Maester’s Collection: Cushing Syndrome

  • Central obesity, arterial hypertension, proximal muscle weakness, diabetes, oligomenorrhea, hirsutism, thin skin, and ecchymosis
  • Today, obesity is common. Anti-androgenic effects of Cushing syndrome can help differentiate it from obesity
    • +LR thin skin 112
    • +LR osteopenia 18
    • +LR ecchymoses 4
    • All 3 have a specificity of 95%
  • Prevalence of Cushing in obese/metabolic type patients 0.2%
    • 24,000 cases of Cushing/12 million patients with metabolic syndrome = 0.2%
  • 24 hour urinary free cortisol
    • 2-forms: 1) unbound to protein or 2) cortisol unconjugated to sulfuric or hyaluronic acid
    • Unbound cortisol is filtered and reabsorbed. 3% remains in urine.
    • Should measure 24-hour urine creatinine with cortisol to ensure adequate collection
      • Repeat if creatinine is less than 1.5g/day for men and 1g/day in women
    • 24-hour urine cortisol > 62mg/day has +LR 11
  • Dexamethasone Suppression test is used to differentiate ACTH dependent from ACTH independent Cushing syndrome.
    • This is now done by directly measuring ACTH levels
    • Should not be used to diagnose or screen for Cushing syndrome
      • Obese patients with depression will fail to suppress cortisol in response to dexamethasone challenge
  • For Cushingoid exam, but low or zero urinary free cortisol and suppressed ACTH levels suggests exogenous steroid and should prompt a review of medications.
  • ACTH-dependent Cushing syndrome can be due to pituitary secretion from an adenoma or ectopic secretion from a malignant source – typically in the chest.
  • Some experts recommend always doing petrosal sinus sampling due to the high prevalence of non-functioning pituitary adenomas and mortality associated with surgery. Some series report the prevalence of asymptomatic pituitary adenomas as high as 15-40%. Mortality associated with transsphenoidal micro-adenectomy is 1%.
  • ACTH-independent Cushing syndrome is usually caused by an adrenal neoplasm.
    • Characteristics of benign tumors: small (<5cm), <10 Hounsfield units, and have > 60% contrast washout at 15 minutes.
      • Benign tumors can be treated laparoscopically, while malignant tumors typically are resected with an open technique.

Flea Bytes: Intensive glycemic control

Flea bytes are quick bits of information.


ACCORD Trial published in 2008 showed in type 2 diabetics, intensive glycemic control increases mortality, particularly cardiovascular mortality. 10,251 type 2 diabetics were randomized to either the intensive arm or to the control arm. The intensive control group targeted a HbA1c < 6%, while the control group targeted an HbA1c between 7 and 7.9%. The median follow up was 3.7 years and the trial was stopped early. There was no difference in the primary outcome of nonfatal MI or nonfatal stroke or cardiovascular death (HR 0.90; 0.78-1.04, p=0.16). Annual rate of all cause mortality was 1.41% in the intensive arm while 1.14% in the control arm, HR 1.22, which amounts to a number needed to harm of 370. Annual cardiovascular mortality rate was 0.79% versus 0.56% in the intensive and control arms respectively .

It remains unclear if the increased use of thiazolidinediones (TZDs) contributed to the increased mortality. Although baseline angiotensin-converting enzyme inhibitor (ACEI) use was similar between the groups, there was slightly decreased use of ACEI in the intensive control group by the end of the study.

The ACCORDION trial, which was a continued follow up of patients included in the original ACCORD trial for a median of 8.8 years and a mean of 7.7 years after randomization. Those in the intervention arm had their glucose liberalized and this study looked at the effects of 3.7 years of intensive glycemic control on clinical outcomes. The authors still noted no difference in primary outcome, but a modest decrease in the hazards of CV death. (HR 1.49->1.20).

This is why we do not target lower HbA1c targets in our type 2 diabetics.


  1. Gerstein HC, et al. “Effects of Intensive Glucose Lowering in Type 2 Diabetes”. The New England Journal of Medicine. 2008. 358(24):2545-59. Link.
  2. ACCORD Study Group Writing Committee. “9-Year Effects of 3.7 years of Intensive Glycemic Control of Cardiovascular Outcomes”. Diabetes Care. 2016. Epub ahead of print. Link.