HOSP #	42170712	WARD	Endocrinology OPD
CONSULTANT	Dr. Heleen Vreede	DOB/AGE	37y female

Abnormal Result

• The patient’s calcium measured 2.91 mmol/L on two occasions, with PTH measuring 40.6 pmol/L
• VitD 13.6 (<50 = deficient)
• TFT’s TSH 0.01 T4 26.7pmol/L

Presenting Complaint

Presented at the GIT clinic in Feb 2020 with persistent vomiting and abdominal cramps, which was ongoing since November 2019.

History

• Patient was diagnosed with hypertension in her early 20’s.
• Initiated on HCTZ – subsequently changed to Atenolol 25mg dly – not overweight at the time
• Gastroscopy was normal
• No psychiatric symptoms reported – mood swings are reported occasionally by the family
• Oligomenorrhoea – started in 2019 – nothing else wrong was noted.
• Normal menarche – normal regular menses until the diagnosis of hypertension was made.
• Amenorrhoeic last 4 years on no medication currently

Examination

• Increased BMI – quite significantly increased
• BP 170/90
• Skin: Significant amount of skin tags, acanthosis nigricans
• No striae or bruising
• No Sx of thyroid disease.
• Physical examination unremarkable.
• Normal pulses
• Essentially a normal examination other than the high BMI

Laboratory Investigations

Repeated bloods (5 days after initial presentation): 

• TSH 3.13 T4 12.5
• PTH 28 pmol/L (1.6 -6.9)
• Ca 2.79
• Inorganic phosphate 0.77 L mmol/L (0.78 – 1.42)
• LFT’s: Normal
• Creat Normal
• U-Ca 5.6 (no creatinine to compare ratio)
• FSH 3.2 IU/L
• LH 2.0 IU/L
• E2 244 pmol/L
• Dehydroepiandrosterone sulphate (DHEAS) 2.4 umol/L (1.7 – 9.2)
• Testosterone 0.5 nmol/L (0.3 – 1.7)
• SHBG 25.9 L nmol/L (32.4 – 128.0)
• Prolactin 11.5
• TSH-Receptor antibodies: Negative

Other Investigations

The patient still had occasional vomiting, abdominal cramps and unexplained muscle pain – other electrolytes apart from calcium, magnesium and phosphate is also advised, as is osmolarity as fluid and electrolyte imbalance may be an effect, rather than a cause of the nausea, vomiting and muscle pain – the sodium and potassium was normal however.

See below, for the hypertension, phaeochromocytoma can be excluded by a 24-hour fractionated urinary metanephrines analysis.

Final Diagnosis

• Primary hyperparathyroidism is on top of the differential diagnosis and is likely the cause of the raised total calcium.
• Another cause of the raised blood pressure could very likely be a phaeochromocytoma.
• It was also advised for replacement of Vitamin D, after a repeat measurement.
• Other features of MEN-1 syndrome needs to be excluded.

Take Home Message

For phaeochromocytoma, 3 separate days’ urine collection is recommended if the suspicion is high, which it isn’t in this case. This increases the sensitivity of the test.

Before testing for MEN-1: one needs to correct Calcium first – since the hypercalcemia could exacerbate gastrin levels.

Increased serum calcium and hypophosphatemia is the net-result of increased PTH. Urinary phosphate will also be high if measured.

HOSP #		WARD	Endocrine Clinic (OPD)
CONSULTANT	Dr. Jody Rusch	DOB/AGE	32 Year female

Abnormal Result

The clinician, an endocrinologist, phoned about discrepant results: Suppressed TSH, Low Free T4 and Normal (upper end of reference interval) Free T3.

Date	09/12/2020
TSH (mIU/L)	0.05 L
Free T4 (pmol/L)	4,8 L
Free T3 (pmol/L)	6,4

Presenting Complaint

The patient was known with Graves Disease complicated by quite severe Graves Eye Disease (orbitopathy).

History

Known with Graves disease with positive antibodies to TSH-receptors.

Examination

The clinical examination for this patient is not available, but the following is important:

Interestingly, patients may have no ocular symptoms at all, but may sometimes be distressed by the appearance of their eyes. The major ocular symptoms include:

• A gritty or foreign object sensation
• Excessive tearing that is often made worse by exposure to cold air, wind, or bright lights
• Eye or retroocular discomfort or pain
• Blurring of vision
• Diplopia
• Color vision desaturation
• Loss of vision in severe cases

The characteristic signs of Graves’ orbitopathy are proptosis (exophthalmos), tearing, and periorbital edema. In more severe disease, there may be severe conjunctival inflammation and ulceration from over exposure.

Laboratory Investigations

Date	09/12/2020	11/05/2020	08/11/2019	24/05/2019	29/01/2019	10/12/2018
TSH (mIU/L)	0.05 L (Rerun 0.05)	0.02 L	<0.01 L		<.01 L	<.01 L
Free T4 (pmol/L)	4,8 L (Rerun 4.9)	65,7 H	δ+>100.0 H	48,4 H	42,7 H	44 H
Free T3 (pmol/L)	6,4  (Rerun 6.4)				19,6 H

As above, the history of Graves disease is clear, which includes a suppressed TSH and raised Free T4 and Free T3.

Other Investigations

The Free T4, Free T3 and TSH was re-run on 10/12/2020, QC checked on these three analytes (all was within normal range) and pre-analytical labeling errors excluded as far we could.

Final Diagnosis

Graves eye disease, now with hypothyroidism.

Take Home Message

In Graves’ disease, the main auto-antigen is the thyroid-stimulating hormone (TSH) receptor (TSHR), which is expressed primarily in the thyroid but is also expressed in adipocytes, fibroblasts, and a variety of additional sites and appears to be closely aligned with the insulin-like growth factor 1 (IGF-1) receptor. TSHR antibodies and activated T cells also play an important role in the pathogenesis of Graves’ orbitopathy by activating retro-ocular fibroblast and adipocyte TSHR and IGF-1 receptors and initiating a retro-orbital inflammatory environment.

The retro-orbital tissue (and ocular muscles) increase in volume due to this inflammatory milieu, fibroblast proliferation and the accumulation of hydrophilic glycosaminoglycans (GAG’s), most notably hyaluronic acid.

Sometimes orbitopathy occurs in patients with hypothyroidism (high TSH, low free T4) due to classical chronic autoimmune thyroiditis (Hashimoto’s disease), and these patients may have stimulating TSH receptor (TSHR) antibodies but inadequate thyroid reserve.

In summary, the most important factors for development of Graves Eye Disease (orbitopathy) seems to be:

• Graves Orbitopathy antigen (which is the TSH-receptor): these are expressed extra-thyroidally, especially retro-orbitally.
• Role of TSH receptor antibodies
• Role of T-cells: Retroocular fibroblasts secrete GAG in response to cytokines such as interferon gamma and tumor necrosis factor (TNF)-alpha secreted by helper (CD4+) T cells of the Th1 type.

In cases of hypothyroidism, the action of deiodinase is increased to protect against the effects of hypothyroidism, likely the explanation of the increased Free T3 in this patient (compared to the low Free T4).