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Adrenal Insufficiency in Adults: A Review

Author/s: 
Anand Vaidya, James Findling, Irina Bancos

Importance: Adrenal insufficiency is a syndrome of cortisol deficiency and is categorized as primary, secondary, or glucocorticoid induced. Although primary and secondary adrenal insufficiency are rare, affecting less than 279 per 1 million individuals, glucocorticoid-induced adrenal insufficiency is common.

Observations: Primary adrenal insufficiency, which involves deficiency of all adrenocortical hormones, is caused by autoimmune destruction, congenital adrenal hyperplasia, pharmacological inhibition (eg, high doses of azole antifungal therapy), infection (eg, tuberculosis, fungal infections), or surgical removal of adrenal cortical tissue. Secondary adrenal insufficiency is caused by disorders affecting the pituitary gland, such as tumors, hemorrhage, inflammatory or infiltrative conditions (eg, hypophysitis, sarcoidosis, hemochromatosis), surgery, radiation therapy, or medications that suppress corticotropin production, such as opioids. Glucocorticoid-induced adrenal insufficiency is caused by administration of supraphysiological doses of glucocorticoids. Patients with adrenal insufficiency typically present with nonspecific symptoms, including fatigue (50%-95%), nausea and vomiting (20%-62%), and anorexia and weight loss (43%-73%). Glucocorticoid-induced adrenal insufficiency should be suspected in patients who have recently tapered or discontinued a supraphysiological dose of glucocorticoids. Early-morning (approximately 8 am) measurements of serum cortisol, corticotropin, and dehydroepiandrosterone sulfate (DHEAS) are used to diagnose adrenal insufficiency. Primary adrenal insufficiency is typically characterized by low morning cortisol levels (<5 µg/dL), high corticotropin levels, and low DHEAS levels. Patients with secondary and glucocorticoid-induced adrenal insufficiency typically have low or intermediate morning cortisol levels (5-10 µg/dL) and low or low-normal corticotropin and DHEAS levels. Patients with intermediate early-morning cortisol levels should undergo repeat early-morning cortisol testing or corticotropin stimulation testing (measurement of cortisol before and 60 minutes after administration of cosyntropin, 250 µg). Treatment of adrenal insufficiency involves supplemental glucocorticoids (eg, hydrocortisone, 15-25 mg daily, or prednisone, 3-5 mg daily). Mineralocorticoids (eg, fludrocortisone, 0.05-0.3 mg daily) should be added for patients with primary adrenal insufficiency. Adrenal crisis, a syndrome that can cause hypotension and shock, hyponatremia, altered mental status, and death if untreated, can occur in patients with adrenal insufficiency who have inadequate glucocorticoid therapy, acute illness, and physical stress. Therefore, all patients with adrenal insufficiency should be instructed how to increase glucocorticoids during acute illness and prescribed injectable glucocorticoids (eg, hydrocortisone, 100 mg intramuscular injection) to prevent or treat adrenal crisis.

Conclusions and relevance: Although primary and secondary adrenal insufficiency are rare, glucocorticoid-induced adrenal insufficiency is a common condition. Diagnosis of adrenal insufficiency involves early-morning measurement of cortisol, corticotropin, and DHEAS. All patients with adrenal insufficiency should be treated with glucocorticoids and instructed how to prevent and treat adrenal crisis.

Keywords 
Adrenal Hyperplasia Congenital Acute Disease Hemochromatosis Injections Intramuscular Nausea Vomiting

Extended follow-up of local steroid injection for carpal tunnel syndrome: A randomized clinical trial

Author/s: 
Hofer, M., Ranstam, J., Atroshi, I.

Importance Local steroid injection is commonly used in treating patients with idiopathic carpal tunnel syndrome, but evidence regarding long-term efficacy is lacking.

Objective To assess the long-term treatment effects of local steroid injection for carpal tunnel syndrome.

Design, Setting, and Participants This exploratory 5-year extended follow-up of a double-blind, placebo-controlled randomized clinical trial was conducted from November 2008 to March 2012 at a university hospital orthopedic department. Participants included patients aged 22 to 69 years with primary idiopathic carpal tunnel syndrome and no prior treatment with local steroid injections. Data were analyzed from May 2018 to August 2018.

Interventions Patients were randomized to injection of 80 mg methylprednisolone, 40 mg methylprednisolone, or saline.

Main Outcomes and Measures The coprimary outcomes were the symptom severity score and rate of subsequent carpal tunnel release surgery on the study hand at 5 years. Secondary outcomes were time from injection to surgical treatment, SF-36 bodily pain score, and score on the 11-item disabilities of the arm, shoulder, and hand scale.

Results A total of 111 participants (mean [SD] age at follow-up, 52.9 [11.6] years; 81 [73.0%] women and 30 [27.0%] men) were randomized, with 37 in the 80 mg methylprednisolone group, 37 in the 40 mg methylprednisolone group, and 37 in the saline placebo group. Complete 5-year follow-up data were obtained from all 111 participants with no dropouts (100% follow-up). At baseline, mean (SD) symptom severity scores were 2.93 (0.85) in the 80 mg methylprednisolone group, 3.13 (0.70) in the 40 mg methylprednisolone group, and 3.18 (0.75) in the placebo group, and at the 5-year follow up, mean (SD) symptom severity scores were 1.51 (0.66) in the 80 mg methylprednisolone group, 1.59 (0.63) in the 40 mg methylprednisolone group, and 1.67 (0.74) in the placebo group. Compared with placebo, there was no significant difference in mean change in symptom severity score from baseline to 5 years for the 80 mg methylprednisolone group (0.14 [95%CI, −0.17 to 0.45]) or the 40 mg methylprednisolone group (0.12 [95%CI, −0.19 to 0.43]). After injection, subsequent surgical treatment on the study hand was performed in 31 participants (83.8%) in the 80 mg methylprednisolone group, 34 participants (91.9%) in the 40 mg methylprednisolone group, and 36 participants (97.3%) in the placebo group; the number of participants who underwent surgical treatment between the 1-year and 5-year follow-ups was 4 participants (10.8%) in the 80 mg methylprednisolone group, 4 participants (10.8%) in the 40 mg methylprednisolone group, and 2 participants (5.4%) in the placebo group. All surgical procedures were conducted while participants and investigators were blinded to type of injection received. The mean (SD) time from injection to surgery was 180 (121) days in the 80 mg methylprednisolone group, 185 (125) days in the 40 mg methylprednisolone group, and 121 (88) days in the placebo group. Kaplan-Meier survival curves showed statistically significant difference in time to surgical treatment (log-rank test: 80 mg methylprednisolone vs placebo, P = .002 ; 40 mg methylprednisolone vs placebo, P = .02; methylprednisolone 80 mg vs 40 mg, P = .37).

Conclusions and Relevance These findings suggest that in idiopathic carpal tunnel syndrome, local methylprednisolone injection resulted in statistically significant reduction in surgery rates and delay in need for surgery.

Trial Registration ClinicalTrials.gov Identifiers: NCT00806871 and NCT02652390

Efficacy of Intra-Articular Hypertonic Dextrose (Prolotherapy) for Knee Osteoarthritis: A Randomized Controlled Trial

Author/s: 
Sit, R.W.S., Wu, R.W., Reeves, K.D., Chan, D.C.C., Yip, B.H.K., Chung, V.C.H., Wong, S.

 

Purpose: To test the efficacy of intra-articular hypertonic dextrose prolotherapy (DPT) vs normal saline (NS) injection for knee osteoarthritis (KOA).

Methods: A single-center, parallel-group, blinded, randomized controlled trial was conducted at a university primary care clinic in Hong Kong. Patients with KOA (n = 76) were randomly allocated (1:1) to DPT or NS groups for injections at weeks 0, 4, 8, and 16. The primary outcome was the Western Ontario McMaster University Osteoarthritis Index (WOMAC; 0-100 points) pain score. The secondary outcomes were the WOMAC composite, function and stiffness scores; objectively assessed physical function test results; visual analogue scale (VAS) for knee pain; and EuroQol-5D score. All outcomes were evaluated at baseline and at 16, 26, and 52 weeks using linear mixed model.

Results: Randomization produced similar groups. The WOMAC pain score at 52 weeks showed a difference-in-difference estimate of -10.34 (95% CI, -19.20 to -1.49, P = 0.022) points. A similar favorable effect was shown on the difference-in-difference estimate on WOMAC function score of -9.55 (95% CI, -17.72 to -1.39, P = 0.022), WOMAC composite score of -9.65 (95% CI, -17.77 to -1.53, P = 0.020), VAS pain intensity score of -10.98 (95% CI, -21.36 to -0.61, P = 0.038), and EuroQol-5D VAS score of 8.64 (95% CI, 1.36 to 5.92, P = 0.020). No adverse events were reported.

Conclusion: Intra-articular dextrose prolotherapy injections reduced pain, improved function and quality of life in patients with KOA compared with blinded saline injections. The procedure is straightforward and safe; the adherence and satisfaction were high.

Keywords: intra-articular hypertonic dextrose; knee osteoarthritis; normal saline; prolotherapy; randomized clinical trial.

Physical Therapy Versus Glucocorticoid Injection for Osteoarthritis of the Knee

Author/s: 
Deyle, GD, Allen, CS, Allison, SC, Gill, NW, Hando, BR, Petersen, EJ, Dusenberry, DI, Rhon, DI

Background: Both physical therapy and intraarticular injections of glucocorticoids have been shown to confer clinical benefit with respect to osteoarthritis of the knee. Whether the short-term and long-term effectiveness for relieving pain and improving physical function differ between these two therapies is uncertain.

Methods: We conducted a randomized trial to compare physical therapy with glucocorticoid injection in the primary care setting in the U.S. Military Health System. Patients with osteoarthritis in one or both knees were randomly assigned in a 1:1 ratio to receive a glucocorticoid injection or to undergo physical therapy. The primary outcome was the total score on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 1 year (scores range from 0 to 240, with higher scores indicating worse pain, function, and stiffness). The secondary outcomes were the time needed to complete the Alternate Step Test, the time needed to complete the Timed Up and Go test, and the score on the Global Rating of Change scale, all assessed at 1 year.

Results: We enrolled 156 patients with a mean age of 56 years; 78 patients were assigned to each group. Baseline characteristics, including severity of pain and level of disability, were similar in the two groups. The mean (±SD) baseline WOMAC scores were 108.8±47.1 in the glucocorticoid injection group and 107.1±42.4 in the physical therapy group. At 1 year, the mean scores were 55.8±53.8 and 37.0±30.7, respectively (mean between-group difference, 18.8 points; 95% confidence interval, 5.0 to 32.6), a finding favoring physical therapy. Changes in secondary outcomes were in the same direction as those of the primary outcome. One patient fainted while receiving a glucocorticoid injection.

Conclusions: Patients with osteoarthritis of the knee who underwent physical therapy had less pain and functional disability at 1 year than patients who received an intraarticular glucocorticoid injection. (ClinicalTrials.gov number, NCT01427153.).

Keywords 
physical therapy glucocorticoids knee osteoarthritis
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