What are the Endocrine causes of hyponatremia following Traumatic brain injury ?

Original Case by Taylor et al

Review by Dr. Om J Lakhani (Endocrinologist)

A 44-year-old male with no substantial medical history was injured falling off his road bike at 25 mph and sustained a traumatic brain injury resulting in a marked expressive dysphasia. CT brain demonstrated a small left subdural haematoma, left temporal contusion and right petrous temporal bone fracture. He did not require surgical intervention. Forty eight hours after injury he developed a lower motor neurone facial weakness secondary to the temporal bone fracture, therefore dexamethasone was commenced.

Q Define traumatic brain injury ?

TBI is a non-degenerative, non-congenital insult to the brain from an external mechanical force causing temporary or permanent neurological dysfunction, which may result in impairment of cognitive, physical and psychosocial functions

Q What are the Endocrine problems associated with traumatic brain injury ?

  1. Post traumatic hypopituitarism (PTHP)
  2. Diabetes Insipidus
  3. Hyponatremia (SIADH , Cerebral salt wasting)

Q Which are the risk factors associated with Pituitary dysfunction after traumatic brain injury ?

  • Diffuse axonal injury
  • Fracture of skull base
  • Older age

Q Does the severity of GCS (Glasgow common scale) associated with pituitary dysfunction ?

  • Yes
  • Lower post resuscitation GCS is associated with more severe pituitary dysfunction

Q Which inflammatory mediator is related involvement leads to SIADH in TBI ?

  • IL6 increases release of Vasopressin
  • It leads to SIADH after TBI

Q Which type of forces damage the Hypothalamic pituitary unit ?

  • Shearing forces tend to cause damage to midline structure- more likely to be involved in Hypothalamic pituitary damage

Q What type of skull fracture can cause direct pituitary damage ?

  • Basal skull fractures

Q Which pituitary hormones increase and which reduce after an acute traumatic event ?

  • ACTH, GH, Prolactin – increase
  • FSH/LH and TSH- reduce

Q When does diabetes insipidus occur in Acute TBI ?

  • It generally manifests on day 5-10
  • It is often transient

Q In what period after brain injury does post traumatic hypopituitarism occur ?

  • Time period is variable from 1 months to 23 years
  • In 75% of patients it occurs within the first year
  • 35% cases within first 3 months

Q What type of damage predominantly leads to PTHP ?

  1. Vascular damage
  2. Shearing axonal injuries

Q Which part of the blood system of pituitary is most vulnerable to damage ?

  • The damage most predominantly occurs in the long hypophyseal portal system that goes through the sellar diaphragm
  • This part is most vulnerable to mechanical damage

Q Describe the percentage of various hormonal injuries following PTHP ?

  1. GHD – 30%
  2. Gonadotropin deficiency – 28%
  3. ACTH Deficiency – 18%
  4. Thyrotropin deficiency – 18%
  5. Diabetes insipidus- 2.7 %
  6. Hyperprolactinemia- 0-12%
  7. Hypoprolactinemia- also reported

Q When should pituitary evaluation be done after TBI ?

  • Generally done 3- 6 months after head injury

On Day 5 of admission his sodium level fell.

Q What are the causes of Hyponatremia following Traumatic brain injury ?

  1. SIADH
  2. Cerebral salt wasting
  3. Central Adrenal insufficiency

Q What are the Diagnostic criteria for SIADH ?

  1. Serum osmolality <280 mom/kg
  2. Urine osmolality >100 mom/kg
  3. Urinary sodium >30 meq/l
  4. Euvoluemic patient
  5. Adrenal insufficiency and hypothyroidism ruled out
  6. Low uric acid
  7. No acid base balance
  8. Normal potassium

Q Describe the management of SIADH ?

  • The management of SIADH deals mainly with management of Hyponatremia.
  • Before correction of hyponatremia you need to answer following questions :
    • How Rapidly did the hyponatremia develop ?
    • How severe is the hyponatremia ?
    • Is the patient symptomatic ?
  • In most cases of asymptomatic chronic , mild to moderate hyponatremia, free fluid restriction is mainstay of treatment.

Initially attributed to SIADH, his sodium continued to fall rapidly despite fluid restriction and slow sodium tablets. Baseline paired serum and urine osmolality were 265 and 595 respectively with urine sodium of 191 mmol/L. He was referred to endocrinology who suspected a diagnosis of CSW on the basis of failure of resolution with fluid restriction, low JVP and high urine output.

 

Q What are the essential features of Cerebral salt wasting ?

 

  • Low circulating volume
  • Low serum sodium
  • Sodium loss in urine

Q What are the theories for pathophysiology of this disorder ?

Two theories

  • Due to BNP increases urine sodium loss and suppresses renin (more likely theory)
  • Due to reduced central sympathetic outflow prevents activation for RAS in state of hypovoluemia loss of Sodium in urine

Q Which is more common SIADH or CSW ?

  • SIADH is more common

Q When is CSW generally seen after neurosurgical procedure ?

  • Generally seen 10 days after neurosurgical procedure

Q What are the CF of CSW  ?

  • Hyponatremia à cerebral edema à altered sensorium
  • Dehydration
  • Polyuria

Q What are the diagnostic criteria for CSW  ?

  • In patient with CNS disorder
  • Serum sodium <135
  • Urine osmolality >100
  • Urine sodium >40
  • Reduced serum uric acid
  • Clinical evidence of hypovolaemia

Q Which is the most important feature to distinguish SIADH and CSW  ?

  • It is the status of circulating volume – which is low in CSW

Q What are the essential points to differentiate Cerebral salt wasting from SIADH ?

  • CSW: With Infusion of fluids there is improvement in hyponatremia and reduction in urine osmolality
  • SIADH- Infusion of fluid à no improvement in hyponatremia and urine remains concentratedà this is because ADH is not suppressed

Urine output assessment was challenging to interpret initially due to extreme confusion, and agitation preventing catheterisation but his urine output was in excess of 3 L a day at this point despite a 1.5 L fluid restriction. During this time the patient recalls having excessive thirst and a craving for the salt tablets, which he later found unpalatable.

Despite hypertonic saline (1.8% saline) being commenced, his sodium continued to fall, with increased cerebral oedema and worsening confusion. This combination necessitated admission to intensive care with a sodium nadir of 116 mmol/L. A graph of his serum sodium, urine sodium and daily intravenous sodium is shown in Fig. 1.

 

Q Why is differentiating CSW and SIADH important from treatment point of view ?

  • Because treatment is opposite
  • SIADH – there is need for fluid restriction
  • CSW- there is need for fluid infusion and not restriction
  • Doing the opposite in both the condition can worsen each of the condition

Q What type of fluid is generally given in CSW ?

  • Generally isotonic fluid
  • This is not the case in SIADH where isotonic fluid will worsen the patient

Q Which Pharmacological agent is used in treatment of Cerebral Salt wasting ?

  • Fludrocortisone

Infusion of 5% saline (>950 mEq of sodium required in first 24 h in ITU) restored serum sodium to low normal levels within 72 h (sodium 134 mmol/L). During his intensive care admission he also required inotropic support which further highlights the extent of his volume depletion. Following the stabilisation of his sodium levels he was stepped back down to the neurosurgical high dependency unit. However, his urinary sodium remained persistently elevated peaking at 254 mmol/L, (urine osmolality 710 mmol/kg) serum sodium fell to 125 mmol/L despite hypertonic saline and he required substantial volume replacement (equivalent of more than 4 L/day of 1.8% saline). Urine output remained persistently high between 3 and 5 L a day over this time.

Fludrocortisone was therefore introduced at 75 µg bd and ultimately increased to 150 µg bd, which resulted in a substantial (threefold) fall in requirements for hypertonic saline that was still required for another 7 days. His sodium remained stable around 130 mmol/L on fludrocortisone alone and he was discharged home 25 days post injury. Fludrocortisone was continued for the next four months.

The dexamethasone initiated at 48 hours was continued for a 1-week course. As a baseline cortisol taken 24 h post the final dexamethasone was 94 nmol/L, he was maintained on hydrocortisone 10 mg bd which was continued until after discharge. A post discharge short synacthen test was normal and hydrocortisone was then stopped.

It took four months to wean him off the fludrocortisone without the occurrence of rebound hyponatraemia suggestive of on-going, albeit mild, CSW. Intriguingly, the attempt in the week after he developed peripheral oedema on fludrocortisone was successful and he has remained stable off fludrocortisone for three months.

Learning points

  1. Post-traumatic hypopituitarism, Diabetes Insipidus, SIADH and Cerebral salt wasting are important Endocrine disorders following traumatic brain injury
  2. Treatment of SIADH and Cerebral salt wasting is different, hence it is important to differentiate the two conditions in patients who present with hyponatremia following TBI
  3. Isotonic fluids with or without fludrocortisone is the treatment of choice in patients with CSW.

 

A Case of Thyroid cancer in Ectopic thyroid tissue (Critical analysis)

Original case by Yanery’s Agosto-VargasMadeleine GutiérrezJosé Hernán MartínezMichelleMangual-GarciaCoromoto PalermoSharon Vélez-MaymiLuis Hernández-VázquezSamayra Miranda-RodríguezAlex González-BossoloErnesto Solá-Sánchez, and Marianne Hernández-Negrón

CRITICAL REVIEW BY DR. OM J LAKHANI (ENDOCRINOLOGIST)

This is the case of a 33-year-old man without significant medical history who was incidentally diagnosed with a right neck cystic mass by computer tomography (CT) after a motor vehicle accident. Patient denied diaphoresis, palpitations, diarrhea, constipation, mood changes, or any other symptoms. Physical exam revealed a right-sided tender neck mass, without any other remarkable findings. He did not have history of neck irradiation, thyroid disease, or family history of thyroid cancer. Thyroid function tests were within normal limits (TSH: 1.5 IU/mL). Excisional biopsy of the neck mass reported metastatic, well-differentiated, thyroid papillary carcinoma within lymph node tissue. Pathologic description consisted of a nodular segment, tannish, rubbery specimen with attached membranous cystic tissue. The pathological specimen (lymph node) was distorted and had a well-defined cystic structure within it. While the cystic structure measured 2 cm × 1.5 cm × 1 cm, the lymph node measured 1.5 cm × 1 cm (Figure 2). Due to previous findings, he underwent total thyroidectomy with right neck dissection in order to rule out occult primary carcinoma of the thyroid. Histopathological findings revealed a normal thyroid gland without evidence of papillary thyroid carcinoma and sixteen right neck lymph nodes without evidence of metastasis. Thyroid pathology was meticulously reviewed, without any evidence of papillary thyroid carcinoma identified.

Q What is your impression of this case ?

It seems there is PTC present in a rare ectopic tissue present in the cervical region since the Eutopic thyroid gland has no evidence of thyroid cancer.

Q So this is a case of Papillary thyroid cancer (PTC) post thyroidectomy. Would you give post operative radioactive iodine in this case ?

All patients with PTC donot require radioactive iodine therapy post operatively.  In all such cases a post-operative re-staging is done to classify the patient into Low risk,  Intermediate risk and high risk.

Radioactive iodine therapy is indicated in those considered to have high risk according to American thyroid association (ATA) guidelines. The following are considered to be high risk

  • Gross extrathyroidal extension
  • Incomplete surgery / gross residual disease
  • Distant metastasis
  • Post op Tg suggestive of distant metastasis

It is considered in those with ‘intermediate’ risk and not indicated in those with low risk.

Q In which risk category would you classify this patient ?

It is difficult to classify the patient according to ATA classification since there is presence of PTC in the ectopic thyroid gland but not in the eutopic thyroid gland. Also there is no evidence of lymph node metastasis. Hence it would be difficult to classify this patient and hence consider the patient as having intermediate risk and CONSIDER radioactive iodine therapy for this patient.

 

Q How will you follow up this patient ?

I would not start the patient on LT4 and follow the patient after 6-8 weeks with TSH. If TSH is >30 , patient sent for Radioactive iodine ablation with 30 mCi.

After surgery, thyroid hormone replacement was started. One month after procedure, thyroglobulin was 133.61 ng/ml (1.15–130.77 ng/ml) and thyroglobulin antibodies were 11.8 uU/ml (negative, less than 45 uU/ml).

Q What is interpretation of these reports ?
We donot know if the Tg is stimulated or unstimulated, however in either case Tg is very high and needs evaluation. This would be classified as ‘Biochemical incomplete response’ or ‘Structural incomplete response’ depending on the presence or absence of any remnant tissue in the neck. So I would order a neck ultrasound from an experienced radiologist as my first line of approach.

In retrospect it suggests that the authors should have considered Radioactive iodine ablation post operatively. However, we have an advantage of hind sight and as described above the post operative staging according to ATA was tricky to begin with.

Thyroid scintigraphy reported functional thyroid remnants at the right thyroid bed. Ultrasonography evaluation revealed hypoechoic foci within the thyroid beds bilaterally, likely secondary to postsurgical granulation tissue versus residual thyroid tissue.

A right, level 2A lymph node seen measured 2.1 × 1 cm with loss of normal lymph node morphology, without microcalcifications or internal increase in vascularity. Another lymph node at level 3 measured 2 cm × 0.7 cm × 8.7 cm, without worrisome features. Fine needle aspiration biopsy of the aforementioned nodules showed papillary thyroid carcinoma.

Q How will you restage this patient now ?

The patient now is re-staged as high risk.

Q What are the treatment options now ?

For residual disease in neck the options are close follow up, surgery and radioactive iodine ablation.

In Gross extensive residual disease surgery is the best option. For minimal residual disease surgery is indicated in cases where size of lateral nodes is >1.5 cm. In this case a repeat surgery for local disease would be a better option.

Final diagnosis was malignant transformation of heterotopic thyroid tissue. Whole-body scan showed functional thyroid tissue remnants in the thyroid bed with multiple enlarged neck lymph nodes. At that time, TSH was elevated (44.3 IU/mL) and free T4 was suppressed (0.58 ng/dl; normal value: 0.75–1.54 ng/dl). The patient was referred to nuclear medicine for radioiodine therapy. Radioiodine ablation 142.2 mCi was given. After appropriate cessation of hormone replacement therapy, whole-body scan showed no nodules uptake.

Q Why this approach is incorrect to an extent ?

Presence of considerable local disease it is difficult to judge and ablate distant metastasis. Hence ideally surgery would have been a better approach followed by Radioactive iodine ablation if needed. In the currently scenario there seems to be a false reassurance of absence of distant mets on a radioactive iodine pre-therapy scan. I would advice the authors for a close post operative follow up of this case.

Learning objective.

  1. This is a rare case where PTC in an ectopic thyroid tissue that too in lateral neck region without evidence of malignancy in the eutopic thyroid.
  2. In cases where post-operative ATA staging is ambiguous, it is better to consider a higher stage than a lower stage.

 

A Case of Disorder of Sexual Differentiation

Original Case by

Filippa Pritsini,1,2 Georgios A. Kanakis,1,2 Ioannis Kyrgios,1 Eleni P.Kotanidou,1 Eleni Litou,1 Konstantina Mouzaki,1 AggelikiKleisarchaki,1 Dimitrios G. Goulis,2 and Assimina Galli-Tsinopoulou1

A girl of 11 years and 3 months was referred to our unit due to enlargement of the clitoris associated with obstructive symptoms at micturition. According to her prenatal history, amniocentesis was conducted due to advanced maternal age, revealing a 46, XY karyotype. Pregnancy was otherwise uncomplicated. Cesarean section was performed at the gestational age of 40 weeks and 3 days due to cephalopelvic disproportion and failure to progress. The newborn was a healthy full-term baby, without electrolyte imbalance, presenting with an inadvertent female phenotype. In order to assess the discordance between chromosomal and phenotypical gender, the SRY gene was examined and found to be present, while imaging of the brain, hypothalamus, and pituitary gland was normal. At that time-point, the family decided to take no further action.

Q What are cause of 46 XY with unambiguous female genitalia at birth ?

  • Complete androgen insensitivity syndrome (CAIS)
  • Complete gonadal dysgenesis  (CGD)
  • 17 alpha hydroxylase deficiency

Q How will you distinguish CAIS from Complete gonadal dysgenesis ?

  • CAIS will have absent Mullerian structures while Complete gonadal dysgenesis may have Mullerian structures present.
  • Gonads are not palpable in complete gonadal dysgenesis while they may be present in the inguinal region or labioscrotal region in CAIS
  • On measuring the Serum testosterone- CAIS will have testosterone in normal male range while CGD will have low testosterone.

Anthropometric characteristics at presentation were in the normal range for girls at the patient’s age, while physical examination revealed excessive clitoriomegaly resembling a phallus of 6 cm and a shallow vaginal orifice.

Q Would you plot the patient’s growth with a female growth chart or in the male growth chart ?

  • You will plot it in female growth chart only, however it is an area of debate.
  • However most studies done have plotted it on female growth chart

While physical examination revealed excessive clitoridomegaly resembling a phallus of 6 cm and a shallow vaginal orifice. No testes were palpable.

Q What do you think of the diagnosis now ?

  • It seems odd that the child had normal female genitalia at birth and now has significant clitoromegaly and ambiguous genitalia.
  • It is more likely the ambiguous genitalia was missed at birth which seems strange because they already knew that the child was 46 XY on amniocentesis !
  • However my DD now would be 1) 5 alpha reductase 2 defect b) 17 beta HSD3 c) PAIS d) partial gonadal dysgenesis

Pubertal maturation, pubic hair, breast, and axillary hair were of Tanner stage III, I, and II, respectively

Q The breast they say is Tanner stage I , what will you narrow down your DD do ?

  • With absent breast enlargement ,5 alpha reductase 2 appears to be a more appopriate diagnosis
  • However it is possible that the child has not reached puberty , hence it would be premature to judge

Imaging of the lower abdomen with ultrasound and MRI revealed bilateral testicular tissue at the intraperitoneal space near the inner inguinal ring, hypoplastic penile cavernous bodies within a sizable clitoris, and the presence of a rudimentary prostate along with seminal vesicles.

Q Are wolffian duct derivatives present in CAIS ?

  • No generally not
  • Even if they are present they are rudimentry

Q There are absent Mullerian structures, which differential seems less likely with this ?

  • The presence of testis and absent of Mullerian derivatives make the diagnosis of partial gonadal dysgenesis less likely.

Basal hormones assessment showed elevated T (84.0 ng/dl) in the male reference range for the given pubertal stage, accompanied by mildly elevated LH (2.11 mU/mL) and follicular stimulating hormone (FSH) concentrations (18.56 mU/mL). Estradiol (E2) on the other hand was inappropriately low (14.45 pg/mL).

The ratio of T to -androstenedione (Δ4A) was >0.8, excluding 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency, while the ratio of T to dihydrotestosterone (DHT) was <20, excluding 5α-reductase deficiency. The high elevation of T concentration (ΔΤ) after the hCG stimulation (>100 ng/dl) indicated the presence of testicular tissue, excluded gonadal dysgenesis, and supported the diagnosis of AIS (Table 2). Imaging control revealed the presence of bilateral testicular tissue. The combination of almost female phenotype with minimal virilization and proper male gonadal function was supportive for the diagnosis of severe PAIS

Q Give a typical protocol for HCG stimulation test ?

  • There are various protocol for HCG stimulation test. We will discuss one protocol which we follow
  • Baseline Testosterone, DHT and Androstenedione are sent
  • HCG is given as a single dose of 5000 IU for an older child IM
  • The sample are repeated after 72 hours

Q What ratios suggest 5 alpha reductase 2 and 17 beta HSD 3 ?

  • Stimulated T:DHT ratio > 27:1  – suggest 5 alpha reductase 2 defect
  • T: A ratio <0.8 suggests 17 beta HSD 3 deficiency

Q What small care you must take while calculating the ratios of T:A in this case?

The values of androstenedione are in ng/ml. Hence when we calculate the ratio, we need to convert it to ng/dl

Q What would you do for further management of this case ?

  • This is a case of PAIS raised as a female.
  • Since the child is already raised as female it would be wise to continue the same gender assignment.
  • I would consider going a gonadectomy and replacing the child with estrogen replacement.
  • I would also consider doing appropriate genital reconstruction.

Q What is the risk of gonadoblastoma in this case ?

  • PAIS with non scortal gonad have high risk of gonadoblastoma.

Reasonably, the assignment of female gender was recommended, since the patient had already been raised as a girl and the relevant interventions would be minimal. In addition, the testes that were found during imaging studies had to be removed, as they were atrophic and of increased risk for malignant change. Interestingly, the parents suggested that the child itself should be fully informed and participate in the final decision, and therefore, from the very first beginning, the patient was involved in all discussions made with the attending physicians. It is noteworthy that, being aware of the condition, she stated: “It does not matter if I am female or male, most of all I am a human being and thus gender assignment will not play any significant role in my future life.” Eventually, female gender was preferred by both the patient and the parents, and gonadectomy as well as cosmetic surgery of the external genitalia were successfully performed.

Learning points

  1. Be careful while calculating the T:A and T:DHT ratios. The units of the numerator and denominator should be the same.
  2. PAIS with non scrotal gonad have a high risk of gonadoblastoma and  gonadectomy must be done , generally before puberty.
  3. Female sex assignment is not inappropriate for PAIS, especially if the child is raised as a female.

A CASE OF HYPOPHOSPHATEMIC RICKETS – OR IS IT ?

Original Case by MD. SHAHIDUL HAQUE1, LE FATMI2, MD. SHAFIQUL ALAM CHOWDHURY3

Editorial note: In this case we have questioned the diagnosis the authors have made. The idea of this is not to criticize the efforts of the authors, but to point out an obvious flaw or error made in the diagnosis in this case. If you disagree with our explanation please feel free to send me an email on endocrinecases@gmail.com

A 11 years old girl of a consanguineous parents belonging to a low socioeconomic status, hailing from Nazirabazar, Dhaka, was admitted at Dhaka Medical College Hospital on 07/03/07 with inward bending of both legs for last 4 years, not gaining height in comparison to other children of same age and dental caries for 2-3 years.

 

She had no history of polyuria, dysuria, jaundice, recurrent chest infections or recurrent attacks of diarrhoea and not on long term anticonvulsant drugs.

 

Q  What is the importance of Polyuria in case of Rickets ?

 

  • Polyuria with rickets is suggestive of Renal tubular acidosis, Barrter’s syndrome and certain cases of CKD.

 

Birth history was uneventful and was partially immunized as per EPI schedule. After birth she was predominantly breast fed for only 5 successive months and currently she is on family diet, i.e., rice, vegetable, fruits but low quantity of fish, meat, milk and egg as they are unable to afford those.

 

Q  Are any of these good sources of vitamin D ?

 

  • Since this case is from Bangladesh, food fortification status of general foods is not known.
  • However, fatty fishes are good source of vitamin D , so the child may be receiving some vitamin D

 

Though her milestones of development were normal, her linear growth and also weight were not satisfactory as compared to that of other children of her age. Exposure to sunlight was adequate as she used to play along with other children in open air. Her father did not have the same disease and died of kidney disease two years back. Her mother and sibs are healthy

 

On examination, her pulse was 40/min, BP-100/60 mm Hg and temperature was normal.

Anthropometric measurement revealed height – 108 cm (74.2% of

NCHS median), weight – 18 kg (55.3% of NCHS median) and weight for height – 98.5% of NCHS median.

Both wrist and knee joints were widened , knocked knee was obvious on standing.

The chest examination demonstrated pegion chest deformity, mild rachitic rosary but there was no Harrison’s sulcus or other deformities of the limbs or joints.

However, dental caries were present in both upper and lower molar teeth

 

Radiologically, cupping, fraying and widening of growing lower ends of femur as well as radius and ulna, thinning of cortex and generalized osteopenia were revealed.

 

Q  What are X-ray features of Hypophosphatemic rickets ?

 

  • Hypophosphatemic rickets will show metaphyseal changes like widening and splaying, but calcipenic changes like fraying and osteopenia will not be seen.
  • Sclerosis may be seen.

 

Laboratory investigations showed TC of WBC 8000/cmm, DC: polymorph 60%, lymphocyte 37%, monocyte 2%, basophil 1%, eosinophil 2%. Total platelet count was within normal range. Anisocytosis and poikilocytosis of RBC and mature WBC were showed in peripheral blood film.

 

Biochemical investigations showed near serum calcium (Ca++) level of 8.4 mg/dL (N: 8.8-10.8 mg/dL), serum phosphate 2.5 mg/dL (N: 4-7 mg/dL), while alkaline phosphatase was 630 IU/L which was much higher than normal range (N: 115-431 IU/L). Serum creatinine was 0.8 mg/dL and SGPT 40 IU/dL. The parathyroid hormone level was within normal limit 11 pg/mL (N: 7-53 pg/mL). Urine examination showed phosphaturia and its level was 24.5 mg/dL. Urinary creatinine was 22.5 mg/dL (N: 15-20mg/dL). As there is no definite range of the urinary phosphate level of 11 years old girl, tubular reabsorption of phosphorus (TRP) was calculated

The TRP was 68% (N: 78-98%) which confirmed loss of excess phosphate through urine. However, serum 1-α-hydroxylase level could not be done. All parameters of electrolytes were normal. Benedict’s test showed no glucosuria.

 

Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets.

 

Q  Do you agree with the diagnosis ?

 

  • No
  • Infact in my opinion the diagnosis in this case is most likely nutritional rickets due to vitamin D deficiency

Q  What is the most important investigation that has been missed out in this analysis ?

 

  • A 25-hydroxy- vitamin D level is not done.

 

Q  What are the points in favour of this being a nutritional rickets ?

 

  • Osteopenia in X-ray is a features of nutritional rickets and it is NOT seen in XLRH
  • 25(OH) vitamin D is not obtained
  • Serum calcium levels are low. XLRH patients generally have normal serum calcium levels.

Q  if it is nutritional rickets, what explains the phosphate wasting ?

 

  • Vitamin D deficiency typically produces secondary hyperparathyroidism.
  • Increase PTH typically causes phosphate loss.
  • The increase TRP can be very well explained by the secondary hyperparathyroidism.

 

Q  You say it is secondary hyperparathyroidism , but the PTH levels is normal !

 

  • PTH assay depends much on the transport.
  • Improper transport of sample in cold chain can lead to reduction in PTH values and hence false low PTH.
  • This is a well known fact and activation of thrombin is responsible for lowering of PTH values in the sample.
  • Hence I believe that the PTH levels were false low.

 

Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets. So, she was treated with Joulie solution, an oral phosphate suspension made up of sodium phosphate (136 gm/L) and phosphoric acid (58.8 gm/L)5 1.5 tsf every 4 hourly. Active form of vitamine D (1-25 dihydroxy cholecalciferol) was also given in the form of Dicatrol capsule (0.25mcg) 6 hourly.

 

Along with treatment we consulted with orthopaedic department. She was advised to continue the treatment and for regular follow up. After 2 weeks of treatment with oral phosphate and dicatrol, significant radiological improvement was documented. Genetic counseling was also done. As the disease is X-linked, the defective gene may come either from father or from mother. Unfortunately, the genetic study is not possible in Bangladesh. As the father died two years back, there is no chance to have any more children.

 

Q  So if the diagnosis was probably incorrect, why did the child respond to treatment ?

 

  • The child was given active vitamin D supplementation.
  • If the child truly has vitamin D deficiency as we are thinking, she would have responded to active vitamin D supplementation as well.

Learning objective

  • When dealing with a case of rickets, it is always important to rule out common things first. Vitamin d deficiency (nutritional rickets) is far more common compared to other forms of rickets and must always be ruled out before further investigations are considered.
  • Vitamin D deficiency with secondary hyperparathyroidism ALSO causes loss of urine phosphate and hence TRP will be reduced in such cases.

A case of Euthyroid Graves’ orbitopathy with negative TRAb antibody.

Original CArshiya Tabasum1, Ishrat Khan1, Peter Taylor1,2, Gautam Das1 and Onyebuchi E Okosieme1,2

A 66-year-old female presented with a 4-month history of double vision, excessive tearing, sticky feeling in the eyes, and orbital pain in all gaze directions.

Q  What is the importance of double vision in a case of suspected thyroid associated orbitopathy (TAO) ?

  • Double vision suggest involvement of extraocular muscles in case of TAO

She had no symptoms of thyroid dysfunction, did not smoke, and denied any personal or family history of thyroid disease.

She was clinically euthyroid and had no palpable goiter

Her visual acuity was 5/6 in both the eyes.

She had fullness of her eyelids on the right side with erythema below the right inferior orbital rim.

 

Q  Why is this finding important “She had fullness of her eyelids on the right side with erythema below the right inferior orbital rim”  ?

 

  • This finding suggests two things
    • The patient has eyelid swelling
    • The patient has erythema of the eyelid
  • Both of these are important points in the clinical activity score of TAO as published by EUGOGO.

 

She had right eye proptosis and diplopia on vertical gaze but with no lid lag or retraction.

Her intraocular pressures were normal and the optic discs were normal on fundoscopy.

 

Q  Which Extraocular muscle is commonly involved in TAO ?

 

  • Inferior rectus is most commonly involved followed by Medial rectus.

 

Q  What are the your differential diagnosis at this stage ?

 

  • This patient has unilateral proptosis with no lid retraction or lid lag.
  • Yet, Thyroid associated orbitopathy still remains my first differential diagnosis as it the most common cause of unilateral proptosis.
  • Apart from that Non specific orbital inflammatory syndrome (inflammatory pseudotumors) would be my second differential diagnosis
  • Orbital tumors , especially those arising from optic nerve (like optic nerve glioma) would be another differential diagnosis

 

At this point, a differential diagnosis of right inferior rectus mass and thyroid eye disease was considered.

 

Q  How will you investigate this case ?

 

  • First I would send thyroid function test with TSH Receptor antibody
  • Also I would consider doing a CT scan or the orbit.

 

 

Thyroid function test was normal: TSH 2.25 U/L (reference range 0.4–4.5), FT4 11.6pmol/L (reference range 11.0–24.0), and FT3 4.3pmol/L (reference range 2.67–7.03) (Table 1)

TRAbs and TPOAbs were negative and thyroid ultrasound scan showed no evidence of thyroid disease. TRAb measurement was performed using a commercial third-generation ELISA kit that detects both thyroid-stimulating (TSAbs) and -blocking antibodies (TBAbs) with manufacturer specificity and sensitivity of 100 and 95%, respectively, and positive cut-off of >0.4 U/L (RSR Laboratories, Cardiff, UK)

In the ELISA, serum TRAbs inhibit the binding of human biotin-labeled monoclonal antibody to immobilized recombinant TSH receptor on the ELISA plate. The amount of M22-biotin bound to the plate is then determined by the addition of streptavidin peroxidase and tetramethylbenzidine and the absorbance of the mixture is read at 450 nm using a plate reader

 

Q  What is the role of measurement of TSH receptor antibody ?

 

  • TSH receptor antibody would help in confirming the diagnosis of Graves’ disease and hence TAO
  • It will also help in assessing the severity of the disease, guide management decision and help in follow up of the patient

 

Q  How do TRAb antibodies predict the outcome of the patient with TAO ?

 

  • Higher TRAb levels at the time of diagnosis are associated with worse clinical course and poor outcomes.

 

Q  What are the subtypes of TSH receptor antibodies ?

 

  • Stimulating – TSI à Graves’ disease
  • Blocking – TBI or TBII – Atropic thyroiditis
  • Neutral

 

Q  What are the methods by which TSH receptor antibodies are tested ?

 

  • There are two major ways in which TSH Receptor antibodies are tested
  • The first is TBII assay (Receptor method) and the other is functional biological assay for TRAb.
  • TBII assay cannot differentiate between stimulating and blocking antibodies while the functional assay can differentiate between the two.

 

Q  Tell me something about TBII assay ?

 

  • TBII assay are based on the principle of TSH binding to the TSH receptor and the antibodies competing with this binding.
  • Naturally they donot distinguish between TSI and TBI (TBAbs)
  • The 2nd generation TBII assay uses radiolabelled TSH receptor for assay
  • The 3rd generation TBII assay uses recombinant TSHR and monoclonal antibody against TSI.

 

Q  Tell me about the biological assay for TRAb ?

 

  • The biological assay are based on the principle of cAMP generation on binding of ligand with TSH
  • TSI activates TSH receptor leading to generation of cAMP and TBI reduces the generation of cAMP
  • Current assays are based on Mc4-CHO cell lines
  • However interpretation of the results is sometimes difficult since the same patient may have blocking as well as stimulating antibodies.
  • Hence these are mainly used in research setting.

 

 

Q  What kind of assay is used in this case  ?

 

  • It is a TBII assay which is used
  • It would not distinguish between TSI and TBI

 

Q  What is your interpretation of the CT scan in this patient ?

 

  • The CT scan clearly shows inferior rectus thickening on both the sides.
  • Hence eventhough clinically the patient has mainly right sided proptosis, based on CT scan both the sides are involved.
  • Thickening of the EOM with sparing of the tendon insertion site is characteristic of TAO.
  • However, in this cases sparing of the tendon is not demonstrated as alternate cuts showing inferior rectus insertion are not provided.

fig1

A CT scan of the orbit showed bilateral asymmetrical enlargement of the inferior rectus, more marked on the right than on the left, and was highly suggestive of GO inflammation (Fig. 1). An MRI orbit (Fig. 2) also confirmed inflammation in keeping with GO (Fig. 2). There was no evidence of structural or other inflammatory lesions on imaging. Serum calcium and angiotensin-converting enzyme (ACE) levels were normal.

 

Q  So what is your diagnosis at end of the investigations ?

 

  • Since now there is CT evidence of bilateral involvement of the EOM, the diagnosis would most likely still be TAO.
  • Again absence of any other tumor or pathology would also favor the diagnosis of TAO, albeit euthyroid TAO.

 

Q  Since there is still no confirmed diagnosis of TAO, what would you consider doing next ?

 

  • Though this seems nothing else other than TAO based on clinical judgement, the patient being euthyroid and absence of significant elevation of TRAb antibody does create doubts about the diagnosis.
  • In option in such a case would be to perform FNAC or biopsy in such a scenario.

 

Q  What is the role of Functional imaging modalities in such cases of proptosis where diagnostic confusion exists ?

 

  • In a study done by García-Rojas et al , FDG- PET is useful for distinguishing EOM in TAO versus other conditions.
  • In their study they found that patients with TAO has higher SUVmax uptake of FDG in EOM compared to those having non thyroidal cause of EOM involvement.

 

 

Q  Assuming it is TAO, Based on the evidence provided, what is the Clinical activity score in this patient ?

 

  • The CAS would be 3 based on the evidence provided which would make it active ophthalmopathy.
  • According to the authors, the MRI is also suggestive of active inflammation.

 

Q  Describe the EUGOGO clinical activity score ?

  • EUGOGO Clinical activity score

fig2

Q  What is the severity of the TAO based on the evidence provided ?

 

  • Based on the ATA grading it would be Grade IV since there is involvement of EOM (NO SPECS classification)
  • It would be difficult to classify the patient based on the EUGOGO assessment of severity since the measurement of proptosis and severity of the soft tissue involvement is not provided.

 

She was treated symptomatically in the regional multidisciplinary Thyroid Eye Disease clinic with topical lubricants and fitted with a corrective prism. She later underwent a surgical recession of 4mm of the inferior rectus muscle with complete resolution of diplopia and headaches. A biopsy of the inferior rectus muscle taken at surgery showed a low-grade infiltrate with B and T lymphocytes. She had no further eye complaints and continued to be followed up with annual thyroid function tests.

 

Twenty-four months after initial presentation, she developed symptoms of anxiety, sweating, tremor, and palpitations. She had no goiter or eye signs. Her thyroid hormone levels were consistent with T3 toxicosis: TSH 0.04U/L, FT3 9.56mol/L, and FT4 15.5pmol/L. At this point, repeat TRAb and TPOAb measurements were positive: 7.6IU/L and 67.9IU/mL, respectively (Table 1). She was commenced on carbimazole initially and subsequently treated with a ‘block and replace’ regimen of carbimazole and levothyroxine. She responded satisfactorily with clinical and biochemical resolution and treatment was discontinued after 12 months. Her vision has since remained intact with no further disturbance of thyroid function.

 

Q  Describe the timing of diagnosis of TAO in relation with Graves’ hyperthyroidism ?

  • Timing with Graves’ hyperthyroidism
    • 20% – Precedes hyperthyroidism
    • 40%- diagnosed concurrently
    • 20%- Follows the diagnosis of hyperthyroidism
    • 20%- Occurs after Radio-active iodine therapy

 

Q  What percentage of people with TAO have hyperthyroidism, euthyroidism and hypothyroidism ?

  • With patients having TAO
    • 80%- Hyperthyroid
    • 10-20%- Euthyroid
    • 1-10%- Hypothyroid

 

Q  What are the features of Euthyroid TAO compared to hyperthyroid TAO  ?

 

  • Euthyroid TAO compared to hyperthyroid TAO are:
  • Milder
    • Less severe EOM
    • Unilateral more often
    • Lesser soft tissue involvement
    • Absence of lid lag and Upper eyelid retraction.
    • Lower degree of TRAb antibody

 

Q  What is the explanation of the absence of TRAb antibody in this case ?

 

  • Absence of TRAb antibody may be due to low titres of this antibody in case of Euthyroid graves orbitopathy.
  • The tests use for TRAb antibody donot have 100% sensitivity.
  • Antibodies against IGF-1 receptor have also been implicated in pathogenesis of TAO.

Learning points

  1. TRAb antibodies are an important test for diagnosis of TAO especially in cases of Euthyroid TAO or in cases where diagnostic confusion exists. However, in some cases of TAO, TRAb antibodies may be negative or in low titres to be detected at the time of early presentation.
  2. CT scan of the orbits is an important diagnostic tool in case of proptosis where diagnosis of TAO is not certain.
  3. FNAC, Biopsy, Surgical resection and FDG PET are other modalities used for differential diagnosis of proptosis.
  4. Onset of TAO may preceed the onset of hyperthyrodisim in patient with Graves’ disease in about 10-20% cases.

A Case of Gonadotropin-independent precocious puberty (GIPP) in a young boy

Original Case by Bahar Özcabı,1 Feride Tahmiscioğlu Bucak,1 Serdar Ceylaner,2 Rahşan Özcan,3 Cenk Büyükünal,3 Oya Ercan,1 Beyhan Tüysüz,4 and Olcay Evliyaoğlu1,*

Abbreviations

  1. PP- Precocious puberty
  2. CPP- Central perocious puberty
  3. GIPP – Gonadotropin independent preocious puberty
  4. GDPP- Gonadotropin dependent preocious puberty. 
  5. FMPP- Familial Male limited precocious puberty

A 1.4-year-old boy was admitted with complaints of pubic hair development, penile enlargement, linear growth acceleration, acne and increased aggressive behavior. His mother had become aware of enlargement of the genitals by 6 months of age

Q What is definition of precocious puberty ?

  • Age of onset of puberty 2 -2.5  SD earlier than normal
  • Ie Onset of puberty before 8 years on girls and before 9 year in boys

Q Classify the various causes of precocious puberty (PP)in boys based on age of onset ?

Onset in infancy

  • Hypothalamic hamartoma
  • Adrenal tumor

Onset in early childhood

  • Hypothalamic hamartoma
  • Familial male limited precocious puberty (FMPP)

Onset in late childhood

  • CNS tumors
  • CAH
  • Idiopathic

He had healthy parents non-consanguineously married and there was no family history of precocious puberty.

At physical examination, his height was 96 cm (+5.38 standart deviation score (SDS)) and weight was 17 kg (+2.0 SDS). He had an extremely muscular body build, a deepened voice and acne. Penile stretch length was 13 cm (>2 SDS); the left testicular volume was 3 mL and the right was 4 mL. Pubic hair was appropriate for Tanner stage 3 (Figure 1a). He did not have any café au lait spots.

Q Can you deduce from this clinical presentation whether the patient has GDPP or GIPP (gonadotropin dependent or independent precocious puberty)

  • From this history  and examination it seems the child most likely has GIPP.
  • Boys with GIPP typically have isosexual precocity with disproportionate penile enlargement compared to testicular enlargement.
  • Testicular enlargement in these cases may often be prepubertal.
  • In this case one of his testis is already pubertal, however if you compare this to the penile growth, the child most likely has GIPP.

Q What are the causes of GIPP in boys ?

  1. CAH (21 hydroxylase deficiency)
  2. Exposure to exogenous testosterone
  3. FMPP
  4. McCune Albright syndrome
  5. Primary hypothyroidism
  6. Androgen producing adrenal tumor
  7. HCG producing germ cell tumor
  8. Leydig cell tumor of testis.

Q Which testicular tumor leads to precocious puberty in boys ?

  • Leydig cell tumor lead to PP

Q why doesn’t HCG producing tumors produce GIPP in girls ?

  • In girls both FSH and LH are required for pubertal activation and just activation of LH receptors as in HCG secreating tumors will not lead to PP in girls

Q  What happens to testicular size in GIPP in boys ?

  • Testis is not enlarged in GIPP
  • This is because testis mass is due to semineferous tubules which in turn is dependent on FSH for enlargement

Q Which are the sites for germ cell tumors ?

  • Brain- mainly pineal region
  • Gonads
  • Anterior mediastinum
  • Liver
  • Peritoneum

Q Which test must be done in males with anterior mediastinal germ cell tumors ?

  • Karyotype must be done to diagnose Klenilfeter’s in all males with anterior mediastinal germ cell tumors

Q What is the etiology of testitoxicosis ?

  • Activating mutation in LH receptor
  • It is autosomal dominant transmitted

Q What are the causes of testicular enlargement associated with GIPP ?

  1. Primary hypothyroidism
  2. Familial male limited precocious puberty
  3. McCune Albright syndrome
  4. HCG secreating tumors
  5. CAH with TART
  6. Testicular tumors (unilateral testicular enlargement) with precocious puberty.

Q Why do patient with Familial male related precocious puberty have testicular enlargement ?

  • FMPP is a form of peripheral precocity with activating mutation in LH receptor.
  • LH receptor activation causes production of testosterone and not the growth of seminiferous tubules.
  • Hence enlargement of testis should not be seen in these patients.
  • However , in practice it is often seen that these patients have mild testicular enlargement.
  • This is because of following possible reasons:
  1. Intratesticular testosterone causing growth of the seminiferous tubule by paracrine effect
  2. Leydig cell hyperplasia which is typically seen in LH receptor activation states which can cause mild testicular enlargement
  3. Secondary activation of the central HPG axis (peripheral precocity causing secondary central precocity)
  • Similar picture may also be seen in boys with MAS and HCG secreting tumors who present with precocity.
  • However the testicular enlargement is mild as it is seen in this case.

Bone age was 4 years by the Greulich-Pyle method. Mid-parental height (MPH) SDS was 0.83. Clinical, auxological and endocrinological findings at admission are summarized in Table 1.

Q What do you derive from the table for patient 1 ?

  1. Patient surely has precocious puberty as evidenced by
  • Growth acceleration
  • Penile enlargement
  • Advanced bone age
  • Testosterone in late pubertal range.
  1. It is most likely GIPP
  • This can be derived form
  • Disproptionate growth of Penis compared to the testis
  • Basal LH in prepubertal range (<0.3)
  • Peak LH post GnRH also in prepubertal range (<3.3)

Q What tests would you perform for further evaluation of GIPP ?

  1. Adrenal androgens –17 OHP and DHEAS to r/o of adrenal causes of GIPP which include CAH and Adrenal tumors.
  2. Clinical examination to look for Café-au luit spot for diagnosis of McCune Albright syndrome
  3. Clinical examination and scrotal ultrasound to look for testicular mass.
  4. HCG level to look for HCG secreting tumor
  5. Thyroid function test (though unlikely diagnosis since the child has obvious growth acceleration)

The patient’s serum testosterone level was very high and gonadotropin-releasing hormone (GnRH) stimulation test revealed a prepubertal response.

Thyroid function tests (free triiodothyronine (T3): 4.4 pg/dL; free thyroxine (T4): 1.1 ng/dL; thyroid-stimulating hormone (TSH): 2.5 mIU/L) and adrenal cortex hormone levels (dehydroepiandrosterone sulfate (DHEA-SO4): 37.2 µg/dL; 17-α-hydroxyprogesterone (17-OHP): 0.9 ng/dL; androstenedione: 0.5 ng/mL; cortisol: 10.7 µg/dL) were within normal ranges.

Peripheral precocious puberty findings with a testicular volume of 4 mL suggested a tumor secreting beta-human chorionic gonadotropin (hCG) or a testicular tumor secreting testosterone; an activating mutation in the LH receptor and McCune Albright syndrome were also considered.

Abdominal magnetic resonance imaging (MRI) revealed normal findings.

A low serum beta-hCG (presence of a beta-hCG-secreting tumor.

He did not have any abnormality in bone scintigraphy screening.

A testicular ultrasonography showed a solid mass of a size of 2×2 mm in the right testicle. A surgical intervention was performed. During the operation, the testis was mobilized by inguinal incision and a 2×2 mass was detected. In cold ischemia conditions, the mass was excised by testis-saving procedure and sent for histopathological evaluation.

Q What is the treatment of GIPP in boys ?

  • For Tumor of Testis, adrenal or GCT: Surgery and/or other modes of therapy for the tumor
  • CAH- glucocorticoids
  • For other causes- anti-androgen therapy

Q What is bicalutamide ?

  • It is a pure androgen receptor antagonist
  • In GIPP – it is given in dose of 2 mg/kg

Q What is done if GIPP patients develop secondary CPP ?

  • GnRH agonist is given additionally

Q What is the treatment of Familial male limited precocious puberty (FMPP) or testitoxicosis ?

  • It is treated with bicalutamide + Anastazole
  • Ketoconazole and sprionolactone have also been used

Pathological examination revealed nodular Leydig cell hyperplasia. After surgery, serum total testosterone level did not decline

Anti-androgen treatment with bicalutamide (50 mg/day) and aromatase inhibition with anastrozole (1 mg/day) were initiated. A normal testosterone level could not be obtained and another surgery was planned. The same inguinal incision was performed and vascular pedicle was secured in cold ischemia conditions. The mass was not localized by visual examination. Intraoperative ultrasonography demonstrated a 3×3 mm mass and with the guidance of the probe, the mass was found and excised by another testis-saving procedure. Histopathological examination revealed the diagnosis of nodular Leydig cell hyperlasia again.

Q What are the typical histological findings of the testis seen in case of FMPP ?

  • Leydig cell hyperplasia is typical
  • Hyperplasia of Sertoli cell and spermatogenesis is also present because of increase intratesticular testosterone concentration.

Since the patient met the criteria for the diagnosis of testotoxicosis, a genetic analysis for LHCGR gene was performed.

Q What is the diagnostic criteria for FMPP ?

FMPP is a diagnosis of exclusion. The criteria are as follows:

  1. Family history with autosomal dominant mode of inheritance
  2. Limited to males
  3. Gondotropin independent precocity (LH response to GnRH agonist prepubertal)
  4. No CNS, Adrenal or testicular abnormality detected.
  5. Premature Leydig cell maturation

Sequence analysis of all coding regions and exon-intron boundaries were done by in house designed primers using Sanger sequencing technique and a novel mutation c.830G>T (p.S277I) (heterozygous) was described (Figure 1b). In silico evaluation tools including Mutation taster, SIFT and Polyphen 2 predict this variant as a disease-causing mutation. Parental analysis was normal, then this variation was most probably a de novo pathogenic variant. Screening of 200 healthy people for this variant was done and no one had this mutation.

Q What is the typical age of presentation of FMPP ?

  • They typically present between 1-3 years of age.
  • However in this case the onset was even before 1 year of age.
  • This may be because of the novel mutation found.
  • Such cases with earlier onset of FMPP have been reported in literature.

Q What is the mode of inheritance of Familial male limited precocious puberty (FMPP)  ?

  • FMPP has an autosomal dominant inheritence with more than 90% penetrance.

Cyproterone acetate was added to the treatment regimen because the suppression of pubertal progression and serum testosterone levels was not sufficient, but it was withdrawn in one month because of increases in liver enzymes which could not be associated with another cause; liver enzymes became normal after the cessation of the drug.

In the 20th month of treatment, GnRH stimulation revealed a pubertal response and a GnRH analogue was added to treatment.

Q Why do children who have GIPP also develop Central precocious puberty secondarily ?

  • Excess sex steroid exposure as in McCune albirght or CAH can lead to secondary CPP
  • Two theories
  1. Priming effect of sex steroids
  2. On reducing Sex steroid with treatment – there is loss of negative feedback à rebound activation of gonadotropin axis

In his follow-up at age 3.8 years, despite bicalutamide (100 mg/day), anastrozole (2 mg/day) and GnRH analogue treatments, sufficient suppression of puberty and decline in serum testosterone levels were not achieved (Table 2). Antiandrogen treatment with bicalutamide (androgen receptor antagonist) was changed to ketoconazole (androgen synthesis inhibitor) in a dose of 10 mg/kg/day. A treatment regimen of ketoconazole, anastrozole and a GnRH analogue led to a decline in serum testosterone level from 900 ng/dL to 490 ng/dL on the 3rd day of the treatment. At the 3rd month of ketoconazole (15 mg/kg/d) treatment, serum testosterone level decreased to 125 ng/dL without any sign of side effects; whether this benefit will be sustained or not needs to be evaluated in the long term.

Learning points

Familial male limited precocious puberty (Testitoxicosis) is an important cause of Gonadotropin independent precocious puberty (GIPP) in boys and generally present between ages 1-3 years but may present earlier.

Absence of testicular enlargement in presence of other features of Precocious puberty points towards GIPP, however FMPP may have mild testicular enlargement because of Leydig cell hyperplasia and/or hyperplasia of seminifeous tubules and sertoli cells due to intratesticular testosterone.

A Case of Prepubertal Gynecomastia

Original Case by Fatma Dursun,1 Şeyma Meliha Su Dur,2 Ceyhan Şahin,3 Heves Kırmızıbekmez,1 Murat Hakan Karabulut,4 and Asım Yörük5

1Ümraniye Training and Research Hospital, Pediatric Endocrinology, 34766 Istanbul, Turkey
2Ümraniye Training and Research Hospital, Radiology, Istanbul, Turkey
3Ümraniye Training and Research Hospital, Pediatric Surgery, Istanbul, Turkey
4Ümraniye Training and Research Hospital, Pathology, Istanbul, Turkey
5Göztepe Training and Research Hospital, Pediatric Oncology, Istanbul, Turkey

A 4-year-old boy was referred to pediatric endocrinology because of bilateral breast enlargement

Q What is importance of age of presentation of gynecomastia ?

  • During neonatal period, puberty and in elderly, gynecomastia is physiological.
  • Gynecomastia in prepubertal children and in young- middle age adults is unusual and pathlogical causes of gynecomastia must be sought in these patients.

Q What are the causes of Prepubertal gynecomastia ?

  1. Drug induced
  2. Aromatase excess syndrome
  3. Chronic liver disease
  4. Chronic renal disease
  5. Testicular tumor
  6. Adrenal tumors
  7. Hyperthyroidism

There was no history of a chronic disease, medication, or a familial disorder.

Q Name some common drugs that lead to gynecomastia ?

  • Spironolactone – used in hypertension and CCF
  • Finesteratide – 5 alpha reductase inhibitor used in BPH
  • Cimitidine- H2 receptor antagonist used in peptic ulcer management
  • Growth hormone
  • HCG
  • Anti-androgen – like flutamide- used in prostate cancer.

Height was 114 cm (+1.2 SDS), weight was 20 kg (+0.7 SDS), and physical examination revealed bilateral gynecomastia.

Breast development appeared as Tanner Stage-2 (Figure 1)

Q What is Tanner stage 2 of breast ?

  • Presence of breast bud is Tanner stage 2
  • Areola starts to develop with small amount of breast tissue.

axillary and pubic hair were absent, stretched penile length was 6 × 1.5 cm, and right testis was 2 mL and left testis was 5 mL 

Q What is unusual here ?

Asymmetrical testicular enlargement.

Q What is the mean streached penile length at this age ?

The mean SPL would be around 5.6 cm. Here it is around 6 cm , which is normal.

Q How will you evaluate this case further on from here ?

  • This is clearly a case of prepubertal gynecomastia which is unusual.
  • I would consider endocrine evaluation as well as scrotal ultrasound to evaluate the asymmetrical testicular enlargement.
  • For the endocrine evaluation, I would order an LH, Testosterone, E2,  and HCG levels.
  • Additional I would ask for a bone age of the child.

Hormone levels were in normal ranges (Table 1); tumor markers were negative while scrotal ultrasonography (USG) exhibited a 8 × 12 mm solid lesion with cystic component in the left testis.

Q What is your interpretation of the  evaluation ?

  • Bone age is advanced.
  • There is a testicular mass which needs assessment.
  • LH and Testosterone are in Normal prepubertal range.
  • Other hormonal investigations are normal.

Q Which testicular tumors are associated with gynecomastia ?

  • HCG producing germ cell tumors of testis
  • Leydig cell tumor
  • Large calcifying Sertoli cell tumors typically seen in Carney’s complex or Peutz Jaghers syndrome.

Q What are DD of testicular mass ?

  1. Testicular adrenal rest tissue (TART)
  2. Testicular tumor
  3. Epididymitis
  4. Epidymoorchitis
  5. Varicocele
  6. Hernia
  7. Hydrocele
  8. Hematoma
  9. Spermatocele

Q Why is testicular biopsy not routinely performed for such lesion ?

This is because there is risk of seeding of the tissue and spreading of the malignant tissue

Q Which is the first and most important step in evaluation of a male with testicular mass ?

Scrotal ultrasound

Q What are the USG apperance of seminoma and non seminoma ?

  • Seminomas- well defined hypoechoic areas without cysts
  • Non seminomas- indistinct margins, calcification, cysts and inhomogenous

Q What is done is incidental testicular lesion is found in scrotal ultrasound ?

  • Go for tumor marker
  • If negative- ultrasound follow up is adequate

Q Which are the tumor markers for testicular Germ cell Tumors ?

  1. AFP
  2. LDH
  3. Beta HCG

Q What is the relation between type of cancer and the tumor markers ?

  • Non Seminomas- beta HCG and/or AFP is elevated in 80% of cases
  • Seminomas- beta HCG is elevated in 20% cases, AFP is not elevated

Q Are tumor makers alone sensitive to diagnose GCT ?

  • No
  • They are not sensitive enough to make a diagnosis without histological confirmation

Q Which is the gold standard for diagnosis of testicular GCT ?

  • Radical inguinal orchiectomy is the gold standard for diagnosis of testicular GCT
  • It gives histopathological confirmation
  • Neither ultrasound nor tumor markers can replace it

Q What is the next step for this child ?

The child has tumor marker for GCT which are negative.

  • However, since the child has gynecomastia and advanced bone age with this testicular mass, evaluation is required.
  • I would consider doing an orchidectomy of the involved testis.

The committee on tumoral diseases agreed on the decision to perform a testis-sparing surgery in the light of examination of frozen sections. However the large and cystic mass left no adequate testis tissue to conserve, so a left orchiectomy was performed.

Abdomen and thorax Computed Tomography (CT) imaging were normal. Histopathological investigation revealed a sertoli cell tumor which had positive staining with inhibin, vimentin, and calretinin. Gynecomastia regressed at the end of three months following the operation.

Q Sertoli cell tumors are associated with which conditions ?

  • Carney’s complex
  • Peutz Jeghers syndrome

Q What is the characteristic of these tumor in Carney’s complex ?

  • They are large cell calcifying Sertoli cell tumors
  • They generally appear in the 2nd decade
  • They are generally non hormonal producing

Q What is the feature of the tumor in Petz Jeghers ?

They have high aromatase activity and hence they often produce gynecomastia

Q What about Sertoli cell tumors which are not a part of the above disorders, are they hormonally active ?

No, They are not

Q Which is the most common testicular tumor in infants ?

  • Juvenile granulosa cell tumor is the most common testicular tumor in infants
  • It occurs in first few months of life
  • They generally have good prognosis
  • They rarely present with ambigious genitalia

Q What about adult granulosa cell tumors ?

  • They are more likely to be hormonally active
  • They present in middle age with gynecomastia and feminizing features

Q Which important immunohistochemical is common in the various sex cord tumors ?

Inhibin Alpha

 

Q Why are sertoli cell tumors more likely to produce estrogen compared to Leydig cell tumors ?

  • Sertoli cell tumors have aromtase enzyme expressed in them.
  • Hence they are more likely to produce estrogen.
  • They mainly produce Estrone from androstenadione in prepubertal boys.

Learning points

  1. Sertoli cell tumors have high aromatase activity and hence can present with gynecomastia. However, most sertoli cell tumors occur in context of PJS or Carney’s complex and are often bilateral. Unilateral Sertoli cell tumor presenting with gynecomastia in prepubertal child without evidence of any syndrome is rare.
  2. Drugs are the most common cause of prepubertal gynecomastia.

 

Remission of Type 1 Diabetes with Sitagliptin and Vitamin D

Original Case by Marcelo Maia Pinheiro1, Felipe Moura Maia Pinheiro2 and Margareth Afonso Torres3[1] Pharmaceutical Assistance Center of the State of Mato Grosso, Cuiaba, Brazil[2] Faculdade de Medicina da Universidade de Cuiabá-UNIC, Cuiaba, Brazil [3] Laboratório Clinico do Hospital Israelita Albert Eistein, São Paulo, SP, Brazil

Patient #1 was a 20-year-old woman with a history of hypothyroidism due to Hashimoto’s thyroiditis treated since the age of 6 years with levothyroxine. In April 2012, she presented with weight loss, polyuria, polydipsia and leg cramps. Her physical examination was normal; she weighed 62 kg, had a body mass index (BMI) of 21.7 kg/m2 and blood pressure of 100/60 mmHg. She had a grandmother with Hashimoto’s thyroiditis and type 2 diabetes mellitus.

Q What percentage of type 1 diabetic have autoimmune thyroid disorder ?

  • 2-5% have overt hypothyroidism
  • 20% have Anti TPO positive

Q What is the effect of subclinical hypothyroidism in type 1 diabetes ?

  • Reduced linear growth
  • Increased risk of Hypoglycemia

Q How and when if TFT monitoring done in children with type 1 diabetes ?

  • At the time of diagnosis
  • If normal repeat every 1-2 years

Q What percentage of type 1 diabetics have celiac disease ?

  • 5%

Q What are concerns with celiac disease in type 1  ?

  • Risk of hypoglycemia
  • Poor linear growth
  • Poor bone accural

Q How is screening for celiac done in type 1 diabetics ?

  • At the time of diagnosis
  • Every 1-2 years after diagnosis
  • Use Anti TTG antibody – if positive then do Duodenal biopsy

Q Which HLA in type 1 has higher risk of autoimmune disease ?

  • HLA DR3 > HLA DR4

Q Enlist some other autoimmune disorder in type 1 diabetes ?

  • Autoimmune adrenalitis
  • APS type 2
  • IPEX syndrome

Patient #2 was a 21-year-old woman who presented in May 2011 with weight loss, polyuria, polydipsia and leg cramps. Her physical examination was normal; she weighed 62.5 kg, had a BMI of 19.5 kg/m2 and blood pressure of 115/70 mmHg. Her mother had Hashimoto’s thyroiditis, and her brother had Crohn’s disease

The diagnosis of diabetes mellitus was confirmed in patient #1 based on her serum glucose and HbA1c levels (Fig. 1 and Table 1). The patient’s anti-GAD antibody was positive (Fig. 2)

Q Enlist the antibodies associated with type 1 diabetes ?

  • GAD 65
  • Insulinoma associated antibody – IA-2 (also called ICA5-12)
  • Insulin autoantibody – IAA
  • Zinc transporter 8 antibody- Znt8

Q Antibodies are formed against which part of GAD65 ?

  • Carboxy terminal of GAD65 antibody

Q What is the other name of Insulinoma associated antibody 2  ?

  • ICA512

Q Tell me something about GAD65 antibody ?

  • Present in 70% of type 1 diabetics
  • Does not reduce with age- most common antibody to check in adults
  • Slowly developing diabetes
  • HLA-DR3 associated

Q Which is the antigenic main target in type 1 diabetes ?

  • The main target seems to be Beta chain of Insulin

Q Which is the first antibody to appear in type 1 diabetes  ?

  • IAA- insulin autoantibody is the first to appear

Q  If IAA is the first to appear, why does it not have more importance compared to GAD65 etc  ?

  • Any person given insulin can develop IAA antibody
  • Hence measurement of antibody anytime after 2 weeks after insulin injection will give a positive result

Q Which is often the last antibody to appear ?

  • Znt8
  • It disappears also first
  • IAA first à then GAD à then IA2 à Last ZnT8

Q Summarize the prevelance of various antibodies in type 1 diabetes ?

  • IAA – almost 100% – but not reliable marker
  • GAD65- 70%
  • IA-2 – 68%
  • Znt8 – 60-80%

Q What do Indian studies say about Antibodies in type 1 ?

  • South Indian study – GAD65 was present in 70% – just like west
  • Cuttuck Study- ICA512 was more common – in 43% , GAD65 only in 7%
  • Her HLA typing was DQA1*01:01, 03:01, DQB1*03:02, 05:01, DRB1*04:01, 10:01. Of note, the occurrence of the haplotype HLA-DQA1*03:01, −DQB1*03:02, −DRB1*04:01 is associated with an increased risk of T1DM.

Q What is the role of MHC ?

  • MHC carry the antigen on the surface of antigen presenting cells and activate the T cells

Q Which 2 haplotypes of HLA  confer the highest risk of type 1 diabetes ?

  • HLA DR3,DQB1*0201 – Also called HLA DR3- DQ2
  • HLA DR4,DQB1*0302 – also called HLA DR4-DQ8
  • 90% of type 1 have either of these two haplotypes
  • 30% have both !
  • The risk of type 1 diabetes is you carry either of these two haplotypes is 5% compared to 0.4 % in controls

Q Which HLA haplotypes protect from type 1 ?

  • HLADRB1*0403
  • HLADPB1*0402
  • Additionally HLA DQB1*0602 – also protective

In patient #2, the diagnosis of diabetes mellitus was also confirmed by serum glucose and HbA1c levels (Fig. 1 and Table 1). The patient’s anti-GAD antibody was positive (Fig. 2), her urinalysis revealed glycosuria without ketonuria, and her serum levels of lipids, BUN and creatinine were normal. Antithyroid antibodies measurement (Table 1) and thyroid ultrasound evaluation confirmed the diagnosis of Hashimoto’s thyroiditis with a normal TSH level (1.83 µIU/mL). Her HLA typing was DQA1*01:01, 01:01, DQB1*05:01, 05:01, DRB1*01:01, 01:01, which is not associated with an increased risk of T1DM.

Q How will you treat these patients ?

  • I would start both the patients on Basal-bolus insulin regimen.
  • I would start with 0.5 unit/kg of total insulin dose with 50% basal and 50% bolus.
  • I would also screen these patients for Celiac disease at baseline.

Patient #1 started treatment with insulin glargine 35 IU once a day and insulin lispro 2 IU before breakfast and 6 IU before lunch and dinner.

On May 2012, she started treatment with sitagliptin 100 mg/day and vitamin D3 5000 IU/day, and on June 6, 2012, she interrupted the administration of insulin.

Patient #2 started treatment with insulin glargine 20 IU once a day, and insulin glulisine 6 IU before breakfast, lunch and dinner. In July 2011, she experienced a honeymoon phase in which she used only insulin glargine 6–10 IU/day. Two months later, she resumed a basal-bolus regimen with the same initial doses. In March 2012, she was started on sitagliptin 100 mg/day and vitamin D3 5000 IU/day.

Both patients were duly informed that treatment of T1DM with sitagliptin and vitamin D3 was off-label and signed an informed consent form, accepting this treatment.

Q What is the objective definition of Honeymoon phase of Type 1 diabetes ?

  • Partial remission of honeymoon phase of type 1 diabetes is defined as follows:
  • HbA1c <6.0%
  • Insulin requirement
  • Stimulated C peptide >0.9 ng/ml

Q How long does the honeymoon phase last ?

  • It lasts for several weeks to months. It rarely lasts beyond 1 year.

Q What is the recommended dose of Vitamin D daily in adults ?

  • Recommended Daily allowance of Vitamin D is 600 IU /day
  • For those having Vitamin D deficiency, it is recommended to give 60,000 IU once a week for 8 weeks followed by 2000 IU once a day.

Patient #1 continues treatment with sitagliptin and vitamin D3. Since June 6, 2012, she has not used insulin and her levels of capillary glucose and serum fasting glucose, HbA1c and C-peptide remain normal (Fig. 1). In May 2014, her glucose levels, determined with a continuous glucose monitoring system (CGMS-72 h), confirmed the persistence of normal glucose values (Fig. 2).

Q Patient #1 has vitamin D levels of 22 ng/ml. According to Endocrine society guidelines, how will you classify her Vitamin D status ?

  • Vitamin D values between 20-29 ng/ml are classified as Vitamin D insufficiency.

Q How will you convert Vitamin D ng/ml to nmol/l ?

  • Vitamin D value of 1 ng/ml is 0.4 nmol/l

After 1 month of treatment with sitagliptin and vitamin D3, patient #2 started decreasing her insulin dose, and in March 2015, she interrupted the administration of insulin glargine. At the time of this report, she was only administering insulin glulisine 2–4 IU before breakfast, lunch and dinner when eating carbohydrates and she maintains use of sitagliptin and vitamin D3. She chose not to interrupt the use of insulin glulisine to maintain flexibility in her diet. She has been maintaining normal levels of capillary glucose, fasting blood glucose, HbA1c and C-peptide (Fig. 1). Results from her CGMS-72 h in May 2014 were normal (Fig. 2).

Both patients maintained normal serum levels of calcium and 25(OH) vitamin D. No side effects related to sitagliptin use have been reported by the patients.

Q Where does the evidence of vitamin D action in type 1 diabetes come from ?

  • Mainly from observation studies which have shown that vitamin D deficiency is associated with increased risk of diabetes

Case control studies have shown that vitamin D reduces risk of type 1 diabetes by 30%

  • However there are no RCT for use of vitamin D in type 1 diabetes
  • Genetic polymorphism in vitamin D has been associated with diabetes

Q How does vitamin D reduce risk of type 1 diabetes ?

  • Immune modulation
  • Increase insulin secretion (see later)
  • Reduce beta cell apoptosis

Q How does vitamin D reduce beta cell apoptosis ?

  • Vitamin D activates- Nf- kb pathway which increase beta cell survival

Q What kind of immune modulation is seen with vitamin D which is beneficial for type 1 diabetes ?

  • Its actions mainly via 1,25 Dihydroxyvitamin D produced by the macrophages
  • Reduces Th1
  • Increases Th2
  • Reduces production of IgG by B cells
  • Increases Treg (Regulatory T cells) cell function
  • Reduce damaging cytokine production

Q What are the potential benefits of Sitagliptin in Type 1 diabetes ?

  • By its incretin effect Sitagliptin can increase the GLP1, which can potentially enhance beta cell survival and function
  • Sitagliptin may potentially have immunomodulatory effects in Type 1 diabetes.

Q What is the effect of Sitagliptin on Immune system relevant to type 1 diabetes ?

  • Sitagliptin is shown to reduce Th1 cytokine (IFN –gamma) and increase Th2 Cytokine (IL-4)

Q What is the effect of DPP IV inhibitors in type 1 diabetes ?

  • Meta-analysis by Guo et al shows that DPP IV use in type 1 diabetes reduces the insulin dose requirement without change in HbA1c.
  • It does not increase or reduce the risk of hypoglycemia.

Q Apart from this case, has it been shown before that DPP IV inhibitors can potentially reverse type 1 diabetes ?

  • In several studies in NOD mice which are models for type 1 diabetes it has been shown that DPP IV can delay the onset of type 1 diabetes or bring an early onset type 1 diabetes in remission.

Learning Objectives

  1. DPP IV inhibitors and Vitamin D have immunomodulatory effects which can potentially reverse and early onset type 1 diabetes and bring it to remission.
  2. Partial remission of type 1 diabetes (Honeymoon phase) is defined as Insulin requirement 0.9 ng/ml.

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.