Impaired enzyme leads to lack of typical Cushing’s signs in patient
Impairment prevents Cushing’s symptoms that are driven by high cortisol
A 46-year-old man with Cushing’s disease in the U.S. lacked many of the typical symptoms due to impairments in the activity of an enzyme called 11 beta-hydroxysteroid dehydrogenase type 1 (HSD-1), according to a recent case report.
HSD-1 is needed for cells to convert cortisone, an inactive form of cortisol, back into cortisol. Impairments in the activity of this enzyme reduce cortisol regeneration and increase its clearance, preventing many Cushing’s symptoms that are driven by elevated cortisol levels.
“When patients present with markedly elevated cortisol but without classic [Cushing’s] features, impaired [HSD-1] should be considered in the differential diagnosis,” researchers note.
The case was described in a study, “Impaired 11β-HSD1 Activity in a Male Patient With Cushing Disease Resulting in Lack of the Full Cushingoid Phenotype,” published in JCEM Case Reports.
Cushing’s syndrome consists of a group of conditions characterized by high levels of cortisol (hypercortisolism). Cushing’s disease, one of its most common forms, is caused by tumors in the brain’s pituitary gland, which lead to the excessive production and release of adrenocorticotropic hormone (ACTH). In turn, ACTH signals the adrenal glands, located atop the kidneys, to overproduce cortisol.
HSD-1 helps control balance between cortisol and its inactive form, cortisone
HSD-1 is one of the enzymes that controls the balance between cortisol and its inactive form, cortisone. Normally, the enzyme works to convert cortisone into cortisol in the liver, fatty tissue, and skeletal muscles. However, when HSD-1’s activity is impaired, the balance shifts in favor of cortisone, leading to a reduction in cortisol regeneration.
In the study, researchers in the U.S. reported the case of a 46-year-old man with Cushing’s disease who was also found to have impaired HSD-1 activity.
The man had decreased sex drive, high blood pressure, sleep issues, high sugar blood levels at night, and a weight gain of 10 pounds over six years. He was taking medications to manage his high blood pressure, sleep issues, mild anxiety, and depression.
He was referred for clinical evaluation after a urine test revealed the presence of high levels of cortisol that did not vary over the course of the day.
On physical examination, he was found to be mildly overweight and muscular, and had a slight rounding of the face. However, he did not experience some of the common features of Cushing’s, such as abnormal fat distribution, thin skin, stretch marks, or bruises.
Laboratory tests showed his blood cortisol and ACTH levels were elevated at different times of the day. Saliva and urine cortisol levels were also elevated. His testosterone levels were in the low-normal range, while blood sugar and cholesterol levels were slightly elevated.
Further urine analysis revealed cortisone levels were also higher than normal. The ratio of cortisol and cortisone metabolites was also low, consistent with reduced HSD-1 activity.
Pituitary MRI shows benign tumor responsible for patient’s excess ACTH levels
A pituitary MRI scan revealed the presence of a microadenoma, a type of benign tumor, that was identified as the source of his excess ACTH levels, consistent with the diagnosis of Cushing’s disease.
The patient underwent transsphenoidal surgery, a minimally invasive procedure used to remove pituitary tumors through the nose, three months after his initial hospital visit. After surgery, his cortisol levels dropped below reference levels, and he was started on hydrocortisone replacement therapy.
One month after surgery, his cortisol levels remained low, while ACTH levels were within the normal range. Hydrocortisone was progressively reduced and stopped in the following months. After 18 months, his cortisol and ACTH levels had normalized, and his testosterone levels had increased.
The patient also reported improvements in sex drive and sleep, a weight loss of about 2.9 pounds, and decreased blood pressure. However, he still had a low cortisol-to-cortisone ratio and higher-than-normal cortisol clearance.
“Our patient’s presentation and previous reports demonstrate the key role of [HSD-1] in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol,” the researchers wrote.
They also noted that in the past two decades, only two women were reported to have impaired HSD-1 activity, resulting in a lack of classic Cushing’s symptoms.
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