Addison's disease : epidemiological and clinical studies

Abstract

Addison’s disease (AD) is a potentially life-threatening condition that often presents with vague and nonspecific symptoms. Patients with AD have increased mortality risk. Data on parity and pregnancy outcome in women with AD are limited. Furthermore, there are no data on fracture risk or drug prescription patterns in patients with AD. Continuous subcutaneous hydrocortisone infusion (CSHI) is a novel treatment modality, but it has not yet been established whether the circadian hormone profiles and insulin sensitivity differ in patients on CSHI compared with conventional oral hydrocortisone treatment (OHC).

The four studies in this thesis aim to enhance knowledge and clinical management of patients with AD. Parity and pregnancy outcome: In all, 1188 women with AD were retrospectively evaluated. Women with AD had a reduced overall parity compared with controls (P < 0.001). Adjusted odds ratios (ORs) (95% confidence interval, CI) for infants born to mothers with deliveries ≤ 3 years before diagnosis of AD were 2.40 (1.27-4.53) for preterm birth, 3.50 (1.83-6.67) for low birth weight and 1.74 (1.02-2.96) for caesarean section. In comparison with controls, women who gave birth after their AD diagnosis were at increased risk for both caesarean delivery (adjusted OR, 2.35, 95% CI; 1.68-3.27) and preterm delivery (adjusted OR, 2.61, 95% CI; 1.69-4.05). No differences were found in risks of congenital malformations or infant death.

Hip fracture risk: Totally, 3219 patients with AD were retrospectively evaluated. Patients with AD had a higher risk of hip fracture (hazard ratio, HR 1.8, 95% CI; 1.6-2.1; p < 0.001) than matched controls. The increased risk was independent of age at diagnosis, sex and calendar period. A positive association between hip fracture and undiagnosed AD was noted with the highest risk estimates during the last year before AD diagnosis (OR 2.8, 95% CI; 1.8-4.2). Drug prescription patterns:We identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. The yearly prevalence of AD increased from 12.2 to 13.1 (Pfor trend = .062); incidence varied between 0.5 and 0.6 (Pfor trend = .131) per 100 000 person-years during the period 2005-2009. Patients with AD received more prescribed drugs than controls. Both before and after AD diagnosis, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives and drugs for obstructive airway disease (pvalues < 0.05). Notably, an increased prescription of several antihypertensive drugs and highceiling diuretics was observed after AD diagnosis. Circadian hormone profiles and insulin sensitivity:CSHI provided a more physiological circadian cortisol curve, including a late night cortisol surge, than OHC treatment. CSHI yielded a normalization of adrenocorticotropic hormone (ACTH) levels and showed a more normal circadian variation than OHC. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. The expected growth hormone (GH) peak during nighttime was more pronounced for CSHI, which, together with the higher insulin-like growth factor type 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, suggest a more anabolic status.

Conclusion: This thesis demonstrates that both undiagnosed and diagnosed AD entail increased risks of unfavorable pregnancy outcome, hip fractures and altered drug prescription patterns compared to controls. In addition, parity is reduced in patients diagnosed with AD. This raises concerns about the conventional replacement therapy. CSHI is a safe and reliable mode of glucocorticoid replacement and might become a treatment option in selected patients.