Hives, Angioedema, and Hashimoto’s Thyroiditis


Question

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

First 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

Second 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


Question

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

Response

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

First 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.

Second 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

Primary vs Secondary Hypothyroidism?–And Financial Problems


Question

One of my patient is a 54 y.o., poor, medically uninsured female suffering evidently from hypothyroidism: since 2 years, she has become progressively fatter, weaker, has menorrhagia, hoarseness of her voice, decrease hearing, and feels depressed. She also complains of dry skin and water retention. Her condition has been attributed to premenopause and depression which are under no treatment because she does not tolerate HRT or antidepressants.On examination, I noticed edema of the face and extremities, bradycardia at 50-60 bpm, and a lag in relaxation of knee jerks. The cranial nerves were intact, the blood pressure was 120/80, the visual fields normal by confrontation, the fundi normal, and the untanned areas of her skin had no discoloration.To minimize her lab cost, I first ordered a TSH($28) only: it came back normal at 1.2 !Subsequent FT4 came low at 7.

Since there is no evidence of adrenal hypofunction on physical examination, can I start Levothyroxine now, and save the patient a costly serum ACTH determination ?

What can I do about the possibility of a pituitary tumor in this patient who cannot afford a $2500 MRI or CT scan ? Would a simple skull x-ray or tomogram of the sella turcica sufficient ? Should I wait for the possible adenoma to shrink under T4 replacement before imaging studies ?

I would appreciate your "off the book" opinion and recommendations based on your experience with central hypothyroidism taking into consideration the limited paying capacity of this patient.

Thank you very much for your work on this website.

Aloha and Mahalo !

Dr. Michel Soucy, P.O.Box 63,Hawi, Hawaii 96755; 808-889-6223 jrlmsoucy@yahoo.com

Response

This is an interesting case because the clinical examination clearly demonstrates hypothyroid signs and symptoms, but the serum TSH comes back normal! Still, serum FT4 is decreased, and the straightforward diagnosis is then central hypothyroidism. The question is if this patient can safely be started on thyroxine without knowing if central hypothyroidism is absent. For, starting thyroxine in a patient with hypocortisolism may provoke an Addison's crisis. Although physical examination didn't give a clue on the existence of cortisol deficiency, this by no means rules out hypoadrenalism. Dr. Soucy is reluctant to order more tests because the finances of the patient do not allow this. Certainly the ACTH assay would be a bad idea, because ACTH in central hypoadrenalism is not elevated and the ACTH assay cannot reliably discriminate between normal and subnormal values. Also a single plasma

cortisol test will not answer the question because a random cortisol may be normal despite the presence of hypoadrenalism. A dynamic test (ACTH stim test, insulin tolerance test, or metyrapone test) would be indicated to diagnose central hypoadrenalism, but this might be too expensive for the patient as well, and can be dangerous if not carefully supervised.

But is it really central hypothyroidism? This entity is not very prevalent. In this age group (54 years) the most likely cause is a pituitary adenoma - the mass effect reduces pituitary hormone secretion. However, in most cases of pituitary adenomas the first hormones which fail are GH and the gonadotropins; TSH and ACTH follow much later. Consequently, isolated TSH deficiency is rare, and in this particular patient should be associated with loss of gonadotropin secretion as well. But, we are informed that the patient is not amenorrheic but has menorrhagia which speaks against central hypogonadism.

So, is the TSH value of 1.2 mU/l a valid one? Is the assumption that there is no interference in the TSH assay by heterophilic antobodies? Could there have been an error in the lab, or switch of samples? After all, the pre-test likelihood of primary hypothyroidism in this lady is pretty high, much higher than that of central hypothyroidism. I would therefore put my money on a repeat TSH-test, or on a TPO-antibody test. If one of these tests results in an elevated value that is clear evidence of primary thyroid failure. Of

course, primary autoimmune hypothyroidism is associated with primary autoimmune adrenal failure, which if unrecognized puts the patient again at risk for developing Addison's crisis if only treated with thyroxine. But the co-existence of these two disorders is less frequent than that of TSH- and

ACTH-deficiency in adults. I think the patient needs thyroxine treatment. If money is lacking to do some

supplementary tests, I would start her on thyroxine alone, under the specific instruction to call or see me directly when in the coming weeks she feels not better but worse, becomes nauseated or dizzy etc. This must be a feasible management plan: after all, Hawaii is not that big an island! ( ED-At least an 8 AM cortisol, FSH, and lateral skull x-ray could be checked despite the financial constraints, and further evaluation done depending on these results. Correct diagnosis is very important here before treatment.)

Sincerely, DR. Wilmar Wiersinga

Add Recombinant TSH to Endogenous TSH for Ablation?


Question

I am a family physician in Toronto, Ontario. I am also unfortunately the patient. I will be undergoing I131 treatment following my near total thyroidectomy last month for a mulitcentric follicular variant papillary thyroid carcinoma. It was completely resected. The primary nodule was 2.4 cm with capsular invasion nut no extrathyroidal spread and no blood or lymphatic spread noted. In the contralateral lobe there were two microfoci noted. My stsh currently is around 80 and rising. My endocrinologist has suggested that using rtsh prior to I131 will give a better result. What stsh level is usually aimed for, and what dose of I131 would you use. Given my age (37), the size of the tumour, and its multicentricity, it has been suggested that 150 mCu of I131 was appropriate, but from what I have read, it would seem that most people are using lower doses.Thanks. (Name lost in Webspace!)

Response

I feel that your TSH is high enough for a successful ablation of any thyroid remnant. I don't see the need for adding recombinant human TSH. In our experience the addition of endogenous and exogenous TSH does not result in additional advantages over endogenous TSH alone. Regarding the dose, 100 mCi is usually effective (nearly 90% of the cases) and even lower doses such as 30 mCi have been associated with successful ablation in 80% of the cases.Sincerely, F. Pacini MD