ACTH/Cortisol Ratio May Be Simple, Reliable Test to Diagnose Cushing’s Disease

The ratio between adrenocorticotropic hormone levels and cortisol levels in the blood is higher among Cushing’s disease patients than in healthy people, a new study has found, suggesting that measurement could be used to help diagnose the disease.

Also, higher values at diagnosis could predict if the disease will recur and indicate larger and more invasive tumors.

The research, “The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing’s Disease,” was published in the Journal of Neurosciences in Rural Practice.

Cushing’s syndrome (CS) is characterized by excess levels of cortisol. In patients with suspected CS, clinicians recommend testing late-night salivary or plasma (blood) cortisol, 24-hour urine-free cortisol (UC), as well as morning cortisol levels after low-dose suppression with dexamethasone, a corticosteroid.

CS may be ACTH-dependent or ACTH-independent, meaning that the high cortisol levels are caused by excess ACTH production.

Patients with CD have elevated levels of ACTH. A tumor, usually an adenoma, causes the pituitary gland to produce excess levels of ACTH, which stimulate the release of cortisol from the adrenal glands. Cortisol usually inhibits ACTH production. However, in CD patients, this feedback mechanism is absent.

Despite extensive research and clinical data, the variable and usually nonspecific signs and symptoms of CD still represent relevant challenges for diagnosis. Clinical manifestations must be associated with biochemical tests, which often have led to conflicting results.

Studies showed that although ACTH levels correlate with the size of the pituitary adenoma, the levels of cortisol do not increase as much. In fact, lower cortisol/ACTH ratios have been reported in patients with macroadenoma – which is greater than 10 millimeters in size – than in those with microadenoma, which is smaller than 10 millimeters.

Conversely, the research team hypothesized that besides their utility for determining the cause of CS, the inverse ratio – ACTH/cortisol – also may be useful for diagnosis.

The team evaluated the pretreatment plasma ACTH/cortisol levels in CS patients with excess cortisol production due to abnormal pituitary or adrenal function. Data from patients were compared with that of individuals without CS.

The study included 145 CS patients diagnosed from 2007 to 2016, 119 patients with CD, 26 with ACTH-independent CS (AICS), and 114 controls with no CS.

Patients’ clinical, laboratory, imaging, postsurgical and follow-up data were analyzed.

Results showed that patients with CD had a significantly higher basal ACTH/cortisol ratio than controls or those with AICS.

“These results showed ACTH/cortisol ratio might be a simple and useful test for the diagnosis of ACTH-dependent CS,” the researchers wrote.

Importantly, the scientists observed that a ACTH/cortisol ratio above 2.5 indicated identified 82 percent of positive CS cases and 63 percent of controls.

Overall, “an ACTH/cortisol ratio [greater than] 2.5 would be beneficial to diagnose CD together with other diagnostic tests,” they concluded.

Patients with recurrent CD showed higher pretreatment ACTH levels and ACTH/cortisol ratio than those who achieved sustained remission. CD patients also exhibited more invasive, atypical and larger tumors, as well as lower postoperative remission and higher recurrence rates.

“Higher ACTH/cortisol ratio might predict poorer prognosis,” the investigators said.


Case Report Shows Rare Adrenal Tumors Associated with Cushing’s Disease

Pituitary tumors that produce too much adrenocorticotropic hormone (ACTH) have been associated with the development of rare tumors on the adrenal glands, called adrenal myelolipomas, for the first time in a case report.

The study, “Case report of a bilateral adrenal myelolipoma associated with Cushing disease,” was published in the journal Medicine.

Myelolipomas, composed of mature fat cells and blood-forming cells, are usually asymptomatic and do not produce hormones. In many cases, these tumors are detected by accident when patients undergo imaging scans for other conditions.

The cause of these tumors is unknown, but due to their benign nature, they do not spread to other parts of the body. However, they can grow up to 34 centimeters (about 13 inches), leading to tissue death and hemorrhage.

Researchers at Soon Chun Hyang University College of Medicine in Seoul, Korea, described the case of a 52-year-old man with myelolipoma possibly caused by an ACTH-secreting pituitary tumor.

During a routine checkup, researchers detected a mass in the patient’s spleen. Further abdominal evaluations identified tissue lesions in both adrenal glands consistent with myelolipoma. Besides the masses, the patient did not show any other Cushing-associated physical characteristics.

However, the patient’s ACTH levels were two times higher than the normal upper limit. Cortisol levels were also increased and unresponsive to low-dose dexamethasone treatment.

No additional lesions were found that could help explain the high ACTH and cortisol levels. But analysis of blood samples collected from the veins draining the pituitary glands revealed the right gland was producing too much ACTH, strongly suggesting Cushing’s disease.

Both the left adrenal gland and pituitary tumor were surgically removed. The samples collected during surgery confirmed the benign nature of the adrenal tumors, and the diagnosis of abnormal, ACTH-positive pituitary gland tissue.

Three days after the surgeries, hormone levels were back to normal. But a follow-up evaluation five months later again showed increased ACTH levels. Cortisol levels, however, were normal.

For the next seven years, the patient was evaluated every six months. During a five-year period, the size of the right adrenal gland was found to have grown. Imaging analysis confirmed the existence of small, new lesions in both pituitary glands.

“This case confers valuable information about the clinical course of adrenal myelolipoma associated with Cushing disease,” the researchers said. It also “supports the notion that ACTH can be associated with the development of bilateral adrenal myelolipomas.”


High Levels of MMP-9 Enzyme May Predict Tumor Recurrence in Cushing’s Patients

Measuring the levels of a specific enzyme in pituitary tumors producing excess adrenocorticotrophic hormone (ACTH) may help predict the recurrence of Cushing’s disease in patients, a study shows.

The study, “Expression of MMP-9, PTTG, HMGA2, and Ki-67 in ACTH-secreting pituitary tumors and their association with tumor recurrence,” was published in the journal World Neurosurgery.

Cushing’s syndrome is characterized by excess cortisol levels in the blood. In 70 percent of cases, this is caused by pituitary tumors making too much ACTH, a hormone that regulates cortisol production. This condition is called Cushing’s disease.

While transsphenoidal adenomectomy, a surgery to remove a pituitary gland tumor, is the first treatment choice, tumor recurrence rates can be as high as 45 percent.

Only a few studies have investigated the association between biomarkers and the risk of ACTH-secreting pituitary tumors recurring, leaving physicians with limited methods to predict which patients will have a recurrence.

Identifying biomarkers that can effectively predict the potential recurrence of Cushing’s disease would allow clinicians to look for early signs in patients and start appropriate follow-up and therapeutic protocols, avoiding long-term mortality.

Many studies have suggested that matrix metalloproteinase-9 (MMP-9) enzymes, the pituitary tumor transforming gene (PTTG), and high mobility group A 2 proteins (HMGA2) all play vital roles in the development of pituitary tumors.

Metalloproteinases (MMPs) are enzymes that work to degrade the cell’s extracellular matrix, which anchors the cell, thus enabling tumor invasion. PTTG is highly expressed in pituitary tumors, and is a marker of malignancy in many types of tumors. HMGA2 is overexpressed in various tumors, and is also associated with high malignancy.

However, whether levels of MMP-9, PTTG, and HMGA2 are related to ACTH-secreting tumor recurrence has not been investigated.

Researchers set out to determine the expression levels of MMP-9, PTTG, HMGA2, and Ki-67 (a marker of cell growth) in ACTH-secreting pituitary tumors, and evaluate their association with tumor behavior and recurrence.

They conducted a retrospective study that included 55 patients with sporadic Cushing’s disease with long-term remission after a transsphenoidal adenomectomy. Their tumor specimens were collected and examined.

Patients were divided into two groups based on whether or not they had tumor recurrence. There were 28 patients in the non-recurrent group, and 27 in the recurrent.

Results showed there was significantly increased expression of MMP-9 in tumor samples of recurrent patients, compared with the non-recurrent group. Levels of MMP-9 were also strongly associated with a shorter time period to recurrence (recurrence-free interval).

On the other hand, PTTG, HMGA2, and Ki-67 expression was not significantly different between the recurrent group and the non-recurrent group.

“ACTH-secreting pituitary tumors with higher levels of MMP-9 were associated with a higher recurrence rate and a shorter recurrence-free interval. MMP-9 could be a valuable tool for predicting recurrence of ACTH-secreting pituitary tumors,” the researchers concluded.


Patient’s Atypical Cushing’s Symptoms Lead to Discovery of Novel Genetic Mutations

New genetic mutations were found in a patient who exhibited atypical symptoms of Cushing’s syndrome, notably an abnormal protrusion of the eye, a case report shows.

The research, “Extensive ARMC5 genetic variance in primary bilateral macronodular adrenal hyperplasia that started with exophthalmos: a case report,” was published in the Journal of Medical Case Reports.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a disorder characterized by multiple lumps in the adrenal glands and excessive cortisol production. It is a rare cause of Cushing’s syndrome.

According to recent research, PBMAH is caused by mutations in the ARMC5 gene, which data suggest may act as a tumor suppressor.

Researchers presented the case of a 52-year-old Chinese woman who exhibited a protrusion of both eyes (exophtalmos), which was first thought to be Graves’ ophthalmopathy. An injection of triamcinolone acetonide, a corticosteroid, into the area behind the eye globe did not improve symptoms.

The patient later was diagnosed with diabetes, which was treated with insulin, and hypertension, treated with insulin and amlodipine. She also developed muscle weakness and bruised easily. She had no other relevant chronic illness or infectious disease, and did not smoke tobacco or drink alcohol.

Physical examination showed skin atrophy, moon face, buffalo hump (between the shoulders), and purplish abdominal striae (stretch marks), which researchers defined as a typical Cushingoid appearance. The patient also experienced elevated pressure inside the eye, and had edema, conjunctival congestion, and lid retraction. No liver, spleen, respiration, cardiac, abdominal, blood counts, urinary, sensory, or motor abnormalities were noted.

Biochemical evaluation showed elevated cortisol and reduced adrenocorticotropin (ACTH) levels. Administering  dexamethasone did not lower the level of cortisol. Abnormal responses of the hormone vasopressin also were detected.

A computed tomography (CT) scan of the adrenal glands showed bilateral multiple lobular masses, and an MRI of the eye orbits indicated bilateral exophthalmos with hypertrophy of the retro-orbital fat, which lines the orbit.

After PBMAH was diagnosed, the patient’s adrenal glands were removed. Pathological findings showed multiple, homogenous, golden-yellow-colored nodules on the glands.

The surgery successfully lowered the level of cortisol and increased that of ACTH. The patient began taking hydrocortisone and metformin for diabetes. After six months, her exophtlamos, blood glucose levels, and blood pressure had improved.

Genetic analysis revealed six specific ARMC5 mutations in five of the seven adrenal nodules analyzed. “All the mutations are novel and not found in available online databases,” the researchers wrote. The mutations may lead to resistance to cell death in the tumor cells, and cause an increase in the production of cortisol, they observed.

As a result of the ARMC5 mutations, gene expression (conversion of genetic information) of the messenger RNA (mRNA, which is converted from DNA in the first step of protein synthesis) was lower in the adrenal tumor samples, in comparison with normal adrenal cortex.

Overall, the study “highlights the importance of early recognition of atypical symptoms of Cushing’s syndrome such as exophthalmos, which would save the patient from harmful effects of excessive cortisol exposure,” the researchers said. Screening for ARMC5 mutations also would help improve diagnosis and genetic counseling, they said.


Common Cushing’s Treatment, Somatostatin Analogs, May Sometimes Worsen Disease Course

Doctors often prescribe somatostatin analogs to manage the hormonal imbalance that characterizes Cushing’s syndrome. However, in rare situations these medicines have paradoxically made patients worse than better.

This recently happened with a 48-year-old Spanish woman whose Cushing’s syndrome was caused by an adrenal gland tumor that was producing excess adrenocorticotropic hormone (ACTH). Her case was recently reported in the study “Ectopic Cushing’s syndrome: Paradoxical effect of somatostatin analogs,” and published in the journal Endocrinología, Diabetes y Nutrición.

Cushing’s syndrome occurs when the body produces too much cortisol. This can happen for many reasons, including an oversupply of ACTH, the hormone responsible for cortisol production, due to a tumor in the pituitary gland.

But sometimes, tumors growing elsewhere can also produce ACTH. This feature, known as ectopic ACTH secretion (EAS), may also cause ACTH-dependent Cushing’s syndrome.

Two-thirds of EAS tumors are located in the thorax, and 8 to 15 percent are in the abdominal cavity. Only 5 percent of EAS tumors are located in the adrenal gland, and up to 15 percent of EAS tumors are never detected.

Doctors usually use cortisol synthesis inhibitors such as ketoconazole or Metopirone (metyrapone) to control EAS, due to their efficacy and safety profiles. But somatostatin analogs (SSAs) such as Somatuline (lanreotide) have also been used to treat these tumors. However, these drugs produce mixed results.

The woman in the case study, reported by researchers at the University Hospital Vall d’Hebron in Barcelona, Spain, had an EAS tumor on the adrenal gland. She experienced s life-threatening cortisol and ACTH increase after receiving high-dose Somatuline.

The patient had been recently diagnosed with hypertension, and complained of intense fatigue, muscular weakness, easy bruising and an absence of menstruation. Laboratory analysis revealed that she had triple the normal levels of free cortisol in the urine, elevated levels of plasma cortisol, and high ACTH levels. In addition, her cortisol levels remained unchanged after receiving dexamethasone. The patient was therefore diagnosed with ACTH-dependent Cushing syndrome.

To determine the origin of her high cortisol levels, the team conducted magnetic resonance imaging (MRI). They found no tumors on the most common places, including the pituitary gland, neck, thorax or abdomen. However, additional evaluation detected a small alteration on the left adrenal gland, suggesting that was the source of ectopic ACTH production.

The team initiated treatment with 120 mg of Somatuline, but a week later, her condition had worsened and become life-threatening. Doctors started Ketoconazole treatment immediately, three times daily. The affected adrenal gland was surgically removed, and tissue analysis confirmed the diagnosis. The patient’s clinical condition improved significantly over the follow-up period.

“We highlight the need to be aware of this rare presentation of EAS, and we remark the difficulties of EAS diagnosis and treatment,”  researchers wrote.

The team could not rule out the possibility that the patient’s clinical development was due to the natural course of the disease. However, they believe “she had a paradoxical response on the basis of her dramatical worsening just after the SSAs administration, associated to an important rise in ACTH and UFC levels.”

For that reason, researchers think a new version of SSAs, such as Signifor (pasireotide) — which has improved receptor affinity — could provide better therapeutic response.


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