Medic Alert Bracelets

Posted on December 16, 2025 by MaryO

Since the last topic was about Adrenal Insufficiency, it seemed that a great next topic would be about Medic Alert Bracelets.

Many doctors insist that everyone who has had pituitary or adrenal surgery have a bracelet – and some will even tell patients what they should say on them.

While I was still a patient at the NIH (National Institutes of Health) after my pituitary surgery, I was given my first bracelet along with my kit in care of adrenal crisis.  I had to learn to give myself a shot before I could go home.

Now, my endo checks mine at every visit to be sure I’m wearing my bracelet and reads it to be sure it’s still legible and checks to see what the text says.

He feels that the bracelets – and he insists that they LOOK like medic alert bracelets, not disguised as jewelry – are life savers.

I’m not so sure – I read stories on the message boards that people have gone into AI (adrenal insufficiency and no one has ever looked at their bracelet.  That was certainly the case for young Sam.  Her mom had instructions everywhere, none were heeded and the situation rapidly turned disastrous.

…We have dealt with Addison’s for 7 years; but I have handled everything. Apparently the vials of solu-cortef with step-by-step instructions hanging on the bulletin board in the kitchen, medicine cabinet and in every vehicle somehow missed his attention…  (read the whole story at survive the journey: Stars Go Blue)

A Paramedic wrote on the message boards:

I’d like to add a couple things from the perspective of a Paramedic…

A lot of us are not taught about adrenal insufficiency during our education….nor do many of us (if any at all) have a protocol to administer Injectable for AI unless we are able to contact the ER doctor for permission. So…if any of you should have an AI crisis please gently nudge your paramedic to contact the receiving physician for permission to administer the medication. I know this sounds like a lot of responsibility on the part of the patient…but you have to realize that we’re taught to recognize the most common life threats and endocrine disorders (other than diabetes) most usually do not present with life threats (we all know that as cushing’s is more recognized that this will change)…and our protocols cover the most common life threats….so while we may recognize that you are hypotensive and need fluids (IV) and are sweaty, nauseated, decreased level of responsiveness etc…we are not equipped to deal with the actual cause unless you help educate us….

Also…please don’t get angry with us….if we are having problems understanding…just gently insist that a call be made to your doctor or the receiving ED (usually not feasible for us to call your doctor since they do not come to the phone for just anybody but if you have access to them, as many cushies do, it would be great to talk to them)…

Paramedicine is evolving….someday soon, hopefully, our education will include more diagnostic skills…untill just in the past 5 years or so we were NEVER to make a diagnosis at all…just treat the symptoms!!!! So there is hope out there for futher understanding of such a critical problem for those without adrenal (or asleep adrenals) glands….

The medical alert jewerly is a life-saver and we do look for it….

So, the questions for discussion are:

  • Do you have a medical alert bracelet
  • Does your doctor check on it or suggest proper wording.
  • If you have one, has any medical staff read it during a crisis
  • And… what does yours say?

Filed under: adrenal crisis, Cushing's, pituitary | Tagged: , , , , | 15 Comments »

Misconceptions About Cushing’s

Posted on December 14, 2025 by MaryO

Cushing’s.  So many people are confused by what it is and what it isn’t.  They may have heard of it because a dog they know has it – or, these days, a horse, ferret, rat.  Seems it’s way more common in lots of animals but not people.

If people have heard of the “animal version” they might say “Yeah, my dog had that and it was easy to diagnose. We just gave him medication…”

When we first started having bios on the website, sometimes people would say that they had Cushions Disease.  At first I wondered about that but then it started to make more sense.  If you’ve never heard of the disease,  the doctor mumbles something.  You know you’re a little “fluffy” and cushions makes a lot of sense.

Twice in the last week I’ve seen Cushing’s described as Crushings Disease.  That sort of makes sense, too.  Cushing’s crushes your plans, relationships, credibility, pretty much everything.

Other misconceptions involve Cushing’s symptoms.  Others, especially doctors, will see you gain weight and assume you’re eating too much and a good diet will fix everything.  Or see that you’re depressed (who wouldn’t be!) and offer anti-depressants.

Doctors may say that Cushing’s is too rare, that they’ll never see a case of it in their practice.  But rare doesn’t mean that no one gets it.  Rare doesn’t mean that doctors shouldn’t test for it.

Then, the anatomy just isn’t right.  People say that they have a brain tumor instead of a pituitary tumor.  I just read this on another site: The pituitary gland is on the bottom of the brain… Umm – not exactly ON the bottom of the brain but maybe close enough for people to get an idea.

What sorts of things about Cushing’s/Cushions/Crushings that just weren’t quite right?

Filed under: Cushing's, Rare Diseases | Tagged: , , , , , , | 1 Comment »

A Case of Adrenocorticotropin-dependent Cushing Syndrome with Osilodrostat Exposure in Early Pregnancy

Posted on December 13, 2025 by MaryO

Abstract

Osilodrostat is a novel treatment for adrenocorticotropin-dependent Cushing syndrome; however, its safety during pregnancy has not been reported. This case involves a patient with Cushing disease who became pregnant while on osilodrostat. She was diagnosed at 31 years of age and underwent pituitary tumor removal. After a relapse at 35 years of age, she was initially treated with metyrapone but switched to osilodrostat and hydrocortisone because of nausea, achieving reasonable cortisol control. At 37 years of age, she unknowingly became pregnant despite irregular periods, and the pregnancy was detected at 16 weeks because of ongoing nausea. Osilodrostat was stopped, and she was started on pasireotide and metyrapone. The pregnancy proceeded normally despite elevated urinary free cortisol levels, although she contracted COVID-19 at 25 weeks. At 26 weeks and 1 day, preterm rupture of membranes and breech presentation led to an emergency cesarean section. The newborn had no adrenal insufficiency and developed normally. This case prompts consideration of whether osilodrostat can be used during pregnancy if risks are justified. Pasireotide is rarely used in pregnancy and may have limited effectiveness, but when given, can cause hyperglycemia because of insulin and incretin suppression and should be monitored carefully.

Introduction

Active Cushing syndrome decreases fertility, which explains its rarity in pregnancy. Fewer than 250 cases have been documented [1]. Whether it is ACTH-dependent or ACTH-independent, this disease poses significant risks to both mother and fetus. Its maternal complications include hypertension, preeclampsia, and diabetes [2], whereas the fetal risks include miscarriage, intrauterine growth restriction, and prematurity [3]. Given its rarity, there is no established standard of care for Cushing disease during pregnancy. Surgery offers a potential cure, but it can cause hypopituitarism and may not be feasible in the absence of a visible tumor [4]. Meanwhile, there are also risks associated with radiotherapy and pharmacological treatments [1, 4]. The use of pasireotide, a somatostatin analog, for the treatment of a GH-secreting pituitary macroadenoma without complications has been reported in only 1 case during pregnancy [5]. To the best of our knowledge, this drug has not been used for Cushing disease before. Osilodrostat, like metyrapone, is a newer steroidogenesis inhibitor that blocks 11β-hydroxylase in the adrenal glands. It is effective for both ACTH-dependent and ACTH-independent Cushing syndrome [6]. However, it is contraindicated in pregnancy because of its proven teratogenic effects in animal studies [7]. As a result, data on its use in human pregnancy are lacking. Understanding the normal physiology of the hypothalamic-pituitary-adrenal (HPA) axis in pregnancy is essential. In normal pregnancy, the maternal levels of corticotropin-releasing hormone, ACTH, and cortisol rise both in the serum and urine because of placental production [8, 9]. Although cortisol levels rise, only about 10% crosses the placenta because of 11β-hydroxysteroid dehydrogenase activity [10]. Fetal cortisol production remains minimal until late gestation, as 3β-hydroxysteroid dehydrogenase activity stays low until then [10]. Thus, most fetal cortisol originates from maternal sources [11]. In late pregnancy, fetal adrenal 3β-hydroxysteroid dehydrogenase activity increases, thereby enhancing fetal cortisol synthesis and promoting maturation of the HPA axis [10]. This case report discusses a female patient with recurrent Cushing disease who conceived while taking osilodrostat, which she took until early pregnancy; she was later treated successfully with pasireotide and metyrapone.

Case Presentation

A 30-year-old woman developed moon facies, central obesity, muscle weakness, and amenorrhea. Elevated levels of ACTH and cortisol, along with a roughly 6-mm pituitary adenoma, confirmed a diagnosis of Cushing disease. At 31 years of age, she successfully underwent transsphenoidal surgery, but 4 years later, biochemical relapse occurred with no identifiable residual tumor on imaging (Fig. 1). The patient was initially treated with metyrapone, but because of nausea, this was switched to osilodrostat. A block-and-replace approach was taken with osilodrostat 3 mg/day and hydrocortisone 10 mg/day, after which her cortisol levels normalized, but the menstrual irregularities persisted (Fig. 1).

 

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Figure 1.

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Diagnostic Assessment

At 38 years of age, the patient presented with nausea. The patient was followed up with an upper gastrointestinal endoscopy revealing no abnormalities. After a prolonged period of nausea, a pregnancy test revealed that she was 16 weeks pregnant.

Treatment

At this point, she had been on osilodrostat, which was immediately stopped and replaced with pasireotide 10 mg every 4 weeks because of pregnancy. Later, 24-hour urinary free cortisol (UFC) levels increased, leading to an early increase in pasireotide dose to 20 mg after 3 weeks before the recommended 4-week period elapsed; the same dose was administered every 4 weeks thereafter. And the same time, the initiation of up to 1000 mg metyrapone daily (Fig. 2). The patient also had hyperglycemia, which prompted insulin initiation, and subcutaneous heparin was also added because of the risk of thrombosis. At 25 weeks of pregnancy, she developed pharyngeal pain and a cough, which quickly resolved. At 26 weeks and 1 day, she experienced preterm premature rupture of membranes with the fetus in breech position, necessitating an emergency cesarean section. During this time, she tested positive for severe acute respiratory syndrome coronavirus 2 via polymerase chain reaction; however, she remained asymptomatic. Hydrocortisone was given before delivery as a steroid cover. Postpartum, osilodrostat was resumed, and pasireotide/metyrapone was discontinued. Two months after delivery, her disease remained stable, with UFC at 62.0 μg/day (171 nmol/day), within the normal reference range of 26.0 to 187.0 μg/day (72-516 nmol/day).

 

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Figure 2.

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Outcome and Follow-up

A live baby girl was born with extremely low birth weight, weighing 871 g. She was admitted to the neonatal intensive care unit with Apgar scores of 2 and 10 at 1 and 5 minutes, respectively, and was temporarily placed on a ventilator because of respiratory distress syndrome. During her stay, no signs of adrenal insufficiency appeared, and blood samples taken at noon showed ACTH levels of 23.3 pg/mL (5.1 pmol/L) and cortisol levels of 2.7 µg/dL (74.5 nmol/L). The normal reference ranges in adults are 7.2 to 63.3 pg/mL (1.6-13.9 pmol/L) for ACTH and 4.5 to 21.1 µg/dL (124.2-582.1 pmol/L) for cortisol. She was discharged at 40 weeks’ corrected gestational age, with subsequent normal growth and development.

Discussion

It remains challenging to manage Cushing disease during pregnancy because of limited treatment options and fetal safety concerns. An important aspect of managing hypercortisolemia in pregnancy is understanding the physiological regulation of the maternal-fetal HPA axis. In infants with very low birth weight, cortisol levels measured within an hour after birth typically range from 3.6 to 10.8 µg/dL (99-298 nmol/L) [12]. Although the neonate in this case had lower cortisol levels (2.7 µg/dL, 74.5 nmol/L), the blood sample was taken around noon, a time when levels are usually lower. Nevertheless, no signs of adrenal insufficiency were observed. Because newborns develop a stable cortisol rhythm within the first month [13], these findings suggest adequate adrenal function. Better obstetric outcomes can be expected when maternal hypercortisolism is successfully managed, such as reduced rates of prematurity and low birth weight [14]. A previous case report noted successful delivery after treatment with metyrapone, targeting UFC levels below 150 µg/day (414 nmol/day) [15]. Metyrapone was necessary in this patient because the cortisol levels were rising despite pasireotide monotherapy. This was gradually titrated to control UFC levels, which achieved some success. We introduced pasireotide during pregnancy based on previous reports of its use in acromegaly without adverse fetal outcomes [5]. However, pasireotide carries significant risk of hyperglycemia because of its inhibitory effects on insulin and incretin secretion [16]; this was seen in our patient, who required insulin therapy. Although rarely used in pregnancy—with only 1 reported case to our knowledge—it may be considered a viable option if other treatments are unsuccessful or unsuitable. Osilodrostat is contraindicated during pregnancy because it has shown teratogenic effects in animal studies, leading to limited human data [6]. In this case, the patient was unknowingly exposed during early pregnancy. However, no fetal malformations were observed, and this could be attributed to the underdeveloped fetal adrenal cortex during early gestation, which mainly relies on maternal hormone supply [10]. Osilodrostat was resumed after delivery, achieving effective disease control and clinical stability. It is also essential to consider that the preterm birth in this case may have resulted from suboptimal cortisol control, maternal COVID-19 infection, and the use of osilodrostat and pasireotide—drugs with minimal clinical data for use during pregnancy. These factors cannot be excluded entirely. However, based on our expertise, the contraindication of osilodrostat in pregnancy may warrant reevaluation.

Learning Points

  • Osilodrostat should not be used during pregnancy. Although preterm birth in this case may have resulted from various factors—including limited clinical data on osilodrostat and pasireotide—that the neonate showed no congenital abnormalities or adrenal problems indicates that the current caution against using osilodrostat in pregnancy might need to be reconsidered.
  • In early pregnancy, the fetal adrenal glands are immature and dependent on maternal hormones, so the effects of drugs that inhibit adrenal steroid synthesis may be relatively minor.
  • Pasireotide is rarely used during pregnancy. If administered, close monitoring is necessary, as insulin and incretin suppression may induce hyperglycemia.

From https://academic.oup.com/jcemcr/article/3/12/luaf269/8327956?login=false

 

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , , | Leave a comment »

Ultrasound-Guided Jugular Vein Access for Inferior Petrosal Sinus Sampling: A Safe and Feasible Technique

Posted on December 11, 2025 by MaryO

Abstract

Pituitary Cushing’s disease (CD) results from excessive adrenocorticotropic hormone (ACTH) secretion, usually due to a pituitary adenoma. This report describes the diagnostic approach and management of a complex case of CD in a patient with multiple comorbidities, highlighting a hybrid technique for inferior petrosal sinus sampling (IPSS) when standard access fails.

A woman with poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension presented with suspected Cushing’s syndrome. Despite normal urinary free cortisol (UFC) levels (likely influenced by renal dysfunction), clinical suspicion prompted further testing, which revealed an inverted cortisol rhythm and lack of suppression on low-dose dexamethasone. High-dose suppression indicated a pituitary source. MRI findings were inconclusive. To confirm the diagnosis, bilateral IPSS was attempted. Right petrosal sinus catheterization via femoral access was successful; however, left-sided access failed. An alternative, ultrasound-guided direct left internal jugular puncture was performed, allowing complete sampling. A central-to-peripheral ACTH gradient >2 at baseline and >3 after desmopressin confirmed a pituitary source. The patient subsequently underwent successful transsphenoidal resection, achieving postoperative biochemical remission.

IPSS remains the gold standard for distinguishing central from ectopic ACTH production. While bilateral femoral access is standard, anatomical variants may necessitate alternative routes. This case demonstrates the feasibility and safety of combining femoral and direct jugular access to complete IPSS when conventional approaches are limited.

This is the first reported case of IPSS performed using a hybrid right femoral and left ultrasound-guided jugular approach, offering a practical alternative when femoral access is not feasible and reinforcing the diagnostic value of IPSS in challenging cases.

Introduction

Pituitary Cushing’s disease (CD) is caused by excessive secretion of adrenocorticotropic hormone (ACTH), typically due to a pituitary adenoma. It represents the most common cause of endogenous Cushing’s syndrome, accounting for approximately 70% of ACTH-dependent cases [1,2]. The diagnostic approach often requires dynamic hormonal testing and neuroimaging; however, distinguishing pituitary from ectopic ACTH secretion remains a clinical challenge [3].

Inferior petrosal sinus sampling (IPSS), first described by Oldfield EH and Doppman JL in 1977, is considered the gold standard for confirming a pituitary origin when biochemical and imaging findings are inconclusive [4-6]. Bilateral catheterization via femoral venous access is the usual approach, guided by digital subtraction angiography (DSA) [4,5]. However, anatomical variants, thrombosis, and technical difficulties can impede standard catheterization, necessitating alternative strategies such as direct ultrasound-guided internal jugular puncture [7].

This report presents a patient with multiple comorbidities and suspected CD in whom a hybrid IPSS approach was successfully performed after failed standard access.

Case Presentation

A female patient with a history of poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension was admitted with suspected Cushing’s syndrome. Initial evaluation revealed normal urinary free cortisol (UFC), likely underestimated due to renal dysfunction. Because of high clinical suspicion, circadian cortisol rhythm was assessed, showing inversion with higher evening than morning levels, supporting hypercortisolism.

A low-dose dexamethasone suppression test (LDDST; 1 mg) failed to suppress cortisol, confirming endogenous hypercortisolism. A high-dose dexamethasone suppression test (HDDST; 8 mg) demonstrated 80% cortisol suppression, suggesting a pituitary source of ACTH overproduction.

Pituitary MRI revealed a poorly defined hypointense nodular area, inconclusive for microadenoma (Figure 1A). To confirm the central origin, bilateral inferior petrosal sinus sampling (IPSS) was performed (Figures 1B–1E).

(A)-Contrast-enhanced-pituitary-MRI-showing-a-hypointense-nodule-in-the-left-half-of-the-gland,-which-was-inconclusive;-(B)-right-internal-jugular-vein-access-achieved,-while-left-jugular-access-was-not-possible-via-this-route;-(C-and-D)-dual-inferior-petrosal-sinus-catheterization-with-right-sided-access-via-the-femoral-vein-and-left-sided-access-via-direct-jugular-puncture;-(E)-ultrasound-guided-placement-of-the-venous-sheath.
Figure 1: (A) Contrast-enhanced pituitary MRI showing a hypointense nodule in the left half of the gland, which was inconclusive; (B) right internal jugular vein access achieved, while left jugular access was not possible via this route; (C and D) dual inferior petrosal sinus catheterization with right-sided access via the femoral vein and left-sided access via direct jugular puncture; (E) ultrasound-guided placement of the venous sheath.

Initial access was established via the bilateral femoral veins with placement of 5 Fr introducer sheaths in both. Due to anatomical complexity and inability to access the left internal jugular vein via the femoral route, a direct ultrasound-guided left jugular puncture was performed. A separate 5 Fr introducer sheath was placed directly into the left internal jugular vein under ultrasound guidance (US guidance). Catheterization was performed using 5 Fr vertebral diagnostic catheters, facilitated by a micro-guidewire.

Correct positioning within the petrosal sinuses was subsequently confirmed by contrast injection. The results demonstrated accurate catheter placement in the inferior petrosal sinuses (adequate prolactin levels), with an ACTH central-to-peripheral gradient greater than 2 at baseline and greater than 3 after desmopressin, thus confirming a pituitary source for the pathology (Tables 1–2).

Peripheral Right IPS Left IPS
16.5 ng/mL 41.2 ng/mL 63.7 ng/mL
Table 1: Prolactin concentrations obtained via inferior petrosal sinus sampling at baseline.

IPS: Inferior Petrosal Sinus.

Time Point Peripheral Right IPS Left IPS
Basal 27.5 pg/mL 77.1 pg/mL 106 pg/mL
Desmopressin 5 min 28.3 pg/mL 168 pg/mL 221 pg/mL
Desmopressin 10 min 27.9 pg/mL 32 pg/mL 80 pg/mL
Table 2: ACTH concentrations obtained via inferior petrosal sinus sampling at baseline and at 5 and 10 minutes after desmopressin stimulation.

IPS: Inferior Petrosal Sinus; ACTH: Adrenocorticotropic hormone.

The patient underwent endonasal transsphenoidal resection of an ACTH-secreting pituitary microadenoma. Postoperatively, serum cortisol fell to <5 µg/dL, indicating secondary adrenal insufficiency, and physiologic glucocorticoid replacement was initiated. Urine output remained normal (no evidence of vasopressin deficiency), and steroid replacement was titrated without adrenal crisis.

Discussion

Diagnostic considerations

CKD can lead to falsely normal UFC values due to impaired renal clearance of cortisol metabolites [8]. Therefore, alternative biochemical tests such as late-night serum cortisol or dexamethasone suppression are recommended in these patients [1,3]. The high-dose dexamethasone suppression observed here supported a pituitary origin, but confirmation by IPSS was critical given the inconclusive MRI findings.

Inferior petrosal sinus sampling

Since its introduction, IPSS has become the reference standard for distinguishing pituitary from ectopic ACTH production, with reported sensitivity and specificity of approximately 96% and 100%, respectively [4-6,9]. The test involves measuring ACTH gradients between central (petrosal) and peripheral samples, values ≥2 at baseline or ≥3 after corticotropin-releasing hormone (CRH) or desmopressin stimulation indicate a central source [5,9].

Desmopressin stimulation

Although CRH has traditionally been used, desmopressin is an effective and safe alternative that achieves comparable diagnostic accuracy [10]. In our case, desmopressin successfully elicited a diagnostic gradient, confirming the pituitary source.

Technical challenges and hybrid approach

Although the conventional IPSS technique uses bilateral femoral access, the procedure was originally performed via direct jugular puncture [2]. Variations in venous anatomy, hypoplasia, or catheterization failure may necessitate alternative routes. Direct ultrasound-guided jugular puncture offers an effective solution, minimizing procedural time and radiation exposure, and reducing the risk of complications such as cervical hematoma. Our case illustrates that combining femoral and direct jugular access allows complete bilateral sampling without compromising safety.

Conclusions

This case demonstrates the feasibility and safety of a hybrid IPSS approach combining right femoral and ultrasound-guided direct left jugular access. This method enabled successful completion of bilateral sampling when standard femoral catheterization failed. The case reinforces IPSS as a critical diagnostic tool for confirming pituitary Cushing’s disease, even in technically challenging circumstances.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-1540. 10.1210/jc.2008-0125
  2. Perlman JE, Johnston PC, Hui F, et al.: Pitfalls in performing and interpreting inferior petrosal sinus sampling: personal experience and literature review. J Clin Endocrinol Metab. 2021, 106:e1953-e1967. 10.1210/clinem/dgab012
  3. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am . 2021, 30:729-747. 10.1016/s0889-8529(05)70209-7
  4. Oldfield EH, Doppman JL, Nieman LK, et al.: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med. 1991, 325:897-905. 10.1056/NEJM199109263251301
  5. Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P: Bilateral inferior petrosal sinus sampling. Endocr Connect. 2016, 5:R12-R25. 10.1530/EC-16-0029
  6. Vassiliadi DA, Mourelatos P, Kratimenos T, Tsagarakis S: Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine. 2021, 73:530-539. 10.1007/s12020-021-02764-4
  7. Yeh CH, Wu YM, Toh CH, Chen YL, Wong HF: A safe and efficacious alternative: sonographically guided internal jugular vein puncture for intracranial endovascular intervention. AJNR Am J Neuroradiol. 2012, 33:E7-E12. 10.3174/ajnr.A2416
  8. Kidambi S, Raff H, Findling JW: Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007, 157:725-731. 10.1530/EJE-07-0424
  9. Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH: The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J Clin Endocrinol Metab. 2013, 98:2285-2293. 10.1210/jc.2012-3943
  10. Malerbi DA, Mendonça BB, Liberman B, et al.: The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf). 1993, 38:463-472. 10.1111/j.1365-2265.1993.tb00341.x

From https://www.cureus.com/articles/429423-ultrasound-guided-jugular-vein-access-for-inferior-petrosal-sinus-sampling-a-safe-and-feasible-technique#!/

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: , , , | Leave a comment »

Diabetic Ketoacidosis as the First Manifestation of Ectopic Cushing’s Syndrome

Posted on December 9, 2025 by MaryO

Abstract

Diabetic ketoacidosis is an exceptionally rare initial manifestation of ectopic adrenocorticotropic hormone (ACTH) syndrome. A 42-year-old woman with multiple cardiovascular risk factors was admitted to the emergency room with diabetic ketoacidosis. During stabilization, florid Cushing’s syndrome was suspected and confirmed biochemically as ACTH-dependent. Further biochemical and imaging surveys led to the diagnosis of a 25×15 mm nodule in the lingula. Thoracic surgery was performed, and pathology revealed a neuroendocrine tumor positive for ACTH.

We reviewed eight additional cases of diabetic ketoacidosis associated with Cushing’s syndrome from PubMed. Clinicians should bear in mind this etiology of diabetic ketoacidosis based on clinical signs and younger patients with multiple, age-atypical comorbidities. This would permit the expedited targeted stabilization of Cushing’s syndrome and the suitable institution of the diagnostic approach and treatment for this challenging syndrome.

Introduction

Endogenous Cushing’s syndrome (CS) is a rare disease resulting from pathological glucocorticoid excess of neoplastic origin, with an annual incidence of two/three cases per 1.000.000 inhabitants [1]. The severity of CS varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (80%) and -independent (20%) forms. ACTH-dependent CS is further divided into Cushing’s disease (68%) when the pituitary is the source of excess ACTH, or ectopic ACTH syndrome (EAS; 12%) when the cause is a non-pituitary neoplasia of neuroendocrine origin. EAS has an annual incidence of one case per 1.250.000 inhabitants and is more frequent in men [1]. It can be secondary to an aggressive small-cell lung carcinoma (19%), but the majority of cases arise from indolent lesions such as bronchial and thymic (combined: 33%) or pancreatic (12%) neuroendocrine tumors (NET) [1-3]. These indolent lesions usually evolve clinically over 6 to 24 months, whereas carcinomas have a faster onset. Symptoms and signs of excess cortisol in EAS are usually indistinguishable from Cushing’s disease. The most discriminatory signs of CS are plethora, purplish striae, proximal myopathy, and spontaneous ecchymosis. Multiple vascular risk factors, namely, hypertension, diabetes mellitus (DM), dyslipidemia, and obesity (especially central adiposity), occurring in a young patient, should also raise suspicion for CS [2]. Diabetic ketoacidosis (DKA) as the inaugural presentation of CS is very rare [1-3]. We searched through PubMed and reviewed articles in English where this association was reported using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”. CS presenting initially with DKA is, as to this day, limited to eight case reports [4-11]. The clinical recognition of this syndrome as a very rare etiology of DKA is of paramount importance, as it is usually severe and relates to sepsis and several biochemical, hematologic, and hemodynamic derangements that should be addressed expeditiously with targeted drugs [3].

Here, we describe a female patient with florid clinical EAS uncovered upon her admission to the Emergency Room (ER) due to DKA. We searched through PubMed and reviewed articles in English where this association was reported, using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”.

This article was previously presented as a meeting abstract at the 2024 ENDO, The Endocrine Society Annual Meeting on June 3, 2024.

Case Presentation

A 42-year-old woman was admitted in June 2022 to the ER due to severe DKA and hypokalemia (Table 1) and mild coronavirus disease. Physical examination at initial presentation was also remarkable for grade 2 hypertension with hypertensive retinopathy. Florid Cushingoid features, including a “buffalo hump”, plethora, hirsutism, abdominal ecchymosis, and marked proximal limb sarcopenia were noted (Figure 1).

Patient's-Cushingoid-features
Figure 1: Patient’s Cushingoid features

The patient was transferred to the intensive care unit (ICU). A multimodal treatment plan was initiated, including intravenous insulin (total daily dose: 1.2U/Kg) as per the protocol for DKA, antihypertensives, and prophylactic doses of low-molecular-weight heparin. After resolution of DKA and hydroelectrolytic disturbances, a gasometric follow-up revealed metabolic alkalosis (pH 7.529). The patient was then able to report a six-month history of weight gain, secondary amenorrhea, impaired concentration and memory, ecchymoses, and proximal myopathy with frequent falls and dependency on relatives for daily life activities. No chronic diarrhea or flushing was reported. She also reported a fungal pneumonia, dyslipidemia, and hypertension in the last four months, and a diagnosis of DM treated with metformin two weeks before her admission to the ER. Family history was unremarkable. Biochemical surveys (Table 1) revealed ACTH-dependent hypercortisolism, low thyroid-stimulating hormone (TSH), and hypogonadotropic hypogonadism. High-dose dexamethasone suppression (HDDS) and corticotropin-releasing hormone (CRH) stimulation tests were not suggestive of a pituitary source of ACTH (Table 1). Pituitary magnetic resonance imaging was normal. While waiting for further investigations regarding the source of excess ACTH, the patient was started on 750 mg/day of metyrapone in three divided doses. The patient was started and discharged from the ward with hydrocortisone 10 mg in the morning and 5 mg at midday and in the afternoon. The dose of metyrapone was carefully adjusted during two months according to morning serum cortisol, but was rapidly decreased and stopped due to spontaneous clinical resolution of CS. In the postoperative follow-up (total: 23 months), Cushingoid features (plethora, dorsal fat pad, ecchymosis, central adiposity) continued to disappear, and she regained muscle mass and independence in her daily activities and remission from all glucocorticoid related-comorbidities was maintained (fasting glucose: 91 mg/dL; glycated hemoglobin (HbA1c): 5.8%; low-density lipoprotein (LDL) cholesterol: 138 mg/dL; triglycerides: 80 mg/dL). Twelve months after surgery, the patient was able to discontinue hydrocortisone upon biochemical evidence of restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). Her last (23 months after surgery) endocrine surveys (midnight salivary cortisol: 0.14 ug/dL; ACTH: 18 pg/mL) and thoracic CT showed no evidence of disease relapse.

Parameter Presentation 12-month follow-up Reference
Hemoglobin (g/dL) 12.8 – 12-15.5
White blood count (×103/uL) 11.3 – 4.0-11.5
Platelets (×103/uL) 331 – 150-400
Fasting blood glucose (mg/dL) 427 76 74-106
HbA1c (%) 9.6 5.6 <6.5
Serum sodium (mmol/L) 146 – 135-145
Serum potassium (mmol/L) 2.7 – 3.5-5.1
Serum creatinine (mg/dL) 0.32 0.59 0.67-1.17
pH 7.17 – 7.35-7.45
HCO3– (mmol/L) 4.4 – 21-26
Anion gap 35 – 7
IGF-1 (ng/mL) 89.8 – 77-234
FSH (mUI/mL) 0.9 –¥ 3.5-12.5
LH (mUI/mL) <0.1 –¥ 2.4-12.6
Prolactin (ng/mL) 8.8 – 4.0-24.3
TSH (UI/mL) 0.02 0.61 0.35-4.94
Free T4 (ng/dL) 1.26 1.02 0.7-1.48
Midnight salivary cortisol (ug/dL) 25.5 2.4* <7.5
UFC (ug/dL) 1072.5 74.5* <176
Cortisol at 1 mg overnight DST (ug/dL) 25.7 – <1.8
Cortisol, baseline (ug/dL) 30.9 11.4* 5-18
Cortisol after HDDS test (ug/dL) 42.1 – Refer to reference 2
ACTH, baseline (pg/mL) 93.4 22.1* 7.2- 63.3
ACTH, maximum after CRH (pg/mL) 101.8 – Refer to reference 2
Table 1: Biochemical surveys of the patient at baseline and at the 12-month follow-up

* After metyrapone washout

¥ Gonadotropins not repeated due to resumption of regular menses

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DST, dexamethasone suppression test; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; HDDS, high-dose dexamethasone suppression; IGF-1, insulin-like growth factor type 1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; UFC, urinary free cortisol

She was referred for inferior petrosal sinus sampling (IPSS) but it was postponed for several months due to healthcare strikes. While waiting for IPSS, she performed a thoracic computerized tomography (CT) scan to exclude EAS, which revealed thymic hyperplasia and a 25×15 mm, well-defined nodule in the lingula (Figure 2).

Thoracic-CT-scan-revealed-a-25x15-mm,-well-defined-nodule-in-the-lingula
Figure 2: Thoracic CT scan revealed a 25×15 mm, well-defined nodule in the lingula

A 68Ga-DOTANOC positron emission tomography-computed tomography (PET/CT) was then performed and showed a single uptake in the same lung region (Figure 3).

68Ga-DOTANOC-PET/CT-showing-a-single-uptake-in-the-lingula.
Figure 3: 68Ga-DOTANOC PET/CT showing a single uptake in the lingula.

Abbreviations: PET/CT, positron emission tomography-computed tomography

The patient was referred to thoracic surgery and underwent lingulectomy plus excisional biopsy of the interlobar lymph nodes. Pathology revealed a typical carcinoid/neuroendocrine tumor (NET), grade one (Ki67<2% and <2 mitosis per high-power field (HPF)) without involved lymph nodes, which showed positivity for ACTH (Figure 4).

Immunohistochemistry-findings
Figure 4: Immunohistochemistry findings

a- hematoxylin and eosin x400 magnification, b- synaptophysin x100 magnification, c- chromogranin A x400 magnification, d- ACTH x400 magnification, e- Ki-67 x100 magnification.

The patient was started on hydrocortisone 10 mg in the morning and 5 mg at midday and afternoon, which was discontinued 11 months later due to restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). In the postoperative follow-up, Cushingoid features continued to disappear, and she regained muscle mass and independence in her daily activities. Her last CT showed no evidence of disease.

Discussion

Severe CS (SCS) is defined by random serum cortisol above 41 ng/dL and/or a urinary free cortisol (UFC) more than fourfold the upper limit of normal and/or severe hypokalemia (<3.0 mmol/L), along with the recent onset of one or more of the following: sepsis, opportunistic infection, refractory hypokalemia, uncontrolled hypertension, edema, heart failure, gastrointestinal bleeding, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism, uncontrolled hyperglycemia and ketoacidosis [3]. SCS results in high morbidity and mortality, requiring a rapid recognition and targeted therapy of the uncontrolled hypercortisolism [3]. Patients with SCS usually have florid signs, and straightforward clinical suspicion is possible, except in cases of ECS due to small-cell lung carcinoma, where the rapid onset of hypercortisolism and related morbidity precedes the development of clinical stigmata [2,3]. The gasometric parameters in DKA associated with SCS can also provide clues for the presence of CS. The mineralocorticoid effect of excess cortisol leads to metabolic alkalosis through increased hydrogen excretion in the distal nephron, which is masked by metabolic acidosis due to excess β-hydroxybutyrate and acetoacetate [6,12,13]. This mixed acid-basic disorder can be suspected by a ratio of ∆anion gap to ∆HCO3 of higher than one, which is not seen in pure metabolic acidosis. Additionally, after treating the DKA by decreasing ketones through the inhibition of its production by insulin and increased renal excretion with improved renal perfusion, metabolic alkalosis may supervene in gasometric monitoring, as seen in our report and others [6,9]. In rare cases, SCS can also lead to diabetic ketoalkalosis instead of DKA [1]. Several factors may contribute to the predominant alkalosis, namely, decreased hydrogen due to high renal excretion (excess mineralocorticoid effect), intracellular shift (due to severe hypokalemia), gastrointestinal losses (vomiting), and hyperventilation due to pulmonary diseases (as in heavy smokers) [13,14].

The main priorities in managing SCS are to control opportunistic infections, hypokalemia, DM, hypertension, and psychosis, and, importantly, investigations of the etiology of CS should be postponed until clinical stabilization [3]. The control of glucocorticoid-induced complications should encompass therapies to stabilize/reverse the CS induced morbidity (e.g., large-spectrum antibiotics for opportunistic infections; spironolactone for hypokalemia; insulin for DM) followed by targeted treatment of hypercortisolism [3]. Several oral adrenolytic agents are available and have proved their usefulness in SCS, namely, metyrapone (onset: hours; UFC normalization: 83%), ketoconazole/levoketoconazole (onset: days; UFC normalization: 70-81%), osilodrostat (onset: hours; UFC normalization: 82%), and mitotane (onset: days to weeks; UFC normalization: 72-82%). They can be used in monotherapy or in combination therapy, the latter strategy increasing the efficacy with lower doses of drugs and a lower risk of side effects [3,14]. Additionally, as first-line therapy for patients with an unavailable oral route (e.g., glucocorticoid-induced psychosis), or as second-line therapy when other adrenolytic agents have failed to control hypercortisolism, the anesthetic etomidate can be used under multidisciplinary supervision in an ICU, and it is highly effective (~100%) in controlling SCS within hours, in doses that do not induce anesthesia [3]. If medical therapy proves unsuccessful, bilateral adrenalectomy may be considered after careful clinical judgement, as it is highly effective in life-threatening SCS uncontrolled by medical therapy. Nevertheless, all attempts should be made to reduce hypercortisolemia with medical therapy before surgery [3].

DKA, as the inaugural presentation of CS, was previously published in eight case reports [4-11] (Table 2). Briefly, and including our case, almost all reports were severe (77.8%), mainly from EAS (55.6%) or pituitary adenomas (33.3%), and with a female preponderance (77.8%).

Reference Gender Age Florid CS signs Severe CS Etiology of CS Definitive treatment
Uecker JM, et al. [4] Female 43 Yes Yes EAS (duodenal NET) Pancreaticoduodenectomy
Kahara T, et al. [5] Male 53 No No ACTH-independent Adrenalectomy
Weng Y, et al. [6] Female 28 Yes Yes Cushing’s disease (macroadenoma) Transsphenoidal surgery
Catli G, et al. [7] Female 16 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Sakuma I, et al. [8] Female 56 Yes Yes EAS (pheochromocytoma) Adrenalectomy
Achary R, et al. [9] Female 48 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Cheong H, et al. [10]* Female 22 Unknown Unknown EAS (medullary thyroid carcinoma) None
Shangjian L, et al. [11] Male 46 Unknown Yes EAS (pheochromocytoma) Adrenalectomy
Our case Female 42 Yes Yes EAS (bronchial NET) Thoracic surgery
Table 2: Review of published cases of DKA as the inaugural presentation of CS

*Deceased

Abbreviations: ACTH, adrenocorticotropic hormone; CS, Cushing’s syndrome; EAS, ectopic ACTH syndrome; NET, neuroendocrine tumor

The etiology of CS should be investigated in diagnostic steps. After confirming hypercortisolism (low-dose dexamethasone suppression test, UFC, and/or late-night salivary cortisol) and its ACTH dependence (usually well above 20 pg/mL in EAS), the source of excess ACTH should be pursued. The CRH test is the most accurate dynamic test to distinguish between pituitary and ectopic sources of ACTH, followed by the desmopressin and HDDS tests. The combination of CRH and HDDS tests has an accuracy close to the IPSS, the gold standard to distinguish pituitary from ectopic sources of ACTH. If the investigation approach points to EAS, the most accurate exam to detect a lesion is 68Ga-DOTA-somatostatin analogue PET/CT, followed by 18F-FDG PET and conventional cross-sectional imaging [1-3].

After being discharged from the ward, our patient showed spontaneous resolution of hypercortisolism requiring the withdrawal of metyrapone and all medications to control glucocorticoid-induced morbidity, suggesting cyclic CS. This very rare variant of CS is present when periods of hypercortisolism alternate with periods of normal cortisol secretion, each phase lasting from days to years, which makes this type of CS very challenging to manage. The pituitary is the main source of cyclic CS, followed by EAS and, infrequently, the adrenal gland. The criteria of three peaks and two periods of normal or low cortisol levels needed to diagnose cyclic CS were not seen in the follow-up period of our patient, as after one peak and trough, we found and removed the source of EAS [1].

Conclusions

In the context of DKA, florid Cushing signs and multiple vascular risk factors occurring in a young patient should raise suspicion for Cushing’s Syndrome. The severity of this syndrome varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Diabetic ketoacidosis precipitated by an endogenous excess of glucocorticoid is usually associated with severe Cushing’s syndrome and more frequently with EAS, which can have an abrupt onset. Prompt recognition and targeted stabilization of severe Cushing’s syndrome are crucial and should precede a definitive etiologic investigation.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Hayes AR, Grossman AB: Distinguishing Cushing’s disease from the ectopic ACTH syndrome: needles in a haystack or hiding in plain sight?. J Neuroendocrinol. 2022, 34:e13137. 10.1111/jne.13137
  3. Alexandraki KI, Grossman AB: Therapeutic strategies for the treatment of severe Cushing’s syndrome. Drugs. 2016, 76:447-58. 10.1007/s40265-016-0539-6
  4. Uecker JM, Janzow MT: A case of Cushing syndrome secondary to ectopic adrenocorticotropic hormone producing carcinoid of the duodenum. Am Surg. 2005, 71:445-6.
  5. Kahara T, Seto C, Uchiyama A, et al.: Preclinical Cushing’s syndrome resulting from adrenal black adenoma diagnosed with diabetic ketoacidosis. Endocr J. 2007, 54:543-51. 10.1507/endocrj.k06-071
  6. Weng YM, Chang MW, Weng CS: Pituitary apoplexy associated with cortisol-induced hyperglycemia and acute delirium. Am J Emerg Med. 2008, 26:1068.e1-3. 10.1016/j.ajem.2008.03.023
  7. Catli G, Abaci A, Tanrisever O, Kocyigit C, Sule Can P, Dundar BN: An unusual presentation of pediatric Cushing disease: diabetic ketoacidosis. AACE Clinical Case Reports. 2015, 1:53-8. 10.4158/EP14284.CR
  8. Sakuma I, Higuchi S, Fujimoto M, et al.: Cushing syndrome due to ACTH-secreting pheochromocytoma, aggravated by glucocorticoid-driven positive-feedback loop. J Clin Endocrinol Metab. 2016, 101:841-6. 10.1210/jc.2015-2855
  9. Acharya R, Kabadi UM: Case of diabetic ketoacidosis as an initial presentation of Cushing’s syndrome. Endocrinol Diabetes Metab Case Rep. 2017, 2017:10.1530/EDM-16-0123
  10. Cheong H, Koo HL: Medullary thyroid carcinoma with diabetic ketoacidosis: an autopsy case report and literature review. Forensic Sci Med Pathol. 2021, 17:711-4. 10.1007/s12024-021-00407-8
  11. Li S, Guo X, Wang H, Suo N, Mi X, Jiang S: Ectopic adrenocorticotropic hormone-secreting pheochromocytoma with severe metabolic disturbances: a case report. Int J Surg Case Rep. 2024, 116:109341. 10.1016/j.ijscr.2024.109341
  12. Kraut JA, Madias NE: Serum anion gap. Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007, 2:162-74. 10.2215/CJN.03020906
  13. Uwaifo G, Varughese AG: ODP245 Syndrome of diabetic ketoalkalosis due to severe hypercortisolemia: a case series. J Endocr Soc. 2022, 6:A334. 10.1210/jendso/bvac150.693
  14. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818

From https://www.cureus.com/articles/426071-diabetic-ketoacidosis-as-the-first-manifestation-of-ectopic-cushings-syndrome#!/

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