Beruflich Dokumente
Kultur Dokumente
com
Medical Therapy
Medical therapy of hypercortisolemia is typically reserved for patients who are
unable to undergo surgery, for patients who have failed to achieve remission with
other treatment modalities, as a bridge to radiotherapy or surgery, or as a
palliative option (Figure 1). A number of potential targets exist for medical therapy
including inhibition of steroidogenesis, inhibition of ACTH secretion and
glucocorticoid receptor antagonism (). The most commonly used agents have
been steroidogenesis inhibitors although other classes of medications are being
actively investigated.
Table 1. Medical therapy for the treatment of Cushing's syndrome.
Drug
Initial dose
Maximum
dose
Major limitations
Steroidogenesis inhibitors
Ketoconazol
e
200mg
b.i.d.
400 mg t.i.d.
Metyrapone
250mg
q.i.d.
1500 mg
q.i.d.
Mitotane
500mg
b.i.d.
Etomidate
ACTH modulators
Pasireotide
600 g bid
900 g b.i.d.
Cabergoline
1mg/week
7 mg/week
Figure 1.
Algorithm for appropriate use of medical therapy in Cushing's disease. TSS:
Trans-sphenoidal surgery.
Steroidogenesis Inhibitors
Steroidogenesis inhibitors control cortisol production by decreasing steroid
hormone production in the adrenal gland through inhibition of one or more
enzymes involved in steroid synthesis. Steroidogenesis inhibitors can be used for
either partial or complete blockade of cortisol production. When used for partial
blockade, the doses of these medications are adjusted to achieve normal urine
cortisol levels. When used for complete blockade, a 'block and replace' strategy
involves steroidogenesis inhibitors at doses that will achieve complete inhibition
of cortisol synthesis, and glucocorticoids to replace physiologic needs.
Ketoconazole
side chain cleavage. [15,20] These effects are dose dependent and completely and
rapidly reversible upon drug discontinuation.
In 1982, Pont et al. evaluated the effects of ketoconazole on steroid synthesis in
healthy subjects. The investigators demonstrated a blunted cortisol response to
synthetic ACTH (Cortrosyn) 46 h after administration of 400600 mg of
ketoconazole. [21] This blunted cortisol response persisted for up to 8 h and was
resolved by 16 h. [21] This was one of the first reports to demonstrate the adrenal
effects of ketoconazole and suggest the potential use of ketoconazole in the
treatment of Cushing's syndrome. A number of small case series using
ketoconazole in the treatment of Cushing's syndrome ensued. [22]In 1991,
Sonino et al. evaluated a larger series of 34 patients with Cushing's syndrome
who were treated with ketoconazole as a palliative measure in preparation for
surgery, before or after radiation treatment or in patients not suitable for surgery.
The patient population consisted of 28 patients with Cushing's disease, one with
an adrenal adenoma, two with adrenal hyperplasia, one with adrenal carcinoma
and two with ectopic ACTH production. Doses ranged from 400 to 800 mg/day
divided into two doses. The patient with adrenal carcinoma received a dose of
10001200 mg/day for 3 months. Doses were adjusted periodically based on
clinical response. Urine-free cortisol decreased from 1296 176 to 270 69
nmol/day (normal range: 55331 nmol/day; p < 0.001). Urine-free cortisol
remained in the normal range throughout treatment in 30 out of 34 patients while
on therapy. [23] Two of the 34 patients developed increased cortisol levels after 6
months of treatment and another two had continued elevated cortisol levels. [23] A
meta-analysis of eight trials involving patients with Cushing's syndrome treated
with ketoconazole as monotherapy reported an average remission rate of 70%
(2593%). [15,18,24]
In 2008, Castinetti et al. published a study evaluating a total of 38 patients with
Cushing's disease between 1995 and 2008 treated with ketoconazole for a mean
duration of 23 months. Initial dosing was 200400 mg/day with dose increases of
200 mg/day every 1015 days up to a maximum dose of 1200 mg/day. Of the
patients included in the study, 17 had previous unsuccessful pituitary surgery, 15
had no visible tumor on MRI, one refused surgery, one had a contraindication to
surgery and four were awaiting the effect of gamma knife radiosurgery. Five
patients discontinued treatment in the first week because of nausea and diarrhea.
One of the five patients also had a fivefold increase in GGT despite normal ALT
and AST. [2] Seventeen patients (44.7%) achieved biochemical control of disease
with normalization of urine-free cortisol within the first 3 months on therapy. [2] In
five patients with diabetes, glycosylated hemoglobin (HbA1c) was improved by
0.53.5%. This study differed from others in having a large proportion of patients
treated with ketoconazole as a primary treatment modality. There was no
difference in study parameters between patients treated with ketoconazole as
primary verse secondary therapy. [2]
The most common side effects of ketoconazole when used as an antifungal at
lower doses of 200400 mg daily are gastrointestinal side effects and pruritis
occurring in 25% of the patients. [18,20,25] A major limiting side effect is elevated
liver function enzymes. Ketoconazole carries a black box warning for
Metyrapone was first introduced in 1956 and was shown to block the production
of cortisol through the inhibition of 11B-hydroxylase, resulting in a dramatic rise in
11-deoxycortisol, a precursor steroid with mineralocorticoid activity formed
immediately proximal to cortisol in the steroid biosynthesis pathway. [18,27] It was
initially used as a diagnostic test of ACTH reserve as well as in the differential
diagnosis of Cushing's syndrome, [27] but it was eventually shown to be effective in
the treatment of Cushing's syndrome.
In 1977, Jeffcoate et al. treated 13 patients with Cushing's disease with
metyrapone for 266 months. The dose varied from 250 mg twice daily to 1000
mg four times daily. Clinical features of Cushing's syndrome rapidly improved.
Although this study was limited by the small number of patients as well as the fact
that urine-free cortisol levels were not reported, it did demonstrate the usefulness
of this agent in the treatment of Cushing's syndrome. [27,28] In a larger study,
Verherst et al. evaluated 91 patients, 57 with Cushing's disease, ten with adrenal
adenomas, six with adrenocortical carcinoma and 18 with ectopic Cushing's
syndrome [29]. Short- and long-term responses to metyrapone were evaluated.
Test dosing with 750 mg demonstrated a decrease in cortisol levels within 2 h of
administration of metyrapone. Fifty three patients with Cushing's disease were
followed on treatment with metyrapone short term for 116 weeks prior to
definitive therapy. Patients were initiated on 250750 mg of metyrapone every 8
h. This dose was titrated after 4872 h based on cortisol levels to a minimum of
250 mg twice daily and a maximum of 1.5 g four times daily. Target cortisol levels
were <400 nmol/l given that levels of 300400 nmol/l reflect normal cortisol
Mitotane reduces cortisol synthesis through the inhibition of 11B-hydroxylase, 18hydroxylase, 3- hydroxylase, hydroxysteroid dehydrogenase and several
cholesterol side chain cleavage enzymes. [18] It is also an adrenolytic agent at
doses greater than 4 g per day, and is used most often for the treatment of
adrenocortical carcinoma.
Mitotane has been studied for the management of Cushing's syndrome from both
ACTH-dependent and ACTH-independent causes. In 1979, Luton et al. studied
62 patients with Cushing's disease treated with mitotane (412 gm/day divided
three-times daily) for an average duration of 8 months [30]. In most cases, the
initial daily dose was 12 g per day for 3 months and then 8 g per day. Forty six
patients received mitotane alone and 16 patients received mitotane in addition to
pituitary irradiation. Remission was achieved in 38 of the 46 patients given
mitotane alone and in all patients who received drug therapy plus
radiation. [30] During long-term follow-up, 20 patients relapsed and required further
treatment. Overall remission rates of Cushing's disease with mitotane are up to
83% short term. [15,18,30] In addition, Luton et al. demonstrated clinical effectiveness
of mitotane in controlling hormonal secretion of adrenocortical carcinoma.
Seventy five percent of the 59 patients with adrenocortical carcinoma receiving
mitotane therapy had control of hormonal secretion. [31] More recent studies have
demonstrated the effective use of combination chemotherapy with mitotane for
the treatment of adrenocortical carcinoma. [32]
Gastrointestinal side effects include nausea, anorexia and vomiting. These side
effects are often dose limiting. Other side effects observed include gynecomastia,
hypercholesterolemia and hyperuricemia. [18,30] More serious neurologic side
effects include ataxia, lethargy, vertigo and confusion. Side effects often limit the
tolerability of mitotane. In addition, mitotane is teratogenic and should be used
with extreme caution in women of childbearing potential. Mitotane also has a slow
(weeks to months) onset of effect as adipose tissue accumulation delays
achievement of therapeutic serum levels. [33] Therefore, it has been advocated to
be used in combination with another drug to attain more rapid control of
hypercortisolism. [1,18,34] In patients with Cushing's disease, if pituitary irradiation is
not used in combination with mitotane, there may be risk of Nelson's syndrome
as the reductions in cortisol achieved by mitotane mimic effects of
adrenalectomy. [18,24] Adrenal insufficiency is an expected side effect due to the
adrenolytic effect of the drug particularly at higher doses. Mitotane increases
cortisol binding globulin, resulting in an overestimation of serum-free cortisol,
making this an unreliable measure of steroidogenesis. Therefore, patients should
be monitored for reduction in steroidogenesis with serum ACTH, plasma renin,
sodium, potassium and urine-free cortisol. Once urine-free cortisol levels are
normalized, replacement glucocorticoids should be initiated. Initiation of
hydrocortisone should start at a dose of 2530 mg/day with titration of
hydrocortisone based on urine-free cortisol and plasma ACTH levels.
Hydrocortisone requirements increase two- to three-fold on mitotane therapy
because mitotane increases its metabolism. [35] An alternative glucocorticoid
replacement is prednisone, as its metabolism is not effected by
mitotane. [15,18]Replacement mineralocorticoids are often not required immediately
as the zona glomerulosa is more resistant to mitotane's adrenolytic effects. [35]
Initial dosing of mitotane in Cushing's syndrome is 0.51 g daily in divided doses
with titration up to a maximum of 3000 mg three-times daily. [1] Dosing of mitotane
for adrenocortical carcinoma begins at 12 g/day with titration by 12 g every 12
weeks up to a maximum of 10 g/day. Serum levels of mitotane should be
measured by a gas chromatography-flame ionization detection assay at 48week intervals initially with goal serum levels of 1014 mg/l. [33] Once appropriate
serum levels are achieved, they should be followed every 3 months. [33] When
using mitotane for adjuvant therapy in patients with adrenocortical carcinoma with
normal urine-free cortisol levels, glucocorticoid replacement should occur with the
start of mitotane therapy or when the dose reaches 2 g/day. [35] In patients started
on mitotane for residual adrenocortical carcinoma with continued
hypercortisolemia, glucocorticoids should be initiated when hypercortisolemia is
controlled as indicated by normalization of urine-free cortisol. [35]
Aminoglutethimide
ACTH Modulators
Agents that directly lower ACTH secretion by a pituitary adenoma represent an
attractive option for the treatment of Cushing's disease, as these drugs directly
target the pathogenesis of disease. Among these are dopamine agonists and
somatostatin analogs. While one would hope that the ACTH modulators would
reduce tumor volume (of particular concern in patients with pituitary
macroadenomas), there is very limited data on effects of these medications on
tumor size.
Dopamine Agonists
Somatostatin analogues are clinically used for the treatment of acromegaly and
have the benefit of both reduction of tumor size and hormonal control of this
disease. Because pituitary corticotroph adenomas express somatostatin
receptors, somatostatin analogues have been investigated as a potential targeted
therapy for the treatment of Cushing's disease.
Octreotide, a somatostatin analogue, which predominantly acts on somatostatin
type 2 receptors (sst2 receptors), has been shown, in vitro, to lower ACTH levels
but is largely ineffective in lowering ACTH levels in vivo in patients with
hypercortisolemia secondary to Cushing's disease. [11,15] This may be a result of
relatively low levels of expression of sst2 in patients with Cushing's disease. [39] By
contrast, somatostatin analogs have been shown to be effective in reducing
pathologic ACTH levels in patients with Nelson's syndrome. The fact that patients
with Nelson's syndrome show an increased uptake of the radiolabeled
somatostatin analog pentetreotide and respond to somatostatin with a reduction
in pathologic ACTH production indicates that the downregulation of sst2 receptors
in patients with Cushing's disease may be a result of hypercortisolemia. [46] A
newer multiligand somatostatin analog, pasireotide, which acts on type 1, 2, 3
and 5 somatostatin receptors (sst receptors) with highest affinity for sst5
receptors, which are highly expressed in corticotroph pituitary adenomas, [39] has
been demonstrated to inhibit ACTH release in human corticotroph
cells. [7,15,47] Pasireotide has a 40-fold higher affinity for sst5 receptors than
octreotide. [39]
In 2006, Batista et al. evaluated fresh tumor tissue from 13 patients with
Cushing's disease who underwent transsphenoidal resection of their pituitary
tumor. [47] Sst5 was highly expressed in 83% of the tumors. Changes in cell
Retinoic acid has been shown to inhibit proliferation, invasion and tumor
growth in vivo. It also induces apoptosis in different cell types (human and animal
cancer cells) mediated by reduction in the binding of transcription factors which
are thought to be essential in the control of the POMC gene, which is crucial in
ACTH production. [50] Animal studies have shown reduction in ACTH, cortisol and
tumor size in dogs with Cushing's disease treated with retinoic acid. [50]
More recently, a prospective, multicenter pilot study evaluated the effectiveness
of retinoic acid in the treatment of Cushing's syndrome. Seven patients with
Cushing's disease were initiated on 10 mg of retinoic acid daily with doubling
every 2 weeks with a maximum dose of 80 mg daily. Urine-free cortisol was
evaluated at 6 months for response. Responders (those with an at least 50%
reduction in urine-free cortisol) continued treatment for a total of 12 months. Five
patients experienced reduction in urine-free cortisol values; of these, three
patients achieved normal urine-free cortisol. [51]
Although this pilot study is intriguing, larger studies are needed to further
evaluate the effectiveness and side effects of treatment with retinoic acid in
Cushing's syndrome. This medication is teratogenic and is not currently approved
for use in the treatment of Cushing's syndrome. [51]
(p < 0.001). Average reduction in HbA1c was 1.1% (p < 0.001). [58] The
primary end point in the hypertension cohort was a 5 mmHg reduction in diastolic
blood pressure. This end point was met in 38% of the patients though mean
diastolic and systolic blood pressure were unchanged. Other benefits observed
were a 3.6% decline in percent total body fat (p < 0.001) and reduction in waist
circumference. Mood, cognition and quality-of-life scores were also improved. [58]
In addition to blocking the peripheral actions of cortisol, mifepristone blocks
central activity as well causing upregulation of the hypothalamicpituitaryadrenal
axis, resulting in increased ACTH and cortisol in a proportion of patients with
Cushing's disease. [52] Seventy two percent of the patients with Cushing's disease
treated with mifepristone had at least a twofold increase in ACTH, cortisol or
both. [52] This is not seen in patients with nonpituitary causes of Cushing's
syndrome. [52]Because of this, there is currently no biochemical test to measure its
antiglucocorticoid efficacy and practitioners must rely on the clinical response.
Doses should be titrated based on the symptoms (mood and cognition), clinical
features (bodyweight and composition and blood pressure) and biochemical
parameters such as glucose and HbA1c.
Adverse reactions occurring in 20% of the patients include nausea, fatigue,
headache, hypokalemia, arthralgia, vomiting, peripheral edema, hypertension,
dizziness, decreased appetite and endometrial hyperplasia. Other laboratory
abnormalities found were a reduction in high-density lipoprotein levels and
asymptomatic elevations in thyroid stimulating hormone. Recommended
monitoring should include measurement of serum potassium, clinical assessment
of adrenal insufficiency and yearly vaginal ultrasound in women to evaluate for
endometrial hyperplasia. [58,59] Because of the inability to biochemically monitor
cortisol levels, patients must be monitored closely for clinical evidence of adrenal
insufficiency. When observed, this should be treated with cessation of
mifepristone and high-dose dexamethasone to overcome glucocorticoid blockade
for 2 weeks given the long half-life of mifepristone. [59]
In addition, mifepristone effects a number of cytochrome P450 enzymes.
CYP3A4 is involved in the metabolism of mifepristone and mifepristone also both
inhibits and induces CYP3A4. Therefore, drugs that are metabolized by CYP3A4
should be avoided or used with caution. Other enzymes affected by mifepristone
are CYP2C8/2C9 and CYP2B6. Drugs metabolized by these pathways should be
used with caution. [59]
Mifepristone was recently approved by the FDA for use in patients with
hyperglycemia secondary to Cushing's syndrome who have either failed to
achieve remission with surgery or are not surgical candidates. Initial dosing is
300 mg/day with titration up to a maximal dose of 1200 mg/day or 20 mg/kg/day.
It is being marketed as Korlym (Corcept Therapeutics Inc., CA, USA) and is
currently available through a central distribution pharmacy. Prescribers must
complete and submit a patient enrollment form to Support Program for Access
and Reimbursement of Korlym (SPARK). SPARK will determine insurance
eligibility and assistance. [102] The cost of Korlym is approximately US$186 per 300
mg pill. Co-pay assistance and patient assistance programs will be available
Combination Therapy
While each drug available for the treatment of Cushing's syndrome has
limitations, combining agents may limit the side effects of each while improving
treatment efficacy, although there are very few systematic studies of combination
therapy. Aminoglutethimide has often been used in combination with another
agent [18,24] due to its limited efficacy and escape phenomenon. Mitotane is also
often used in combination with another agent due to its delayed onset of action,
while the combination of metyrapone with another steroidogenesis inhibitor would
be expected to reduce the accumulation of cortisol precursors with
mineralocorticoid or androgenic properties that is seen with metyrapone alone.
Kamenicky et al. reported successful combination of mitotane (35 g/day),
metyrapone (34.5 g/day) and ketoconazole (4001200 mg/day) in 11 patients
with Cushing's syndrome. Initial dosing was 2.25 g/day of metyrapone, 800
mg/day of ketoconazole and 3 g/day of mitotane. [37] These doses were adjusted
based on the clinical severity, urine-free cortisol excretion and tolerance. All
patients experienced a marked clinical improvement as well as a rapid decrease
in urine-free cortisol from 2737 at baseline to 50 g/24 h (normal range: 1065
g/24 h; p < 0.001) within 2448 h of treatment. [34] After 3.5 months, seven
patients remained on mitotane alone with control of urine-free cortisol. The most
common side effects were nausea and vomiting occurring in 63% of the patients
although this did not require drug discontinuation and was manageable with
antiemetics. Hypercholesterolemia, hypokalemia and elevated LFTs were also
observed. [34]
Following Boscaro et al. pilot study of pasireotide, [48] Feelders et al. evaluated the
usefulness of stepwise combination therapy with pasireotide, cabergoline and
ketoconazole hypothesizing a synergistic effect. [60] This prospective, open-label
multicenter trial enrolled 17 patients with Cushing's disease in an 80 day trial. The
primary outcome was normalization of urine-free cortisol levels. [60] All patients
were started on pasireotide 100 g three-times daily. This dose was increased to
250 g three-times daily at day 15 if urine-free cortisol was not normalized.
Cabergoline, 0.5 mg every other day, was added on day 28 if urine-free cortisol
had not normalized on pasireotide alone. This dose was increased to 1.0 mg
every other day after 5 days and 1.5 mg every other day after 10 days if urinefree cortisol was not normalized. Ketoconazole, 200 mg three-times daily, was
then added on day 60 if urine-free cortisol had not normalized on the combination
of pasireotide and cabergoline therapy. [60] Pasireotide alone induced remission in
29% of patients, the addition of cabergoline induced remission in an additional
24% and adding ketoconazole induced remission in an additional 35% of
patients. [60] Clinical features of Cushing's syndrome also improved. The most
significant adverse event was hyperglycemia with HbA1c increasing from 5.8
0.2 to 6.7 0.3% (p < 0.01). [60]
Expert Commentary
The management of Cushing's syndrome continues to be challenging. Primary
treatment is surgery for the majority of patients with both ACTH-dependent and
ACTH-independent causes of Cushing's syndrome, but a substantial proportion
of patients with Cushing's disease, adrenocortical carcinoma and the ectopic
ACTH syndrome will have residual or recurrent hypercortisolemia.
Pharmacological treatment continues to be an important adjunctive therapy in
these patients. Although mitotane remains the treatment of choice in patients with
adrenocortical carcinoma due to its cytotoxic effects, in most cases of Cushing's
syndrome with residual hypercortisolemia, ketoconazole has been used as firstline medical therapy. Ketoconazole is inexpensive, often effective and generally
well-tolerated, although LFT abnormalities and male hypogonadism can be
problematic. Metyrapone has typically been used in combination with
ketoconazole or in patients who cannot tolerate ketoconazole. In addition to the
above strategies, pasireotide (available in the EU and recently approved by the
FDA in the USA) and cabergoline can be used as tumor-directed therapy in
patients with Cushing's disease. Etomidate is rarely used due to its limitations.
While combination therapy remains common and has the potential advantage of
improved efficacy with reduced side effects, it is important to keep in mind that
knowledge of combination therapy comes largely from case reports and small
open-label studies.
Five-year View
The recent approval of mifepristone in the US represents an exciting
development in the management of residual or recurrent hypercortisolemia in
patients with Cushing's syndrome. On the other hand, mifepristone is very
expensive and monitoring of therapy is difficult due to the lack of biochemical
markers of treatment efficacy. Furthermore, most physicians presently lack
experience with its use. Because of this, mifepristone will likely be used as
second- or third-line medical therapy, alone or in combination with other agents.
Pasireotide, recently approved in the EU and in the USA, could represent an
attractive tumor-directed medical therapy, although the increased incidence of
hyperglycemia seen with this agent is potentially problematic.
Sidebar
Key Issues
45.Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C. Nelson's
syndrome: complete remission with cabergoline but not with bromocriptine
or cyproheptadine treatment. Horm. Res. 62(6), 300305(2004).
46.de Herder WW, Lamberts SW. Is there a role for somatostatin and its
analogs in Cushing's syndrome? Metab. Clin. Exp. 45(8 Suppl. 1), 83
85(1996).
47.Batista DL, Zhang X, Gejman R et al. The effects of SOM230 on cell
proliferation and adrenocorticotropin secretion in human corticotroph
pituitary adenomas. J. Clin. Endocrinol. Metab. 91(11), 44824488(2006).
48.Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitary-dependent
Cushing's disease with the multireceptor ligand somatostatin analog
pasireotide (SOM230): a multicenter, Phase II trial. J. Clin. Endocrinol.
Metab. 94(1), 115122(2009).
** Evaluated the effectiveness of pasireotide in 39 patients in a Phase II,
open-label, single-arm multicenter study. Seventy six percent of the
patients had a reduction in urine-free cortisol with 17% of the patients
achieving normal urine-free cortisol.
49.Colao A, Petersenn S, Newell-Price J et al.; Pasireotide B2305 Study
Group. A 12-month Phase 3 study of pasireotide in Cushing's disease. N.
Engl. J. Med. 366(10), 914924(2012).
* Evaluated pasireotide in a double-blind, Phase III trial of 162 adults with
Cushing's syndrome treated with 600900 g of pasireotide administered
subcutaneously twice daily. Urine-free cortisol decreased by approximately
50% in both groups but 118 of the 162 patients had an adverse event
related to hyperglycemia.
50.Castillo V, Giacomini D, Pez-Pereda M et al. Retinoic acid as a novel
medical therapy for Cushing's disease in dogs.Endocrinology 147(9),
44384444(2006).
51.Pecori Giraldi F, Ambrogio AG, Andrioli M et al. Potential role for retinoic
acid in patients with Cushing's disease. J. Clin. Endocrinol. Metab. 97(10),
35773583(2012).
52.Johanssen S, Allolio B. Mifepristone (RU486) in Cushing's syndrome. Eur.
J. Endocrinol. 157, 561569(2007).
53.Nieman LK, Chrousos GP, Kellner C et al. Successful treatment of
Cushing's syndrome with the glucocorticoid antagonist RU 486. J. Clin.
Endocrinol. Metab. 61(3), 536540(1985).
54.Chrousos GP, Laue L, Nieman LK et al. Glucocorticoids and glucocorticoid
antagonists: lessons from RU 486. Kidney Int. Suppl. 26, S18S23(1988).
www.medscape.com
Mineralocorticoid Resistance
David S. Geller
Clin Endocrinol. 2005;62(5):513-520.
potassium channel. [26] Unlike patients with other forms of Bartter's syndrome, who
present with hypokalaemia and metabolic alkalosis, patients with this form of
Bartter's syndrome often present with a clinical picture similar to PHA1, with the
neonatal onset of salt wasting, hyperkalaemia and acidosis. However, the
hyperkalaemia and acidosis present at birth in patients with Bartter's syndrome
type 2 disappears with sodium resuscitation, and the more characteristic clinical
picture of Bartter's syndrome, including hypokalaemia and metabolic alkalosis,
becomes apparent. [27]The transient hyperkalaemia these patients experience at
birth suggests the crucial role of ROMK in aldosterone-dependent potassium
secretion at birth and suggests that other distal nephron aldosterone-dependent
potassium secretory channels develop postnatally.
In the kidney, ENaC is expressed in the distal nephron, localizing primarily to the
cortical collecting tubule's principal cell. Electrogenic sodium reabsorption via
ENaC into the principal cell results in a net negative charge in the tubular lumen,
creating a powerful charge stimulus for the distal nephron either to resorb a
negatively charged chloride ion via paracellular transport pathways or
alternatively to secrete a positively charged potassium or hydrogen ion into the
tubular lumen. The absence of a functional ENaC in PHA1 patients prevents
principal cell sodium reabsorption, resulting in salt wasting and, furthermore, an
inability of the distal nephron to appropriately secrete potassium and hydrogen
ions. Thus, the characteristic hyperkalaemia, metabolic acidosis, elevated renin
and aldosterone levels and salt wasting of PHA1 can all be explained on the
basis of the loss of function in the epithelial sodium channel. The remarkable
inability of arPHA1 patients to regulate potassium and hydrogen ion balance
highlights the crucial role of ENaC-mediated sodium reabsorption for electrolyte
homeostasis.
The severe phenotype of patients with arPHA1 comes perhaps as a bit of a
surprise, as primers on kidney function have long suggested a relatively minor
role of the collecting duct in the reclamation of the filtered sodium load.
Traditional estimates have suggested that two-thirds of filtered sodium is
reclaimed in the proximal tubule, a further 2025% is reabsorbed in the loop of
Henle, via the Na-K-2Cl cotransporter (NKCC2), 7% is reclaimed in the distal
convoluted tubule via the thiazide-sensitive cotransporter (TSC), and only 2% is
reabsorbed via ENaC in the collecting duct. It is thus somewhat surprising to note
that although patients who lack NKCC2 (Bartter's syndrome) [28] or TSC
(Gitelman's syndrome) [29] do indeed have reduced arterial blood pressure, the
primary clinical sequelae are more often caused by electrolyte disturbances
related to potassium, calcium and magnesium handling; these patients do not die
of salt wasting. [30] Similarly, mice deficient in NHE3, believed to be the principal
sodium transport pathway in the proximal tubule, have low blood pressure, but
again, their principal problems stem from altered electrolyte balance. [31,32] In
contrast to humans lacking these more proximal sodium transport systems,
humans lacking ENaC function have a catastrophic course, with frequent
neonatal death from volume depletion and hyperkalaemia. The severity of
disease in these individuals makes it clear that aldosterone-mediated sodium
transport through ENaC plays a much more important role in sodium and
adPHA1 is caused by mutations in MR. The identity and location of all published
mutations in the mineralocorticoid receptor causing arPHA1 are depicted. fr,
frameshift; spl, splice-site mutation; X, stop codon.
It is perhaps surprising that heterozygous loss-of-function mutations in the MR
result in a clinical phenotype, as one functional MR copy is still present and would
presumably make up for the missing allele. As the MR is known to function as a
dimer, we therefore wondered whether mutant MR peptides might be produced
by PHA1 patients that could interfere with the function of the wild-type allele,
either by forming an inactive heterodimer or perhaps by binding to and
inactivating necessary transcription factors. We answered this question by the
study of kindred PHA30, a large dominant French kindred that has been well
described in the literature. [17] We identified a disease-causing mutation in MR in
an individual in this kindred, a C
mediated decay, [40] and that it is therefore not expressed. It is thus clear that
haploinsufficiency of MR is sufficient to cause the adPHA1 phenotype.
The ability to assign affection status on the basis of genotype rather than
phenotype allowed us recently to perform genotypephenotype correlation
studies. We extended two large kindreds from a small village in the north-west of
Spain by recruiting all first-degree relatives of genotypically affected individuals.
Although not known to be related, these two kindreds share the same R537X
mutation. [36] In all, we studied 14 affected and 22 unaffected adult kindred
members. We found no difference among all indices of aldosterone function we
could measure the groups were clinically indistinguishable from each other in
terms of systolic blood pressure, diastolic blood pressure, serum sodium, serum
potassium, fractional excretion of sodium, and trans-tubular potassium gradient.
The only significant difference between the two groups was in serum aldosterone
level. Adult family members with PHA1 had serum aldosterone levels
approximately 15-fold higher than their unaffected brethren, indicating that they
were able to maintain salt homeostasis by markedly up-regulating aldosterone
synthesis (Geller et al. , manuscript in preparation).
Pregnancy and infancy are two periods of intrinsic aldosterone resistance, and so
we were curious to determine whether patients with PHA1 would be at risk during
these two phases of life. Although we noted a number of spontaneous
miscarriages in pregnant women with adPHA1, the incidence of miscarriage did
not differ from that in the general population, and so we cannot assert that PHA1
played a role in antepartum difficulties. On the other hand, we identified four
deaths in neonates at risk for adPHA1, and others have noted this as
well. [41] Although genotypic data are not available on the deceased infants, the
high infant mortality rate coupled with the known importance of aldosterone in the
neonatal period makes it reasonable to wonder whether PHA1 may have played
a role in these infants' deaths, and we therefore recommend prophylactic salt
supplementation and early definitive diagnosis for infants known to be at risk for
adPHA1 (Geller et al. , manuscript in preparation).
The clinical severity of disease in adPHA1 patients early in life highlights the
essential role of aldosterone-sensitive sodium transport in the neonate and raises
the question as to the reasons underlying the apparently diminished requirement
for this system in later years. One possibility relates to the low sodium content of
human breast milk, [42,43] which may render neonates particularly sensitive to renal
salt wasting; this sensitivity lessens as the infant transitions to the high salt intake
characteristic in the industrialized world. This suggests a gene-by-environment
interaction, in that, on a low-sodium diet, humans are dependent on maximal
activation of the reninangiotensinaldosterone system, and MR
haploinsufficiency results in volume depletion and hyperkalaemia, but on a highsalt diet, adPHA1 is clinically silent. An alternate explanation for the improvement
in the adPHA1 phenotype after the neonatal years involves the development of
the renal tubule. Aldosterone-mediated sodium transport through ENaC in the
cortical collecting duct (CCD) is coupled to K + secretion via a potassium
secretory channel ROMK. ROMK is expressed postnatally, [44] potentially allowing
improved efficiency of the reninangiotensinaldosterone system, and possibly
References
1. Grundy, H.M., Simpson, S.A. & Tait, J.F. (1952) Isolation of a highly active
mineralocorticoid from beef adrenal extract. Nature, 169, 795796.
2. Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B.,
Bittman, R., Hurley, S., Kleiman, J. & Gatlin, M. (2003) Eplerenone, a
selective aldosterone blocker, in patients with left ventricular dysfunction
after myocardial infarction. New England Journal of Medicine, 348,
13091321.
3. Pitt, B., Zannad, F., Remme, W.J., Cody, R., Castaigne, A., Perez, A.,
Palensky, J. & Wittes, J. (1999) The effect of spironolactone on morbidity
and mortality in patients with severe heart failure. Randomized Aldactone
Evaluation Study Investigators. New England Journal of Medicine, 341,
709717.
4. Epstein, M. (2003) Aldosterone receptor blockade and the role of
eplerenone: evolving perspectives. Nephrology, Dialysis, Transplantation,
18, 19841992.
5. Rachmani, R., Slavachevsky, I., Amit, M., Levi, Z., Kedar, Y., Berla, M. &
Ravid, M. (2004) The effect of spironolactone, cilazapril and their
combination on albuminuria in patients with hypertension and diabetic
nephropathy is independent of blood pressure reduction: a randomized
controlled study. Diabetic Medicine, 21, 471475.
6. Sato, A., Hayashi, K., Naruse, M. & Saruta, T. (2003) Effectiveness of
aldosterone blockade in patients with diabetic nephropathy. Hypertension,
41, 6468.
27.Finer, G., Shalev, H., Birk, O.S., Galron, D., Jeck, N., Sinai-Treiman, L. &
Landau, D. (2003) Transient neonatal hyperkalemia in the antenatal
(ROMK defective) Bartter syndrome. Journal of Pediatrics, 142, 318323.
28.Simon, D.B., Karet, F.E., Hamdan, J.M., DiPietro, A., Sanjad, S.A. & Lifton,
R.P. (1996) Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria,
is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature
Genetics, 13, 183188.
29.Simon, D.B., Nelson-Williams, C., Bia, M.J., Ellison, D., Karet, F.E., Molina,
A.M., Vaara, I., Iwata, F., Cushner, H.M., Koolen, M., Gainza, F.J.,
Gitleman, H.J. & Lifton, R.P. (1996c) Gitelman's variant of Bartter's
syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the
thiazide-sensitive Na-Cl cotransporter. Nature Genetics, 12, 2430.
30.Cruz, D.N., Simon, D.B., Nelson-Williams, C., Farhi, A., Finberg, K.,
Burleson, L., Gill, J.R. & Lifton, R.P. (2001) Mutations in the Na-Cl
cotransporter reduce blood pressure in humans. Hypertension, 37,
14581464.
31.Ledoussal, C., Lorenz, J.N., Nieman, M.L., Soleimani, M., Schultheis, P.J.
& Shull, G.E. (2001) Renal salt wasting in mice lacking NHE3 Na+/H+
exchanger but not in mice lacking NHE2. American Journal of Physiology.
Renal Physiology, 281, F718F727.
32.Schultheis, P.J., Clarke, L.L., Meneton, P., Miller, M.L., Soleimani, M.,
Gawenis, L.R., Riddle, T.M., Duffy, J.J., Doetschman, T., Wang, T.,
Giebisch, G., Aronson, P.S., Lorenz, J.N. & Shull, G.E. (1998) Renal and
intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger.
Nature Genetics, 19, 282285.
33.Lorenz, J.N., Schultheis, P.J., Traynor, T., Shull, G.E. & Schnermann, J.
(1999) Micropuncture analysis of single-nephron function in NHE3deficient mice. American Journal of Physiology, 277, F447F453.
34.Frindt, G. & Palmer, L.G. (2004) Na channels in the rat connecting tubule.
American Journal of Physiology. Renal Physiology, 286, F669F674.
35.Rubera, I., Loffing, J., Palmer, L.G., Frindt, G., Fowler-Jaeger, N., Sauter,
D., Carroll, T., McMahon, A., Hummler, E. & Rossier, B.C. (2003) Collecting
duct-specific gene inactivation of alphaENaC in the mouse kidney does not
impair sodium and potassium balance. Journal of Clinical Investigation,
112, 554565.
36.Geller, D.S., Rodriguez-Soriano, J., Vallo Boado, A., Schifter, S., Bayer, M.,
Chang, S.S. & Lifton, R.P. (1998) Mutations in the mineralocorticoid
receptor gene cause autosomal dominant pseudohypoaldosteronism type
I. Nature Genetics, 19, 279281.
37.Huey, C.L., Riepe, F.G., Sippell, W.G. & , A.S. (2004) Genetic
heterogeneity in autosomal dominant pseudohypoaldosteronism type I:
exclusion of claudin-8 as a candidate gene. American Journal of
Nephrology, 24, 483487.
38.Viemann, M., Peter, M., Lopez-Siguero, J.P., Simic-Schleicher, G. &
Sippell, W.G. (2001) Evidence for genetic heterogeneity of
pseudohypoaldosteronism type 1: identification of a novel mutation in the
human mineralocorticoid receptor in one sporadic case and no mutations
in two autosomal dominant kindreds. Journal of Clinical Endocrinology and
Metabolism, 86, 20562059.
39.Sartorato, P., Khaldi, Y., Lapeyraque, A.L., Armanini, D., Kuhnle, U.,
Salomon, R., Caprio, M., Viengchareun, S., Lombes, M. & Zennaro, M.C.
(2004) Inactivating mutations of the mineralocorticoid receptor in type I
pseudohypoaldosteronism. Molecular and Cellular Endocrinology, 217,
119125.
40.Hentze, M.W. & Kulozik, A.E. (1999) A perfect message: RNA surveillance
and nonsense-mediated decay. Cell, 96, 307310.
41.Tajima, T., Kitagawa, H., Yokoya, S., Tachibana, K., Adachi, M., Nakae, J.,
Suwa, S., Katoh, S. & Fujieda, K. (2000) A novel missense mutation of
mineralocorticoid receptor gene in one Japanese family with a renal form
of pseudohypoaldosteronism type 1. Journal of Clinical Endocrinology and
Metabolism, 85, 46904694.
42.Morton, J.A. (1994) The clinical usefulness of breast milk sodium in the
assessment of lactogenesis. Pediatrics, 93, 802806.
43.Neville, M.C., Keller, R., Seacat, J., Lutes, V., Neifert, M., Casey, C., Allen,
J. & Archer, P. (1988) Studies in human lactation: milk volumes in lactating
women during the onset of lactation and full lactation. American Journal of
Clinical Nutrition, 48, 13751386.
44.Benchimol, C., Zavilowitz, B. & Satlin, L.M. (2000) Developmental
expression of ROMK mRNA in rabbit cortical collecting duct. Pediatrics
Research, 47, 4652.
45.Disse-Nicodeme, S., Achard, J.M., Desitter, I., Houot, A.M., Fournier, A.,
Corvol, P. & Jeunemaitre, X. (2000) A new locus on chromosome 12p13.3
for pseudohypoaldosteronism type II, an autosomal dominant form of
hypertension. American Journal of Human Genetics, 67, 302310.
46.Wilson, F.H., Disse-Nicodeme, S., Choate, K.A., Ishikawa, K., NelsonWilliams, C., Desitter, I., Gunel, M., Milford, D.V., Lipkin, G.W., Achard,
J.M., Feely, M.P., Dussol, B., Berland, Y., Unwin, R.J., Mayan, H., Simon,
D.B., Farfel, Z., Jeunemaitre, X. & Lifton, R.P. (2001) Human hypertension
caused by mutations in WNK kinases. Science, 293, 11071112.
47.Wilson, F.H., Kahle, K.T., Sabath, E., Lalioti, M.D., Rapson, A.K., Hoover,
R.S., Hebert, S.C., Gamba, G. & Lifton, R.P. (2003) Molecular
pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl
cotransporter is inhibited by wild-type but not mutant WNK4. Proceedings
of the National Academy of Sciences of the United States of America, 100,
680684.
48.Yang, C.L., Angell, J., Mitchell, R. & Ellison, D.H. (2003) WNK kinases
regulate thiazide-sensitive Na-Cl cotransport. Journal of Clinical
Investigation, 111, 10391045.
49.Kahle, K.T., Wilson, F.H., Leng, Q., Lalioti, M.D., O'Connell, A.D., Dong, K.,
Rapson, A.K., MacGregor, G.G., Giebisch, G., Hebert, S.C. & Lifton, R.P.
(2003) WNK4 regulates the balance between renal NaCl reabsorption and
K+ secretion. Nature Genetics, 35, 372376.
50.Pearce, D. (2003) SGK1 regulation of epithelial sodium transport. Cellular
Physiology and Biochemistry, 13, 1320.
51.Wulff, P., Vallon, V., Huang, D.Y., Volkl, H., Yu, F., Richter, K., Jansen, M.,
Schlunz, M., Klingel, K., Loffing, J., Kauselmann, G., Bosl, M.R., Lang, F. &
Kuhl, D. (2002) Impaired renal Na(+) retention in the sgk1-knockout
mouse. Journal of Clinical Investigation, 110, 12631268.
52.Kuhnle, U., Guariso, G., Sonega, M., Hinkel, G.K., Hubl, W. & Armanini, D.
(1993) Transient pseudohypoaldosteronism in obstructive renal disease
with transient reduction of lymphocytic aldosterone receptors. Results in
two affected infants. Hormone Research, 39, 152155.
53.Schoen, E.J., Bhatia, S., Ray, G.T., Clapp, W. & To, T.T. (2002) Transient
pseudohypoaldosteronism with hyponatremiahyperkalemia in infant urinary
tract infection. Journal of Urology, 167, 680682.
54.Bantle, J.P., Nath, K.A., Sutherland, D.E., Najarian, J.S. & Ferris, T.F.
(1985) Effects of cyclosporine on the reninangiotensinaldosterone system
and potassium excretion in renal transplant recipients. Archives of Internal
Medicine, 145, 505508.
55.Kamel, K.S., Ethier, J.H., Quaggin, S., Levin, A., Albert, S., Carlisle, E.J. &
Halperin, M.L. (1992) Studies to determine the basis for hyperkalemia in
recipients of a renal transplant who are treated with cyclosporine. Journal
of the American Society of Nephrology, 2, 12791284.
56.Deppe, C.E., Heering, P.J., Viengchareun, S., Grabensee, B., Farman, N.
& Lombes, M. (2002) Cyclosporine A and FK506 inhibit transcriptional
activity of the human mineralocorticoid receptor: a cell-based model to
investigate partial aldosterone resistance in kidney transplantation.
Endocrinology, 143, 19321941.
www.medscape.com
Abstract
Background
The aim was to survey current practice in glucocorticoid replacement therapy and
self-perceived health outcomes in patients with adrenal insufficiency.
Methods
Participants were recruited via patient organizations to respond anonymously to a
web-based survey developed by clinical experts. Unique entries were set up for
each patient organization enabling geographical localization of the entries.
Results
1245 participants responded (primary adrenal insufficiency: 84%; secondary
adrenal insufficiency: 11%; unsure: 5%). Therapies included hydrocortisone
(75%), prednisone/prednisolone (11%), cortisone acetate (6%) and
dexamethasone (4%). Dosing regimens were once daily (10%), twice daily
(42%), thrice daily (32%) or other (17%). Compromised subjective health
necessitating changes to physical activity or social-, work- or family life was
reported by 64% of the participants. 40% of the participants reported absence
from work/school in the last 3 months. Irrespective of diagnosis, 76% were
concerned about long-term side-effects of therapy, mainly osteoporosis (78%),
obesity (64%) and cardiovascular morbidity (46%). 38% of the participants had
been hospitalized in the last year.
Conclusions
Glucocorticoid replacement therapy among the respondents consisted primarily
of hydrocortisone administered twice or thrice daily. A majority reported impact of
their disease or treatment on subjective health requiring alterations in e.g.
physical activity or family life. Three quarters reported concerns about long-term
side-effects of the treatment. These data demonstrate from the patients'
perspective a need for improvement in the management of adrenal
insufficiency.
Background
In the two largest registry-based studies on mortality in patients with Addison's
disease, the relative risk of death was more than 2-fold compared to the
Methods
This was an open cross-sectional survey. Participants were recruited via patient
organizations (e-mail contact lists and newsletters) to respond anonymously to
the web-based survey. The following patient organizations actively approached
their members to participate in the survey and had links to the survey on their
home page: National Adrenal Diseases Foundation (NADF) in the US, Australian
Addisons Disease Foundation, Addisons Disease Self Help Group (ADSHG) in
the UK and Cushings Support and Research Foundation (CSRF) in the US.
Some additional patient organizations also had information about and/or links to
the survey on their respective websites: CARES foundation in the US,
Association Surrnales in France, two Swedish associations (The Swedish
Addison Association and Hypofysis), two Danish associations (Addisonforeningen
in Denmark and Danish Morbus Addison Site), the Dutch Addison & Cushing
Society (NVACP) and Associazioni Italiana Pazienti Addison in Italy. A link was
also set up on the sponsors website for other patients wanting to complete the
survey.
Results
A total of 1281 persons visited the webpage of the survey whereof 1245
responded to at least the first question (In which country do you live?). The
respondents were from (by number of participants): US (801), Australia (90),
France (81), UK (80), Canada (37), Sweden (35), Denmark (19), the Netherlands
(8), Germany (7), Belgium (6), New Zealand (5), Mexico (4), Ecuador (3), Ireland
(3), Spain (3), Chile (2), Dominican Republic (2), India (2), Norway (2),
Philippines (2), Poland (2), South Africa (2), Switzerland (2), Argentina (1), Dubai
(1), Greece (1), Hungary (1), Israel (1), Italy (1), Jamaica (1), Martinique (1),
Portugal (1), Serbia (1) and Uruguay (1).
When asked What type of cortisol deficiency are you suffering from?, 939
participants (84%) defined their AI as primary (Addisons disease, congenital
adrenal hyperplasia, adrenal disease causing dysfunction of adrenal glands or
removed glands) and 125 (11%) as secondary (pituitary or hypothalamic disease)
while 51 (5%) were unsure.
Glucocorticoid Treatment Regimen
One quarter (23%) of the participants were dissatisfied or very dissatisfied with
their current treatment, 18% were indifferent and 59% were satisfied or very
satisfied. Patients with secondary AI reported less satisfaction with their current
therapy than patients with primary AI. The ratings of satisfaction were similar
among the different therapies.
Multiple daily dosing was reported as a problem by 38% of the participants
whereof 15% were on OD, 35% on BID, 32% on TID and 17% on another
regimen. Of those who did not find multiple daily dosing to be a problem 7% were
on OD, 45% on BID, 32% on TID and 16% on another regimen. Among
respondents answering that multiple daily dosing was a problem 94% reported
one or more of the following: difficulties to remember/forgetting doses (particularly
the midday and afternoon doses), difficulties in taking the medication at a specific
time every day and/or difficulties to remember to bring the medication. Many
reported that their days are planned according to their dose intake and for those
who lead a busy life and are working, this was found to be challenging as some
also reported that they do not want to be seen by their colleagues when taking
their medication. Several reported that multiple daily dosing becomes very
restrictive to an active life and that multiple daily dosing is a reminder several
times per day that they have this disease. Many also reported health issues such
as being fatigue and exhausted in the day, evening and the following day(s) if
missing a dose. In addition, many reported that taking a missed dose too late
disrupts their sleep and causes issues with insomnia. Some reported instability of
physical and mental well-being with mood swings and ups and downs in energy
levels. The patients who reported multiple daily dosing to be a problem also
reported higher frequencies of impacted QoL, more fatigue and more activities
altered due to their disease (data not shown).
Enduring efficacy over 24 hours was considered the most important feature of an
optimal replacement medication (29%) followed by few side effects (25%) and
low risk of adrenal crisis (22%). Similar responses were obtained from patients
with primary and secondary AI.
Health-Related Questions and Hospitalizations
A majority of the patients (648 of 1026 [64%]) reported impacted quality of life
(QoL) due to their illness, 87% (99 of 114) of patients with secondary AI and 60%
(515 of 857) of the patients with primary AI. Approximately three quarters (73 of
99 [74%]) of the patients with secondary AI graded the impact on QoL as quite a
lot or very much, . The proportion of patients who reported impaired QoL varied
with dosing regimen (OD > BID > TID). However, the level of impairment did not
differ between the dosing regimens. A lower proportion of patients treated with
hydrocortisone reported impaired QoL compared with patients receiving cortisone
acetate or prednisone/prednisolone but the level of impairment did not differ
between the therapies (data not country-adjusted).
Table 3. Impact of adrenal insufficiency on quality of life (QoL) captured in an
international survey
All patients were asked What activities do you need to alter due to your AI?,
regardless of whether they had answered that their QoL was impaired or not. A
large percentage of the participants reported that they had had to alter their
physical activity (56%), social life (40%), work life (39%) or family life (31%) due
to their illness (the participants were allowed to choose more than one
alternative). A higher proportion of patients with secondary AI (90%) than with
primary AI (68%) reported that they had had to alter work life, social life, physical
activity or family life, Figure 1.
Figure 1.
Change in activities due to adrenal insufficiency. Responses to the question
What activities do you need to alter due to your adrenal insufficiency? in an
international patient survey. A total of 1001 subjects responded to this question.
A majority of the participants reported fatigue in the morning (57%) and during the
day (65%) to be a problem. Fatigue was more pronounced in patients with
secondary AI than in patients with primary AI, . Of those reporting morning fatigue
to be a problem, 75% also reported fatigue during the day to be a problem.
Similarly, of those reporting fatigue during the day to be a problem, 85% also
reported morning fatigue to be a problem.
Ads not by this site
Table 4. Fatigue in the morning and during the day reported by patients with
adrenal insufficiency in an international patient survey
In this survey, 61% of the respondents considered themselves fit to work while
17% did not. Additionally 5% of the respondents both considered themselves unfit
to work and were on sick leave, 10% were retired and 7% were unemployed. Of
those considering themselves fit to work, 72% considered themselves fit to work
full-time, while 18% could work 75%, 9% could work 50% and 1% could work <
50%. Overall, 40% of the participants had been absent from work in the last 3
months and, again, this was more common among patients suffering from
secondary AI (50%) than for patients with primary AI (38%). Almost one third
(28%) of those being away from work or school reported more than 3 weeks
absence in the 3 months preceding their participation in the survey, . A higher
percentage of patients treated with prednisone/prednisolone reported
absenteeism compared with patients on hydrocortisone and they also reported
more lengthy absenteeism (data not shown).
Table 5. Absenteeism from work or school due to adrenal insufficiency in the
last 3 months reported in an international patient survey
A majority of the participants were worried about long-term side effects. The
participants were most worried about osteoporosis (79%), followed by obesity
(64%), fatigue (52%) and cardiovascular problems (46%) (more than one
alternative could be chosen), . A higher proportion of those treated with
prednisone/prednisolone were worried about long-term side effects than those
treated with hydrocortisone (data not shown).
Table 6. Worries about long-term effects reported by patients with adrenal
insufficiency in an international patient survey
Overall, 32% of the participants reported that they increased their dose due to
physical activity at least once per week (primary AI patients: 30%; secondary AI
patients: 49%) and 66% increased their dose due to illness at least once per
month (primary AI patients: 65%; secondary AI patients: 76%).
Overall, 38% of the participants responding to the question about hospitalizations
(N=977) answered that they had been hospitalized at least once during the last
12 months (37% of patients with primary AI and 43% of patients with secondary
AI). One third of the patients (32%) had been hospitalized more than once during
the last 12 months. The reported reason for hospitalization was adrenal crisis,
vomiting or an acute infection for 17% of the patients who had been hospitalized.
Discussion
The conduct of this survey was similar to previous cross-sectional surveys with
participants recruited via patient organizations. [5,11,12] The current survey of 1245
respondents is to our knowledge the largest patient survey to date in patients with
AI. Previous studies have shown that outcomes in patients with AI are
compromised. [12-14] The responses from this survey provide more information on
the impact of the disease and its treatment on patient-perceived outcomes, and
support previous data showing a large impact of the disease and its treatment on
the daily life of these patients.
Therapy traditions differ to some extent between countries but hydrocortisone
was the most commonly used therapy in this survey (75%), irrespectively of
country, which is also in line with previous studies from Europe. [4,20] The
distribution of therapies, i.e. type of glucocorticoid, was similar between patients
with primary and secondary AI. Three quarters of the patients were on a BID or
TID regimen. One unexpected observation in this survey was the high
percentage (58%) of patients on prednisone/prednisolone who were on a BID or
TID regimen.
That multiple daily dosing is a problem from a compliance point of view is well
known from other therapies. [21] The free-text answers to the open questions of
this survey confirmed that multiple daily dosing is not optimal in AI and has an
impact on patients social life and work life. More specifically, 4 of 10 patients in
this survey found multiple daily dosing to be a problem. The impact on leading a
normal life was attributed both to multiple dosing and to fluctuations in
mental/physical energy over the day as multiple daily dosing with
hydrocortisone/cortisone acetate causes peaks and low trough values in-between
dosing occasions. When asked about the most important features of an optimal
replacement medication, the patients ranked efficacy over 24 hours first and few
side effects second. More patients on TID were satisfied with their treatment
compared to those on BID or OD treatment. This might be attributable to the
better cortisol coverage of TID during the active part of the day [22,23]over the
convenience of fewer dosing times.
The results from this survey are in line with a recently published clinical
study [24] which showed that a majority of the patients preferred the four-daily
dosing regimen to twice daily when comparing equal doses of hydrocortisone
given either twice daily or four times daily. The reasons reported were less
fatigue, more alertness during the day, less headache and a feeling that the
treatment effect was less varying during the day. The patients had complaints
after the study that a four-dose regimen may be difficult to manage in the long
run. [24] Another study has shown that a thrice-daily administration with weightadjusted doses provides a better PK profile within the constraints of immediaterelease hydrocortisone formulations. [25] 85% of the patients opted to remain on
the TID regimen given in that study. These data suggest that patients experience
benefits of having increased cortisol coverage during the active part of the day.
One caveat of the above studies is that the total exposure of cortisol is higher
when the same daily dose of hydrocortisone is administered divided into three or
four daily doses than at BID administration. This is due to the fact that increasing
the dose of hydrocortisone at one dose occasion does not result in a proportional
increase in total exposure of cortisol due to the non-linear bioavailability of orally
administered hydrocortisone. [26]Thus, there might be a short-term perceived
benefit of the increased cortisol exposure whereas the long-term risk may
increase.
It is difficult to mimic physiological cortisol profiles with immediate release
hydrocortisone replacement therapies. [22,25]Therefore, attempts to better mimic the
normal cortisol profiles have been made by developing new treatment regimens
using the concept of chronotherapy, i.e. considering circadian rhythms in
determining the timing and amount of the medication to optimize the desired
effects and minimize the undesired ones. [17,27] A once-daily treatment with dual
action, combining immediate release and extended release hydrocortisone has
shown benefit over immediate release hydrocortisone with the same daily dosing
administered thrice daily in patients with adrenal insufficiency. [28]
Two thirds of the participants reported impacted QoL from their illness. In line with
this being a patient survey (capturing the patients general perception of their
subjective health at only one time point) and not a clinical trial, the questionnaire
used in this survey did not include validated QoL questions from specific QoL
questionnaires. Instead, the included questions were focused on the patients
general perception of how and to what degree their disease and/or treatment
affected their QoL. This survey showed that patients with secondary AI perceived
their QoL as more impaired than patients with primary AI, which is in agreement
with a previous study using validated QoL questionnaires showing that patients
with AI have compromised QoL and that the impairment of QoL is worse in
patients with secondary AI. [14] The current survey did not collect data on comorbidities. Patients with secondary adrenal insufficiency may have other
hormone deficiencies which could impact on QoL. However, data from previous
studies are inconsistent and while some impact was observed in a Norwegian
study of patients with Addisons disease, [13] another study [14] showed that the
impairment in health-related subjective health status in AI patients is largely
independent of concomitant diseases.
More than half of the AI patients needed to alter their physical activity and many
needed to change their social life, work life or family life due to their illness. The
level of impact on social life is in line with data from another international survey,
conducted in 2003, in which one-third reported that their condition impacted on
their ability to participate in social activities. [29] A Dutch patient survey reports
similar impact on lifestyle. [5] Detailed questions on fatigue were included in the
current survey as fatigue is the most commonly reported subjective health-related
problem in AI. [5,11-13,29,30] This survey showed that 57% of the participants
experienced fatigue in the morning as a problem and 65% reported fatigue during
the day to be a problem. This response is in some contrast to the general
perception that morning fatigue is a much larger clinical problem than fatigue
during the day in patients with AI who have low or undetectable serum morning
cortisol levels when using hydrocortisone BID or TID. Fatigue was more common
in secondary AI than in primary AI and often necessitated changes in daily
activities or changes in dose or the timing of dosing.
The current survey demonstrated a high absenteeism from work or school. More
specifically, 4 of 10 patients reported absenteeism from work or school due to AI
in the last 3 months and one third of those reported more than 3 weeks absence.
Furthermore, 17% of the participants did not consider themselves to be fit to
work. Among those who considered themselves fit to work, 28% worked part-time
instead of full-time. These data are similar to those of a survey conducted across
the UK, Canada, Australia and New Zealand (n=850), [29] in which over 10% of the
respondents reported that they were unable to work compared with 1% in the
matched control group. Moreover, in the study by Hahner et al., [14] 18% of the AI
patients (primary and secondary) did not work vs. 4% in the general population.
In a Norwegian study, working disability amounted to 26% among patients with
primary AI vs. 10% in the general population. [13]
Patients with AI are educated to increase their glucocorticoid dose in stressful
situations and in association with other illnesses. This survey showed that 6075% of the patients increased their replacement dose due to illness every month.
The high rate of hospitalizations in this survey (38% of the patients had been
hospitalized at least once in the last year) is in line with the Dutch survey in which
3 of 10 patients had been hospitalized. [5] The reported reason for hospitalization
was adrenal crisis, vomiting or an acute infection in 17% of the patients. As a
comparison, the incidence rate of adrenal crises was 6.3 per 100 patient years in
a study by Hahner et al. [31] The reason for this discrepancy is most likely the
differences in methods of collecting data and that the definition of adrenal crisis is
not the same, e.g. only cases of hospitalization necessitating i.v. glucocorticoid
administration were counted as adrenal crises in the study by Hahner.
Because of the relatively small disease population, age and gender were not
included in the questionnaire in order to protect personal integrity and anonymity.
Internet use and behaviours linked to it are hypothetical confounding factors in
the interpretation of the survey results. Patients who seek information about their
disease usually tend to be more active than other patients, which can also affect
the results. Despite the fact that congenital adrenal hyperplasia (CAH) constitutes
one form of primary AI, it would have been interesting to analyse data on this
patient group separately as recent data published by Arlt et al. (2010) showed
significantly impaired health status and adverse metabolic and skeletal health in
adult CAH patients,[32] however, data were not separately collected for patients
with CAH in this survey.
Conclusions
This international survey showed that the glucocorticoid replacement regimens in
AI differ to some degree between countries. Three quarters of the AI patients
participating in the survey received hydrocortisone administered two or three
times daily. A large majority of the participants reported that their disease and the
current treatment have an impact on QoL leading to alterations in physical
activity, social life, work life and family life. Furthermore, 76% of the participants
reported concerns of long-term side-effects of their treatment. These data
demonstrate from the AI patients' perspective an obvious need for
improvement in the management of AI including the regimen of glucocorticoid
replacement therapy.
References
32.Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS,
Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM,
Ross RJ: United Kingdom Congenital Adrenal Hyperplasia Adult Study
Executive (CaHASE): Health status of adults with congenital adrenal
hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab2010,
95:5110-5121.
Acknowledgments
We thank the participants in the survey and the patient organizations supporting
their members to participate and share their experience. We also thank Karin
Gewert, Writewise, who provided medical writing services on behalf of DuoCort
Pharma.
Competing Interests
This survey was funded by DuoCort Pharma. MF works for DuoCort Pharma AB.
GB, SS and GJ have equity interests in DuoCort AB.
Authors Contributions
All authors contributed to the design of the survey and writing/review of the
manuscript. All authors read and approved the final manuscript.
BMC Endocr Disord. 2012;12(8) 2012 BioMed Central, Ltd.
Ads not by this site
Ads not by this site