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LIST OF TOPICS IN ORDER OF PRESENTATION BELOW---CLICK FOR HYPERLINk

CUSHING’S  PROBABLY DUE TO ECTOPIC ACTH--  SOURCE-UNCLEAR -- 9 May 2012
QUESTION-I have a patient who I believe has Cushing's syndrome secondary to ectopic ACTH, but have been unable to find a source and have had difficulty managing her profound hypercortisolism.
The patient is a 28 year old female, who was diagnosed with Cushing’s syndrome in February 2012.  Work-up revealed ACTH-dependent hypercortisolemia.  24-hour urine cortisol was markedly elevated (> 600 mcg) and 1-mg dexamethasone suppression test revealed a non-suppressed cortisol level of > 60 mcg/dL.  ACTH has ranged from 150 to 250 pg/mL.  MRI (02/23/12) revealed just a prominent pituitary, but no adenoma.  Subsequent 03/21/12 IPSS revealed central-to-peripheral ACTH gradient < 2:1 before and < 3:1 after CRH, with ACTH increase < 50% (actual data from the IPSS is attached), suggestive of ectopic ACTH.  An 8-mg overnight dexamethasone suppression test on 04/09/12, also suggested ectopic ACTH with cortisol > 60 (ACTH not run by the lab) prior to the dose and ACTH 173.5 and cortisol 51 after the dose.
Work-up for the source of the ectopic ACTH has thus far been negative. CT of the abdomen/pelvis on 02/22/12, was unremarkable. CT of the neck/chest on 03/26/12, revealed thyroid nodules only, but no other masses. An ultrasound of the thyroid on 02/22/12, revealed two subcentimeter nodules in the right lobe, but calcitonin level on 03/26/12, was negative. Additional labs checked on 03/26/12, were also normal, including normal 24-hour urine metanephrines, 24-hour urine 5-HIAA, and gastrin (only mildly elevated at 103 [N < 100], but while non-fasting). MRI was repeated again on 04/03/12, during a hospitalization for hypertension and headache, which also revealed a prominent pituitary, but no clear adenoma.  Chromogranin A checked on 04/16/12, was negative.  Octreotide scan on 04/23/12, was normal.
She started ketoconazole at 200 mg BID on 04/11/12.  I increased the dose to 400 mg BID after two weeks, and just yesterday increased her to 400 mg TID.  Prior to her most recent dose change, her serum cortisol remained > 60 (24 hour urine cortisol is pending).
My questions for the expert would include:  
1)  Do you have any suggestions regarding the next step in localizing the ACTH source?  
2)  Do you have recommendations regarding the medical management of her hypercortisolism at this time?  I am thinking about adding metyrapone to her ketoconazole therapy, but was wondering if you have additional suggestions? Brandon Chock, M.D    Ontario, California
RESPONSE- Thanks, all the right things seem to have been done, and it certainly looks very like an ectopic source.My own plan in such cases is to get the chest CT reviewed by a real expert (that worked with our last patient; a 'negative' CT was reviewed by our local Head of Dept., a source found, and then video-thorascopically removed).
 However, in terms of therapy I would now move towards bilateral adrenalectomy. In the short-term I would add metyrapone up to 1g 4x/daily, with careful assessments of cortisol levels as these may fall abruptly. A block-and-replace regime may be required. Then book for adrenalectomy in the near future. These patientrs are at significant risk of overwhelming sepsis or pulmonary embolism and effective therapy should not be delayed. Ashley Grossman, MD

HYPERCALCEMIA    26 March 2012
QUESTION-I have a patient who presented with severe hypercalcemia  at 15.6mg/dl. With rehydration her calcium lowered to 12.3 mg/dl.
Concomitant intact PTH was 15 and 12.7 respectively.  D-25 and 1, 25 were 56.3 ng/ml and 95 pg/ml with a gfr of  26 on no vit d supplement for months.  24 hour urine calcium was 438 mg/dl . She had normal thyroid function tests and normal cosyntropin stim test. She had negative malignancy work-up including bone marrow biopsy.  ACE level was elevated at 157 so presuming increased  1,25 vitamin d production in sarcoid I placed her on prednisone 10 # 4 a day with taper. Her calcemia normalized in 1week. Pulmonary was consulted and felt that she did not have sarcoid and sent her back to me. I do not see and endocrine problem here and I am not sure where to go from here. Dr. Mary Lynn Kemick
RESPONSE-Your patient had increased serum 1,25(OH)2D with a somewhat high 25OHD(especially for someone not taking supplements) and 24 hr urine calcium that was also on the high side. The increased 1,25(OH)2D seemed to be the culprit in causing the hypercalcemia because PTH was low (although not suppressed—but this may be an assay problem) and the patient`s hypercalcemia responded well to steroids. This is all consistent with increased 1,25(OH)2D production either due to a non-infectious granuloma, an infectious granuloma or a lymphoma. (Does she have fever or weight loss?)The increased ACE level is consistent with sarcoid but not diagnostic. Although there is pulmonary involvement in over 90% of cases of sarcoid, there may not be hilar adenopathy and sometimes the alveolitis needs special imaging(eg high resolution CT)  for diagnosis. Diagnosing sarcoid therefore may depend on how hard the pulmonary physician looked. Were there any skin or eye manifestations of sarcoid? As you know  sarcoid may involve just about any system. I don`t know the age of your patient, but the GFR of 26 is quite low for any age and makes one wonder what the underlying renal pathology is. Interestingly the 1,25(OH)2D was elevated and the PTH was suppressed (presumably by the hypercalcemia) despite the low GFR. You may wish to consult a nephrologist if the low GFR is reproducible, and the nephrologist may decide a biopsy is warranted which could reveal non-caseating granulomas.
Overall therefore  the most likely diagnoses, I would say are 1 Sarcoidosis 2 Lymphoma3 Other granulomatous disease. While she is being worked up you might recommend that she not take supplements that contain vitamin D, and stay out of the sun or use sunscreen. If she does have another episode of hypercalcemia, clearly rehydration and prednisone would be indicated until the underlying disease can be treated. David Goltzman, MD

FOLLOW-UP TESTING NEEDED AFTER BILATERAL ADRENALECTOMY IN MEN  12/10/2011
QUESTION-A 62 yo male patient with multiple endocrine neoplasia had bilateral adrenalectomy- one in 2003, the other in 2004. The man also had 4 gland parathyroidectomy and thyroidectomy. He is on synthroid and hydrocortisone. I am trying to locate the operative reports to see if both adrenalectomy surgeries were complete, but my question in general is in patients who have undergone bilateral adrenalectomy for pheochromocytoma, do you recommend annual biochemical profile work up such as 24 hour urine studies or is it unnecessary since in theory the patient should be cured due to bilateral adrenal removal? Does it depend on the genetic cause of the pheochromocytoma ? This patient is not currently having any typical symptoms of pheochromocytoma and the lesions were nonmalignant at the time of surgery based on pathology, but just was wondering about long term follow up. Gay Story, MD, , Baton Rouge Clinic
RESPONSE- Patients with MEN2-associated pheochromocytomas rarely (< 4%, see Lenders J et al., Lancet 2005) develop malignant disease / metastases. Also, such patients almost never develop extra-adrenal tumors (Neumann HP et al., NEJM 2002; 346:1459). In contrast, patients with germline mutations in the VHL gene or SDHD, SDHB gene, may present with extra-adrenal pheochromocytomas in 13% (VHL), 36% (SDHD), and 50% (SDHB), respectively. Certainly, one big problem with pheochromocytoma recurrence, similar to recurrence of thyroid cancer, is the extent / completion of primary surgery. In other words, if microscopic tumors cells were left behind in the adrenal bed (for instance, by performing adrenal sparing adrenalectomy or alike), it is very conceivable that over time pheochromocytoma regrowth might occur (I actually myself encountered such a patient in whom MEN2A-pheochromocytoma reappeared 11 years after the initial bilateral adrenalectomies). As symptoms in such patients may develop very slowly and are predominantly related to the epinephrine / metanephrine biochemical phenotype in MEN2-pheochromocytomas, it may take a while before the diagnosis is clinically (BP rise, tachycardia) suspected. For longterm follow-up, it is recommended to follow BP, annual plasma free and urinary fractionated metanephrines, and an adrenal MRI every 3 years. Depending on MEN2A or MEN2B status, serum calcium and PTH (MEN2A) as well as plasma calcitonin (and CEA) levels should be checked annually (Armstrong R et al., Arch Dis Child 2008). One might argue that this longterm follow-up approach is not costeffective and more longterm data are needed to help decide which is best for the future patient. However, one thing is clear: each patient should be assessed individually based on her/his individual history (surgeon, pathology report, interfering medications, etc.). Sources of variable interferences with measuring catecholamines and catecholamine metabolites including tricyclic antidepressants with false elevations of plasma and urine norepinephrine and normetanephrine should be considered (Lenders J et al., Lancet 2005). Patients with asymptomatic pheochromocytoma have been reported in up to 35% of pts with von Hippel-Lindau disease (Walther MM et al., J Urology 1999), in 19 of 33 pts with adrenal pheochromocytoma incidentalomas (Motta-Ramirez et al., AJR Am J Roentgenol 2005), and 15 of 150 patients seen at the Mayo Clinic (Kudva et al., The Endocrinologist 1999). The patient here seems to not require fludrocortisone which raises the question if complete (or adrenal sparing) bilateral adrenalectomies had been performed. Christian A. Koch, MD, PhD,

PITUITARY TUMOR NEITHER SHRINKING NOR GROWING  16 Oct 2011 
QUESTION: I would appreciate suggestions regarding treatment for the following case.
Patient is Male age 44.  
 June 2010 – Prolactin level at  251 ng/ml with total testosterone 197 ng/dl and TSH 6.65 ulU/ml normal  T3 and T4 . Subsequent MRI revealed tumor 1.9 x 1.8 x 1.5 cm with extension into the left cavernous sinus and rightward displacement of the pituitary gland and stalk deviation. Cortisol and other hormones for pituitary reserve were normal. Initial diagnosis of Prolactinoma with treatment of .5mg of Cabergoline in addition to Levothyroxine, and Testosterone replacement therapy. 
 July 2010 – Prolactin levels dropped to 12.3, testosterone and TSH normal. 
Dec 2010 – Prolactin 10.8, testosterone and TSH normal. MRI results – no gross change in lesion, measurement 2.0 x 1.5 x 1.6 cm.  
 April 2011 – Prolactin 11.2, testosterone and TSH normal.  
Patient came under my care in Sept 2011.  
Sept 2011 – Prolactin 8.3 ng/mL. MRI shows no change in size of the tumor. Complete MRI text.. “Pituitary: Stable size and morphology of the sella turcica. Intrasellar lesion is reidentified resulting in some expansion of the sella turcica. Gross stability in height and morphology of this intrasellar lesion relative to 12/30/2010. Again, portions of the lesion extend into the suprasellar cistern on the left side. Deviation of the pituitary stalk to the right is noted. Probable involvement of the medial aspect of the left cavernous sinus again noted, stable. Preserved flow voids of the cavernous and supraclinoid segments of the bilateral internal carotid arteries. Stable signal characteristics of this lesion. Soft tissue signal intensity noted on the unenhanced coronal T1 images. The T2 signal characteristics are also stable. Avid enhancement following contrast administration. This lesion currently measures 2.0 x 1.6 x 1.5 cm in the respective craniocaudal, AP and transverse dimensions. Suprasellar Cistern: No impingement on the optic chiasm present.Hypothalamus: No mass, signal abnormality, or abnormal enhancement.Cavernous Sinus: Signal voids of cavernous internal carotid arteries present. Meckel cave is bilaterally fluid filled.Brain: Ventricles and sulci are age appropriate. Midline and basal cisterns are preserved. No focal signal abnormality, mass effect, or abnormal enhancement present. No change.Skull/Extracranial Structures: No mass, signal abnormality, or abnormal enhancement.Impression: 1. No change from 12/30/2010. 2. Intrasellar solid mass reidentified with some stable extension into the suprasellar cistern on the left side in the medial aspect of the left cavernous sinus. 3. Routine whole brain MRI images unremarkable. Negative for acute CVA or enhancing intra-axial mass.”  
 At this point  prolactin levels are normal on  cabergoline0.5mg twice weekly dosage, the tumor is stable at 2 cm in its maximal dimension  wit normal thyroid  and testosterone levels on replacement . He had normal visual fields examination.  He came to me looking for a third opinion. My diagnoses  is  a non functioning pituitary adenoma  that  caused elevation of the prolactin level by compression; since the tumor is not shrinking  with normal prolactin  level and therefore my recommendation will be surgery.
Would you consider  a prolactin producing tumor that is resistant to treatment ?  even though his prolactin level is now normal. 
would increasing dosage present any chance of reducing the size of the tumor? Is surgery the best path of treatment at this time?
Thank you again for your support. M. Montoya , M.D.
RESPONSE- Based on pre-treatment data, your patient could most likely harbor a macroprolactinoma, as hyperprolactinemia secondary to pituitary stalk disconnection very seldom is above 100 ng/mL 1, unless associated with macroprolatinemia2. Furthermore, in the case of nonfunctioning pituitary macroadenomas we should expect very low or even undetectable serum prolactin levels during cabergoline therapy instead of normal values, even in low doses.
Concerning treatment, first of all I would suggest to withdraw testosterone therapy and, if still low,  introduce  clomiphene instead  3. As neurophtalmologic evaluation and MRI ruled out chiasma compression, medical treatment with cabergoline (in the same dose, as no clear data on the benefits of increasing doses in tumor shrinkage is available when prolactin is already within the normal range). Some prolactinomas may exhibit shrinkage in the long-term treatment. Of course surgery can be performed at any time. I also would advice to follow the patient with echocardiograms, as the issue of cardiac valvular disease in prolactinoma patients on cabergoline is still under debate 4.
Marc ello Bronstein, MD|
Wass JA, Karavitaki N. Nonfunctioning pituitary adenomas: the Oxford experience. Nonfunctioning pituitary adenomas: the Oxford experience. Nat Rev Endocrinol. 2009 Sep;5(9):519-22
Glezer A, Soares CR, Vieira JG, Giannella-Neto D, Ribela MT, Goffin V, Bronstein MD.Human macroprolactin displays low biological activity via its homologous receptor in a new sensitive bioassay.J Clin Endocrinol Metab. 2006 Mar;91(3):1048-55
Ribeiro RS, Abucham J.Recovery of persistent hypogonadism by clomiphene in males with prolactinomas under dopamine agonist treatment. Eur J Endocrinol. 2009 Jul;161(1):163-9

• h41+ female, H ypothyroid since birth [uncertain of any presence of gland]
• medicated from 18mths
• oroxine medication monitored every few months. blood pathology indicating appropriate dose.
• dose for many years: 400mg daily.
• no notable deformities, other than stunted thumbs.
• patient treated for depression over past 12 months with cipramil 20-40mg. unsuccessful.
• recent agitation, anxiety, and depression led to hospitalisation;
• recently additional: feeling hot all the time; shakes internal and to some degree externally; worsening of agitation, anxiety and depression..
• blood tests reveal: free T4 @ 33.6H [normal upper limit of 19]; free T3 @ 7.5H [normal upper limit of 6.2]; TSH @ <0.01 [normal lower limit of 0.3]
• dose dropped to 300mg 3 days ago
• the concerns are a) could these extraordinary thyroid levels be contributing to the patient's crises; b) is there any permanent damage possible; and c) does the pathology suggest another condition or complication?
  thanking you in advance..Have a happi day ,
  Dr. Sifu Crockett ,HAPPI Foundation Ltd , www.happi.org.au
  RESPONSE--I do not connect stunted thumbs and congenital hypothyroidism, but maybe another reader can help. Regarding the blood hormone levels, certainly it seems that the patient has been under excessive thyroid hormone dosage, and needs to be reduced gradually to a level that keeps the TSH preferrably around 1-1.5, and the freeT4 in the high normal range. It probably will take many months for the pituitary to return to normal as you lower the dose. Regarding the future, I guess you wait and see. If the patient was untreated for 18 months after birth, that suggests a major developmental problem unless there was in fact significant endogenous thyroid hormone production at that time.  L De Groot,MD

THYROID HORMONE RESISTANCE vs. TSH-OMA ?
QUESTION- I wonder if I might get an opinion on what you would do next: 74 year old male had routine physical exam and labs done by his primary care physician in May. As part of laboratory panel a TSH and free T4 were done. The TSH was 1.64 (0.4-4.0) and the free T4 was 2.03 (0.68-1.76). These were repeated 7/8/04. TSH was 1.77, free T4 was 1.98 and T3 was 149(58-184). Patient then sent to endocrinology for evaluation. Per history he has been well and specifically denied any symptoms suggestive of hyperthyroidism. He has a daughter with a history of hypothyroidism. On examination his pulse was 68, EOMI, no lid lag, visual fields were intact to confrontation, thyroid was without goiter, nodules or bruits, no hyperreflexia or tremor was present. Labs were repeated 7/29/04 with TSH 1.60 (0.4-4.0), free T4 2.24 (0.68-1.76) and T3 134 (58-184), alpha subunit was 2.2ng/ml (normal < 1.0).
Thyroid hormone resistance syndrome vs TSH secreting adenoma vs other?? What would be recommended as the next step. T3 suppresion test? Get TFTs on family members? MRI?
K K, M.D. Fontana, CA 92335
RESPONSE- Dear Dr. K,
Thank you for your recent email. Dr. DeGroot has asked me to respond. The patient you describe appears to have elevated free T4 with normal TSH and normal T3 levels. The absence of an elevated TSH makes the diagnosis of RTH or TSHoma unlikely, but does not completely rule it out. It is possible that there is a binding protein abnormality or an antibody that is interfering with the free T4 assay used (or conversely there is something interfering with the TSH measurement). Given the elevated alpha subunit at this point I would agree that an MRI of the pituitary should be done. Your suggestion to get blood tests on other family members is a reasonable approach. If you and the family are interested we can evaluate the thyroid function along with binding proteins in our laboratory at the University of Chicago. While there would be no charge for the blood tests, the family members would be responsible for the expenses of phlebotomy and shipping of the blood. I have attached instructions for shipping as well as a consent form that should be signed by all the subjects. We should obtain blood from the propositus as well as his children and their spouses for starters. If other family members have a similar thyroid phenotype genetic testing may then be performed.
Roy E. Weiss, MD, PhD, FACP   rweiss@medicine.bsd.uchicago.edu

CHROIC URTICARIA, THYROXINE TREATMENT, THYROID CANCER

QUESTION-I ask to you to help me for curing this patient. She is 48 years old women, in 1996 diagnized that she have papillary carcinoma of thyroid gland, and then she did total thyroidectomy operation in same year outside Iraq. And postoperatively she took radioactive iodine. And after 6 monthes she did scaning , and from scanning it appear that she not need radioiodine therapy , and also after 6 monthes she also did another scanning also it appear that she not need radioiodine therapy, and after1 year she also did another scanning also it appear that she not need radioiodine therapy, and after 3 tears also she also did scanning it appear that she not need to take radioiodine therapy.(all of the scanning she did it outside of Iraq), after these scanning doctors outside Iraq decided that she is not needing to do any more scanning.She is from the date of her surgery of (total thyroidectomy)she is on thyroxine(T4)(0.1 mg)therapy. She is taking 2 tablets a day at morning, now her TSH is 0.05 UIU/ml.
Since 2 years she is suffering from a sever itching during night but also some time this itching occur during the day, with vaginal itching, the size of the wheals is 2 cm or less in diameter. Nearly she have this itching every night. I prescribed for her to take and she taken allermine, loratidine, betametazoneLA ampule for three weeks but there was no benefit. But when she apply Calamine lotion she is for a while feeling better. And I advised her to avoid some food like egg, onion, melon, potato, and nuts, and to be away from some types of flowers and clothes but also there was no benefit. I do not know how to solve her itching problem, to make her comfortable. WHAT CAN WE DO FOR HER TO SOLVE HER ITCHING PROBLEM? NOTES: We can not change the dose of thyroxine(T4) that she is taking which is 0.2 mg, because by this dosage we keep the serum TSH level slightly suppressed . In Iraq now there is no any specialized center for doing hypersensitivity test. Thanks for all, Dr. Muhamed Aydin, MD Iraq
RESPONSE- Urticaria is associated with Graves disease, but not to my knowledge with thyroid cancer. Possibly she has two unrelated diseases. Excess thyroid hormone can cause skin sensitivity, as happens in hyperthyroidism, and would possibly worsen urticaria. It is also possible, though unlikely, that she is allergic to the dye in the 100ug T4 tablet. Also, she may be cured of her thyroid tumor, especially if she had three valid scans with no evidence of disease (although we do not have data on TG).
Thus you might try giving her the 50ug tablets which have no dye in them. You also might cut down her T4 dose. It only takes a small increment above replacement to keep the TSH low, and in fact it is not clear that she needs to have her TSH suppressed, assuming she is really free of disease. Often steroids are needed for a time. If one antihistamine dose not work, one can try another-hydroxizine, cetirizine, and even cyproheptidine- and also try to eliminate allergenic contacts. Detergents, perfumes, jewelry, drugs, cosmetics, special foods, can be serially eliminated, but unfortunately often without benefit. In my experience after a time the problem subsides, but it is very difficult. I am not aware that there is a better or more specific set of answers.There is a recent review of this problem in IMMUNOL ALLERGY CLIN NORTH AMERICA, MAY 04, if you can somehow get a copy.Best regards,  L De Groot, MD

HURTHLE CELL CARCINOMA,  RESIDUAL DISEASE POST-OP

RESPONSE--I am unaware of any connection between such stomach complaints and Hashimoto's thyroiditis.  It is not clear whether the stomach pain comes on only at the time she has episodes of urticaria, which might then tie these 2 together (there is a known association of the latter with Hashimoto's - see below).  Another rare association is with serositis (but the patient has no evidence of peritoneal fluid as I see it) and there is, finally, an increase in H pylori in one study of autoimmune thyroid disease patients (J Clin Gastroenterol,1998,26,259) but again I am sure this has been excluded.  Has she had a biopsy at the time of an attack to see if there is any inflammation or oedema in the stomach wall?

Regarding the other questions I would only increase the thyroxine if the TSH suggests the need for it, but in this unusual case I would be tempted to keep the TSH as low as possible within the reference range, since the cause of the problem is obscure and therefore optimising thyroid replacement may have some inexplicable effect.  If the attacks are brief I cannot see that there will be an effect of TPO antibodies and finally I have never seen such a case, so don't know whether thyroid function tests would be indicated - having heard about this lady I guess I would do them! Prof Anthony Weetman

Response--This is an interesting patient with Hashimoto’s thyroiditis. At first I would like to know the reason why this patient had subtotal thyroidectomy. Do the episodes of severe stomach pain associate with the attacks of urticaria or angioedema?  Do the two occur at the same time?

1.       I am taking care of many patients with Hashimoto’s thyroiditis every day but I have never seen such a case. I don’t know any literatures on this problem.

2.       If the patient shows increased serum TSH , you should increase the amount of replacement dose but I don’t think that these episodes are related to the condition of hypothyroidism.

3.       There are several reports that there is association between urticaria and autoimmune thyroid diseases, either Hashimoto’s thyroiditis or Graves’ disease (Lanigan et al. Clin Exp Dermatol 12:335, 1987; Heymann J Am Acad Dermatol 40:229, 1999). Urticaria is induced by several mechanisms including allergy and autoimmunity. If urticaria and stomach pain occur at the same time, both may have intimate relation, but not relate to Hashimoto’s thyroiditis. I don’t know the tests to clarify this relationship.

4.       As you know, anti-thyroid antibodies are frequently found (around 10% ) in adult women and may not have direct effect on stomach

  Prof Nobu Amino

ABNORMAL THYROID TESTS IN PREGNANCY
QUESTION- Mrs. S is a 28 year old female with no significant past medical history, who is at 27 weeks gestation. Her pregnancy to date has been normal, some nausea during the first trimester, but she has put on an appropriate amount of weight and is tolerating foods well. Her thyroid function tests done are as follows:
8/17/04:
TSH: 0.046 (low )
T4: 9.9
T3 Uptake: 16.1( low)
Free thyroxine index: 1.6
8/24/04
TSH: 0.20 (0.34-5.60)
FT4: 0.50 (0.58-1.64)
FT3:2.6 (2.3-4.2)
8/26/04
TSH; 0.246 (0.350-5.500)
FT4: 0.88 (0.89-1.80)
FT3: 2.4 (2.3-4.2)
The patient has a normal thyroid on exam and no clinical features of hyper or hypothyroidism. Does she have secondary hypothyroidism? If so how do I work her up in pregnancy? Thank You,
Bindubalbalan@aol.com

RESPONSE-1 Typically the elevated hCG levels in early pregnancy can suppress the TSH modestly. Also, free T4 or T3 assays may perform erratically in the presence of high TBG, which your patient should have. Please check the total T4, and the TSH again. Total T4 should be elevated. Probably she is well, and the tests are a bit off for these reasons. Kind regards,
L De Groot,MD

RESPONSE 2
1) I do not really know whether this patient has 'central hypothyroidism' since this diagnosis was solely based on the absence of a rise in serum total T4 during pregnancy, with real data not provided , no measurement of free T4 done, and in addition normal serum cortisol (whatever this really means !).
2) In any case with hypothyroidism during a pregnancy (be it primary or supposedly secondary), I think that it is important to confirm the etiology of the condition before embarking on therapy : ultrasonography; thyroid antibodies; other pituitary hormone measurements; 24-hr urinary cortisol excretion; etc.
3) the absence of a rise in total T4 might have other potential explanations : iodine deficiency (unlikely in Goa probably) or congenital absence of TBG (hemizygote in the case of females) for instance.
4) if the patient has delivered now, it should be possible to re-evaluate the diagnosis of central hypothyroidism.
Prof Daniel GLINOER

PROGRESSIVE OPHTAHALMOPATHY IN AN ELDERLY MAN

QUESTION-I hope you will be able to provide information or direct me to 

literature on the following....my 82 year old father was diagnosed with 

Hashimoto Hypothyroidism 2 years ago. One year later, he developed significant 

thyroid associated ophthalmopathy including diplopia and proptosis (one eye 

worse then the other).  After 4 months of worsening symptoms, orbital X-ray was 

performed. Initially, follow-up exams indicated improvement. Now, 2 years after 

the initial diagnosis of Hashimoto Hypothyroidism, he has Graves Disease, and 

the eye that initially had minimal involvement now has significantly proptosis. 

My dad is being seen at Columbia Presbyterian for the Thyroid Associated 

Opthalmopathy, and his endocrinologist recently stopped the thyroid supplement 

as he has now gone from hypo to hyperthyroidism. One other worthy note - 

Myesthneia Gravis was ruled out 

>             The outstanding question I have is - how long does Thyroid Associated 

Opthalmopathy tend to last in seniors, and is thyroid related medical treatment 

different for someone in his age group?              Any information, or reference 

to literature on TAO in seniors would be greatly appreciated.   

           Thank You,Birdie D'Andrea,RN

RESPONSE-Dear Ms. D'Andrea,  

Thyroid-associated ophthalmopathy is most common in women in their 40s and 50s, 

and is fairly uncommon in elderly men. I know of no study concerning differences 

in the eye problems or responses to treatment in the elderly. However, in my 

experience and in that of others, there does seem to be more involvement of the 

eye muscles with diplopia in the elderly, while younger patients tend to have 

more enlargement of the fat tissues behind the eyes with proptosis and extensive 

inflammation. That said, clearly your father has a combination of both. I would 

recommend the same eye treatment for him as I would for a younger person. As the 

specifics would depend on the details of his eye exam and discussions with him, 

I can not tell you exactly what (if any) eye treatment I would recommend for him 

at present.The duration of eye problems varies considerably from patient to 

patient, ranges from about 6 months to several years' time, and does not seem to 

be related to the age of the patient. The type of treatment needed for his 

hyperthyroidism is also not directly age-dependant, but would depend on his 

general health status. It is particularly important in the elderly to maintain 

normal thyroid hormone levels as older individuals are especially prone to heart 

problems when hyperthyroid. Rebecca Bahn, MD

HYPOTHYROIDISM, DELAYED PUBERTY, MENTAL RETARDATION

QUESTION-Thank you very much for taking my questions.  I have recently seen a 15 yo boy 

with severe hypothyroidism (TSH 506 uIU/ml and total T4 of 1.05 ug/dl).  He also 

has significant short stature, being 4 feet 5 inches.  He is Tanner 2 and has a 

low testosterone of 64.  Unfortunately for him, his epiphysis are 90% closed by 

his bone age.  I am concerned that if I treat him with thyroid replacement 

alone, he is going to go through an accelerated puberty, and will not end up 

with an acceptable height.  So, we are contemplating starting him on a GnRH 

analog (leuprolide acetate) to shut down his puberty and supplement him with 

growth hormone at 0.37 mg/kg/week to improve his growth potential.  Since this 

requires a lot of work and a lot of financial resources, I was wondering if I 

could ask you a few questions...

1. What is the mechanism for pubertal delay in boys with severe hypothyroidism 

(ie why do we see precocious puberty in girls with severe primary 

hypothyroidism, but see the opposite in boys)?

2. Are there any other studies (other than the one that I attached) that treated 

peripubertal boys with bone age delay in hypothyroidism with a GnRH analog 

and/or growth hormone?  Do you think this is a reasonable approach?

3. This boy is also mildly retarded.  Are there any syndromes that have mental 

retardation, severe short stature, hypogonadotropic hypogonadism and primary 

hypothyroidism?  I thought of Laurence- Moon- Biedl syndrome, but this boy did 

not have polydactaly, he has no kidney or vision problems, so I think this 

particular diagnosis is unlikely for him.

I eagerly await your response.  Thanks so much!

 Alexandra L. Haagensen, MD, Children's Hospital Boston

RESPONSE-

#1.--Thyroid hormone is essential for bone growth, and, therefore, bone age advancement.  It appears that th CNS maturation that is necessary for puberty has the same determinants as those necessary for bone age maturation.; therefore, any disorder associated with delayed BA is associated with delayed puberty.  In both sexes.  The sex precocity seen in a tiny minority of hypothyroid children is poorly understood (see my chapter on female puberty in Sperling's textbook of pediatric endocrinology).

#2.--You can search PubMed as well as I for the latest.  But this is a standard approach.

CONGENITAL THYROID DEFICIENCY, NO RAIU, AND THYROID CANCER

ABNORMAL THYROID TESTS IN PREGNANCY

NORMAL THYROID TESTS EXCEPT FOR ELEVATED RT3

SURGERY WITH ADRENAL MASS ; “INCIDENTAL” MEDULLARY CARCINOMA

HYPOTHYROISIM, RENAL INSUFFICIENCY, AND RAI THERAPY

THYROTOXICOSIS AND PREGNANCY. 14 Jul 2004

“SUBCLINICAL HYPOTHYROIDISM” WITH NORMAL freeT4 AND TSH

THYROID CYST, AND MILD HYPERTHYROIDISM, IN PREGNANCY

THYROTOXIC HYPOKALEMIC PARALYSIS AND 131-I THERAPY

THYROTOXICOSIS, VENTRICULAR FIBRILLATION, HYPOKALEMIA

OPHTHALMOPATHY ONSET LONG AFTER THYROTOXICOSIS

"INCIDENTAL" MEDULLARY CARCINOMA

GROWING HOT NODULE

MALABSORPTION OF THYROXINE?

CENTRAL HYPOTHYROIDISM ?

NEONATE WITH LARGE GOITER

THYROID CARCINOMA DIAGNOSED BY BRONCHOSCOPY

SUBLINICAL HYPERTHYROIDISM AND SUBSTERNAL GOITER

NODULES, POSITIVE ANTIBODIES, AND TREATMENT?

AMIODARONE AND RECURRENT GRAVES’DISEASE

Therapy of a patient with a solitary vertebral metastasis

ATYPICAL GRAVES’ DISEASE

THYROIDITIS: RELATION TO SERTRALINE, AND LACK OF MELANIN

131-I TREATMENT IN RENAL FAILURE (13 May 03)

THYROXINE DOSAGE AND SURGERY, OR AFTER 131-I TREATMENT (10 May 03)

POSITIVE ANTIBODIES, AND GROWING NODULES (5 May 03)

THYROID HORMONE AND TSH LEVELS DURING PREGNANCY

Followup in differentiated thyroid cancers under 1cm

Hurthle cell nodule and Hyperthyroidism in Hashimoto’s gland(31Mar03)

HIVES, ANGIOEDEMA, AND HASHIMOTO'S THYROIDITIS

HYPERTHYROIDISM IN PREGNANCY?

HYPERTHYROIDISM IN PREGNANCY--CAUSE??, AND TREATMENT??

CONGENITAL THYROID DEFICIENCY, NO RAIU, AND THYROID CANCER

QUESTION- Thanks for taking the time to read this. I am a registrar from South Africa with an interesting young patient in whom your opinion would be greatly Appreciated. This young male first presented as a neonate with congenital hypothyroidism. At that time a thyroid uptake scan showed no thyroid tissue anywhere and a diagnosis of congenital thyroid agenesis was made. He was started on thyroxin, followed up for a while, and then was lost to follow up.

A few years later he returned to the clinic with a mass in the neck which clinically appeared to be a thyroid mass! Reviewing his initially uptake scans showed no uptake, and a repeat isotope scan again showed no uptake, however an ultrasound of his neck showed a multinodular thyroid gland. Too cut a long story short, he was found to have follicular Ca ofthe thyroid (most likely due to unsuppressed TSH) and a total thyroidectomy was performed. The diagnosis was then altered from thyroid agenesis, to an Iodine trapping defect or some form of dyshormonogenisis as uptake scan remained completely negative. He was treated with thyroxine post operatively and again absconded from follow up.

He is now 15yrs old. Of normal height and weight for his age, and has returned to our services with a lump in his neck. He is otherwise asymptomatic. A Fine needle aspiration of the lump (which is a lymph node in the cervical chain) shows follicular cells and the presumption is that the follicular Ca ( which on initial removal had extended through the thyroid capsule and invaded the vessels) has disseminated. A SPECT scan has shown uptake in a chain of lymph nodes in the neck extending into the thorax.

My question is: In lieu of his iodine trapping defect it will not be possible to treat this with Radio-active iodine, do you have any suggestions in management of this young man.

Kind regards,
Jonathan Mervis (paediatric registrar)

RESPONSE- This is a very interesting and intriguing case. I can try some comments.

1. Iodine trapping defect can cause hypothyroidism but is always associated with goiter. Thus this cannot be the cause of the patient's congenital hypothyroidism, unless in addition the patient had also an other genetic defect responsible for thyroid agenesis (such as absence of thyroid specific transcription factor TTF1,2 or others).
2. Whatever the reason for his thyroid agenesis, I guess that it was not a complete agenesis, but rather the patient might have some small thyroid tissue not visible in the scan. The follicular tumor may have developed from this remnant.
3. Another possibility to explain the lack of uptake (is this true also in the metastatic tissue? this is not clearly stated in your report) may be a defective TSH or a TSH-receptor. Measurement of serum Tg (and Tg immuno-staining in the tumor tissue) would also be interesting to know.
4. Regarding treatment, I think that I would try stimulation with recombinant human TSH (Thyrogen) to see whether it is possible to elicit iodine uptake and Tg production. A part from that I think that surgery is the only other option.

Thank you for giving me the opportunity to know about this case,
Furio Pacini, MD

ABNORMAL THYROID TESTS IN PREGNANCY

QUESTION- Mrs. S is a 28 year old female with no significant past medical history, who is at 27 weeks gestation. Her pregnancy to date has been normal, some nausea during the first trimester, but she has put on an appropriate amount of weight and is tolerating foods well. Her thyroid function tests done are as follows:

The patient has a normal thyroid on exam and no clinical features of hyper or hypothyroidism. Does she have secondary hypothyroidism? If so how do I work her up in pregnancy?

Thank You,
Bindubalbalan@aol.com

RESPONSE- Typically the elevated hCG levels in early pregnancy can suppress the TSH modestly. Also, free T4 or T3 assays may perfrom erratically in the presence of high TBG, which your patient should have. Please check the total T4, and the TSH again. Total T4 should be elevated. Probably she is well, and the tests are a bit off for these reasons.

Kind regards,
L De Groot,MD

NORMAL THYROID TESTS EXCEPT FOR ELEVATED RT3

QUESTION-I am a physician who practice in El Paso, TX. I just got a patient complaining of fatigue with the following thyroid panel results:

TSH - 2.04 uIU/mL
T4 Total - 8.55 ug/dL (4.87 - 11.72)
T Uptake - 43.3 % (32 - 51)
Free Tiroxine Index - 9.26 ug/dL (5.93 - 13.13)
T3 Total - 1.03 ng/ml (0.58 - 1.59)
T3 Free - 2.90 pg/ml (1.7 - 3.7)
T4 Free - 1.37 ng/dL (0.70 - 1.48)
Thyroglobulin Autoantibodies - 14 U/mL (Reference range <60)
Thyroid Peroxidase Autoantibodies - 19 U/mL (Reference range <60)
Reverse T3 - 741 pg/ml (90 - 350)

All of the above tests were within range except Reverse T3 (normal ranges-90 to 350 pg/mL). I also read in some articles that TSH levels above 2.0 could be a sign of hypothyroidism. Do you colleagues think that a T3 thyroid replacement will benefit my patient in his fatigue?. Also any idea of why he got high Reverse T3 values?. He is currently taking the following drugs:

Amytriptiline: 125mg daily
Pherpenazine: 4mg daily
Indera (propanolol): 20mg daily

As fas as depression, he is now very stable and no showing signs or symptoms of depression.

I would appreciate your feedback regarding this patient.

Thanks in advance,
Roberto Meza M.D., El Paso, TX

RESPONSE- The explanation of the situation is possibly as follows. Even to the more recent stringent criteria his TSH is normal as well. The increase in rT3 may be caused by the use of propranolol. I patch the abstract of a study that we did, below. It shows, see attachment, that in healthy subjects the effect of propranolol on parameters of serum T3 and serum T4 is moderate but huge on serum rT3. I assume that, because the dose of propranolol that your patient is using is low, only rT3 falls out of range, but not T3 and T4 parameters. However the situation is not completely comparable as our subjects were healthy young men treated for the purpose of the study with 200 micrgr. T4/day, and 3 times daily with 80 mgr propranolol. Furthermore the dose of propranolol that your patient is using is so low as compared to our subjects that I am surprised that rT3 is affected to such an extent. It may be that your patient also has a mild non-thyroidal illness where there is an early rise of rT3. Maybe, that a combination of these 2 factors explains the hormone profile of your patient. At any rate I am pretty sure that the thyroid function of your patient is normal and does not explains his complaints

Kind regards,
Georg Hennemann

Am J Physiol. 1988 Jul;255(1 Pt 1):Three-compartmental analysis of effects of D-propranolol on thyroid hormone kinetics. van der Heijden JT, Krenning EP, van Toor H, Hennemann G, Docter R.

Tracer thyroxine (T4), 3.3',5-triiodothyronine (T3), and 3,3',5'-triiodothyronine (rT3) kinetic studies were performed in normal T4 substituted subjects before and during oral D-propranolol treatment to determine whether changes in thyroid hormone metabolism in a propranolol-induced low-T3 syndrome result from inhibition of 5'-deiodination or inhibition of transport of iodothyronines into tissues. Data were analyzed according to a three-compartmental model of distribution and metabolism. T4 plasma appearance rate decreased by 16% (P less than 0.01), reflecting a decreased intestinal absorption of orally administered T4 during propranolol. Serum T4 and free T4 levels increased significantly by 14%, whereas T4 metabolic clearance rate (MCR) was lowered by 26% (P less than 0.001). No changes were observed in size of the three T4 compartments or in fractional and mass transfer rates of T4 from plasma to the rapidly (REP) and slowly (SEP) equilibrating pools. Serum T3, free T3, T3 plasma pool, T3 mass transfer rate to REP and SEP, and the T3 pool masses were all significantly decreased during propranolol to a similar extent as the T3 plasma production rate (PR). T3 MCR decreased by 14% (P less than 0.05). Serum total and free rT3 increased, whereas the rT3 MCR was substantially lowered during propranolol (P less than 0.001). The rT3 plasma pool, rT3 REP and SEP, and the mass transfer rates to REP and SEP increased, whereas no alterations were observed in rT3 PR and fractional transfer rates of rT3 to

SURGERY WITH ADRENAL MASS ; “INCIDENTAL” MEDULLARY CARCINOMA

Question
Thank you so much for responding to my e mails. I wish to get your views on these cases. 1) 43 year old male diagnosed with NHLymphoma 1991,post surgery,post RT.Incidental finding of 1.3 cm adrenal adenoma right, serial ct/mri of the adrenals showed increase in size 2003 1.8 cm,2004 1.6 cm. He is clinically ok, non hypertensive, the nodule looks silent and benign, HU <10. My questions are: a) he is to undergo a nasal surgery under general anesthesia, is it safe to proceed with surgery or do we have to r/o functioning adrenal nodule first? b) he also has subclinical hypothyroidism,ft4 11,tsh 12,anti tg>2000,anti tpo 130,thyroid scan, hyperfunctioning and warm nodules. Can his subhypo be attributed to the radiation he received while during treatment for HL ymphoma of the axillary node or is this definitely thyroiditis alone? can we also consider the thyroid nodules to be radiation exposure related? 2) female late 20s, 2002 presented with subclinical hypothyroidism and a discreet solid nodule on the right lobe.FNAC was colloid nodule. She received t4 suppression for about a year before finally deciding to have thyroidectomy. NO FROZEN section, surgery done at the suburb. Histopath showed medullary ca. Problem: surgery done was subtotal. Parathyroids were normal looking says the surgeon, patient non hypertensive .Should we subject patient to completion thyroidectomy, can we be guided by calcitonin level and cea alone at this time. 3) What exactly is the clinical significance of (histopath reading) HYPERPLASTIC nodules.We see a lot of these lately. Thanks so much sir for your time and wisdom.
Lynn F.W.Bilar,MD

Response

1. The adrenal mass seems to be a non functioning incidentaloma. The only test that I would recommend in view of a general anasthesia is measurement of plasma/urinary epinephrins just to exclude the rare possibility of pheocromocytoma. Regarding the thyroid, definitely the patient has autoimmune thyroiditis with subclinical hypothyroidism. This can develop spontaneously on a genetic background but that are also convincing evidence that autoimmune thyroiditis may be triggered by exposure to external radiation. Clinically it makes no difference, except that true cold nodules in the setting of radiation exposure have higher chance to be malignant and thus must be submitted to FNAC.
2. Medullary thyroid cancer is a potentially lethal disease and frequently presents with lymph node metastases, either clinically evident or unsuspected. In my opinion the patient should undergo a careful ultrasound of the neck for lymph nodes and calcitonin measurements before and after pentagastrin stimulation. If the results are fine, I would procede with completion thyroidectomy and dissection of the central node compartment. If there is suspicion of lateral lymph node involvement surgery should be more aggressive. In addition, being the patient young one should screen blood DNA for germline mutations of the ret proto-oncogene. This is because about 5-7% of apparently sporadic MTCs are indeed hereditary cases or "de novo" disease misdiagnosed as sporadic.
3. In my view hyperplastic nodule should refer to nodules as those found in the context of goiter where the disease is expression of minor TSH hyperstimulation, These leions are usually policlonal in origin as opposed to true adenomas which are usually monoclonal proliferations. I hope that this information answers your questions.

HYPOTHYROISIM, RENAL INSUFFICIENCY, AND RAI THERAPY

QUESTION
I am a physician with a 3.5 cm papillary thyroid cancer 5.5 weeks post total-thyroidectomy (no macroscopic extension, no known distant mets, but a few positive lymph nodes) about to undergo ablation with 150 mCi iodine next week. I was otherwise healthy, 43 years old, with no meds and no prior medical problems. Post operative calcium has been low 8.7 (reference 8.9-10.3), PTH - 48 (reference 14-72) - 48 hours off of calcium supplements. My concern is that my creatinine has crept up from 1.2 to 1.7 over the past two weeks as my TSH has risen above 65 - with BUN 5 to 8, C02 31 and otherwise normal electrolytes, normal albumin, total protein. I have read a few small series about renal insufficiency with profound hypothyroidism induced decreases in GFR [Kreisman SH. Arch Intern Med 1999; 159: 79-82]. A few related questions. What is your experience with this phenomenon - if any? Is it fully reversible? Is there anything I can do to ameliorate this decline and the potential for long term renal injury? Does my dose of radioactive iodine need to be cut due to renal insufficiency?
S Rothrock MD, Orlando, Florida

ANOTHER RESPONSE
The answers to your questions are a bit complicated You should also consult with a nephrologist to be sure there is no underlying renal disease.. However, my thoughts are as follows. Definitely severe hypothyroidism can reduce GFR and increase Cr, and this should be fully reversible. I am surprised that the BUN is so low, but perhaps this is also due to a decrease in diet and decreased metabolism . Generally a TSH above 30 is considered adequate for treatment. Severe hypothyroidism can be avoided by using the "Half dose protocol" , or recombinant TSH, as described in THYROIDMANAGER. There are wide variations in the dose chosen for ablation, with reasons for most choices. Your dose is on the "highish" side , I believe. The whole body radiation exposure will be increased by hypothyroidism and diminished GFR. Generally the whole body radiation is reasonably low in this proceedure, but can only be determined by knowing the dose administered, thyroid uptake, and retention time. It often is about 1/3 to 1/2 rad per mCi given, but this is only true if there is little RAIU in the thyroid. A nuclear medical person could give more accurate figures when RAIU is known. Renal insufficiency would increase whole body radiation to some extent, but its effect on treatment of the residual thyroid would not necessarily be in the same direction since retention of stable iodine might tend to decrease fractional RAIU. Your nuclear medical therapist is really in the best position to answer these questions, which involve several factors that are not available to me. In general keeping well hydrated would help reduce 131-I retention in the body, but perhaps this should also be done with caution, since there is a recent report of severe hyponatremia occurring in this situation. I hope these rather scattered comments are of use.
L De Groot,MD

THYROTOXICOSIS AND PREGNANCY. 14 Jul 2004

QUESTION
Dear Sir- What one would do with a 20 years old lady with a recently diagnosed graves disease who would like to get married next week. Her partner refused to delay the wedding and will not accept her to be on contraception. What would be the optimum management. Should we operate on her. Would it be better to do total or subtotal thyroidectomy. Is thyroid replacement therapy safe in pregnancy.
Dr Tarek Elatrozy, Gharbia, Egypt

RESPONSE
Thyroid replacement is certainly perfectly safe in pregancy. I hesitate to say what is optimum management, not knowing all about the patient. However it is common to carry patients thru pregnancy on antithyroid drugs, with caution not to overdose the antithyroid drug. If there is difficulty with medical management, it is also considered safe to prepare the patient with antithyroid drugs, and operate in the mid trimester. Usually the operation is a subtotal thyroidectomy, but some people prefer a more complete thyroidectomy if the surgeon is skilled and has a low risk of parathyroid or nerve damage in practice. Does this provide what you need?
L De Groot,MD

“SUBCLINICAL HYPOTHYROIDISM” WITH NORMAL freeT4 AND TSH

THYROID CYST, AND MILD HYPERTHYROIDISM, IN PREGNANCY

RESPONSE- The situation is surely complicated. It is unlikely that the TSH suppression is due just to the normal high hCG of early pregnancy. It is also surprising that it could be due to a thyroid cyst. So one wonders about a functional thyroid lesion (probably adenoma) associated with the prior cyst, or Graves disease, since she does not have hyperemesis syndrome. 

 I would recheck TSH, freeT4 and T3 to be certain of the degree of hyperthyroidism. I would also do an US, and anti-TPO and anti-TG antibodies, as well as TSAb.

Although one can argue the merits, I would trend to treat the hyperthyroidism with anti-thyroid drugs, even if mild. If the US shows one lesion with a cystic and solid component, it would be of interest to biopsy the solid area. Fortunately the chance of malignancy would be small.  If the antibodies are positive, it would suggest that the cyst/adenoma is incidental, and that the patient has mild Graves' Disease. Let us know what further develops.  L De Groot,MD  15 Apr 2004

THYROTOXIC HYPOKALEMIC PARALYSIS AND 131-I THERAPY

THYROTOXICOSIS, VENTRICULAR FIBRILLATION, HYPOKALEMIA

OPHTHALMOPATHY ONSET LONG AFTER THYROTOXICOSIS

RESPONSE- Although the natural first assumption is that she has only central hypothyroidism, it seems  to me that the situation is probably more complicated than that. She began with an elevated TSH, which is  possible in central hypothyroidism, but it responded to treatment, she has no sign of tumor, and the rest of the evaluation is negative. Further, without treatment, her hormone levels are near normal and her RAIU is near normal (depending on Iodine supply). We do not know findings by thyroid US or antibody tests, which should be evaluated. 
     TRH testing would be of interest, if a good response occurred, but it often does not tell more than the basal TSH. It is rare for the TSH to be 0.00 in any situation except suppression by elevated thyroid hormone, or some sort of TSH testing error. I would guess that she has some hypothalamic/pituitary problem making her TSH set point low and easily suppressed, and this has been reported in elderly patients. This is also hard to prove. I think she also was exposed to higher than normal levels of T4 at some point so that her pituitary was suppressed.
     I would follow her without treatment at this point and see if her TSH gradually returns toward normal. It would be of interest to measure TSH in a different lab to rule out some error due to heterophile antibodies. The duration of suppression of her TSH while off T4 is truly prolonged , but not incompatible with this evaluation of the problem.  If the evaluation provides no further avenues of understanding, and hormone levels remain at the current level, mild T4 supplementation could be reinstituted. Please let us know any follow-up.  Leslie J De Groot,MD

NEONATE WITH LARGE GOITER

Full term newborn male with a hx of IUGR in utero born to a mother who smoked during pregnancy but who has no hx of thyroid problems, who at birth has some respiratory distress and is noted to have a large neck mass. TSH is 775mcIU/ml and free T4 is 0.39 ng/dl so he was started on 37.5 mcg/day of synthroid then was transferred to another hosp. lat neck film shows ant displacement of the trachea and retropharyngeal fullness. CT of the neck mass showed "large heterogeneous soft tissue mass with septated and lobulated components, likely representing a goiter. enlarged thyroid lobes measure approximately 2.2 x 2 cm in cross-section, and the isthmus in the anterior neck measures 1.4 cm in width.the thyroid gland appears to extend behind the laryngopharyx at the level of the hyoid, displacing the airway anteriorly, and the carotid arteries and the jugular veins are displaced posterolaterally bilaterally. There is distortion of the tracheal cross-section, with a possible reduction in its transverse dimension." The baby is stable on RA, has no audible stridor, but desats to 60's occasionally with feeds or agitation.  

The diagnosis seems most likely to be thyroid dyshormonogenesis questions:

1. by treating the hypothyroidism, in what percentage of cases does the
   goiter shrink in size? and if it does shrink, on what kind of time
   period would you see shrinkage(weeks, months?)?
2. the TSH in 2 days came down to 335. most kids don't get a
   pertechnetate scan once started on treatment, but to prove that this
   truly is all thyroid tissue could we still do the scan since the TSH
   hasn't totally corrected?
3. does anyone else have experience with management of a pt like this?
   there is reluctance on part of ent to remove the goiter because the baby
   is small (2.2 kg) and risk of damage to the recurrent laryngeal nerves
   would be high. the child's is relatively stable but if the mass doesn't
   shrink, he may not go home anytime soon given his occasional desats
   Thank you. Dr Joyce Lee, Fellow in endocrinology, University of Michigan, joyclee@med.umich.edu

RESPONSE--Your infant presents a most interesting and unusual problem as we rarely see goiters of this magnitude in infants these days.
In general, the most common etiology would be maternal antithyroid medicine for treatment of maternal Graves', but that does not appear to be the case in your patient. Although the mother smokes and cigarettes contain thiocyanate, I doubt that this is a factor in the absence of iodine deficiency. Nonetheless it would probably be worthwhile to ascertain the mother's dietary habits.I certainly agree that the most likely cause, therefore, is an abnormality of thyroid hormonogenesis. It would be most helpful to do a 123-I uptake and scan (rather than pertechnetate), if that were possible since by following the kinetics of the iodine release (i.e., check uptake early, then at 6 hrs and 24 hrs) you could not only verify that the swelling is thyroid, but determine whether an organification defect is present as well. Also, there is an animal model of congenital hypothyroidism in goats, I believe, that is associated with a large goiter and in which there is an abnormality of thyroglobulin synthesis. Therefore, I would certainly want to check a serum thyroglobulin level in your infant and obtain a urine sample not only for urinary iodine and creatinine but to be used for assessment of an abnormal thyroglobulin molecule as necessary as well.
If the neck swelling is thyroid, as it almost certainly is, then I would think that it should shrink relatively rapidly- days and weeks, not months, and surgery is not indicated. However, for the moment if you are concerned about the possibility of respiratory compromise because of its size, then I would push the L-T4 dose by giving an amount that brings the T4 (and free T4) to the high normal range (say 50 mcg. qd) ASAP, and then cut back to 37.5 mcg once this is achieved. I have seen TSH values normalize surprisingly quickly in infants- in a matter of 1 or 2 weeks.
I hope that these comments are helpful to you. Please feel free to contact me should you have any further questions or concerns. I would be most interested in learning about the outcome of your patient. Rosalind Brown MD,

THYROID CARCINOMA DIAGNOSED BY BRONCHOSCOPY

SUBLINICAL HYPERTHYROIDISM AND SUBSTERNAL GOITER

RESPONSE- Firstly, I would get a CAT of the chest if I was considering resection for his MNG, to be sure we know what the anatomy really is. I assume the TSH has been checked more than once, and that there has not been any recent exposure to iodine that might cause a transient episode of hyperthyroidism. So his problem is a (possibly significant) substernal extension, an FNA report that is meant to be disquieting to you although it probably is a benign lesion, and very mild hyperthyroidism which may be due to his nodules.  With all of that, in a 46 year old man in presumed good health, my approach would be to recommend resection by a skilled surgeon, expecting a very easy and safe course. Probably he could be operated with a short preparation under methimazole and later added KI  for a week, since the degree of hyperthyroidism is clearly minimal. If it was not for the FNA result, one could treat with RAI, and RAI is used to shrink sub-sternal goiters, a point that Dr Hennemann may comment on. Leslie J De Groot,MD

A SECOND RESPONSE-Thanks for the opportunity to comment as well.The probability that a multinodular goiter (mng) is at an increased risk for carcinoma is controversial. My personal opinion and that of many Europeans, who have a lot of experience with this entity since it occurs frequently in Europe, is that this is most probably not the case. On the basis of this notion it is “dangerous” to do FNA for every cold nodule in such a goiter as many of these presumed benign nodules have a follicular structure. The first treatment choice in mng in Europe is administration of RAI. It is of no influence if these goiters are partially or even completely intrathoracically located. Even goiters of more than one kilogram are easily (really!) treated with RAJ. I have not treated any mng anymore with surgery since the last 20 years.
My definition of a mng is that it should be longstanding, the thyroid is mostly asymmetrical, no X irradiation to the neck in the past, no hoarse voice, no rapid growth, no suspect lymph nodes in the neck and preferably a familiar tendency for mng. Some also include the presence of a “prominent” nodule  what ever that may be. If most of these points are met, I do not perform a scan neither a FNA. The treatment of choice is then RAJ.In this particular patient there are 2 aspects that deserve further consideration

1. The patient is a male and mng is more frequently occurring in females. This point argues only weakly against the goiter being benign.
2. The fact that a FNA has been done that shows some follicular structures, carries the consequence of surgery. The possibility however is great that there is no malignancy at all.

 SUMMARIZING: Considering the approach that has been adopted in this patient and the results as a consequence of this approach, I see no other way then to operate. The reason that we in Europe are so reluctant to have mng operated is that even in experienced hands, the risk for permanent hypoparathyroidism and vocal cord paralysis is about a few percent in this continent, but may be lower in the US. Georg Hennemann, MD, PhD, FRCP, FRCP(E)

NODULES, POSITIVE ANTIBODIES, AND TREATMENT?

RESPONSE-Dear Dr Atakis,If I may summarize this patient, then she has a multinodular goiter, is euthyroid and no cold nodules. No growth of 2 out of 3 nodules have been
documented over the last year and follow up size of the smallest nodule lacks or this nodule was not seen at the second ultra sound. I assume that no suspect lymph nodes have been detected. There are no mechanical complaints.
       If my summary is OK then there is no doubt in my mind that only follow
up of this patient is the maximum that should be considered. If there is
a family history of multinodular goiter one could be even more sure
about the absence of malignancy in this goiter, but even without this
suspicion for cancer is really low. I am not in favour of treatment with
thyroid hormone,that caries more risks than benefits as growth is rarely
reversed or inhibited but that thyrotixosis may ensue because of
autonomous function of parts of the gland. Neither is there any
indication for FNA or operation because suspicion for malignancy is low
to absent.
If any treatment should be considered then this should be administration
of radio-active iodine, but only then in the case that the thyroid
becomes subclinically- (suppressed TSH but normal T4 and T3
paparameters) or full blown hyperthyroid or that serious trachea
stenosis develops. In the case of tracheal deviation but no or only mild
stenosis, RAI treatment is optional but not necessary. I do not
understand the reasoning about TBG. I understand that this value is
elevated? So what?  This has nothing to do with thyroid function and FT3
and FT4 are corrected for this and I assume normal. Maybe this patient
is using oestrogens or TBG maybe congenitally elevated?Georg Hennemann, MD, PhD, FRCP, FRCP

A SECOND RESPONSE-The patient must have Hashimoto’s thyroiditis in view of the antibodies and the scan without nodules. Pseudo-nodules are common on US of Hashimoto’s glands, but usually are not distinct. Thus she may well have two thyroid diseases. In the USA, where multinodular goiter is less common (how about Crete?), I believe that in this young woman the usual approach would be to biopsy both nodules under US guidance. If benign on FNA, and they remain static and asymptomatic, and whether the final Dx is Hashimoto’s or MNG, no treatment is clearly required.  However some of us still prescribe replacement ( not suppressive) doses of T4 in patients with benign nodules and MNG. The goals, especially at age 34, would be the occasional (25% of cases) reduction in size, possible help preventing further growth in lesions that are in part TSH dependent, and certain help in keeping in touch with the patient. Leslie J De Groot,MD

AMIODARONE AND RECURRENT GRAVES’DISEASE

The patient is a 60 year old oriental lady. In 1978, age 36, this lady

developed quite severe Graves' disease (non-goitrous) that failed to respond

to medical treatment, and she eventually required radio-iodine treatment,

which was successful, in 1979.  She remained well until 1985 when she

suffered a relapse, and was treated successfully on this occasion with a one

year course of antithyroid medications, which we assume was carbimazole,

though we do not have the old records to confirm this.

This lady subsequently remained well and euthyroid until Augusr 2001, when she developed paroxysmal ventricular tachycardia of uncertain aetiology.

Corornary angiography ruled out any significant ischaemic heart disease, and

she was commenced on simvastatin 20 mg od, dipyridamole and amiodarone which was eventually reduced to 100 mg after 1 year as she had remained so stable. Her baseline pre-amiodarone TFT was : FT4 = 16.2 pmol/l, TSH = 2.2 mu/l . The TSH rose to borderline levels after about 1 year of treatment, but

subsequently settled to within the normal range of 0.35 - 5.5 until

recently. 

She was completely well and euthyroid until around July 03, when she started to feel non-specifically unwell with fatigue and occasional palpitations. A

TFT in mid September 2003 showed FT4 = 19.4, FT3=  6.7, TSH = 0.02 . During the subsequent weeks , she became gradually more symptomatic, with increased palpitations and fatigue and feeling shaky. Repeat TFT at the end of October showed FT4 = 25, FT3 = 8.9 and TSH = <0.01. TSH receptor antibodies were

also found to be markedly elevated at 20 (normal <1). Anti-TPO antibodies =

219 iuml . CBC, LFT and renal function were all normal. Recurrence of

Graves' disease was confirmed, and she has been commenced on carbimazole, initial starting dose 20 mg od. 

The plan is now for the patient to return to her Cardiologist to discuss

other treatment options than amiodarone, as her Endocrinologist recommended

that the radioiodine treatment be repeated whenever possible. However, she

would need to be off the amiodarone for at least 6 - 9 months before this

would be feasible, as we understand thyroid iodine uptake would otherwise be

very suppressed whilst she remains on this drug. 

We now have a real therapeutic dilemma, as an effective treatment to avoid a recurrence of the paroxysmal VT will need to be found before amiodarone could be withdrawn. Thyroidectomy was not really recommended by her Endocrinologist, as she does not have a goitre and in addition is terrified of surgery !  As previously, I have some specific queries I would very much appreciate your and your team's comments on: Dr AT, adt_2004@yahoo.co.uk

RESPONSE-THERE ARE 2 WAYS TO TREAT THIS PATIENT WHILE CONTINUING WITH AMIODARONE:

1. Continued co-administration of carbimazole

2. Destruction of the thyroid with ethanol injection and subsequent substitution with T4. This procedure has just been described for patients with Graves' disease and has been used for quite some years for thyroid nodules and also recently even for lymph node metastasis of thyroid carcinoma.

My suggestion would be to start with carbimazole in a titrated dosage to keep the TSH normal. You should realize that T3 and T4 parameters are often unreliable during amiodarone treatment in that values are (falsly) increased due to transport inhibition into tissues. Carbimazole can be used for many years without side effects in many patients. If serious side effects do occur so that carbimazole has to be discontinued, while it is clear that the amiodarone has to be continued, then the other option becomes into focus.

Georg Hennemann,MD 

RESPONSE- May I offer other thoughts on this problem?  Whether or not amiodarone induced this recurrence seems uncertain.. It would have been interesting to have an RAIU prior to starting carbimazole (could be zero  or low), possibly IL-6 assay, and an US. It is hard to believe that the iodine load was not in some way involved, although it usually would induce hypothyroidism in patients with autoimmune thyroid disease, especially those with  borderline hypothyroidism.
           Be that as it may, carbimazole may well induce a remission if the amiodarone can be stopped. (Propylthiouracil might be a more interesting choice, since it would further decrease T4->T3 conversion, in contrast to carbimazole.) Some patients with amiodarone induced hyperthyrodism require addition of KClO4 (cautiously!) for a response, and of course there is a subset of patients who respond to prednisone.
           Surgical resection with beta blocker preparation is a very valuable standard resort when other methods fail, and has helped us out of several difficult situations involving the fear of recurrent cardiac arythmias.  The possibility of ethanol seepage outside of a small partially fibrotic, twice-treated, thyroid remnant should be kept in mind if considering what must be considered a novel treatment with ethanol. In the absence of significant published experience with this approach, I personally can not recommend it.
Leslie J De Groot,MD

Therapy of a patient with a solitary vertebral metastasis

RESPONSE-Solitary mets are of course rare. The two that I cared for involved lung (resected and cured) and the humerus (treated with 131-I then resected, and cured). I believe that embolization has been used in patients with large tumor deposits, which I think your patient does not have, and helps, but does not cure the lesion.
One option would be to re-treat with 131-I, and this seems the most probably useful. I presume the maximum radiotherapy was given. The TG of 7 (on T4?) is low enough to mean that growth is not rapid. After repeat 131-I it may be logical to follow the situation on suppressive doses of T4 and wait for a sign of growth by increasing TG. This might take years. I have never been involved in resection of a vertebrae, so I can not comment on that approach.  I have installed Harrington rods in a few patients to stabilize their spine when multiple vertebrae had mets, and some contemporary version of this procedure may also be useful. Leslie J De Groot,MD

ATYPICAL GRAVES’ DISEASE

Dear Sir,  I am a Family Physician from the UK. I am writing about the case of a 37 year old female patient, who was recently diagnosed with Graves' disease, but the presentation and clinical course to date have been most atypical.

The patient first presented four months ago with an acute maculopapular rash, which had started 2 days following a five-day course of amoxycillin taken for a minor dental infection. The rash was a a non-specific rather florid eruption from neck to feet but sparing the face, palms and soles of the feet, and lasted five days. Clinically it could equally be either a penicillin allergy or a non specific viral exanthem. However, there were no preceding symptoms suggestive of a viral infection, and there was no previous history of penicillin allergy, the patient having taken various penicillins without any problems on various occasions in the past.

Coincidental with the rash, there was a low-grade fever, a resting tachycardia of around 90 - 100 bpm, and she was noted to be 'shaky'. She had also lost around 2kg in weight in about 2 weeks, and started to become breathless on moderate exertion. Her eyes were also noted to have become larger, with evidence of lid lag and lid retraction. Other symptoms included insomnia, restlessness, polyuria, loss of appetite but constant hunger, heat intolerance and a persistent fever between 37.7 - 38.2 Centigrade.

Clinical examination showed no evidence of a goitre. The only unusual clinical finding of note, that may or may not be relevant, was the appearance of several (at least 5) longitudinal pigmented streaks on at least 4 of her fingernails during the previous few months.The exact timing of the appearance of the streaks was uncertain, but they had certainly not existed before the past year. There is evidence of at least 1 new streak forming during the past month. I believe these streaks are normally only described in association with either dark-skinned races (the patient is of Oriental race and would not exactly be described as being of dark-skinned race), or Addison's disease, but the patient did not appear to belong to either category.

The complaints of palpitations, weight loss and particularly the eye changes prompted a suspicion of thyrotoxicosis, and thyroid function was checked about 2 weeks after the onset of the rash and other symptoms. Results as follows: FT4 46.2 pmol/l (normal 10 - 23), Free T3 12.8 pmol/l (normal: 3-6.5), TSH <0.05 (0.35-5.50). CBC, ESR, CRP, LFT were all normal. Anti-TPO antibodies were elevated at 330 iu/ml at two weeks rising to 662 iu/l at three weeks (normal<100 iu/ml). Viral antibody testing for rubella, measles and parvovirus were negative.

In view of the rash and the very acute onset of symptoms of thyrotoxicosis, specific therapy was deferred pending further investigations, as this could be silent thyroiditis for which antithyroid treatment would not be appropriate. The patient was only treated symptomatically with propranolol prn whilst various investigations were arranged.

Subsequent investigations were as follows: thyroid isotope uptake scan showed increased uptake in both lobes of the thyroid which is uniform and typical of Graves' disease. I understand TSH receptor antibody was also elevated at 3 (normal <1).

Clinically and biochemically, the thyrotoxicosis appeared to peak about 1 month after the rash's and other symptoms' first onset, followed by gradual resolution without specific treatment during the subsequent two months. After about one month of clinical euthyroidism, however, during the last 3 -4 weeks (since 1st September 03) there has been evidence of a gradual return of mild hyperthyroidism with a recurrence of symptoms such as palpitations, mild resting tachycardia of about 90 - 100 bpm, breathlessness on moderate exertion such as swimming or walking uphill, heat intolerance, fever between 37.5 - 38 Centigrade and mild 'shakiness' and sleep disturbance. The patient also started to complain of her eyes having become irritated during the past few weeks, with watering and a foreign body sensation, together with intermittent injection of the lateral and circumcorneal conjunctival blood vessels . She has still not yet been commenced on any treatment to date.

Serial TFTs were as follows: FT4 40.8 on 9th June, FT4 46.2 & FT3 12.8 on 13th June, 30.4 & 7.2 respectively on 7th July, 21.4 and 6.1 on 24th July, and 24.5 & 6.4 respectively on 1st September 03. TSH remained suppressed <0.05 throughout. Another TFT is due to be repeated.

Past medical history: There was no past history of any medical problems at all, the patient having had no signs or symptoms suggestive of thyroid disease at all prior to the onset of the rash. A normal screening TFT in 1996 had been normal.

Family history: her mother developed Graves' disease age 36 and required RAI. There was a further exacerbation of hyperthyroidism in her early forties, but the disease is now quiescent.

Clinically, until a few weeks ago the presentation had been more typical of silent thyroiditis, including the sudden rapid onset, the relatively mild symptoms, the absence of a goitre and the spontaneous resolution of symptoms and normalisation of FT4 and FT3 levels after around 2 months. However, the family history and all the investigations to date have suggested Graves' disease, although the clinical course to date has been rather atypical.

My main questions are : 1) Have there been any other reports of Graves' disease presenting so acutely and with a rash, followed by such rapid spontaneous resolution ? 2) What are your thoughts about a definitive diagnosis, and would you suggest any other investigations? 3) Do you have any thoughts on the 'pigmented nail streaks, and 4) What would you suggest in terms of long-term management and follow-up?

Your thoughts and comments are very much appreciated. I attach an image of the patient's hand, for your further information. Though not too well focused, the pigmented streaks described earlier can be clearly seen on the thumb, index and middle fingernails.

                                                                 Dr. A T

Dear Dr. T,I will try to answer you in the order of your questions.

1. Have there been any other reports of Graves' disease presenting so acutely and with a rash, followed by such rapid spontaneous resolution ?
   I do not know a similar case from the literature or my own experience. Did she have contact with a moderate amount of iodine? In that case both the rash may be explained as the acute onset of Graves’ disease. There is a familial tendency of Graves’ disease and any iodine “contamination” my have brought a latent thyroid autonomy to the surface. In the case of moderate iodine ingestion and thyroid autonomy, iodine uptake of the thyroid may not be blunted when measured several weeks later.
2. What are your thoughts about a definitive diagnosis, and would you suggest any other investigations?
   If the TSI test, that was used, is highly specific and the value of 3 definitive abnormal, then it is difficult to “escape” the diagnosis of Graves’ disease. If eye signs were indeed present as observed by an expert and preferably measured and objectively found to be typical for Graves’ophthalmopathy then there is no doubt about the diagnosis, I think. What you could do is take up contact with Prof Weetman in Sheffield and ask him if he can organise an in vitro test with the patient’s serum that measures cAMP production in cells transfected with the TSH-receptor. This type of test is probably the most specific test available.
3. Do you have any thoughts on the 'pigmented nail streaks:
   No thoughts, what does the dermatologist say?
4. What would you suggest in terms of long-term management and follow-up?
   If I am correct than there has been no complete resolution, but a continuation of thyroid overactivity at a lower level until to date. If that is true, then there is an untreated hyperthyroidism for at least 3 months. I think that there is sufficient reason not to wait any longer for treatment if the next lab results are about unchanged. Although I am an advocate of treatment with radio-active iodine as a first choice in Graves’ disease, in this case I would suggest a short term treatment with a titrated dose of an anti thyroid drug, because if iodine ingestion is the cause then one might expect a favourable response and maybe long term remission. Because of the rash that she experienced I would closely monitor any adverse reaction to the anti thyroid drug keeping in mind that she may have an allergic constitution.

I do thank you for presenting us with this interesting case and I like to compliment you with your excellent description of the patient. I would appreciate to hear the follow up of this patient if possible.Georg Hennemann

Dear Professor Hennemann,

Your comments about erythrocin has intrigued me so much it has prompted me
to investigate.
I have discovered the standard AMOXYCILLIN capsules supplied in the UK are
red and yellow and do indeed contain the inactive ingredient erythrocin.
Furthermore, although the patient in question had taken various penicillins
in the past, she had never taken amoxycillin in this particular form
previously. She does not normally eat sweets or red-coloured food otherwise.

Do you think the amount of erythrocin contained in 15 capsules of
amoxycillin would have been sufficient to trigger off an attack of
thyrotoxicosis? If so, it does make perfect sense and would account for the
suddenness of the attack and the equally rapid resolution of symptoms within
2 months.

Once again, thank you so very much indeed for your most helpful advice and
comments, and for sparing the time to respond to my queries.   Dr A. T (adt_2004@yahoo.co.uk)

THYROIDITIS: RELATION TO SERTRALINE, AND LACK OF MELANIN

131-TREATMENT IN RENAL FAILURE
QUESTION-Thank you so much for providing this service. My question is about the safety of I131 therapy in a patient renal dysfunction. Her serum creatinine runs from 220umol/L to 310umol/L. (2.5-3.5mg/dL). She is a 65 year old woman who is hyperthyroid on the basis of an autonomously functioning nodule in a longstanding multinodular goitre. I recognize that with her renal dysfunction she may have a larger iodine pool. I also recognized that the I131 should take longer to be excreted. She is not on renal dialysis as she does not have endstage renal failure. Does the I131 therapy have the potential to worsen her already tenuous renal function? Thank you for your time! Lois Donovan M.D. FRCP(c),Univ. of Calgary. ldonovan@telusplanet.net
RESPONSE- Your question raises several interesting issues which are probably often ignored. I think the possibility of significant direct radiation damage to the kidney is highly unlikely, since the kidney can probably withstand doses that exceed 1000 rads and survive. Another aspect is the potential radiation dose to the whole body. I presume that in the presence of a thyrotoxic nodule the RAIU, even in the face of renal failure, is proably +/- 20% or so. You are probably planning to give a dose in the order of 20-30mCi. (You can provide the details if you wish.) The body dose from such treatment comes both from the transient iodide phase and the more prolonged metabolism of labeled hormone. With normal iodide excretion half-time of 1 day it is small. However if excretion is very prolonged due to renal failure, the body dose could be significant. It could reach 100-200 rads depending on dosage, body size, and turnover rate. Most likely (assuming a 30 mCi dose and normal size and iodide half time of 3 days) it would be in the order of 100 rads and safe. Calculating the exact dose is complicated. To be absolutely safe, the ideal method would be to do a tracer uptake and whole body turnover curve counting the % dose retained each day. Probably your Nuclear Medicine people can help calculate the body dose. I will also ask Dr Kenneth Ain to repond to your query. Leslie J De Groot,MD
Second response-My experience with I-131 administration, in the context of renal
dysfunction, is mostly with therapy of metastatic thyroid carcinoma.
In such patients, additional factors make dosing issues even more
complicated. The induction of a sufficiently hypothyroid state to
effect radioiodine uptake in tumor metastases decreases the GFR of a
patient to around one third of what it would be in the euthyroid
state. In these circumstances, using whole body and blood dosimetry
analysis (setting the maximum red marrow exposure at 200 REM), in
elderly women with chronic renal insufficiency (yet not so bad as to
need dialysis), the lowest I-131 dosage I've seen to be associated
with the red marrow radiation exposure limit is in the range of 95
mCi. In this euthyroid patient from Calgary, with chronic renal
insufficiency, I-131 administration in the range if 20 - 30 mCi seem
unlikely to draw near to any level of significant marrow toxicity.
As stated by Dr. De Groot, the kidney itself is not likely to be
damaged by this radiation. Also, with the considerable re-uptake of
I-131 into autonomous regions of her thyroid from her reduced renal
clearance, she might not require dosages as high as 20 mCi to effect
a resolution of thyrotoxicosis (this could be modeled with a small
I-131 tracer dose). Lastly, it should always be remembered that
surgical thyroidectomy is a reasonable option in some patients,
producing additional benefits of: rapid restoration of euthyroidism,
elimination of potential thoracic outlet obstruction, and the
opportunity to obtain histological analysis of the goiter. Dr Kenneth B Ain

THYROXINE DOSAGE AND SURGERY, OR AFTER 131-I TREATMENT
Question-I very much appreciate your answers to my questions. They have been quite helpful. May I ask you another clinical question? Would you recommend lowering the dose of thyroid hormone prior to thyroid surgery in patients with thyroid cancer who have suppressed TSH, normal FT4? Also, when do your recommend restarting thyroid hormone therapy in a patient who has received hi doses ie 150 mci of I131 Rx who will have a whole body scan 1 week post treatment? Best regards, Lisa Wisniewski, MD,lwisn@earthlink.net
Response- Although such patients are by definition chemically thyrotoxic, usually they receive something like 125% of the "normal" T4 daily requirement, not the 200-1000 % excess seen in spontaneous thyrotoxicosis. I believe that in most cases there is no need to be concerned. Obviously if the patient has a history of heart disease or arrhythmias, the treatment would already be different and more caution would be required- that is, use of beta blockers, reduction in T4 dose.
After administration of the therapeutic 131-I to a patient who has become hypothyroid and has an elevated TSH, the logical goal is to keep the absorbed iodine in the thyroid tissue or tumor, which should be fostered by decreasing iodide turnover in the thyroid tissue if possible. For that reason it seems logical to promptly suppress TSH, and I restart T4 treatment with (usually) double the prior dose (for 3 days) beginning 24 hours after treatment is given. I know that some MDs wait longer, but do not understand why. One could make a case for beginning treatment immediately after administering the 131-I, but I have never pursued that approach. L De Groot,MD

POSITIVE ANTIBODIES, AND GROWING NODULES
I have a puzzling case. 37 M seen by PCP April last year, felt ?enlarged thyroid . TSH normal . No antibodies done . USG showed multiple nodules, on R there were 2 solid nodules about 17 mm and 10 mm respectively and on L , there was a 12 mm circumscribed nodule in inferior aspect and larger 2.0-2.5 cm nodule in the posterior aspect of midportion of the L lobe. Pt had no sxs and have not noticed any enlargement.
In March this year, pt now noticed sudden enlargement on left side while shaving more prominent when he hyperextended his neck. No hoarseness, dysphonia, dysphagia. No Neck pain. Again , PCP did US, on R multiple nodules ranging in size from 5 mm to 2 cm , the last being hypovascular. There was this nodule , solid, hypovascular in posterior aspect measuring 3.9 x 2.8 x 2.8 cm. Thyroid scan cold nodule on left correlating with the palpable entity which was really prominent on scan., on the right multiple cool nodules TSH now= 6.5 slightly high ( N=0.34 - 5.6 uIU/ml)
Thyroid peroxidase Ab = 48 slightly high (N = 0-2 IU/ml)
Thyroglobulin Antibodies = > 90 ( N=0-2 IU/ml) -don't know why this was ordered.
No radiation exposure. + FHx = maternal aunt= Hashimoto's ; mother = lupus; father= rheumatoiod arthritis. On PE, no eye signs; thyroid about 2-3 X normal size; approximately 2.5 cm left nodule , nontender, firm , not hard thyroid gland, -LN, normal reflexes. FNAB (reviewed with pathologist) on the L nodule- no lymphocytes suggestive of Hashimoto's; there was NO colloid; cellular smear with follicular cells with
groups showing nuclear overlapping. R thyoid gland= follicular cells, NO colloid.
1. I am at a loss what he has, his biopsy does not show a lot of inflammation suggestive of Hash, given the size and sudden growth, and no colloid , would you recommend surgery, how extensive? total or partial? or thyroid med suppression?
2. What do you think about thyroglobulin antibodies?
Thank you very much for your help and opinion.Sincerely,Cheryl Almirante, MD
RESPONSE- Given the positive antibodies and elevated TSH, one can be sure that he does have Hashimoto's and is mildly hypothyroid. In this setting often the US reveals "pseudo-nodules" that represent differences in texture in the thyroid caused by the thyroiditis. However his nodules sound like real new growths, maybe follicular adenomas and it may be that he has both Hashimoto's and a multinodular goiter. Considering the histology which is meant to imply some degree of danger, young age, male sex, 4 cm size, and growth, removal by a surgeon specializing in this field would be a good option. Leslie J De Groot,MD

THYROID HORMONE AND TSH LEVELS DURING PREGNANCY
QUESTION- I am a reproductive endocrinology and infertility specialist in Quito Ecuador. First of all congratulation for your thyroid website. It is very good and a great help. Knowing your great experience in thyroid problems I want to know if you could please be so kind to comment about the new TSH reference range. Last year the The National Academy of Clinical Biochemistry published a Laboratory Medicine Practice Guidelines LABORATORY SUPPORT FOR THE DIAGNOSIS AND MONITORING OF THYROID DISEASE where is stated that a TSH greater than 4.0 is considered abnormal. However, the American Association of Clinical Endocrinologist published some guidelines stating that treatment should be considered when the TSH level is greater than 3.0. In our infertility practice we have many patients with TSH levels between 3.0 and 5.0. We have adopted a policy of testing for anti-thyroid antibodies in these patients and recommend re-testing 6 month later if the antibodies are negative. However, if the patient is positive for the antibodies we are recommending treatment with low dose thyroid hormone. Almost 50% of our patients are testing positive. The problem is that there is no information in the literature to support our practice, yet, so we are feeling a little concern that maybe we are overtreating and stressing our patients.
Could you please comment a little about the TSH range. Are you recommending treatment when the TSH is greater than 3.0.? Do you think we should treat our infertile patients only if the TSH level is greater than 5.0? Do you think in recurrent miscarriage patients with a TSH level between 3 a 5 are worth to treat with levothyroxine? What do you think about our current practice?Thank you very much for your time and your comment will be greatly appreciate.
Ivan Valencia MD, Centro Medico de Fertilidad y Esterilidad CEMEFES, Quito, Ecuado, Ph 2468068
ANSWER- In the first place my sincere congratulations that you, "avant la lettre", were already aware of possible problems when the TSH value was between 3.0 and 4.0. You may have learned form the publication you refer to that many persons with a TSH level in that range have circulation thyroid auto-antibodies as well, like your patients, suggestive of developing subclinical hypothyroidism . My personal strategy with regard to the serum TSH is perhaps even more radical than yours, in that I mistrust TSH values already if they are above 2.5. I would suggest that if you find a TSH above 3.0 (and may be even above 2.5) at least twice in your special category of patients, that you treat with thyroxine even in the absence of antibodies and titrate the TSH to a level of not higher than 1.5 or maximally 2.0. The reason for this low normal range in patients substituted with T4 is that, as the T3 contribution to the plasma by the thyroid (being 20% of total plasma T3) is lacking, one need to give more T4 to reach about normal T3 plasma values. In doing so TSH decreases to a plasma level not higher than 2.0 or even 1.5.
When no antibodies are present you can discontinue the T4 substitution in your patients, after a successful pregnancy if that happens or after attempts to have fertilization are stopped and then see what happens to the TSH. My position is that in patients with TSH levels in the range that we discuss PLUS the presence of antibodies one should seriously consider permanent T4 substitution as these subjects have a risk of 70 times the normal risk to develop overt hypothyroidism in the (near) future.
I hope that this reaction is of some help and please do not hesitate to contact me if I have not been clear or for any other reason. Kind regards, Georg Hennemann

Follow-up in differentiated thyroid cancers under 1cm
QUESTION- 4/19/03 -I am very impressed by WWW.THYROIDMANAGER.ORG and wish there were more like this. I have a question about the treatment and f/u of incidental or minimal pap thyroid cancer. Do you have any literature sources you could recommend reading re: this common problem? As an example, I have a 47 yo female patient with a 3mm. pap found incidentally, who underwent a near total thryoidectomy.
My questions are:
1. Would you recommend rx with I131 remnant ablation?
2. If not, how would you follow this pt for recurrence? (Serial TG's? TG 10 during thyroid hormone tx.as indic. for further eval?)
3. In general, is lobectomy sufficient for treatment if no significant nodules in opposite lobe? If so, how do you follow these pts for recurrence?
Thank you for your advice, Best regards, Lisa Wisniewski, MD--- Lisa Wisniewski, MD----- <lwisn@earthlink.net>
RESPONSE- I believe that the general recommendation for post-op follow-up in a patient with what is effectively an incidentally discovered papillary or follicular cancer under 1 cm and under age 45, would be that no further surgery or RAI was needed, assuming that the rest of the gland was entirely normal. Further management should include T4 replacement, and serial physical exams, TGs, and ultrasounds at 1-2 year intervals. The TG response to TSH can not be fully informative if the thyroid remnant is in place.
If there are nodules elsewhere in the gland, or multicentricity, or if the patient is >45 and the lesion is follicular, or if the pathology seems more invasive, traditional 131-I ablation and follow-up would be appropriate.
I think you will find a reference or two in the section on Thyroid cancer in Thyroidmanager. Best regards, L De Groot,MD

HIVES, ANGIOEDEMA, AND HASHIMOTO'S THYROIDITIS (27 March 03)
I have a female patient 38 yo dx with hashimoto's in late adolescense. She suffered from hyperthyroidism in her early childhood and was tx with PTU until
the age of 16. She was dx with hashimoto's thyroiditis after the delivery of her first chold at 23 yrs and has been on Synthroid .125 since that time. She
presents with severe urticaria and angioedema X 5 months now and has seen 4 other physicians including allergists, intensivists, internal med and endocrinology. Non with an answer to date.
Her labs: CBC, UA, Chem Panel - wnl. Her TSH 7.3, Thyroxine 11.6, T7 3.1, and T Uptake 26.7. Her thyroglubulin AB is 47, with a thyroid peroxidase of
710. Uric Acid 2.3, ASO <100, Rheumatoid factor <20, C-Reactive Protein <.5, sed rate 21, and a positive ANA with a titer of 1:1280. The only other
positive on the panel was her thyroid microsomal AB at 367. Because they think her hives may be related to her hashimoto's, her endocrinologist has
been trying to "put her thyroid asleep" by incrementally increasing her synthroid doses in an attempt to zero out her TSH. They have been working on this
for 2months with what they hope to be the last increase started this week. She reports, however, that her symptoms have worsened since starting this
process. Whether or not that is related to the change in dose of synthroid or simply coincidental I don't know. I am very interested in your thoughts on this.
Other lab work was performed to r/o hereditary angioedema Functional C1 esterase inhibitor > 100 and total C1 esterase inhibitor of 11. C3 Complement is
156 and C4 - 13. She has had a negative response to all allergy tests. Other labs done by a variety of people include a positive Circulating immune
complex 0 25.1 and a neg IGE. Her LH, FSH and ACTH are also WNL.
She has had one of her hives Bx - pathology neg
I am trying to find current case studies on the relationship of chronic urticaria and hashimoto's thyroiditis. I have found a few showing unremarkable results
with increasing thyroxin doses, but heard of a case that a colleague in town tx by ablating a patients thyroid. Her hives were gone and she has remained
hive free for almost 2 years now. I also read a case study from 1997 in Europe where a patient had a total thyroidectomy for the same reasons with
immediate relief of urticaria and angioedema. I'm of course, very hesitent to recommend this drastic tx without more information. This patient is desparate,
unable to work bcause of the debilitatin condition sheis in. Her current meds are synthroid .175, BCP's, Allegra 180mg tid, Tagamet 400mg tid, Zyrtec 10
mg bid, Atarax 50mg q4h prn. She has been on prednisone 60 mg for several weeks now with moderate relief, but can not wean off,due to the immediate
return and the serious nature of these hives, covering 70 % of her body, angioedema affecting her eyes, lips, ears, larynx, throat and respiratory tract. She
presents to the ER for respiratory Tx's and IV Solumedrol and/or epinephrine when things are escalating. Even on 60 mg of prednisone she is not hive free.
Any input you have would be greatly appreciated by all of us involved. Thank you very much. Please respond to my assistant at lwenham@patientshospital.com.
James Tate MD
Response-Dr Anthony Weetman will provide the official answer. However in the interim I will offer some comments. Certainly there is a statistical association between these two autoimmune diseases, but the relation is quite obscure. Suppressing the thyroid with excess T4 is an interesting approach, but hyperthyroidism might well exacerbate the hives and edema. I do not think there is any basis on which one can advise for thyroidectomy as a treatment. However as a trial in a terrible problem it is reasonable, and if done, I would suggest near total thyroidectomy followed by 131-I ablation.
Leslie J De Groot,MD
RESPONSE BY DR ANTHONY WEETMAN-My understanding is that chronic urticaria has been reported to be more frequent in autoimmune thyroid disease and thyroid antibodies occur in up to 27% of patients with urticaria (J Allergy Clin Immunol 1989 84
66-71) . There is no specific feature of skin biopsy in patients with or
without thyroid disease however and the urticaria does not improve with
thyroxine (J Clin Immunol 2001 21 335-346).
I have no extensive personal experience but these findings had always
made me think the association was simply one between 2 immunologically
mediated diseases, and not a direct cause and effect as the
correspondent is proposing. If it is simply an association, then
thyroidectomy would be no more successful or logical than undertaking
the same thing for Addison's disease, say, when it is associated with
autoimmune hypothyroidism.
It certainly makes sense to get this patient's TSH normal on first
principles but I doubt that further approaches to the thyroid will help
and total thyroidectomy would be difficult in a patient with long
standing hypothyroidism (subtotal thyroidectomy would have no
theoretical benefit). Chronic urticaria is notoriously difficult to
treat and the only other clue in this patient is the positive ANF. I am
sure this must have been followed up but it would be worth repeatedly
assessing for a collagen vascular disease.

HYPERTHYROIDISM IN PREGNANCY (20 MAR 03)
I received your email address through thyroidmanager.org and have a case I would like help with from your group of thyroid experts.
A 29 yo G5P1A3( none spontaneous) referred to me 3/06/03 at 12 wks gestation for ?hyperthyroidism.
HX: Admitted for hyperemesis 2/26-3/3. Had a normal 8 wk u/s. Normal fetal heart rate. Asx except for vomiting which had improved since discharge, although still present. Also weight loss improving. Had lost 25 lbs over 8 wks before admission. At time of d/c wieght was 116(3/3). At time of visit 3/6 regained to123lbs. No tremor/palp//heat intoler
Meds: Zofran. FHX neg for thyroid dz.
PE: wt 123 94/34 P:100.No thyroid enlarg, no tremor no signs of Graves or hyperthyr.
DATA: 2/26 TSH 0.02, ft4 2(.59-1.17) T3 363(85-205) HCG: 116,9813/6/03: TSH 0.02 fT4 1.48 (.58-1.64) T4:18 T3: 404 T3RU:24(24-39)fT4 eq dial (Nichols) 2.5 (.8-2.7) BUT 1st trimester (.7-2) 2nd trimester (.5-1.6)fT3 530 (pregnancy ref: 200-380) T3:328 (Nichols) AntiTPO/TG Abs neg.
F/U 3/18/03: 14 wks gest , still vomiting but better. No other sx. Wt 120 1/2 (down 2 lbs in 2 wks). I am ordering a repeat fT3 and fT4(eq dial) , TSAb and HCG. Would you treat her with AT Drugs or beta blocker?Any further dx tests or treatment recs? Lisa Wisniewski, MD lwisn@earthlink.net
Reply=This case looks like the typical patient with "GTT" (gestational transientthyrotoxicosis), without manifestations of thyrotoxicosis, except for those associated to emesis (such as weight loss, etc) and with progressive and spopntaneous improvement. Typical is also the high hCG value, above 100,000. I would certainly not give ATD nor beta-blocking agents, in view of the spontaneous amelioration.In all the similar cases we have followed (over 50 now), symptoms disappeared before mid-gestation and the remainder of the pregnancy was uneventful, with delivery of normal babies.A last word: it may be useful to carry out a thyroid ultrasonography (nowor later) or to see the patient again once after the delivery. This is intended to diagnose those rare instances in which thyroidal overstimulation, due to the high and sustaioned hCG levels, is associated with an underlying thyroid abnormality (such as micronodular autonomous goiter, etc).Dr Daniel GLINOER
MORE on this case-Dear Dr. Glinoer, Thank you very much for your response re: my patient. I twas very helpful.The patient was seen in early April and is clinically doing fairly well. She was 16-17 wks gestation with weight stable, still vomiting though less.
But biochemically ft4 and ft3 have increased. FreeT3: 595 (200-380 pregn)
Up from 530 at 13 wks. FT4: 3.2 (.5-1.6 2nd trimester). Up from 2.5 at 13
weeks. do you still feel it is best to hold off on antithyroid drugs? I
will re-draw these as she is further in to the 2nd trimester.
Best regards, Lisa Wisniewski, MD

HYPERTHYROIDISM IN PREGNANCY--CAUSE??, AND TREATMENT??
My wife is a 37 year old female with no significant past medical history. She
is presently in the 15th week of a twin gestation which has been otherwise
uneventful.The pregnancy is a natural conception. She is gravida 3 para 2
with a 9 week miscarraige during her first pregnancy. During routine screening for hypothroidism, a TSH of 0 was detected. Further labwork perfomed at approximatley 10-11 weeks (1/7/03) disclosed TSH of 0, Free T4 - 2.5 (0.78-2.19), T3 - 656 (230-420). The labs were repeated on 1/9/03 and revevealed TSH -0, Free T3 - 568 (230-420), TPO - undetectable, TSI -WNL. She has had intermittent vomiting which would not be described as hyperemesis. Note, during her first two uneventful pregnancies no vomiting
was experienced. The patient is asymptomatic and physical examination was unremarkable except for presence of a barely palpable thyroid gland and a pulse of 105. No tremor was demonstrated. There was no exophthalmos or pretibial myxedema.
At that time she was referred to an endocrinlogist who suggested instituting PTU tx. He did not feel that this was necessarily purely Hcg mediated, and even if it was, treatment would still be appropiate to help decrease risk of miscarraige and other potential complications of hyperthyroidism. Her high risk obstetrician felt PTU should not be instituted. Give this difference of opinion a second endocrinologic opinion was sought who suggested close observation but no treatment at this time. He was, however, somewhat "on the fence." Fourteen week OB ultrasound was normal and demonstrated appropriate
growth.The most recent labwork (2/3) revealed a TSH of 0, a free t3 of 527
(230-420), t4 - 1.9 (0.8-1.8) and a total t3 EIA of 411 (60-181).
At this point there is still uncertainty as to whether treatment with PTU is
appropriate. Again, her only abnormality on physical exam is a pulse which
now occasionally will go as high as 112 but typically at rest is 94-102. My main questions are (1) to treat or not to treat with PTU? (2) Beta blocker before tx with PTU if pulse increases? (3) Is there a risk of miscarriage without tx and when does this or any other comlication associated with hyperthyroidism occur in the second or third trimester? (4) If even in Graves disease hyperthyroidism improves in the second trimester, is it worth
waiting as even patients with preexisiting hyperthyrodism may be treated to maintain
a borderline hyperthyroid state in pregnancy? (5) Is there any other advice with respect to monitoring the pregnancy? Your input would be greatly appreciated. Thank you,
Philip Lakritz, MD, University Radiology Group, East Brunswick, NJ 08816
RESPONSE-The patient is a 37-yr old woman presently pregnant with a twin pregnancy.
She has no personal nor familial history of Graves' disease nor apparently
any related autoimmune thyroid disorder. Her lab tests clearly demonstrate
thyrotoxicosis, albeit with mild symptoms & signs (increased vomiting;
tachycardia; barely palpable thyroid gland). It would have been useful to
learn more about her weight changes since conception, because it is our
experience that the major symptom in pregnant mildly hyperthyroid women
(due to hCG, which this case almost certainly is) is the absence of weight
gain (or weight loss) in the first 10 weeks of gestation. No information
was provided concerning her hCG levels.
RESPONSE-This woman presents almost typically the pattern of GTT (gestational
transient thyrotoxicosis) due to hCG. As originally reported in the Journal of Clinical Endocrinology andMetabolism in 1990 (vol: 71; pp 276-287) and the Journal of
Endocrinological Investigation in 1993 (vol:16; pp 881-888) by Glinoer et
al., approximately 1/5 of normal pregnant women have a transient blunting
of serum TSH around the time of peak hCG values, associated with higher
peak hCG values (compared with those women without a TSH blunting). In
1/10 of the latter cases (thus, in 2 % of unselected pregnancies), thyroidal
stimulation due to high hCG lasts more than the "classical short time
pattern" of about one week, and hence leads to supranormal free T4 (and
often free T3), thereby fulfilling the definition of GTT (non autoimmune
gestational transient thyrotoxicosis). The syndrome starts around 10 weeks
of gestation, is transient, and may last for up to 2 months. Thyrotoxic
symptoms usually remain mild; excess vomiting is frequently associated and
may become the main clinical concern (with hyperemesis gravidarum). In our
experience, the administration of PTU was only required in 5-10 % of these
cases, mainly when hyperemesis was severe and/or weight loss important. In
the other cases, we either did nothing (except to reassure the patient and
the family about the transient nature of the disorder) or we administered
inderal for 1-2 months. For reasons that remain somewhat unclear, but are
presumably related to the etiology of hyperemesis in this setting,
beta-blocking agents rapidly improve the symptoms and signs. When PTU must
be given, thyroid function should be checked quite often (every two
weeks), in order to avoid hypothyroxinemia. If hCG measurements can be obtained
(either total hCG or the free beta subunit), this can help predict the
outcome since serum free T4 decreases in parallel with hCG (see Figure 6
in Thyroid Today; vol: 18; N° 2; page 7; 1995; by Glinoer).
As reported by us in Clinical Endocrinology in 1997 (vol: 46; pp 719-725),
the occurrence of GTT is significantly enhanced in twin pregnancy, because
of the higher hCG levels. It is therefore both the amplitude and the
duration of peak hCG values that drive the prevalence and clinical
severity of GTT.
Also, it should be remembered that abnormal variants of hCG, with a higher
thyrotropic activity, have been reported and, in one family with two cases
(mother and daughter), GTT without hCG elevation that was related to a
TSH-receptor mutation yielding a gain of function to the TSH receptor for
the stimulatory effect of normal circulating levels of hCG.
Finally, we believe that TSH receptor antibodies should always be measured
in such cases because of the possible (although exceedingly rare) double
occurrence of Graves' disease and GTT. Similarly, the fortuitous double
occurrence of a solitary hot ("pretoxic") thyroid nodule and GTT does
exist but is extremely rare in our experience, and has been seen only once in
all the cases with GTT that we have witnessed over the last 15 years.
In summary, and to answer the practical questions asked :
1) this woman most probably has thyrotoxicosis due to hCG and directly
related to her twin pregnancy.
2) I would not have given PTU (unless clinically necessary, which does not
seem to be the case from the description given).
3) I would have given inderal 40-60 mg/day (if no contra-indication) for a
few weeks (until free T4 reverts to the normal range).
4) There is, to my knowledge, no increased risk of a miscarriage.
5) TSH-receptor antibodies should perhaps be checked again near the end of
the second trimester, if one wants to be absolutely certain that one is not
dealing with an atypical form of Graves' disease (which I do not believe,
but one can never be totally sure).
Prof Daniel Glinoer

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