In 1849, Thomas Addison identified adrenal insufficiency (AI) and named it Addison’s disease (AD). He termed it a “remarkable form of anemia” and attributed it to dysfunctions of the “supra-renal capsules.”1 Each of these human adrenal glands is located on top of one of the kidneys, and can release four types of hormones in response to physiological stimuli: glucocorticoids (e.g., cortisol) that control inflammation; mineralocorticoids that regulate kidney and cardiovascular functions; catecholamines (e.g., adrenaline, noradrenaline, and dopamine) that regulate heart rate, blood pressure, and other functions; and adrenal androgens (e.g., dehydroepiandrosterone [DHEA]) that are precursors to testosterone and estrogen.2
The adrenal glands commonly are studied in the context of the hypothalamic-pituitary-adrenal axis because these glands collectively produce hormones that affect each other and regulate a variety of physiological processes: For example, the hypothalamus signals the pituitary to release adrenocorticotropic hormone (ACTH), which in turn affects the production and secretion of hormones from the adrenal cortex. Furthermore, increased cortisol levels from the adrenal glands can signal the pituitary to reduce ACTH production, which in turn reduces the production of cortisol.2,3 Cushing’s syndrome (CS) is caused by excess cortisol and may follow over-administration of prednisone, dexamethasone, or prednisolone.4 Cushing’s disease (CD) is a form of CS that causes overproduction of ACTH.5
Three types of AI are generally recognized: primary, secondary, and tertiary; Table 1 lists common characteristics of AI.
Greater than 90% loss of adrenal tissue;
Increased ACTH production;
Lifetime therapy required.
Autoimmune in 70-90% of US cases;
Infection (e.g., present in 30% of advanced HIV cases);
Acute Addisonian crisis following infection, stress, hemorrhage, or shock.
Loss of glucocorticoid function;
Intact mineralocorticoid function;
Decreased or absent ACTH;
Pituitary depression or dysfunction;
Tumor or postpartum complication.
|Tertiary||Caused by hypothalamic or pituitary depression or absence.||
Iatrogenic corticosteroid therapy with suppression of the hypothalamic-pituitary-adrenal axis;
Hypothalamic failure or dysfunction.
Abbreviations: ACTH, adrenocorticotropic hormone; HIV, human immunodeficiency virus; US, United States; AD Addison’s disease
Source: Betterle et al. 20116 and NIDDK, 20142
In 2002, researchers reported the prevalence of primary AI as 40-100 cases/million and the incidence as 6 cases/million/year.2,6 Recent data from Europe indicate that the prevalence of chronic primary AI rose from 47-70 cases/million in the 1960s to 93-144 cases/million by the end of the past century, and the current estimated incidence is 4.4-6.0 new cases/million/year.7 The European data also suggest that genetic causes of primary AI are more common among children than in the adult population. In one group of children with primary AI, autoimmune disease appeared in only 13% of cases, but congenital adrenal hyperplasia and other genetic causes accounted for 78% of cases.7
Many studies of the burdens associated with adrenal insufficiencies have focused on patients’ quality of life (QOL) (Table 2), but few reports estimated direct costs.
|Norway, N=79 AD patients||Patient with AI had impaired general health, vitality, social functioning, and emotional states.||Lovas et al. 20028|
|Denmark, N=989 AI (primary or secondary) patients, N= 124,854 osteoarthritis patients||Patient with AI had a 2.68 times greater rate of readmission for affective disorder and 2.12 greater rate of readmission for depressive disorder compared to those with osteoarthritis.||Thomsen et al. 20069|
|Germany, N=256 AI patients||Patient with AI had impairment of subjective health status and greater depression; 18.3% were unemployed compared to 4.1% in the general population||Hahner et al., 200710|
|Germany, N=216 primary or secondary AI patients||< 30% of women and < 50% of men were diagnosed within the first 6 months of symptom onset; > 67% consulted ≥ 3 physicians, and 68% were incorrectly diagnosed.||Bleicken et al. 201011|
|International, N= 1,245 primary or secondary AI patients (5% were unsure of diagnosis)||64% reported making changes to physical activity or social, work, or family life because of subjective health concerns; 40% missed school or work; 76% were concerned about long-term side effects of therapy.||Forss et al. 201212|
|Netherlands, N=54 primary AI patients, N=54 matched controls||Maladaptive personality traits were positively associated with hydrocortisone dose, as were depression and impaired QOL.||Tiemensma et al. 201413|
|A systematic literature search identifying 102 papers about QOL in pituitary adenoma patients||Surgical and pharmacological interventions improved but did not normalize QOL; psychosocial interventions possibly helped. Greater focus on QOL, better questionnaires, and more follow-up may lead to improvements.||Andela et al. 201514|
Abbreviations: AI, adrenal insufficiencies; QOL, quality of life; N=number; AD, Addison’s disease
A United Kingdom (UK) study15 calculated the direct and indirect cost of illness associated with AI over a 1-year period. AI patients do not produce cortisol and require glucocorticoid replacement therapy to survive, which is predominantly immediate-release hydrocortisone in the UK. With current therapy, AI patients have increased morbidity, premature mortality, and reduced QOL. Costs include the cost of glucocorticoid replacement therapy, primary and secondary care costs (general practitioner and outpatient appointments, admissions for adrenal crises, diagnosis and management of AI), and costs associated with reduced productivity (absenteeism). The costs associated with premature mortality, the treatment and management of co-morbidities, and the burden associated with reduced QOL were not included due to lack of data.
There are ~20,000 AI patients in the UK. The estimated cost of illness (in 2016 dollars) associated with AI is ~$4,768 per patient or ~$95 million over 1 year: replacement therapy, ~$52 million; general practitioner appointments, ~$4.3 million; secondary care, ~$10.6 million; and reduced productivity, ~$28 million.15
The high health care and social costs associated with AI highlight the clinical and economic need to improve glucocorticoid replacement therapy. Indeed, as some consequences of the disease were not included in the calculations, ~$95 million is likely a considerable underestimate of the true burden of disease.15
Researchers in New Zealand and Ireland reported that follow-up of incidentally detected adrenal masses identified few (< 1% of patients) functional carcinomas, and during follow-up, the false positive rates for identifying adrenal carcinomas typically were 50 times greater than true positive rates.16 Both the direct costs of treatment—including radiation exposure—and the indirect emotional costs to patients warrant a review of current guidelines.
CD is a rare disorder resulting from ACTH-secreting pituitary tumors, in commercially insured patients in the United States (US).
A cost of illness study identified patients with CD in 2010 using the IMS Health PharMetrics and Truven Health Analytics MarketScan claims databases.17 Because there is no diagnosis code for CD, patients were identified as having CD if they had a claim for CS plus either benign pituitary adenoma or hypophysectomy.
The study identified 685 CD patients (81% female; mean age, 41.7 years; mean Charlson comorbidity index, 1.6; mean number of chronic conditions, 4.2). Patients had a mean of 3.2 CD-related office visits per year, 26.9% had CD-related hospitalizations, 0.9% had CD-related emergency department visits, and 36.8% had CD treatments. Annual costs were $14,310 (CD treatment costs, $9,353; other CD-related costs, $4,957).17
The study also reported that CD patients have a high burden of illness. Among CD patients in this study, 30.5% had diabetes, 22.5% had psychiatric disturbances, 21% had infections, 8.6% had osteoporosis, 8% had cardiovascular disease/stroke, and 5.5% had kidney stones. Patients had 19.8 office visits per year, and > 34% of patients were hospitalized. Mean total cost of care was approximately $35,000 per year.17