TSHOMA

1
TSH-OMA

• Pascual De Santis
• Endocrinology Grand Rounds
• April 6, 2006

2
History of Present Illness

• LB is a 81 y/o WM who was diagnosed with a TSH
  producing adenoma in May of 2004.
• During the endocrine w/u at SLU the tumor was
  found to co-secrete GH.
• The patient was on treatment with octreotide and
  pegvisomant, but his insurance refused to pay for
  the pegvisomant. Therefore, he presented to the
  VA seeking a second opinion and financial
  assistance for his treatment.

3
Past Medical/Sx History

• Anemia, initially found in the 60s. Current w/u
  at the VA revealed chronic disease anemia
  hemoglobinopathy that responds to erythropoietin
• 1968 Nephrolithiasis surgery
• 12/94 Bladder tumor s/p bladder cauterization.
• 9/96 Swelling of the ankles
• 6/02 CHF/Afib, and elevated TSH
• 9/2002 Hydrocele removal
• 2/04 Frank hyperthyroid symptoms with ? TSH
• 5/04 Pituitary tumor dx as an incidental finding
• Goiter noticed on 5/03 ? R. hemythyroidectomy on
  9/05 due to evidence of compression on CT.

4
Past Medical/Sx History

• HTN-long standing
• DM newly diagnosed around the time of diagnosis
  of the pituitary tumor
• OA
• Hearing loss

5
Family History

• Father Lung CA, HTN, died at 69 from CVA
• Mother died at 66 from complications during
  gallbladder surgery.
• Brother alive 73-Prostate Ca.
• Brother died at 82 with Alzheimers
• Brother died at 72 from Lung Ca.
• Niece and her son on thyroid hormone
• Negative for endocrine tumors or nephrolithiasis

6
Social History

• Married for 55 years
• Denies ETOH, Tobacco or drugs
• Retired.

Allergies

• PCN rash

7
Medications

• Loratadine 10 mg QD
• Ranitidine 150 mg QD
• Celebrex 200 mg QD PRN
• Procrit 10,000 U 1X/week
• Metoclopramide PRN
• Ultracet PRN
• Vit E
• Calcium Vit D
• Folic Acid
• Glucosamine

• Sandostatin LAR 10 mg IM 1X/month
• Pegvisomant 10 mg SQ 1X/day (off x 3 w)
• Methimazole 5 mg BID
• Prednisone 5 mg QD
• Glipizide 2.5 mg QD
• Warfarin 4/2 mg
• Carvedilol 25 mg BID
• Furosemide 20 mg QD
• Digoxin 0.125 mg QD
• Lisinopril 40 mg QD

8
ROS

• Fatigue, Dyspnea on moderate exertion.
• LBP and general joint pain that improved on
  Pegvisomant.
• Denies palpitations, CP, PND, orthopnea
• Denies, diaphoresis, diarrhea, constipation,
  weight or appetite changes.
• Denies H/A, visual changes, changes in shoe, ring
  or hat size.
• Denies major changes in his facial features

9
Physical Examination

• BP 166/65, HR 69, RR 16, T 97.5, WT 169 Lb
• General Appears frail but not in acute distress.
• HEENT Normal visual fields by confrontation.
  Wide nose base and protuberant lower lip. No
  evidence of prognathism. No lid lag or
  exophthalmos
• Neck supple, no JVD, large left thyroid lobe.
• CV irregularly irregular and bradycardic HS.
• Lungs CTA bilaterally
• Abdomen no HSM
• Extremities No edema
• Skin Normal thickness, no skin tags
• Musculoskeletal Normal muscle strength
  bilaterally, no major joint deformities
  appreciated
• Neuro AOX3, nonfocal, DTR NL, no distal tremor

10
Laboratory Data on 5/18/2004

• TSH 27.13 (0.4 5.5)
• FT4 6.9 (0.8 2.7)
• FT3 1124 (230 420)
• SHBG 79 (7 50)
• ? sub-unit 42.8 (? 1)
• GH 10.5 (0 10)
• IGF1 567 (71 290)
• LH 2 (2 36)
• FSH 1.6 ( 0 87)
• Total Test 77 (241 827)
• Free Test 14 (34 194)

• ACTH 20 (0 70)
• Cortisol 17 (4 22)
• ADH 2.6 (1 13.3)
• DHEA-S 63 (10 285)
• Calcium 9.7
• Albumin 3.8
• Electrolytes Normal
• Glucose 131
• Creatinine 1.0
• TPO Ab 41 (0 2)

11
Pituitary MRI
12
Concepts and Historical Notes

• TSH-secreting Pituitary Tumors includes two
  opposite clinical conditions True neoplasia
  resulting in central Hyperthyroidism TSH-oma,
  and Pituitary hyperplasia resulting from long
  standing hypothyroidism.
• Syndromes of Inappropriate secretion of TSH
  (IST) include the Syndrome of Resistance to
  Thyroid Hormone (RTH) and TSH-omas.
• The first case of TSH-oma was documented in 1960
  Remission of Graves disease following
  radiotherapy of pituitary neoplasm

13
Reported TSH-oma Series

• Beck-Peccoz et al. 1996 Thyrotropin-Secreting
  Pituitary Tumors., Endocrine Rev. 17610 638.
  Reviewed and analyzed 280 cases reported up to
  January 1996
• Brucker-Davis et al. 1999 JCEM 84 476 486. NIH
  series of 25 patients
• Valdes-Socin et al. 2003 European Journal of
  Endocrinology 148 433 442. 43 patients from 6
  Belgian and French centers

14
Occurrence

• Represents ? 1 of Pituitary adenomas

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

15
Pathogenesis

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

16
Pathogenesis

• Decreased expression of TR in 2 TSH-omas. Gittoes
  et al 1998 Thyroid 89-14
• Somatic mutation of the TR? in 1 patient at the
  NIH. Ando et all 2001 JCEM 86(11)5572 5576.
• Aberrant alternative splicing of THR in 1 patient
  at the NIH. Ando et all 2001 Molecular
  Endocrinology 15(9)1529-1538
• Loss of heterozygosity at the SS receptor type 5
  locus in 1 patient. Filopanti et al., 2004 J.
  Endocrinol. Invest. 27 937-942.

17
Secretion Pattern
Beck-Peccoz et al. 1996 Endocrine Rev. 17610
638.
Valdes Socin et al. 2003 European Journal of
Endocrinology 148 433 442.
18
Clinical Findings

• 1/3 of pts present with previous thyroid
  intervention
• They can occur at any age (11 84 y)
• No preferential incidence in females
• Clinical features of hyperthyroidism are
  progressive and often milder than expected
• Goiter is present in ? 94
• 90 are macroadenomas

19
Clinical Findings

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

20
Clinical Findings

• Brucker-Davis et al. 1999 JCEM 84 476 486.

21
Baseline Laboratory Findings

• Non-suppressed TSH high free thyroid hormones.
• -1/3 of patients without previous thyroid
  intervention had normal TSH.
• -1/10 of patients with previous thyroid
  intervention had normal TSH
• Elevation of free ?-subunit, as well as
  ?-subunit/TSH molar ratio

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

22
Baseline Laboratory Findings

• Elevation of free ?-subunit.
• - lt 3 ?g/L in males and pre-menopausal
  women
• - lt 5 ?g/L in post-menopausal women
• Maximal values for controls
• - Normal TSH, FSH and LH 1.1
  ?g/L
• - Normal TSH, ? FSH and LH 4.2 ?g/L
  
• - ? TSH and normal FSH and LH 5 ?g/L
• - ? TSH, FSH and LH
  6.2 ?g/L

• Brucker-Davis et al. 1999 JCEM 84 476 486.

• Beck-Peccoz et al. 1992 Trends Endocrinol Metab
  341-45

23
Baseline Laboratory Findings

• ?-subunit/TSH molar ratio maximal values for
  controls
• - Normal TSH, FSH and LH 5.7
• - Normal TSH, ? FSH and LH 29.1
• - ? TSH and normal FSH and LH 0.7
• - ? TSH, FSH and LH 1.0

• Beck-Peccoz et al. 1992 Trends Endocrinol Metab
  341-45

24
Baseline Laboratory Findings

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

25
Parameters of Peripheral Thyroid Hormone Action

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

26
Dynamic Testing
TRH stim test
T3 suppression test

• Normal ? 200
• Decreased 120-200
• Flat ? 120

27
Dynamic Testing

• Brucker-Davis et al. 1999 JCEM 84 476 486.

28
Assessment of Diagnostic Tests

• For patients with intact thyroid the best
  combined sensitivity and specificity was seen
  with the TRH test and the ?-subunit measurement.
• For patients with previous thyroid treatment the
  best combined sensitivity and specificity was
  seen with ?-subunit and the ?-subunit/TSH ratio

• Brucker-Davis et al. 1999 JCEM 84 476 486.

29
Differential Diagnosis
30
Diagnosis
31
Differential Diagnosis

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

32
Octreotide Test

• Short course of 100 ?g TID x 72 h. vs LAR 30 mg Q
  month x 2

Mannavola et al. 2005 Clinical Endocrinology
62,176-181
33
Treatment and Outcome
52.7

• 2 pt wating for sx
• 2 pts declined sx
• 1 pt not surgical candidate
• 2 pt without visible adenoma

Valdes Socin et al. 2003 European Journal of
Endocrinology 148 433 442.
34
Criteria for Cure

• Euthyroidism and absence of visible tumor on
  imaging is not enough.
• Undetectable TSH 1 7 days after SX.
• T3 suppression test.
• Normalization of ?-subunit and/or ?-subunit /TSH
  molar ratio.

Losa et. al JCEM 1996, 81(8)3084-3090
35
Medical TherapyShort-acting Octreotide

• In 73 cases, Octreotide (50 750 ?g BID or TID)
  was effective in reducing TSH and ?-subunit
  around 90 of the cases
• Normalization of TSH in 79 of cases.
• Only in 4 of the cases, true resistance to
  increasing doses of Octreotide
• Shrinkage of tumor detected in 52 of cases
• Vision improvement in 75 of cases

• Beck-Peccoz et al. 1996 Endocrine Rev. 17610
  638.

36
Medical TherapyOCT-LAR
Caron et al. 2001 JCEM 86(6)2849-2853
37
Medical TherapyOCT-LAR
Caron et al. 2001 JCEM 86(6)2849-2853
38
Sandostatin LAR 10 mg Methimazole 30 mg QD
Methimazole 10
Sandostatin 150 mcg TID PTU 200 TID
Pegvisomant 10 mg Sandostatin LAR 10
mg Methimazole 30 mg QD
Sandostatin LAR 20 mg Methimazole 30 mg QD
PTU 200 TID

• IGF1

Hemythyroidectomy

• TSH

• GH

• FT4

39
Discussion

• Treat the hyperthyroidism?
• Maximize octreotide dose before re-starting
  pegvisomant?
• Re-evaluate the possibility of Neuro-surgery
  and/or XRT?

40
Discussion

• Treat the hyperthyroidism?
• Maximize Octreotide dose before re-starting
  pegvisomant?
• Re-evaluate the possibility of Neuro-surgery
  and/or XRT?

41
Is the Combination Worse?
4 patients with unsuppressed GH, when
hyperthyroidism was diagnosed, had ?LVMi and
worse ?LVEF() when compared to pts with
controlled GH
Marzullo et. Al JCEM 2000, 85(4)1426-1432
42
Hyperthyroidism and Mortality
Parle et. Al Lancet 2001 358861-865
43
Cappola et. JAMA 2006 295(9)1033-1041
44
Discussion

• Treat the hyperthyroidism?
• Maximize Octreotide dose before re-starting
  pegvisomant?
• Re-evaluate the possibility of Neuro-surgery
  and/or XRT?

45

• Normal IGF-1 values in 70 of pts.
• The best predictors of final hormonal values
• - GH lt 5
• - IGF-1 ? 500
• Tumor size was not predictive
• Basal hormonal levels at baseline were not
  predictive.

At six months of maximal therapy
Cozzi et. Al JCEM 2006 91(4)1397-1403
46
Discussion

• Treat the hyperthyroidism?
• Maximize Octreotide dose before re-starting
  pegvisomant?
• Re-evaluate the possibility of Neuro-surgery
  and/or XRT?

47

• Surgical tumor removal ? 75 enhances the
  response to SSA

Colao et. Al JCEM 2006 91(1)85-92
48

• Pt not a candidate for gamma-knife or any
  stereotactic XRT because of the tumors close
  proximity to the optic chiasm.
• No outcome reports of IMRT on pituitary adenomas.

49
Conclusions

• If pt fails maximal Octreotide therapy, re-start
  pegvisomant to maintain normal IGF-1 levels
• Continue Octreotide to normalize TSH to see if
  euthyroidism can be achieved without methimazole
• Consider IMRT

50
Thank You !