Primary amenorrhoea with ulcerative colitis

HOSP # WARD
CONSULTANT   DOB/AGE 15 y girl

Abnormal Result

This patient was discussed at a combined Endocrinology / Chemical Pathology meeting.

Total bilirubin: 281 umol/L

Presenting Complaint

The patient was a candidate for a liver transplant, but was referred to the endocrinology department for the short stature and primary amenorrhoea prior to surgery.

History

She was diagnosed with ulcerative colitis in 2016 (@ 12y age) and primary sclerosing cholangitis. Breast development started in 2018 (@14 years), but no menstrual cycles started ever since.

She has one younger sister which is well currently at 4 y age.

Birth weight was 3.8 kg.

Medication

Patient was receiving steroids and sulfasalazine intermittently.

For portal hypertension she is also receiving furosemide and spironolactone

Vitamin D supplements are also given

Examination

Height (114cm) for age: <3rd percentile

Weight 35 kg

Breasts well developed – Tanner IV,

No armpit hair growth, parse pubic hair – Tanner II

Laboratory Investigations

Test Result
Total bili (umol/L)   281 H
Conj bili (umol/L)   246 H
ALT (U/L)    58 H
AST (U/L)   151 H
ALP (U/L)   524 H
GGT (U/L)    65 H
TSH mIU/ml  1,74  
Free T4 (pmol/L)  16,4  
Free T3 (pmol/L)   2,8 L
FSH (IU/L)   8,2  
LH (IU/L)   6,2  
E2 (pmol/L   462  
Prog (nmol/L)   0.9  
Prolactin (ug/L)  15,4  
INR 2.09
IGF-1 (ug/L) 107.8 – 541.5
Tanner stages:
Boys Girls
Stage I 63 – 271 ug/L 71 – 394 ug/L
Stage II 114 – 411 ug/L 122 – 508 ug/L
Stage III 166 – 510 ug/L 164 – 545 ug/L
Stage IV 170 – 456 ug/L 174 – 480 ug/L
Stage V 161 – 384 ug/L 169 – 400 ug/L
23.5
Table 1 – Results

Other Investigations

Histology (Colonoscopy)

MICROSCOPIC:
Right, transverse and left colon:
Sections show large bowel type mucosa with maintained crypt architecture with no cryptitis or crypt abscess formation noted. No significant increased intra epithelial lymphocytes or subepithelial collagen deposition is present. The lamina propria shows normal inflammatory cells with no giant cells, granulomas, infective organisms, viral inclusions, epithelial atypia or malignancy identified. Colon mucosa morphologically within normal limits

Rectum:
Sections show large bowel mucosa with preserved crypt architecture and increased chronic inflammation in the lamina propria. Active inflammation is absent. There is no evidence of granulomas, viral inclusions, parasites or dysplasia. Non-specific increase in chronic inflammation in the lamina propria.

The other proposed additional examination is a pubic ultrasound to evaluate the ovaries, fallopian tubes and uterus.

It was also proposed that IGF binding protein 3 be measured, as low levels may yield IGF-1 shorter biologically active.

Final Diagnosis

Primary amenorrhoea most likely due to a physiological delay. Although the pelvic ultrasound hasn’t been done at the time of writing, the low IGF-1 likely indicates a low growth due to chronic systemic disease – see other possible aetiologies below.

Take Home Message

Amenorrhea can be a condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina.

The most common aetiologies include:

  • Gonadal dysgenesis, including Turner syndrome – 43%
  • Müllerian agenesis (absence of vagina, sometimes with absence of uterus) – 15%
  • Physiological delay of puberty (constitutional delay of puberty, chronic systemic disease, acute illness) – 14%
  • Polycystic ovary syndrome (PCOS) – 7%
  • Isolated gonadotropin-releasing hormone (GnRH) deficiency – 5% (possible selection bias)
  • Transverse vaginal septum – 3%
  • Weight loss/anorexia nervosa – 2%
  • Hypopituitarism – 2%



Discrepant TFT’s

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).