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 ?

VINDICATE

  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.
  • Inj CALCITONIN (inj BIOCALCIN)
    • 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
  • CINACALCET (Tablet PTH)
    • 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.

Figure 

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

https://www.hindawi.com/journals/crie/2017/2608392/tab1/

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.

 

A CASE OF MEDULLARY THYROID CARCINOMA WITH A TWIST !

Original case by I Huguet et al 

A 63-year-old woman was referred to our clinic following the incidental finding of a 1 cm thyroid nodule.

Q  What tests would you order on finding the thyroid nodule ?

  1. Review the ultrasound and physical examination findings
  2. A thyroid function test
  3. FNAC of the thyroid nodule if indicated

Q  What is the indication for FNAC according to new ATA 2015 guidelines ?

 

  1. High suspicion and intermediate suspicion- FNAC if nodule > 1 cm in size
  2. Low suspicion – FNAC if nodule > 1.5 cm in size
  3. Very low suspicion- FNAC if nodule > 2 cm in size
  4. Benign – avoid FNAC

 

Q  What are the high and intermediate risk features on ultrasound for which FNAC would be indicated in this case ?

Intermediate suspicion

  1. Hypoechoic with regular margins

High suspicion

  1. Hypoechoic + one of the following:
    1. Microcalcification
    2. Irregular margins
    3. Taller than wider
    4. Extrathyroidal extension
    5. Suspicious lymph nodes
    6. Interrupted calcification

Fine-needle aspiration cytology revealed a MTC.

Q  What are typical findings of MTC on FNAC ?

 

  1. Spindle shaped cells
  2. Cells have eccentric nuclei
  3. Amyloid like material in background

Q  How will you enhance the specificity of FNAC finding ?

Use of calcitonin staining in the FNAC smear- which will confirm the diagnosis of MTC.

Subsequently, plasma calcitonin levels were found to be elevated at 84 pg/ml (normal <11.5 pg/ml).

Q  What is the cutoff used for calcitonin in patients with Thyroid nodules for diagnosis of MTC ?

 

Basal calcitonin >20 pg/ml is suggestive of MTC and Pentagastrin stimulated Calcitonin >100 pg/ml confirms the diagnosis.

There were no other abnormal findings.

Q  What other tests would you perform ?

Since this patient has MTC, there is a high possibility of patient having MEN2. I would rule out pheochromocytoma and Hyperparathyroidism. I would clinically look for mucosal neuromas and marfanoid habitus.  (though MEN2B is less likely in this case considering the age of the patient).

The presence of a co-existing phaeochromocytoma was biochemically excluded (normal urinary catecholamine and metanephrine levels). Q  What is the ideal  surgery for this patient ?

Since the patient does not have lymph nodes involvement or metastasis and Calcitonin is between 20-200 pg/ml, the guidelines suggest total thyroidectomy with prophylactic central node dissection.

The patient was subjected to total thyroidectomy with clearance of central and lateral lymph node compartments.

The pathology demonstrated a calcified 1 cm nodule consisting of polygonal cells showing positive immunostaining for chromogranin, calcitonin, S-100 and carcinoembryonic antigen (CEA; Fig. 1). The lymph nodes were clear of disease.

Q  What is the next step for the disease ?

Genetic analysis is important to ascertain family risk and person risk of MEN2.

Genetic analysis of peripheral lymphocytes of the RET oncogene (automated sequencing of the flanking exons 10, 11, 13, 14, 15 and 16) did not reveal any germline mutation.

 

Q  How will you follow up this patient ?

I would repeat the Calcitonin and CEA after 3 months.

 

The patient recovered well from the operation, but exhibited persistently elevated plasma calcitonin levels, although she remained asymptomatic. Over the following 3 years, her plasma calcitonin levels were persistently elevated, although with no clear signs of progression (106, 116, 83, 173, 212, 279 and 114 pg/ml).

Q  What is done if calcitonin is persistently high after surgery ?

  1. If it is >150 pg/ml- then imaging is done
    1. USG/CT of neck
    2. CT thorax and abdomen
    3. Bone san
  2. If <150 pg/ml- follow-up.

Since this patient has calcitonin above 150 pg/ml on several occasions, an imaging is indicated.

Her circulating CEA levels remained normal. We suspected persisting or metastatic disease, but further repeated and detailed imaging including computed tomography (CT) and magnetic resonance (MR) scanning of the neck, chest and abdomen failed to reveal any evidence of tumour. Functional imaging with radiolabelled octreotide (Octreoscan) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning demonstrated mild uptake of both tracers in the midline, adjacent to L2, and further CT scanning was undertaken concentrating on this area. No clear abnormality was observed, and it was concluded at this stage that the apparent uptake was due to duodenal ‘physiological tracer elimination’.

However, after 3 years, the patient was found to have developed an iron-deficiency anaemia associated with positive faecal occult blood testing. Endoscopy was undertaken, and it showed chronic atrophic gastritis with intestinal metaplasia, but in addition a large (3 cm) polyp was found in the second part of the duodenum, which was biopsied.

The duodenal biopsy showed a NET, and the patient was subsequently re-explored surgically and partial duodenectomy was performed. Pathological examination confirmed a 2.8 cm well-differentiated NET with positive immunohistochemistry for CAM5.2, ac1-AE3, enolase, chromogranin, synaptophysin and serotonin; the Ki-67 index was <2% .

Q  What does a Ki-67 of <2% suggest ?

That it is a well differentiated neuroendocrine tumor.

Q  What is done for non-metastatic well differentiated carcinoid ?

Surgery and follow up.

Surprisingly, after resection of the duodenal tumour, circulating calcitonin levels remained repeatedly undetectable, and thus the tissue was immunostained for calcitonin; this was strongly positive.

Currently, the patient remains asymptomatic with persistently undetectable serum calcitonin levels and no further anaemia. She remains with mildly elevated serum chromogranin A and gastrin levels (last determination of serum gastrin levels: 591 pg/ml, normal <40; Fig. 3), which we attribute to her chronic atrophic gastritis.

Q  Can calcitonin be produced by other NET ?

Yes. It has been reported to be produced by other neuroendocrine tumors also.  In this case the association between the two seems coincidental.

 

AN IMPORTANT CLARIFICATION ABOUT THE’CHOLESTEROL MESSAGE’

VERY IMPORTANT CLARIFICATION. PLEASE READ

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:

FIRST SOME TRUTH IN THE POST:

  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 FOR SOME LIES.

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 !

NOW THE REAL TRUTHS

  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. http://www.nejm.org/doi/full/10.1056/NEJMoa1600176. 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 https://twitter.com/omlakhani

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 !)

MISINFORMATION

 

 

 

 

ENDOCRINE ROUNDS CASE 8 -WEEKLY BONE AGE QUIZ

WEEKLY BONE AGE ESTIMATION QUIZ

Learning Objective- Sharpen Skills for bone age estimation

Q. What is the bone age of a male whose X ray is shown below ?
(You may use atlas method or Tanner Whitehouse)

DR8.jpg

Q. What is the approximate bone age based on clinical assessment ?

1. The epiphysis of the distal phlaxanx has fused – bone age is surely more than 14 years
2. The distal ulnar epiphysis has not fused – age is <17 year
3. 14-17 years is approximate bone age (wide variation- I would need Atlas of Tanner Whitehouse for perfect estimation)

Q. What is the bone age based on Tanner Whitehouse ?
• TWII- 14.9 years
• TWIII- 15.9 years

Q. What is the bone age by Greulich Pyle method ?
15- 16 years

Q. What is the bone age by Gaskin and Kahn atlas ?
It says 15 years 6 months

Q. Please give the explanation for the bone age based on the Atlas ?

1. The epiphysis of distal phalanges have fused
2. Fusion is about to begin in distal part of 2nd -5th epiphysis of metacarpals
3. 1st metacarpal epiphysis has fused
4. Distal ulnar epiphysis has not fused

Q. What is the key area here ?

The key differentiating feature is fusion of the 1st metacarpal epiphysis which fuses at 15 years and 6 months

NOTE: SOME OF THE VIEWS ARE BASED ON MY PERSONAL KNOWLEDGE AND EXPERIENCE. YOU MAY DIFFER IN YOUR VIEWS. PLEASE FEEL FREE TO EXPRESS YOU OPINION.

 

ENDOCRINE ROUNDS CASE 7 – ABNORMAL UTERINE BLEEDING WITH HYPOTHYROIDISM

ENDOCRINE ROUNDS CASE 7 – ABNORMAL UTERINE BLEEDING WITH HYPOTHYROIDISM

Learning Objective: Menstrual disorders and Hypothyroidism

A 35 year old Nurse came to the endocrine OPD with complaints of heavy menstrual bleeding during menstrual periods since last 4-6 months. She also had complaints of constipation on and off and generalized weakness.

She had menarche at age of 14 years. Her menses were always regular.  At present she was menstrual flow for 4 days, which are heaviest during the first 2 days. The length or her menstrual cycles is 24 days and has been the same as long as she can remember. She had similar problems about 1 year back for which she consulted a gynecologist who diagnosed her to have an ovarian cyst which ‘resolved’ with oral contraceptive pills.  The problem recurred again 4 months back.

The patient was diagnosed to have ? Subclinical hypothyroidism during her pregnancy for which she was prescribed levothyroxine. She stopped the medication on her own after delivery.

At present she is not on any medications. She works in the ICU and has shift duties. She says she has difficulty in sleeping when she is off duty. She claims she has gained a little weight since last year or so and she feels little depressed.

The patient’s mother has history of Hypothyroidism (Autoimmune). There is no family history of diabetes.

On examination she has

  1. Hirsutism (modified FG score of 10) and acne over the face
  2. Acanthosis nigricans
  3. No goiter
  4. No others signs or virilization.
  5. BMI is 23.5 kg/m2
  6. Waist circumference is 95 cm

 

She attributed her problems to the thyroid and got herself a thyroid function test which shows overt hypothyroidism. Anti TPO antibody is positive. She has Hb of 10 g/dl with microcytic hypochromic features and increased RDW

Here are the questions:

Q  Describes the attributes of a normal menstrual cycle

  • Frequency every 21 to 35 days
  • Occurs at fairly regular intervals
  • Volume of blood ≤80 mL ( < 1 tampon every 2 hours)
  • Duration is 5 days

Q  Define polymenorrhea and oligomenorrhea

  • Polymenorrhea- menstrual cycles <21 days
  • Oligomenorrhea – > 35 days

Q  What is the difference between amenorrhea and oligomenorrhea ?

Oligomenorrhea is increased length of menstrual cycle but the upper limit is not defined hence the differentiation between oligomenorrhea and amenorrhea is arbitrary. Amenorrhea is generally absence of menses for period > 3 months (some people use a cut off of 6 months) while oligomenorrhea is 35 days – 3 months or <9 cycles in a year.

Q  From a patient point of view, what is normal menstrual blood flow ?

 

  1. Need to Change tampon > 3 hours
  2. < 21 tampons required during the menstrual cycle
  3. No need to change tampon at night
  4. Patient is not anemic
  5. Clots are < 1 inch in diameter

Q  How much blood does 1 tampon soak ?

  • About 5 ml
  • A ‘super’ tampon may soak about 10 ml of blood
  • A pad may soak – 5-10 ml

Q  What is abnormal uterine bleeding ?

It refers to abnormalities of amount, duration or schedule of blood flow.

It could be either :

  1. Heavy menstrual bleed
  2. Prolonged menstrual bleed

The term menorrhagia should not be used any more

Q  What is heavy menstrual bleed ?

  1. More than 80 ml of blood flow during menstrual cycles
  2. Need to change tampon or pad every 2 hours
  3. Volume of bleeding interfering with daily activities

Q  What are some common causes of AUB is non pregnant women ?

It is given by PALM- COIEN classification

  • Polyp
  • Adenomyosis
  • Leiomyoma
  • Malignancy
  • Coagulopathy
  • Ovulatory dysfunction
  • Iatrogenic
  • Endometrial
  • Not otherwise classified

Q  What type of menstrual irregularities are seen with hypothyroidism ?

 

Women with hypothyroidism may have either oligomenorrhea or amenorrhea or Hypermenorrhea (menorrhagia)-AUB

 

Q  What is the frequency of menstrual irregularities in hypothyroidism ?

  • Evidence suggests that menstrual irregularity is less common than previously thought in patients with hypothyroidism.
  • In a study by Krassas et al
    • 77% had normal cycle
    • 16% has oligo-amenorrhea
    • 7% had hypermenorrhea
  • Oligomenorrhea and Hypermenorrhea were the most common patterns of menstrual irregularities.
  • Another study found no difference in incidence of hypermenorrhea in patients with hypothyroidism in comparison to controls. However, the same study found that patients with severe hypothyroidism were more likely to have menstrual irregularities than mild hypothyroidism. (Kakuno et al)

Q  Does the menstrual irregularity correlate with severity of hypothyroidism?

In the study quoted above, the menstrual irregularity was more common in women with overt hypothyroidism vs subclinical hypothyroidism and it did correlate with severity of hypothyroidism. However, the difference was not statistically significant.

Q  Does the presence of Anti-TPO antibody correlate with menstrual irregularities?

No.  Karassas et al did not found any difference in menstrual irregularities in patients with anti-TPO positive vs the entire group.

Q  Do the menstrual abnormalities improve with LT4 treatment?

It persists in almost half of the patients with treatment.

 

Q  What are the possible etiologies of AUB in hypothyroid patients?

 

  1. Estrogen breakthrough bleeding secondary to anovulation
  2. Decreased level of coagulation factors- VII, VIII, IX and XI seen in hypothyroid patients

Q  Is there any difference in menstrual irregularities reported from recent studies vs older studies ? If so why ?

  • Older studies showed a much higher prevalence of menstrual irregularities in hypothyroidism.
  • This was possibly due to delay in diagnosis of hypothyroidism leading to much severe symptoms

CONCLUSION

  1. Menstrual irregularities are often seen in hypothyroidism. However, prevalence of menstrual irregularities in hypothyroidism is reported less commonly in recent studies compared to older studies because of early diagnosis of hypothyroidism
  2. Oligomenorrhea is the most common menstrual irregularity reported in recent studies. Hypermenorrhea (AUB) is reported in about 7% of hypothyroid patients in comparison to 1% in controls.
  3. The menstrual irregularities may have an association with severity of hypothyroidism, but this needs more robust evidence.
  4. It has not relation with the presence of Anti-TPO antibodies.
  5. Menstrual irregularities may correct after treatment of hypothyroidism in about 50% of cases.

 

ENDOCRINE ROUNDS CASE 6- 6TH CASE IS OF 6TH NERVE PALSY !

A 66 year old female with long standing uncontrolled type 2 diabetes and hypertension presented to us with complaints of diplopia since last 2 months. There was no history of trauma and no other clinical complaints

On examination patient had esotropia in primary gaze in the left eye and reduced abduction of the left eye suggestive of lateral rectus palsy. Rest of neurological examination was normal. Patient had an isolated left 6th nerve palsy.

 

Q. What are the etiologies for 6th nerve palsy ?

1. Traumatic
2. Vascular- diabetic cranial mononeuropathy is one of them
3. ICSOL
4. Raised ICT including Idiopathic intracranial hypertension
5. Cavernous sinus involvement
6. Stroke
7. Vasculitis (including giant cell arteritis)
8. Sarcoidosis

Abducens nerve is the most common nerve involved in Diabetic patients.
Q Would a neuroimaging be required ?

This is controversial. Patel et al published a paper in 2004 in which they suggested that isolated non-traumatic sixth nerve palsy with no other neurological signs do not require a neuroimaging and require a close follow up. (1)

Q How common are diabetic and hypertension a cause of 6th nerve palsy

A population based study by Patel et al showed that diabetes was present in 23% of patients with isolate 6th nerve palsy which was more compared to controls. Isolated hypertension was similar to controls. Hypertension plus diabetes was present in 18% of patients with isolated 6th nerve palsy. (2)

Q What is the management of this condition ?

Diabetic Cranial neuropathy resolves on its own and requires no management apart from good glycemic and blood pressure control. It generally resolves over 6-12 months. Prisms may be used for symptomatic correction of the diplopia.
A paper by Broniarczyk-Loba et al suggest that injection of botulism toxin in the medial rectus can help in early resolution of the diabetic 6th nerve palsy. They suggest that this approach can be used for patients in whom the diplopia interferes with their work and function. (3)

REFERENCES:

1. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology2004;111(2):369-75.
2. Patel SV, Holmes JM, Hodge DO, Burke JP. Diabetes and hypertension in isolated sixth nerve palsy: a population-based study. Ophthalmology2005;112(5):760-3.
3. Broniarczyk-Loba A, Czupryniak L, Nowakowska O, Loba J. Botulinum Toxin A in the Early Treatment of Sixth Nerve Palsy-Induced Diplopia in Type 2 Diabetes. Diabetes Care2004 March 1, 2004;27(3):846-7.

ENDOCRINE ROUNDS CASE 5- PERIPHERAL ARTERIAL DISEASE

An elderly female with long standing history of uncontrolled diabetes mellitus presents with non-healing ulcer over the tip of the 2nd right toe with blackening of both left and forefoot since last 2-3 months.
The ABPI was 0.55 on the right side and 1.36 on the left

Q. What is the interpretation of the ABPI ?

On the right side ABPI is suggestive of significant PAD on the with ABPI >1.3 is difficult to interpret with ABPI alone and would suggest a non compressible vessel.
Right arterial doppler showed biphasic flow in the ATA with reduced pressure and PTA was found to be Stenosed at the origin.
The CT peripheral angiography of the lower limb was done and show below

Right

1- Popliteal

2- Anterior tibial

3- posterior tibial

4- peroneal

Left

1- Popliteal

2- Ant. tibial

3- tibioperoneal trunk

5- peroneal

6 – posterior tibial

Q. What is your interpretation of CT angiography ?
The posterior tibial on both side has attenuated lumen and significant reduction in flow

Q. What would be the next step for this patient ?
The next step would be to perform a revascularization procedure

Q. How to decide which revascularization procedure to perform in this case.
It depends on TASC classification of lesion.

Q. Which TASC stages would do well with Angioplasty
TASC A- single lesion < 5 cm
TASC B- multiple lesions, each <5 cm

Q. Is infrapopliteal angioplasty successful ? What is the long term patency rate ?
Success is >90%, however the term patency rate is 42% at 2 years with conventional balloon angioplasty.

Q. Which TASC lesions would require surgical revascularization ?
TASC C – Multiple stenosis with total length of occlusion > 10 cm
TASC D- Occlusion length >10 cm with dense lesion calcification and non visualization of collaterals