamethasone as
their glucocorticoid, so the numbers in each dosage lack significance.
Florinef (fludrocortisone acetate) is
also used by 80.2% of Addison's respondents. Unfortunately, there was much confusion over the decimal point
placement in the milligram dosage of Florinef used. The only tablet made is
the 0.1 mg pill, but many individuals listed daily doses of 1 and 2 mg by
mistake. Therefore, an accurate breakdown of the Florinef dosage for the
Addison's population could not be calculated. When asked if they felt the
current daily medication was right for them, 92.1% replied yes, with only
7.9% indicating no.
Current Doctor
Respondents were asked to check off which type of doctor they currently
see for their Addison's disease. 67.9% see an endocrinologist, 18.9% see an
internist, 12.0% see a general practitioner, and 1.2% some other type of
doctor [Figure 21].
Emergency Management
Respondents were asked to check off how many times they had been to an
emergency room or been admitted to a hospital for their Addison's disease.
26.6% checked never; 27.7% once; 15.0% twice; 17.9% 3 to 5 times, and 12.8%
over 5 times.
When asked if they take extra medication when
acutely ill, 95.5% answered yes, only 4.5% no. When asked the
number of times they had to take injectible steroids at home for an adrenal
crisis, 83.7% replied never, 5.7% once, and the remaining more than once. Medic Alert bracelets or necklaces are worn by 89.9% of the
respondents.
Current Condition
All Addison's disease respondents were asked to check off the frequency
of symptoms that apply to their current condition. The list included all the
symptoms enumerated at the presentation of the Addison's disease, plus many
more that would reflect their current well-being. Some of the symptoms were
meant to be specific for Addison's disease, and some were meant to be
symptoms of other aspects of the autoimmune polyglandular syndromes.
Respondents were asked to check if a symptom was occurring "always",
"sometimes", "seldom", or "never". Many respondents skipped over some of the
symptoms.
The average number of responders to each symptom was 580. Of the 44 symptoms listed, there were 16 symptoms that were cited by
at least 50% of the Addison's disease responders in the "sometimes" or
"always" column. These most frequent current complaints are ranked in
descending order.
As with the symptoms enumerated at presentation of the
Addison's disease, fatigue was the most common complaint in the currently
treated population. A tendency to gain weight was second,
suggesting that difficulty with over-replacement of steroids causes a lot of
concern. The only very specific symptom for Addison's disease to appear on
this list of top complaints was salt cravings, ranked fifth.
Social Aspects
All respondents to the survey, regardless of the type of
adrenal disease, were asked to indicate if they were experiencing difficulty
in their social or financial life due to the disease. 52% replied yes, 48%
no. Those that answered yes were asked to check the type of
problem they experienced from the following list:
- loss of self confidence
- loss of social life
- nervousness when traveling
- nervousness when shopping
- loss of reading/writing capacity
- inability to work outside the home
- inability to accomplish tasks at home
- difficulty with relationships
- fear
of new experiences
- marital problems
None of these were cited by more
than 30% of the respondents. The most frequent social complaints were
nervousness when traveling, loss of self confidence, loss of social life,
and inability to accomplish tasks at home. When asked if they
were able to work, 69.2% replied yes and 13.3% no; 17.2% were retired and
0.3% were students.
Summary
This report presents the data collected in the first North
American survey of Addison's disease. 700 individuals returned the completed
survey questionnaire indicating that they had adrenal disease. Of these, 665
had Addison's disease. In the Dutch Addison Society report, 91% of the
Addison's disease cases were autoimmune. In our survey, 63.0% listed
autoimmune as the cause, with 7.2% surgical, 1.7% hemorrhage, and 0.6%
infection. However, a large number of the respondents, 27.5%, did not know
the cause of their Addison's disease. It is very likely that most of these
would fit into the autoimmune category, but they were simply not informed
adequately by their doctors about the etiology of their disease.
Although it
is impossible to conclude that the group would approach the 91% seen in the
Dutch report, where each individual could be interviewed, it is clear that
autoimmune Addison's disease is the predominant form seen today, in contrast
to the frequency of tuberculosis as a cause in the nineteenth century. As in
the Dutch report, we found that the onset of the disease was most frequently
in the 20- to 50-year age range. The sex ratio of 77% female to 23% male is
slightly higher than the 66% female to 34% male balance in the Dutch report.
However, this corresponds to the statistics published by the American
Autoimmune & Related Diseases Association which indicate that autoimmune
diseases, as a whole, affect women 3 times as often as men. Virtually all of
our respondents were Caucasian, but the design of the survey does not permit
any conclusions on race incidence in North America.
One striking difference between the Dutch report and our survey is in the
ease of diagnosis. The Dutch found that on average it took 3 years from the
onset of symptoms to the correct diagnosis. They concluded that this was due
to the predominance of the use of general practitioners as the initial
physician, and the lack of specificity of the presenting symptoms. They
found that 99% of their addisonians complained of fatigue or weakness, but
noted that as many as 97% also had hyperpigmentation, a very specific sign
of Addison's disease. The other highly suggestive symptom, salt craving,
occurred in 78% at presentation. In contrast, in our North American survey,
62.3% reported having the diagnosis made within the first year of symptoms.
The vast majority (80.6%) did need to see more that one doctor, and 34.5%
required an endocrinologist to make the diagnosis. The incidence of
hyperpigmentation in our population was only slightly lower, 89.2%, but the
incidence of salt craving, 80.3%, was almost identical to the Dutch group.
Indeed, the incidence of all the other presenting symptoms in the two groups
is remarkably consistent. Therefore, the earlier diagnosis made in North
America reflects a greater degree of clinical suspicion by the medical
community and a greater ease of specialty referral, rather than any
difference in the way the two groups present.
When the Dutch report was published, 47% of their Addison's disease
population had at least one other autoimmune disorder, and the authors were
surprised to find that as much as 20.5% had hypothyroidism. A significant
observation in the North American survey is that a striking 76.7% had
autoimmune thyroid disease, with 69.6% having hypothyroidism and 7.1%
hyperthyroidism. The incidence of the other forms of autoimmune endocrine
disease seen as part of the APS-2 family was also quite large. The incidence
of autoimmune thyroid disease within APS-2 is simply more common than
previously thought, and there may be some genetic differences between the
Dutch population and the more heterogeneous North American group. The family
history data reflects the individual statistics in showing a high incidence
of genetic susceptibility to thyroid disease in these families.
The management of Addison's disease appears to be the same in North
America as it is in the Netherlands. The predominant use of hydrocortisone
and cortisone acetate over prednisone and dexamethasone is no different. The
use of Florinef (fludrocortisone acetate) is similar. The doses of glucocorticoid and
mineralocorticoid were also about the same in the two study groups. Because
they were able to physically examine a significant number of their study
participants, the Dutch Addison Society was able to look for any correlation
between medication dosage and physical signs and persistent symptoms. They
were unable to find any such association. They did complain that the
availability of hydrocortisone in only the 20 mg. pill size limited the
ability of their addisonians to fine-tune their dosages. In North America,
10 and 20 mg. pills are more readily available. An interesting finding in
the Dutch study was the high incidence of elevated plasma renin activity,
suggesting that 37% of the addisonians were under-replaced with Florinef.
The North American population at least appears to be more informed about the
need for treatment, with 95.5% indicating that they did know to take extra
medication when acutely ill, and 89.9% wearing Medic Alert bracelets or
necklaces, higher percentages than in the Dutch study.
Unfortunately, there is no cure for Addison's disease. Even when the
diagnosis is made and replacement treatment with glucocortioids and
mineralocorticoids is begun, the therapy itself remains less than ideal. The
use of hydrocortisone or any of the other glucocorticoids plus Florinef does
not duplicate the normal adrenal physiology that existed before the onset of
the disease. As pointed out in the Dutch study, the current use of oral
glucocorticoids produces blood levels of hydrocortisone that deviate above
or below the normal blood levels for significant portions of each day. With
the loss of the normal automatic feedback between the adrenals and the
pituitary, oral dosing for typical days, and especially for stressful days,
can only roughly approximate the needs of the addisonian individual.
It is
therefore not surprising that people with Addison's disease report that they
often do not feel well despite their medication. Given a long list of
possible symptoms, the addisonian population in the North American survey
listed 16 frequent complaints that continued to be a problem while on
appropriate replacement medication. The subjective sense of fatigue topped
the list. A tendency to gain weight was second, suggesting unhappiness with
the effect that glucocorticoid replacement was having on weight control.
Easy bruising, ranked sixth, was another symptom that may reflect frequent
over-treatment. Most of the other prevalent complaints were non-specific,
and some of them may reflect concurrent hypothyroidism or menopause. The
only symptom in this list of frequent complaints that suggests
under-treatment is salt craving, ranked fifth.
Addison's disease did not prevent most of the North American survey
respondents from actively working. Only 13.3% replied that they were not
able to work, with 69.2% working, 17.2% retired and 0.3% students. In the
Dutch report, only 54% were actively employed. In general, the North
American survey group seemed to be less socially affected by the disease
than the earlier Dutch group. Although 52% did report experiencing some sort
of social or financial effect of the disease, this was much less than in the
Netherlands. The most frequent social complaints were nervousness when
traveling, loss of self confidence, loss of social life, and the inability
to accomplish tasks at home.
Conclusion
Analysis of the data showed that North American addisonians,
with almost identical incidences of salt craving and hyperpigmentation as
their Dutch counterparts, were better able to receive a diagnosis in a
shorter period of time. This suggests that there is a greater degree of
clinical suspicion of Addison's disease by North American primary physicians
when the classic signs and symptoms are present, and there is a greater ease
of specialty referral here.
Perhaps the most startling statistic drawn from this survey was the 76.7%
incidence of autoimmune thyroid disease in those with autoimmune Addison's
disease. 69.6% had hypothyroidism and 7.1% had hyperthyroidism. This not
only strengthens the argument that autoimmunity is the predominant cause of
Addison's disease, it also proves that APS-2 specifically is the most common
genetic factor in the etiology of Addison's disease. The incidence of
thyroid disease in APS-2 is more common than previously thought. The family
history data shows that there is a high incidence of genetic susceptibility
to thyroid disease in the relatives of addisonians.
The North American population appears to be highly informed on the
treatment of their condition, handling the many facets of replacement
therapy with knowledge and competency. However, the current use of oral
glucocorticoids produces blood levels of hydrocortisone that deviate above
or below the normal blood levels for significant portions of the day. The
loss of normal automatic feedback between the adrenals and the pituitary
contributes to the addisonians' complaints of fatigue. Our survey showed
that even with this issue, most survey respondents reported being able to
work and were less socially affected by the disease than their Dutch
counterparts.
Acknowledgments
The Biostatistics Department of North Shore University
Hospital, Manhasset, New York provided valuable assistance with the
statistical analysis of the survey data.
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