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.

#3.--I wouldn't worry about DD unless he remains hypogonadotropic, which I presume he is (although polyclonal RIA's for LH and FSH may give inaccurate results in hypothyroidism) after thyroid replacement.

Robert Rosenfield,MFD, Pediatrics, Univ of Chicago 10 Nov 2004

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

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

First 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

Second Response

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

Hashimoto’s , Urticaria, and Stomach Pains


Question

38 YOWF with Hashimoto's - she has subtotal thyroidectomy (elective) about 4 years ago and takes unithroid daily (85mcg).She has had bouts of Uticaria and Angioedema and I am relating this to the Hashimoto's.In addition she gets episodes of sever stomach pains with vomiting. I am suspicious that this too is related to the Hashimoto's but I do not see much discussion of the stomach complaints in the places I have been looking on line etc.Her GI workup is unremarkable.My thought is that the stomach pain is caused by an acute autoimune inflamation of the GI tract.With any of this she generally snapps out of this with Benedryl and or Prednesone (if she gets the later is it usually IV in the ER and followed by a Medrole Dosepack).In consultation with her allergist she is taking Claratin and Zantac prophyllactically in an attempt to kep these episodes to a minimum and for the most part this has worked fairly well in that she has not had any major episodes of Hives or Angioedema.Regardless, I have the following questions if you are inclined.

1. Is there a known connection between the stomach episodes as described and Hashimotos. If so can you point me to some literature on this.

2. Is the presence of these episodes suggestive of deficiency of thyroid and should we consider that she might need greater supplimentation.

3. Are there tests that I can suggest while in the throws of one of these episodes that might support my contention (thyroid antibody perhaps).

4. Do you feel that thyroid antibody is something that should be considered routinely on a patient of this type.

Dr. Steven Rosenzweig, Middle Village, NY

First 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

Levy Y, Segal N, Weintrob N et al. Chronic urticaria: association with thyroid autoimmunity. Archives of Disease in Childhood 88: 517-519,2003

Verneuil L, Leconte C, Ballet JJ, et al. Association between chronic urticaria and thyroid autoimmunity: a prospective study involving 99 patients. Dermatology 208: 98-103,2004

Second 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

Hurthle Cell Carcinoma, Residual Disease Post-Op


Question

54 year old found to have a right sided nodule which, on biopsy, was felt to be Hurthle cell. Total thyroidectomy performed 4/04. Tumor was 7 x 3 x 2.5 cm with invasion of tumor through capsule. Although margins of excision were free of tumor. lymphatic invasion was present. An additional microscopic focus of papillary was present on the left.

Patient had 150 mCi I-131 in late May. Post treatment scan documented uptake in the right superior mediastinum as well as neck. Thyroglobulin at time of RAI tx was > 4,000. Ultrasound in July noted a single node in right mid lateral neck measuring 2.8 cm. Repeat ultrasound (10/04) now shows 3 enlarged lymph nodes although none are as big as the 2.8 cm previously measured in July.

T4 dose has been increased and he is currently taking 175 mcg. However, his most recent TSH is still elevated (18.9 U/ml). His thyroglobulin level is down from 4921 to 1065 ng/ml.

Would you recommend a modified neck dissection to try and remove the adenopathy?

Will removing the nodes increase the potential for additional RAI uptake (I plan to check him next in 7/05)?

Is there any value in waiting to see how low the TG levels go down to when the TSH is more fully suppressed or seeing whether the nodes decrease in size further? > Thanks very much for the input.

Response

This patient seems to have Hurthle cell carcinoma with node metastases, probably able to take up radioiodine. From your description It is not clear whether initial surgery included lymph node dissection (probably not). In this case, I would suggest to performed a modified radical neck dissection on the right side of the neck and immediately after I would go on with a second dose of radioiodine. Looking at the levels of serum Tg, I would also check for the presence of distant metastases in the lungs or bones by CT and/or FDG-PET. Furio Pacini, MD

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

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