An interesting case of Hypercalcemia of malignancy.

Original case by Cheng Cheng, Jose Kuzhively, and Sanford Baim

A 26-year-old African American male, with no significant past medical history, presented to the emergency department in early November 2016 with complaints of fever, malaise, 18 lb weight loss over 2 weeks, and multiple neck masses

Q  What is definition of clinically significant weight loss ?

>5% weight loss over period of 6-12 months

Q  What is Cachexia and Sarcopenia ?

  1. Sarcopenia- reduction in muscle mass, strength or function with or without weight loss- eg: Sarcopenia can also occur in obese
  2. Cachexia= weight loss + loss of muscle mass

Q  Enlist the causes of unintentional weight loss ?


  1. Vascular- CCF- Cardiac cachexia
  2. Infective- HIV, tuberculosis
  3. Neoplasm – malignant – GI and Non GI malignancies
  4. Drugs
  5. Autoimmune – Lawrence syndrome- acquired generalized lipodystrophy
  6. E- Endocrinopathies- see next page
  7. Non maligant GI disorder
  8. Pulmonary disorder- COPD, Pulmonary chachexia
  9. Pyschiatric problems- anorexia nervosa, depression
  10. Neurological disorders
  11. Rheumatological disorders
  12. CKD
  13. CLD

Q  What are endocrine causes of weight loss ?

  1. Adrenal insufficiency
  2. Hyperthyroidism
  3. Type 1 diabetes
  4. Glucogonoma
  5. Pheochromocytoma
  6. Endocrine malignacies

Medications prior to admission consisted of cyclobenzaprine, meloxicam, tramadol, and recreational use of marijuana. Initial imaging revealed an anterior mediastinal mass with intrathoracic lymphadenopathy, bilateral pulmonary nodules, and spine lesions on CT

Q Name some important causes of anterior mediastinal mass ?

  1. Thymic mass- thymic enlargement or thymic carcinoma
  2. Lymphoma
  3. Substernal/ ectopic goiter
  4. Germ cell tumor- mediastinum is the most common site for extragonadal germ cell tumors

Q Which endocrine related condition must be ruled out in case of mediastinal germ cell tumors ?

  • Klienfelter syndrome

Physical exam demonstrated bilateral supraclavicular lymphadenopathy that was tender to palpation, pain on palpation of the cervical and lumbar spine, and normal neurological exam.

Labs on admission were notable for corrected total calcium (Calc) of 15.1 mg/dL, ionized calcium (iCa) of 1.59 mg/dL (ref: 0.95–1.32 mg/dL), PTH of 4.8 pg/mL (ref: 8–85 pg/mL), phosphorus (Phos) of 2 mg/dL (ref: 2/5–4.6 mg/dL), creatinine of 1.16 mg/dL (ref: 0.75–1.2 mg/dL), and blood count with no atypical cells seen on the differential

Q What is your interpretation of the cause of hypercalcemia in this case ?

  • This is hypercalcemia with clearly suppressed PTH.
  • This is most certainly a case of PTH independent hypercalcemia.
  • Q What PTH value suggest PTH independent hypercalcemia ?
  • Typically PTH <20 pg/ml generally suggest PTH independent hypercalcemia ?

Aggressive IV hydration with normal saline at a rate of 250 cc/hr was promptly started and maintained throughout this admission with administration of pamidronate 90 mg on hospital day 2.

Q Give the proposed line of treatment for severe hypercalcemia ?

  • Injection Normal Saline
    • 250 ml/hr for 2 hrs followed
    • 150 ml/hr for next 20 hrs
    • 100 m/hr for next 24 hrs
    • Diuretics not used routinely and given only if the patient develops fluid overload or has congestive cardiac failure.
    • TEST DOSE : 4 units / kg subcutaneously stat (Approximately 200 units) – repeat serum calcium after 3 hrs. If there is no fall in calcium or patient has reaction to calcitonin then it is not continued any more – If the response is seen then give a dose of 4 units/kg subcutenously every 12 hrs
    • Increase the dose to 8 units/kg every 12 hrs if little response seen in 1-2 days. The dose and frequency may be further increased upto maximum dose of 8 units/kg every 6 hrs
    • Effect seen for generally 3-5 days only . After this tachyphylaxis to calcitonin often develops
    • Patient may develop nausea and vomiting with calcitonin. Inj EMSET (ondensatron) may be given sos if nausea/ vomiting develops
  • Inj Zolendronic acid (Inj NATZOLD)
    • Given on first or second day itself
    • Avoided if Parathyroid surgery is planned within 1-2 days
      • 150 ml of Normal saline f/b
      • Inj NATZOLD 5 mg (100ml) infusion over 15 min f.b
      • 150 ml of normal saline
    • W/f fever, joint pain etc for 24 hrs- if this develop NSAIDs may be given
    • Take 2-5 days for onset of effect
    • Effect lasts for 2-8 weeks. In patient with malignancy associated hypercalcemia which cannot be treated otherwise- the dose may be repeated after 1 month
    • 30 mg OD starting dose ( Maximum of 90 mg QID)
    • Given as alternate to Zolendronate in patients with hyperparathyroidism in whom surgery is planned
  • Hemodialysis
    • Considered in patients with acute renal failure and/or Serum Calcium >18 mg/dl with neurological symptoms
  • Denusomab
    • Indications
      • Hypercalcemia with renal failure
      • Hypercalcemia refractory to bisphosphonates
    • Dose
      • Inj XGEVA – 120 mg subcutaneously weekly for 4 weeks followed by monthly
    • Glucocorticoid
      • Inj Hydrocortisone (Inj Effcorlin) 100 mg IV /8hrly
      • Or if patient takes orally T. Prednisolone ( Wysolone) 40 mg per day
      • Given in case of vitamin D toxicity or granulomatous disease associated hypercalcemia
    • Once the patient becomes better and the etiology for hypercalcemia not treated then patient advice
      • Good oral hydration- 6-8 glasses of water /day
      • Low calcium diet
      • Avoid prolonged bedrest
      • Avoid thiazide diuretics
    • Check serum calcium and serum creatinine daily

Additional studies included supraclavicular lymph node and bone marrow biopsies consistent with Epstein-Barr virus positive metastatic undifferentiated, non-keratinizing, lymphoepithelioma-like carcinoma of thymic origin. After undergoing staging with additional imaging, the patient completed his first cycle of chemotherapy with cisplatin, doxorubicin, and cytoxan in the next 2 weeks. His Calc decreased to 10.5 mg/dL at the time of discharge.

Approximately 2 weeks after discharge, the patient was readmitted for a second admission with increasing somnolence. Laboratory analysis disclosed Calc of 15.4 mg/dL and iCa of 1.72 mg/dL for which IV hydration with normal saline at 250 cc/hr was initiated followed by pamidronate 90 mg and calcitonin 300 U with improvement of iCa to as low as 1.16 mg/dL.

PTH-related peptide (PTHrP) and 1,25-dihydroxyvitamin D (calcitriol) were sent during this admission but results were not available.


Q Why did they send 1,25 dihydroxyvitamin D ?

    • Granulomatous disease increase produce of 1 alpha hydroxylase enzyme leading to increase 1,25 dihydroxyvitamin D levels.

Q What is the differene in actions of PTHrP and PTH in relation to calcium and phosphate ?

    • PTHrP does not increase 1,25 dihydroxy vitamin D, however it does cause phosphaturia.
    • Hence in case of a PTHrP producing tumor the typical biochemical picture is as follows:
  1. Serum calcium- high
  2. Serum phosphate- low
  3. PTH- low
  4. 1,25 dihydroxyvitamin D – low

Repeat MRI of the entire spine noted new hyperintense metastatic lesions.

Over the ensuing 3 days, iCa slowly increased to 1.46 mg/dL and required administration of zoledronate 4 mg resulting in normalization of iCa between 1 and 1.1 mg/dL for the rest of the admission (Figure 1). The patient subsequently began cycle 2 of cisplatin, doxorubicin, and cytoxan which was completed prior to discharge with a plan to initiate denosumab as an outpatient

During outpatient follow-up and 5 days after discharge, a rapid rebound in hypercalcemia occurred with Calc of 12.6 mg/dL and iCa of 1.46 mg/dL, requiring administration of denosumab 120 mg which decreased iCa to 1.25 mg/dL (Figure 1). A second dose of denosumab 120 mg was given 1 week later with concurrent Calc of 12.7 mg/dL.

Q What percentage of calcium is ionized  ?

  • 50% of calcium is in ionized form
  • 40% – protein bound
  • 10% – bound to inorganic acids
  • Q In which conditions is measurement of ionized calcium important ?
  1. Acid base disorder
  2. Hypoalbuminemia
  3. CKD

Q How is mmol/l converted to mg/dl ?

  • Mmol/lt = (mg/dl x 10 ) / mol wt

Q What is the conversion for calcium ?

  • Mol wt is 40 and valence is 2
  • Mg/dl divide by 4 = mmol/lt

Q How is calcium adjusted for albumin ?

  • Correct calcium = measured calcium + 0.8 x (4- measured serum albumin)
  • Total calcium falls by 0.8 mg/dl for every 1 g/dl fall in albumin

Q What happens in patients with multiple myeloma ?

  • They have pseudohypercalcemia
  • This is because of increase of calcium bound to myeloma cells
  • Since MM itself may be associated with increase calcium, it is important to use ionized calcium for the same

Q How do acid base disorders change ionized calcium ?

  • Alkalosis – there is increase binding of calcium to albumin thus reducing ionized calcium

Q What is the effect of PTH on ionized calcium ?

  • PTH sepearates calcium from albumin and increases the ionized calcium

Q What is the effect of phosphate on ionized calcium ?

  • Acute hyperphosphatemia will reduce the ionized calcium
  • This is because it will bind with the ionized calcium
  • Gradually the total calcium will also drop

Q Why is total calcium and calcium calculations not reliable in patients with CKD ?

  1. CKD patients have metabolic acidosis hence higher ionized calcium
  2. The albumin correction formula overestimates the ionized calcium in CKD patients

Hence in CKD patients it is preferable to measure ionized calcium directly

Q What is the normal ionized calcium value in adults ?

  • In adults normal values of ionized calcium is  64 to 5.28 mg/dl
  • This is equivalent to 1.15 to 1.3 mmol/ (approx)

One month later, the patient was readmitted with altered mental status with Calc of 13.6 mg/dL, iCa of 1.53 mg/dL, Phos of 1.6 mg/dL, and normal renal function. The patient received prompt administration of IV hydration with normal saline and pamidronate 90 mg. Although iCa level decreased to 1.3–1.4 mg/dL within 2 days, it rebounded over the next 24–48 hours to 1.64 mg/dL, requiring further administration of zoledronate 4 mg

At this time, it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL) and PTHrP at 27 pg/mL (ref: 14–27 pg/mL). Methylprednisolone 60 mg per day was subsequently instituted over the next 2 days with decrease in iCa level to 1.3–1.4 mg/dL

However, the patient continued to clinically deteriorate, despite iCa being maintained at 1.3–1.4 mg/dL (Figure 1) with development of multiorgan failure, and he expired shortly after. It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively.

Q What will you suspect in a case of hypercalcemia associated in malignancy where PTHrP and 1,25 dihydroxyvitamin D are normal, PTH is suppressed and there is no evidence of osteolytic metastasis ?

  • Think of Hypercalcemia of malignancy associated with cytokine/chemokine associated bone resorption.

Q Enlist the etiologies for hypercalcemia of malignancy ?

  1. Local osteolytic hypercalcemia – due to osteolytic metastasis
  2. Increase 1,25 dihydroxy vitamin D production
  3. Ectopic PTHrP production
  4. Ectopic PTH production
  5. Cytokine/chemokine associated hypercalcemia

Q What is the possible etiology of hypercalcemia in this case ?

  • In this case multiple reasons for hypercalcemia may be present either togather or evolving over time.
  • The patient has
  1. Metastasis to the bones which may have been osteolytic (“Repeat MRI of the entire spine noted new hyperintense metastatic lesions)
  2. Increase 1,25 dihydroxyvitamin D levels due to tumor producing 1 alpha hydroxylase.  (it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL)
  3. Ectopic PTHrP production (It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively)
  4. Hypercalcemia secondary to cytokine / chemokines.

Learning objective

  • In a patient with hypercalcemia of malignancy , multiple causes of hypercalcemia may exist in the same patient.
  • Denusomab is useful in case of hypercalcemia refractory to bisphosphonate therapy.




Since last couple of months, lots of people have asked me about a message that has gone viral about ‘Cholesterol’ The post I am talking about is in the picture below and I am sure many of you have read it. Infact, many people I know stopped taking their anti-cholesterol (Statins) medications after reading the Whataspp message !

Now I cannot do anything for people who stop medications after reading a Whatsapp message but even doctors are circulating this post without verifying the information.

Hence, I did my research to find out the TRUTH ABOUT THIS POST and found that this post is a combination of half-baked news report first published in ‘The Washington Post’ combined with some ‘masala’ some people have added while circulating the post.

Here is a clarification, so if you are really interested in your health , READ ON:


  1. The first part of the post was actually published in ‘The Washington post’ and though misleading it is not wrong.
  2. The US Department of Agriculture in their new dietary guidelines have removed Dietary cholesterol from list of harmful substances. This is a fact and it is verifiable. Now, why the said US agency has made this recommendation is difficult to say, however, let us assume it is evidence based and factually correct.

But remember, the recommendations are about DIETARY CHOLESTEROL and not the Cholesterol present in your body. Previously it was recommend to restrict intake of cholesterol in diet, however now they are saying not to restrict cholesterol in your diet. THEY ARE NOT TAKING ABOUT CHOLESTEROL IN YOUR BODY, THEY ARE TALKING ABOUT CHOLESTEROL IN YOUR DIET !!


Now there are a lot of ‘masala’ added by some people as the post circulated. This is mainly concentrated in the second part of the message.

  1. ‘Cholesterol is the biggest medical scam of all time’ – WHAT ? LIE !
  2. ‘There is no such thing as bad Cholesterol! ‘ – Biggest misinformation in this message.
  3. ‘So you can stop trying to change your Cholesterol level. Studies prove beyond a doubt, cholesterol doesn’t cause heart disease and it won’t stop a heart attack. The majority of people that have heart attacks have normal cholesterol levels’ – NO STUDY EVER HAS SAID THIS
  4. ‘Experts say that there is nothing like LDL or HDL’- WHO ARE THESE SO CALLED EXPERTS ?

What the message is done is to combine a half-baked knowledge about Dietary cholesterol and COMBINED IT WITH CHOLESTEROL PRESENT IN YOUR BODY !


  1. Taken, even if the American agency quoted above is true, you probably don’t need to worry about the cholesterol in your diet, however, you still need to worry about SATURATED AND TRANS-FAT which will produce more cholesterol inside your body , all of which will clog your arteries and will kill you ! Period !
  2. LDL , ‘the bad cholesterol’ is produced in your body . If is actually a misnomer and it is not cholesterol it is an actually a lipoprotein which carries the ‘Bad’ cholesterol and ‘Bad fat’ in your body. If this LDL is in excess it will block your arteries and kill you … again Period !
  3. Don’t stop medication after reading Whatsapp messages ! If you are prescribed anti-cholesterol medications called ‘Statins’ (Atorvastain, Rosuvastatin etc), by your physician, you probably badly need it. If you stop this medication, your cholesterol will increase and It will deposit in your heart and kill you. Period again !
  4. There is now even more evidence that cholesterol is harmful for you based on a new clinical trial called HOPE 3. Statins save lives and there is more evidence for it now than ever before.
  5. Finally (and true for doctors too) don’t spread rumors and misinformation without verifying the facts first.

So a final word,  stop listening to Social media and listen to your doctor.  You are free to email me for more information.  This is my twitter handle

Good luck and Wish you a healthy life.

Dr. Om J Lakhani, MD

(If you were one of those people who shared the previous ‘Wrong message’ , I hope you share the current ‘Correct message’ too !)







This is a case of a middle age lady from Kashmir who came with incidentally detected thyroid nodule. A thyroid ultrasound was done, a picture of which is shown below. Thyroid function tests were suggestive of Overt hypothyroidism.

Q Ultrasound Characteristics of this lesion show Benign or malignant etiology ?
1. Doppler shows peripheral vascularity with no central vascularity
2. No visible microcalcifications
3. It is isoechoic or hyperchoic compared to surrounding area (Mixed echogenicity)
4. Regular margins
5. Spongiform appearance
6. More wide than tall (Wider > Taller)
The lesion can be characterized as ‘Low suspicion’ according to ATA 2015 guidelines
Q. What does the FNAC show ?

Q. What is the next step for the patient ?
1. Levothyroxine for the Overt hypothyroidism and follow up after 6 weeks
2. For the nodule- Repeat ultrasound after 6 month- If there is growth of 20% in two axis or new suspicious imaging features- Consider Repeat FNAC

CASE 22- Not really Non functioning !

Original case by Mana et al


A 51-year-old man was admitted to the hospital because of cranioencephalic trauma following seizures. He had a 10-year history of altered behavior, obesity, depression, sphincter incontinence, and recent visual troubles. Physical examination revealed amaurosis of the right eye with blurred vision in the left eye, signs of hypogonadism, and increased bilateral testicular volume (Prader orchidometer >25 mL). Magnetic resonance imaging (MRI) showed a voluminous lesion in the sellar-suprasellar area with mass effect on the brain and projection toward the floor of the third ventricle (Fig. 2).

Q What are the causes of Macroorchidism ?

  1. Fragile X syndrome
  2. Testicular adrenal rest tumor
  3. Testicular malignancy
  4. FSH secreting pituitary adenoma
  5. Uncontrolled hypothyroidism in a child
  6. Lymphoma
  7. Aromatase deficiency in males

Q What is the Hardy Staging of the Pituitary lesion ?

Hardy Grade E (Parasellar extension into the cavernous sinus)

Q What would you do next ?

I would do an anterior pituitary evaluation

  1. Baseline 8:00 am Cortisol and ACTH stimulation test
  2. IGF1 and GH stimulation test
  3. FSH/LH and testosterone
  4. Free T4 and TSH

Hormone testing showed an FSH level of 517 mIU/mL (normal, 1.5 to 12.4 mIU/mL), luteinizing hormone (LH) level of 2.2 mIU/mL (normal, 1.7 to 8.6 mIU/mL), testosterone level of 1.3 ng/mL (normal, 2.9 to 8.0 ng/mL), prolactin (PRL) level of 21.2 ng/mL (normal, 4.6 to 21.4 ng/mL), thyroid-stimulating hormone (TSH) level of 1.37 mIU/mL (normal, 0.27 to 4.20 mIU/mL), free thyroxine level of 0.8 ng/dL (normal, 0.9 to 1.7 ng/dL), cortisol level of 4.2 μg/dL (normal, 6.2 to 19.4 μg/dL), and insulin-like growth factor 1 (IGF-1) level of 33 ng/mL (normal, 87 to 200 ng/mL).

Q What is your interpretation of the anterior pituitary profile ?

  1. FSH is very high with hypogonadism
  2. Central hypothyroidism
  3. Cortisol is on the lower side, I would do a ACTH stimulation to confirm
  4. IGF1 is low- most likely to have GH deficiency


A surgical approach was performed in 2 stages by fronto-pterional access with partial resection of the tumor. Histopathologic examination showed a proliferation of neoplastic cells arranged in nests showing a papillary pattern, consisting of cells with amphophilic and eosinophilic cytoplasm. Immunostaining showed a high percentage (almost 70%) of wide and heterogeneous markers for FSH but was negative for other hormones. Ki-67 was <1%. Final diagnosis was of an FSH-producing gonadotropinoma. Postsurgical hormone assessment showed a decline in FSH to 22.3 mIU/mL.

The patient presented torpid evolution requiring ventricle-peritoneal bypass for hydrocephalus and presented infectious complications needing mechanical ventilatory assistance and hemodynamic support, ending in death.


A 36-year-old woman was referred to our hospital with a history of regular menstrual cycles and 2 pregnancies with normal deliveries. Two years before consultation, she had developed secondary amenorrhea, and multiple bilateral ovarian cysts were detected; she started oral contraceptive treatment, but the cysts continued to increase in number and size. A surgical intervention with wedge resection of both ovaries was performed, but the cysts and amenorrhea persisted after surgery (Fig. 3 A).

Q Was this approach correct ?

Not exactly. The secondary amenorrhea should have been more thoroughly evaluated. I would done a prolactin.

One year later, moderate hyperprolactinemia (69 ng/mL; normal, 4.6 to 21.4 ng/mL) was found, and an MRI showed a pituitary macroadenoma (Fig. 4 A).

Q What would you do next ?

I would do the following

  1. Repeat prolactin with 1:100 dilution
  2. Perform the anterior pituitary profile

Cabergoline 0.5 mg per week induced normalization of PRL, but neither tumor shrinkage nor resolution of amenorrhea was observed.

Q What this approach correct ?

No. The Prolactin was mildly elevated and no consistent with the Pituitary adenoma. It was more likely to be a non-functioning adenoma with stalk compression.

Hormone assessment showed: TSH, 2.6 mIU/mL; thyroxine, 10.3 ng/mL (normal, 4.5 to 12.5 ng/mL); IGF-1, 221 ng/mL (normal, <494 ng/mL); PRL, 66 ng/mL; FSH, 20.2 mIU/mL (normal, <12 mIU/mL); LH, 0.5 mIU/mL (normal, <12.6 mIU/mL); and estradiol, 288 pg/mL (normal, <161 pg/mL)

Q What would be your approach to this patient ?

I would offer pituitary surgery since she is having amenorrhea

Transsphenoidal extirpation of the pituitary adenoma was performed. Immunostaining was positive for PRL and FSH, confirming the diagnosis of an FSH-producing gonadotropinoma. After surgery, the patient recovered regular menstrual cycles. Disappearance of ovarian cysts on ultrasound and almost complete absence of the adenoma on MRI were shown. Blood test showed normalization of PRL (18 ng/mL), FSH (13.1 mIU/mL), LH (10.5 mUI/mL), and estradiol (5.7 pg/mL) values.


Q What is the composition of nonfunctioning adenomas ?

They are more likely to be gonadotropinomas as in this case.

Q What are the characteristics of FSH secreting adenomas in males ?

They are generally clinically non-functioning. They sometimes have Macroorchidism.

Q How do they present in women ?

They present with large ovarian cysts.

Q What is the importance of LH in these females ?

Suppression of LH and high FSH goes in favour of FSH secreting pituitary adenoma. This would help differentiate it from Primary ovarian insufficiency and menopause.



  1. FSH secreting pituitary adenomas may present as Macroorchidism in male and bilateral multicystic ovaries in females
  2. Low LH and high FSH in females would help to differentiate it from POI and menopause.


Case 21: An unusual and fatal cause of Cushing’s syndrome

Original case by Thomas Dacruz et al

Mrs. XX, a 60-year-old woman was hospitalised with 5-month history of worsening fatigue, leg swelling, and difficulty in walking. Her past medical history included primary hypothyroidism and hypertension. She had been diagnosed with an acinic cell carcinoma of the left parotid gland, which was resected 3 years prior to current admission. She was under follow-up of the surgical team with no obvious evidence of disease recurrence or relapse at the time of presentation.

On examination in medical assessment unit, she had florid features of CS including central obesity, plethoric face, skin thinning, purplish abdominal striae, and proximal muscle weakness. Her blood pressure was elevated with rest of the general physical and systemic examination being unremarkable.

Q How will you investigate this patients ?

  1. First 8:00 am cortisol to rule out exogenous vs endogenous Cushing’s
  2. Next step would be to confirm the diagnosis of Cushing’s with Overnight dexamethasone suppression test


  1. ONDST– 28 mcg/dl (High)
  2. LDDST- 20 mcg/dl (high)

Q What would be the next step ?

To confirm ACTH dependent vs ACTH independent Cushing’s. I would do a ACTH level for the same

ACTH- 106 pg/ml

Q What is the next step ?

This is ACTH dependent Cushing’s, I would do a MRI Sella with contrast

Magnetic Resonance Image of the Pituitary. It showed normal pituitary gland.

Q What is the next step ?

Most likely Ectopic Cushing’s. MRI is normal and ACTH is >90 pg/ml- strongly in favour of ectopic Cushing’s.  What is the potassium , I would ask ?

Serum Potassium – 2.6 meq/l

With this Potassium, all evidence point to Ectopic Cushing’s.

Q What would be the next step ?

Ideally an IPSS would be required to confirm ectopic Cushing’s. However, the evidence points towards Ectopic Cushing’s. So I would investigate for presence of Ectopic Cushing’s. I would do a CT chest, abdomen and pelvis.

Abdomen/Pelvis/Thorax CT. It shows a lytic lesion on the left ischium bone suggestive of a metastatic carcinoma. A collection of gas around the sigmoid colon was noticed which was suggestive of perforated sigmoid diverticulitis.

Q Next step ?

I would consider doing a biopsy of the bone lesion

Biopsy of ischial lesion showed features consistent with a metastatic poorly differentiated acinic cell carcinoma with negative staining for ACTH. However, the previously resected primary parotid tumour of acinic cell carcinoma were stained positively for ACTH.


Q What is the final diagnosis ?

Ectopic ACTH-Secreting Primary parotid tumor.

Q How will you treat the patient ?

Since the patient is probably having florid Cushing’s, I would consider doing a bilateral adrenalectomy.

Our patient was commenced on metyrapone therapy on day 6 of admission with a gradual up-titration of the dose. The course of her disease was aggressive with subsequent development of intestinal perforation. Interestingly, she had minimal symptoms and signs on clinical examination suggestive of intestinal perforation with this diagnosis being only established based on the radiological investigations.

She later developed sepsis and was managed in intensive care unit. Unfortunately, despite the best possible care her condition continued to deteriorate and she died due to complications related to her ectopic ACTH related CS secondary to a metastatic salivary gland tumour.

Q Is intestinal perforation common in Cushing’s ?

Yes  Cushing’s especially exogenous Cushing’s can present with intestinal perforation and sepsis.


  1. Carcinoma of parotid gland can be associated with Cushing’s Syndrome
  2. Intestinal perforation can be a complications of Cushing’s syndrome.



Original case by Óscar Aramburu-Bodas et al 

A 67-year-old woman was hospitalized with a 2-month history of asthenia without weight loss, neurologic, or respiratory symptoms. Her medical history included hypertension. Her medications at admission were enalapril and lorazepam. The physical examination revealed the patient to be alert, clinically euvolemic, and with a blood pressure of 147/90 mm Hg.
Laboratory tests showed a serum sodium (SNa) level of 112 mmol/L; low plasma osmolality (POSM), 250 mOsm/kg; high urine osmolality (UOSM), 562 mOsm/kg; and urine sodium (UNa) level of 88 mmol/L. Potassium was 4.9 mmol/L; urea, 12 mg/dL; creatinine, 0.4 mg/dL; and glucose, 95 mg/dL.
Q. What is your interpretation of these reports ?
Since the patient is euvolemic my differentials for the hyponatremia would be
2. Adrenal insufficiency
3. Hypothyroidism
Q. What are the criteria for SIADH ?

1. Serum osmolality <280 mom/kg
2. Urinary osmolality >100 mom/kg
3. Urinary sodium > 30 meq/l
4. Clinically euvolemic
5. Hypothyroidism and Adrenal insufficiency have been ruled out
Q. What would be your approach to treating hyponatremia in this case ?
This is based in European society of endocrinology protocol
1. 3% NaCl @75-100 ml/hr
2. Recheck Sodium after 4 hrs. If Serum sodium raise by 4 meq/l – I would go to next step else continue the 3% NaCl and recheck every 4 hours. Sodium should not raise by >10 meq/l in 24 hrs
3. Next I would search for the cause of SIADH
4. I would advice free fluid restriction additionally
5. Furosemide may be added if urine osmolality remains > 500 mom/kg

Upon admission, uric acid was 2.1 mg/dL; cortisol, 12.2 μg/dL; and thyroid-stimulating hormone, 2.28 mU/L. Tumor markers were within reference range. A computed tomography (CT) scan of the brain, chest, and abdomen revealed small nodes located in the mediastinum as the only finding.

Q. Can Adrenal insufficiency be ruled out with this baseline cortisol ?

Yes. Some guidelines suggest cortisol >10.8 ug/dl generally rules out adrenal insufficiency.

During hospitalization, enalapril was replaced with amlodipine, since angiotensin-converting enzyme (ACE) inhibitors are a potential cause of SIADH. The patient began with fluid restriction. Despite severe hyponatremia and a Furst formula of 1.09, there was only slight improvement in sodium level (from 112 to 126 mmol/L), but the symptoms disappeared. The patient was discharged with the recommendation to limit fluid intake and referred for outpatient follow-up.

Read : ACEI leading to SIADH (

Q. What is Furst formula ?
Furst formula gives the estimate of how much free fluid is lost and helps estimate the degree of free water restriction to be prescribed.
The formula is in a spot sample of urine – Urine Na + Urine K / Plasma Na
If the interpretation is as follows:
1. Value > 1.0- patient is not excreting any free water- advised 0 litre of free fluid
2. Value 0.5-1.0 – 500 ml of free fluid allowed
3. <0.5- good free fluid excretion- upto 1 litre of free fluid allowed
Q. What can explain the improvement in Sodium ?

Probably because of stopping of ACEI which can cause SIADH

Chest CT scan and laboratory tests were repeated 6 months later. CT revealed nonspecific mediastinal lymph nodes only (similar to the previous scan). New blood tests were within normal range, except for a SNa of 127 mmol/L and POSM of 250 mOsm/kg. Uric acid was 2.3 mg/dL. The patient remained asymptomatic. After a 2-year follow-up, she presented with marked weakness. Physical examination was normal. A chest X-ray was similar to the previous one. She was therefore prescribed tolvaptan 15 mg/day, and the dose was progressively increased to 60 mg daily. SNa rose to 136 mmol/L, with an excellent tolerance and clinical response. The evolution of laboratory variables is showed in Table 1.
One year after tolvaptan was initiated, she complained of progressive asthenia once more. SNa was 115 mmol/L despite receiving tolvaptan at the maximum recommended dose, and without changes in dietary habits, fluid intake, or medication. The patient was admitted to the hospital for further evaluation. The patient was euvolemic. Hypothyroidism and adrenal insufficiency were ruled out. Renal function, potassium, and tumor markers were normal. UNa was 109 mmol/L; urine potassium, 26 mmol/L; POSM, 249 mOsm/kg; and UOSM, 410 mOsm/kg. The diagnosis was made of SIADH of unknown origin resistant to tolvaptan treatment. A chest X-ray revealed that the mediastinum was slightly widened. A chest CT scan (Fig. 1) showed an anterosuperior mediastinal mass located in thymus gland. Plasma AVP concentration was determined, revealing extremely high levels (63.5 pg/mL; normal, <7.6 pg/mL).
The patient was treated with continuous 3% hypertonic saline (27 mL/hour) and the maximum dose of tolvaptan, which resulted in a marked improvement in SNa, although hyponatremia persisted throughout the hospitalization. She was discharged 10 days after admission, asymptomatic, with sodium levels of 130 mmol/L and was referred to thoracic surgery. Before surgery, she continued treatment with 60 mg of tolvaptan and sodium supplements daily (a salt diet with approximately 10 g of sodium). The patient underwent video thoracoscopy with total thymectomy.
Macroscopically, the tumor measured 7.2 × 6 × 4 cm. It was encapsulated, showing a heterogeneous cut surface with areas of necrosis, hemorrhage, and punctate calcifications. Microscopically, it consisted of a diffuse growth of small uniform cells with hyperchromatic nuclei, arranged in an eosinophilic fibrillar matrix consistent with a neuropil and vascular pattern. Immunohistochemical analysis was performed using the Ventana Benchmark System (Roche Laboratories, Basel, Switzerland) on formalin-fixed paraffin-embedded tissue sections cut to a thickness of 4 μm. The following antibodies were used: chromogranin A, synaptophysin, neuronal-specific enolase, CD56, S100 protein (prediluted, Roche Labs), and AVP (1:100, Merck-Millipore, Billerica, MA). AVP was positive in neuropil and cytoplasms of neuroblasts. Molecular analysis revealed no amplification of N-Myc and c-Myc.
SNa levels (140 mmol/L), blood osmolality, and plasma AVP concentration (<1.2 pg/mL) completely normalized 2 weeks after tumor removal. The treatment with tolvaptan was withdrawn

Q. What is the importance of measuring plasma AVP levels ?

Plasma AVP levels help determine etiology of SIADH. Very high AVP levels are generally seen in patients with cancer causing SIADH as in this case. Also in cancer patients it can be help to monitor response to therapy

Q. What is the side effect with chronic tolvaptan therapy ?
It can cause liver enzyme elevation and potential liver failure

Q. What are the two trials which have studied Tolvaptan use ?
1. EVEREST trial for heart failure
2. SALTWATER trial

Learning points from this case
1. Measurement of AVP may be useful to define etiology in patient with SIADH
2. Tolvaptan may be ineffective in patients with SIADH with very high AVP levels due to cancer.


Original case Soham Mukherjee et al

A 42-year-old female patient presented with complaint of pain and swelling in the right calf for the last 2 months (Fig. 1a). There was no history of fever. She was a known case of type 2 diabetes mellitus (T2DM) for the last 11 years, hypertensive for the last 1 year and hypothyroidism for the last 2 months. Patient underwent hysterectomy 3 years back. There was no history of trauma, i.m. injection, arthralgia or other systemic symptoms.

Q What would you suspect when a diabetic patient presents with history of pain and swelling of calf muscles ?

My differential diagnosis would be

  1. Cellulitis
  2. Deep vein thrombosis
  3. Lymphedema
  4. Baker’s cyst
  5. Calf muscle tear
  6. Venous valvular insufficiency.
  7. Diabetic myonecrosis

On examination, right leg was swollen, tender and indurated.

Q What investigation would you order ?

  1. Compression ultrasonography of the lower limb (venous doppler with compression)
  2. D-Dimer

Q  Is diabetes a risk factor for DVT ?

It is controversial. Diabetes per se is not a risk factor for DVT. In a study conducted by Heit et al ,they found incidence of DVT in diabetics no different from general population.

On evaluation, patient had all microvascular complications of diabetes.

  1. What is the importance of knowing that this patient has other diabetic microvascular complications in this case ?
  2. Presence of other microvascular complications increases the risk of patient have diabetic foot with cellulitis
  3. Diabetic myonecrosis is also considered a vascular complication of diabetes and presence of other microvascular complications increases the likelihood of patient having diabetic myonecrosis.

Investigation revealed hemoglobin of 7 g/dl (11–15 mg/dl), total leucocyte count 10 200/mm3 (4000–11 000/mm3), platelets 293×103/mm3, peripheral blood film suggestive of microcytic hypochromic red blood cell, urea 72 mg/dl (10–50 mg/dl), creatinine 3.2 mg/dl (0.5–1.2 mg/dl), HbA1c 8% (3.8–5.6%), thyroid-stimulating hormone (TSH) 10.8 μIU/ml (0.27–4.2 μIU/ml), thyroxine (T4) 6.98 μg/dl (4.8–12.7 μg/dl), tri-iodothyronine (T3) 0.8 ng/ml (0.8–2.0 ng/ml), 24 h urinary protein 550 mg/day and CK 403.5 U/l (26–308 U/l). ANA, ANCA, RA factor, dsDNA, SSA/RO, SSB/LA, Sm, Sm/RNP, Scl70, Jo1 were negative and coagulation profile was normal.

  1. What other condition in this patient could have led to myalgia and raised CK levels ?


Fundus examination revealed hard exudates. Blood culture was sterile. Deep vein thrombosis (DVT) was excluded by compression ultrasonogram (USG).

Q What would you consider next ?

Since the diagnosis is still not clear, I would advise and MRI of the limb.

USG of the right leg was suggestive of diffuse thickening and increased echogenicity of skin and subcutaneous tissue along with marked swelling and hypoechogenicity of muscles without any localized collection. MRI right leg revealed thickening and edema of the skin/subcutaneous tissue with hyperintensity in muscles of all the compartments of the right leg in short tau inversion recovery (STIR) sequence (Fig. 1b and c). Electromyography (EMG) was suggestive of inflammatory myositis. Muscle biopsy (Fig. 1d) from right gastrocnemius was performed as calf muscle involvement is relatively uncommon in Diabetes myonecrosis. Patient was diagnosed to have Diabetes myonecrosis and was treated conservatively with paracetamol and tramadol with complete recovery within 6 weeks. The dose of levothyroxine was also optimized.


Q What is diabetic myonecrosis ?

It is spontaneous infarction of muscles in diabetic patients which is unrelated to atheroembolism or occlusion of any major arteries.

Q It is common in what type of diabetics ?

It is more common in long standing uncontrolled diabetics.  It is more common in type 1 diabetics.

Q Which muscles are commonly involved in this conditions ?

Muscles of thigh and calf are commonly involved. Quadriceps muscle is most commonly involved. It may present acutely and the involved muscle may be tender. Patient may run mild fever. The condition tends to recur after resolution.

Q Is the creatinine kinase elevated in these patients ?

As seen in this case CK may be elevated but only mildly in patients with Diabetic myonecrosis.

Q What does MRI in such cases show ?

  1. High signal intensity in T2W image in the involved muscles
  2. Post gadolinium contrast there is patchy enhancement of the involved muscles. While the infarcted muscle shows no enhancement , the surrounding edema and inflammation shows reasonable enhancement.
  3. Loss of fatty intermuscular septae

Q What is the treatment of diabetic myonecrosis ?

Treatment is mainly conservative with rest and NSAIDS. It spontaneously resolves in a few weeks.