Diagnostic pitfalls in Cushing’s disease impacting surgical remission rates; test thresholds and lessons learned in 105 patients

Posted on September 7, 2021 by MaryO

This article was originally published here

J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print.

ABSTRACT

CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection.

OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD.

DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD.

MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI.

RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion.

CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

PMID:34478542 | DOI:10.1210/clinem/dgab659

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Thyroid dysfunction highly prevalent in Cushing’s syndrome

Posted on February 9, 2021 by MaryO

Central hypothyroidism is prevalent in about 1 in 2 adults with Cushing’s syndrome, and thyroid function can be restored after curative surgery for most patients, according to study findings.

“Our study findings have confirmed and greatly extended previous smaller studies that suggested a link between hypercortisolism and thyroid dysfunction but were inconclusive due to smaller sample size and short follow-up,” Skand Shekhar, MD, an endocrinologist and clinical investigator in the reproductive physiology and pathophysiology group at the National Institute of Environmental Health Sciences, NIH, told Healio. “Due to our large sample and longer follow-up, we firmly established a significant negative correlation between hypercortisolemia measures — serum and urinary cortisol, serum adrenocorticotropic hormone — and thyroid hormones triiodothyronine, free thyroxine and thyrotropin.”

Shekhar and colleagues conducted a retrospective review of two groups of adults aged 18 to 60 years with Cushing’s syndrome. The first group was evaluated at the NIH Clinical Center from 2005 to 2018 (n = 68; mean age, 43.8 years; 62% white), and the second group was evaluated from 1985 to 1994 (n = 55; mean age, 37.2 years; 89% white). The first cohort was followed for 6 to 12 months to observe the pattern of thyroid hormone changes after surgical cure of adrenocorticotropic hormone-dependent Cushing’s syndrome. The second group underwent diurnal thyroid-stimulating hormone evaluation before treatment and during remission for some cases.

Urinary free cortisol and morning thyroid hormone levels were collected for all participants. In the second group, researchers evaluated diurnal patterns of TSH concentrations with hourly measurements from 3 to 7 p.m. and midnight to 4 p.m. In the first group, adrenocorticotropic hormone and serum cortisol were measured.

In the first cohort, seven participants were receiving levothyroxine for previously diagnosed primary or central hypothyroidism. Of the remaining 61 adults, 32 had untreated central hypothyroidism. Thirteen participants had free T4 at the lower limit of normal, and 19 had subnormal levels. There were 29 adults with subnormal levels of T3 and seven with subnormal TSH.

Before surgery, 36 participants in the first group had central hypothyroidism. Six months after surgery, central hypothyroidism remained for 10 participants. After 12 months, the number of adults with central hypothyroidism dropped to six. Preoperative T3 and TSH levels were negatively associated with morning and midnight cortisol, adrenocorticotropic hormone and urinary free cortisol. In post hoc analysis, a baseline urinary free cortisol of more than 1,000 g per day was adversely associated with baseline and 6-month T3 and free T4 levels.

In the second group, there were 51 participants not on thyroid-modifying drugs who had a thyroid function test 6 or 12 months after surgery. Before surgery, free T4 levels were subnormal in 17 participants, T3 levels were subnormal in 22, and TSH levels were in the lower half of the reference range or below in all but one participant.

After surgery, two participants had below normal free T4, one had subnormal T3, and TSH levels were in the lower half of the reference range or below in 23 of 48 participants. Before surgery, there was no difference in mean TSH between daytime and nighttime. A mean 8 months after surgery, the second group had a normal nocturnal TSH surge from 1.3 mIU/L during the day to 2.17 mIU/L at night (P = .01). The nocturnal TSH increase persisted as long as 3 years in participants who had follow-up evaluations.

“We found a very high prevalence of thyroid hormone deficiency that appears to start at the level of the hypothalamus-pituitary gland and extend to the tissue level,” Shekhar said. “Some of these patients may experience thyroid hormone deficiency symptoms, such as fatigue, depression, cold intolerance, weight gain, etc, as a result of systematic and tissue-level thyroid hormone deficiency. We also noted a strong correlation between hypothyroidism and hypogonadism, which implies that hypothyroid patients are also likely to suffer adverse reproductive effects. Thus, it is imperative to perform thorough thyroid hormone assessment in patients with Cushing’s syndrome, and thyroid hormone supplementation should be considered for these patients unless cure of Cushing’s syndrome is imminent.”

Researchers said providers should routinely screen for hypothyroidism in adults with Cushing’s syndrome. Even after thyroid function is restored, regular follow-up should also be conducted.

Further research is needed to investigate thyroid dysfunction in iatrogenic Cushing’s syndrome and the impact of these findings on euthyroid sick syndrome, Shekhar said.

For more information:

Skand Shekhar, MD, can be reached at skand.shekhar@nih.gov.

From https://www.healio.com/news/endocrinology/20210208/thyroid-dysfunction-highly-prevalent-in-cushings-syndrome

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Muscle Weakness Persists in Cushing’s Syndrome Despite Remission

Posted on October 3, 2020 by MaryO

People with Cushing’s syndrome experience muscle weakness that persists even when the disorder is in remission, a new study shows.

The study, “Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission,” was published in The Journal of Clinical Endocrinology and Metabolism.

Cushing’s syndrome is characterized by abnormally high levels of the hormone cortisol. This can result in a variety of symptoms, including muscle weakness. However, it’s unclear the extent to which treatment of the underlying syndrome affects muscle weakness in the long term.

In the new study, researchers analyzed data for 88 people with endogenous Cushing’s syndrome diagnosed between 2012 and 2018 who had undergone regular muscle function tests. The data were collected as part of the German Cushing’s Registry, and the assessed group was mostly female (78%), with an average age of 49.

Of note, not all individuals had data available for every time point assessed — for example, at four years of follow-up, data were available for only 22 of the people analyzed.

Of the 88 individuals assessed, 49 had Cushing’s disease (a form of Cushing’s syndrome driven by a tumor on the pituitary gland). All 88 underwent curative surgery. The median time between diagnosis and remission was two months.

The researchers measured muscle strength in two ways: by grip strength and the chair rising test.

On average, and after statistical adjustments for age and sex, grip strength at diagnosis was 83% (with 100% reflecting the average for people without Cushing’s syndrome). Six months after surgery, average grip strength had decreased to 71%. A year after surgery, average grip strength was 77%. At all time points measured, up to four years after surgery, grip strength was significantly lowered in people with Cushing’s syndrome.

The chair rising test (CRT) involves measuring how quickly a person can rise from a seated position. Generally, being able to do so more quickly indicates greater muscle strength. People with Cushing’s syndrome showed improvement in the CRT six months after treatment (median 7 seconds), compared to the beginning of the study (8 seconds).

However, no further improvement was observed at subsequent time points up to four years, and compared to controls, CRT remained abnormal over time (7 seconds in Cushing patients at three years of follow-up vs 5 seconds in controls).

“The main finding of our study is that muscle strength remains impaired even after years in remission,” the researchers wrote.

“Another interesting finding is that at 6 months follow-up grip strength and CRT performance show opposite effects. Whereas grip strength has worsened, CRT performance has improved,” they added.

The investigators speculated that this difference is probably due to changes in body weight. Cushing’s syndrome commonly results in weight gain, and treatment resulted in significant decreases in body mass index in the analyzed group. As such, it may have been easier for individuals to stand up because there was less mass for their muscles to move, not necessarily because their muscles were stronger.

“Why patients with CS in remission showed a temporary worsening in grip strength 6 months after surgery remains unclear in terms of pathophysiology,” the researchers wrote.

They speculated that this could be due to treatment with glucocorticoids, which may affect muscle strength, but added that, “Whether the necessity of a long-term glucocorticoid replacement influences muscle strength or myopathy [muscle disease] outcome remains controversial.”

The researchers also conducted statistical analyses to determine what patient factors were associated with poorer muscle function outcomes. They found statistically significant associations between poor muscle function and older age, higher waist-to-hip-ratio, and higher levels of HbA1c (a marker of metabolic disease like diabetes).

“Influencing factors for myopathy outcome are age, waist-to-hip-ratio and HbA1c, suggesting that a consistent and strict treatment of diabetic metabolic state during hypercortisolism [high cortisol levels] is mandatory,” the investigators wrote.

The study was limited by its small sample size, the researchers noted, particularly at longer follow-up times, and by the fact that only a few measurements of muscle strength were used. Additionally, since all the data were collected at one of three centers in Germany, the analyzed population may not be representative of the worldwide population of people with Cushing’s syndrome.

Adapted from https://cushingsdiseasenews.com/2020/09/30/muscle-weakness-persists-in-cushings-syndrome-despite-remission-study-finds/

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The Effect Of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome

Posted on May 25, 2020 by MaryO
Braun LT, Fazel J, Zopp S
Journal of Bone and Mineral Research

|
May 22, 2020

This study was attempted to assess bone mineral density and fracture rates in 89 patients with confirmed Cushing’s syndrome at the time of diagnosis and 2 years after successful tumor resection.

Researchers ascertained five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. Via chemiluminescent immunoassays, they assessed bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide, alkaline bone phosphatase, CrossLaps, and TrAcP 5b in plasma or serum. For comparison, they studied 71 gender‐, age‐, and BMI‐matched patients in whom Cushing’s syndrome had been excluded.

The outcomes of this research exhibit that the phase immediately after surgical remission from endogenous CS is defined by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients.

Read the full article on Journal of Bone and Mineral Research.

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Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

Posted on September 25, 2019 by MaryO

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

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