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Any physician may submit a question regarding a thyroid patient to <ljdegroot@comcast.net> or g@hen.demon.nl and one of our panel of expert thyroidologists will attempt to provide an answer as soon as possible by return Email. Physicians should provide adequate clinical information about the problem, and provide their name, office address, and telephone number. We will send an answer by Email to the address provided, and will publish the question and the response on this page. The name of the questioning physician WILL be published unless specific instruction not to do so is provided in the original Email. This service is available only to physicians.
Please note that Thyroidologists who hold opinions that differ from the advice we have offered are welcome to send in responses, and we will publish these comments. Commentators should kindly include name, office address, and Email address.

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

ADD RECOMBINANT TSH TO ENDOGENOUS TSH FOR ABLATION?

AMIODARONE INDUCED THYROTOXICOSIS

What condition does this person suffer from?

T4 Suppression Therapy Post Radiation Exposure

MANAGING HASHIMOTO,S IN PREGNANCY

INFANT WITH CHYLOTHORAX AND APPARENT HYPOTHYROIDISM

WHAT TO DO WITH AN INCIDENTAL 1MM PAPILLARY CANCER?

INFANT WITH CHYLOTHORAX AND APPARENT HYPOTHYROIDISM

THERAPY OF THYROID CANCER WITH KNOW POSITIVE NECK NODES, ELEVATED TG, AND NEGATIVE SCAN? 1 Nov 02

HASHIMOTO’S, TRANSIENT HYPOTHYROIDISM, AND AN ELEVATED RAIU

IS THIS GRAVES’ DISEASE? 1 Oct 02

QUESTION- WHEN IS A PENTAGASTRIN TEST ADVISED IN FOLLOWING MTC/

How to manage existing hypothyroidism perioperatively in a patient NPO ?

QUESTION- HOW LONG TO WAIT AFTER OPERATION BEFORE RAI ABLATION?

DO WE REALLY NEED TO DO BOTH fT4 AND TSH IN EVALUATING PATIENTS?

HOW TO TREAT SUB-CLINICAL HYPOTHYROIDISM?

HOW TO MANAGE FETAL HYPOTHYROIDISM AND GOITER

ADD RECOMBINANT TSH TO ENDOGENOUS TSH FOR ABLATION?
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

AMIODARONE INDUCED THYROTOXICOSIS (10 Feb 203)
I am a 67year old cardiologist. I recently had a succesful pulmonary vein ablation for paroxysmal AF. Prior to the ablation I ceased taking Amiodarone which had been administered for two years. Approximately 6 weeks after stopping Amiodarone I had lost 14kg in weight and had a tremor and heat intolerance and other symptoms. TFTs were TSH <0.02, T4 46 and T3 20. These are now (7weeks later) almost normal.
Is the thyrotoxicosis related to the Amiodarone?
Other findings:Increased mucus in the throat plus cough.,Minor dysphagia, Decreased libido, These have receded with the normalisation of the TFTs. Could they be related to thyrotoxicosis?
Initially it was noted that I had a mild normochromic anemia(118) and a neutropenia which was thought to be due to the Carbimazole I was taking. However on checking all the blood results it was found that both these values had been recorded on two occasions before the Carbimazole was commenced. Are anemia and neutropenia associated with thyrotoxicosis? I look forward to your comments. Ian E Langbein, MD. langbein@bigpond.net.au
RESPONSE-Amiodarone may indeed cause thyrotoxicosis. Amiodarone induced thyrotoxicosis (AIT), may occur early after taking the drug, during usage for several years and even (long time) after with-drawl of the drug because it is stored in tissues and slowly released from them.There are 2 ways of induction of thyrotoxicosis:

AIT type I: this type is caused by the load of iodine load released from Amiodarone leading to increased thyroid hormone synthesis. The exact mechanism is obscure in that it is not known why contra regulatory mechanisms such as inhibition of uptake and/or organification do not operate sufficiently. Type I may occur in thyroids with pre-existing thyroid disorder like thyroid autoimmunity or nodularity but not necessarily so. The drug contains about 37% iodine by weight. A daily Amiodarone dosage between 200 and 600 mg releases a 50 to 100 fold iodine excess compared to the optimal iodine intake between 150 to 200 µg per day. In patients living in areas of iodine deficiency, RAI uptake of the thyroid gland is often inappropriately elevated despite the iodine load, but always low when iodine intake is normal. In AIT type I, serum interleukine 6 (IL-6), is normal or only slightly elevated indicating that thyroid destruction is not prominent in this sub type of AIT (see below). Color flow Doppler sonography shows hypervascularity as is seen in Graves ’’ disease. Treatment starts with administration of methimazole 40 to 60 mg daily, or propylthiouracil 600 to 800 mg daily to inhibit thyroid hormone synthesis, and perchlorate 1 gram daily, to inhibit iodine entry in thyroid cells. Both the serum IL-6 levels and sonographic findings are useful to distinguish AIT type I from type II, see below.
AIT type II, is caused quite differently in that Amiodarone induces destructive thyroiditis. This destruction is both caused by the drug itself and by the released iodine. Because of the damage to the thyroid cells, stored thyroid hormone is released into the circulation causing the thyrotoxicosis. Contrary to type I, IL-6 levels are elevated and color flow Doppler sonography does not show increased vascularity. Treatment consists of administration of glucocorticoids, such as prednisone. Sometimes mixed forms of type I and II are encountered and both treatment modalities should be applied together.

Further answers to your questions: Amiodarone really has very many different side effects and I would not be surprised as the ones you mention are also due to the drug and/or the thyrotoxicosis itself. Throtoxicosis may indeed cause normochromic anemia and neutropenia.Further reading: Bogazzi et al. Thyroid 11, 511-519, 2001 .
Georg Hennemann, MD, PhD

At 07:46 AM 2/3/03 -0600, you wrote:
What condition does this person suffer from?>
HISTORY: Mrs. M is an 87-year-old woman who is referred for treatment of
hyperthyroidism. The patient was recently admitted to our institution for
chest pain and shortness of breath resulting from CHF. During evaluation
of this illness, the patient had thyroid function studies drawn (see
laboratory section below). The patient gives a history of fluctuating weight
associated with a decreased appetite, intermittent cold intolerance,
intermittent constipation, decreased energy level, and a mild tremor. She does not
complain of perspiration, hair loss, eye problems, goiter, or anterior neck
pain. She states that she has not had previous irradiation to the neck or
face or I-131 therapy. She gives no family history of thyroid disorders.
Her current medications are metoprolol, Prevacid, subcutaneous heparin,
enalaprilat, aspirin, and a sliding scale regular Insulin. She denies any
recent oral or intravenous radiocontrast or other exogenous sources of iodine
such as health food supplements or medications.
PHYSICAL FINDINGS: The patient's blood pressure is 102/58 mm Hg. Heart
rate is 102/minute. Examination of the head reveals no proptosis or lid lag.
The thyroid is approximately 40 grams; there is
no dominant nodularity, no bruit, or thrill overlying the thyroid. It is
non-tender, and there is no associated lymphadenopathy. The heart is
regular, but tachycardic; she has a 3/6 systolic ejection murmur. The lungs
reveal minimal basilar crackles bilaterally. There is 2+ lower extremity
edema. Neurologically, there is a mild distal tremor; the deep tendon reflexes
are 2/4 without delay.
LABORATORY FINDINGS: On the day she was admitted for CHF her TSH was 0.04
uIU/ml (reference
range 0.4-6.2). Two days later the free T4 was 1.5 ng/dl (0.7-1.8), and
the total T3 was 46.6 ng/dl (45-132). Thyroid uptake of I-131 completed
three days after admission was 38% (normal range 10-30%). Her Blood Urea
Nitrogen was 48 mg/dl (8-25) and Creatinine 3.0 mg/dl (0.6-1.5).
Is she hyperthyroid?
Is she sick euthyroid?
Does she have central hypothyroidism?
Confounding factors: ? subcutaneous heparin falsely elevating FT4; ? renal
insufficiency falsely elevating I-131 uptake.
Thanks for your help in advance, Mike DeRosa, Endocrine Fellow, Washington University School of Medicine,
RESPONSE-Obviously the diagnosis is uncertain, or you would not be writing! However, she probably has an element of "Non-thyroidal illness syndrome", plus effects of renal failure, ASA, and maybe background thyrotoxicosis. Heparin can raise the free T4 by dialysis, but I do not think it would effect the test you do, which is probably a one-tube lab assay, not dialysis. ASA will lower her T4 and FT4 especially if the dose is .6gm/day or up. Renal failure usually causes a lower RAIU since there is retention of iodine, but if the changes are acute, it might produce a different effect. NTIS, which is probably central hypothyroidism, could explain her TSH, and blood tests, but not the RAIU. Also the TSH is lower than usually seen in NTIS. It would be of interest to add anti-thyroid antibodies, and to do a thyroid US, thinking of the Graves/Toxic MNG differential diagnosis.
I believe that currently she is not toxic, because it is hard to conceive that someone with a T3 of 46 can be toxic. However I also suspect that she may have hyperthyroidism which will emerge if and when she recovers from her acute illness. I will ask other members of our editorial group to comment on your case and add their remarks if substantially different. L De Groot, MD
PS- A poll of THYROIDMANAGER editors found most supported the diagnosis of NTIS as the main problem, with agreement that thyrotoxicosis could be present but masked. LD

T4 Suppression Therapy Post Radiation Exposure
A 65 year old white female with history of irradiation as an infant, apparently as a treatment for an enlarged thymus. The patient has been on T4 suppression therapy since age 20. Thyroid function tests show normal T4 and suppressed TSH, compatible with her treatment goals. Thyroid gland is non-palpable and the latest thyroid ultrasound done three months ago showed no evidence of thyroid nodules. The patient otherwise is asymptomatic, with no history of documented osteoporosis and no history of atrial fibrillation. Should this patient continue to be on T4 suppression therapy?
Thank you, and best regards. Ahmad A. Tarhini, MD,Internal Medicine Resident
University of Pittspurgh Medical Center,Mckeesport Hospital
RESPONSE-Your question is an excellent one, but there is no answer that is proven
to be correct. It is hard to believe that after nearly 60 years that a neoplasm could suddenly begin. One thinks more likely such mutational events happen near the time of the radiation, and slowly grow over the years. The fact that her exam and US are normal is also supportive of stopping treatment. Thus the risk of stopping medication must be very low, especially if you do a follow exam and US annually. On the other hand, if her heart and bones are perfect, and her TSH is at the bottom end of normal ( not truly suppressed) below normal, it would also seem that the risk of continuing treatment in this patient is negligible.I think I would finally end on the side of cautiously continuing
treatment, so long as there are no contraindications.
Leslie J De Groot,MD

MANAGING HASHIMOTO,S IN PREGNANCY
What are the current recommendations regarding > treating Hashimoto's during pregnancy? How frequently should the woman be monitored with thyroid tests? Should she be followed a high risk OBGYN? Thank you. Dr. Amy Handler, Katonah, NY
RESPONSE- This question demands an answer subdivided in several parts. Concerning thyroid function, most patients (but not all) with Hashimoto's disease already take l-T4 before pregnancy (this was not specified in the question asked). - If it is the case, thyroid function tests should be carried out rapidly after conception (say, within 8-10 weeks and no later than 12 wks) and the l-T4 dosage adapted. Depending on the functional capabilities of the thyroid gland to adapt to the increased hormonal demands during gestation (see article by Mike Kaplan in Thyroid), the daily dosage should be increased (usually by 30-60 % eventually, above preconception dosage), but it is important to note that the l-T4 increment may vary widely individually. The main objective in these early stages is to avoid a raise in serum TSH and obviously a fall in free T4 (risk for the fetal development, etc). After this early adaptation, we check thyroid function in such patients every 2 months until 5-6 months gestation. Thereafter the dosage usually remains unchanged until parturition. - If this Hashimoto patient does not yet require l-T4 before pregnancy because she is euthyroid, I suggest to follow the algorithm that I have proposed in 1998 (see Trends in Endocrinology & Metabolism, vol. 9; N° 10; December 1998). In this scheme, we base our attitude on the titers of thyroid antibodies and serum TSH levels (when these are still within normal range) to decide whether to treat or monitor. If l-T4 treatment is given, the buckle rejoins the first option discussed above. If l-T4 treatment is not warranted (TSH below 2.5 mU/L; low Ab titers; normal free T4 around mid-gestation), we later monitor thyroid function tests (TSH and free T4) around 27-28 and 34-35 weeks gestation. - An additional difficulty could be those (extremely rare) patients who would only have a low-normal free T4 without serum TSH elevation during early gestation. We don't encounter such patients (but others do ??) and it has been proposed by some authors to give the mother (and perhaps the fetus ?) the potential benefit of l-T4 treatment in such instances. - In all cases patients with Hashimoto's disease should see an endocrinologist during and after the pregnancy (because of the risk of postpartum thyroiditis). During pregnancy, we follow these patients in close collaboration with the ObGyn, but high risk ObGyn is not mandatory (in my opinion). - It should also be remembered that Hahimoto's patients have an increased risk of early miscarriage (see article by Poppe et al. in Thyroid, November 2002 and a review in press by Glinoer in Human Reproduction Update). This risk could justify the opinion of a "high risk ObGyn", even though there is not much that can presently be done to reduce the miscarriage risk (except to have a normal thyroid function, probably ?); in rare cases trials have been initiated using steroids or iv IG (in women with recurrent abortions).
Prof Daniel Glinoer

INFANT WITH CHYLOTHORAX AND APPARENT HYPOTHYROIDISM (11 Jan 02)
I would be greatful for advice over management of this case. A one month old girl with Down Syndrome was admitted in the PICU due to respiratory distress 20 days ago and bilateral chylothorax was diagnosed. Bilateral drainages tubes were placed and fluid analysis confirmed chylothorax. Debt is more or less 500 ml/day and albumin fell to 2 g/dL. She has not any congenital cardiac defect. Now she is on mechanic respiratory assistance due to respiratory distress and she needs inotropic support with dopamine and adrenaline. She does not look like severe hypothyroidism. At neonatal screening TSH was 15, now TSH is > 45 mU/l, FT4 0.6 ng/dl , T4 4.5 mcg/dl, T3 70 ng/dl. Questions: Is she really hypothyroid? Is it only a transport problem due to TBG or albumin leak or both, due to thyroid hormone leak? We start LT4 replacement by nasogastric tube (25 mcg/day), but how about LT4 transport to systemic circulation. Is it by portal system or lymphatic route ? Thanks in advance.
Guillermo Alonso, MD Pediatric Endocrinology, Hospital Italiano de Buenos Aires, Argentina
Response-Dr Alonso- The tests described to not clearly identify a lack of TBG, since the drop in freeT4 and T4 are more or less equal. However in this situation TBG is probably reduced along with other proteins. It would be of interest to have the old-fashioned T3 Resin uptake / T4 combination which would clarify that issue, or a direct measure of TBG by RIA. I believe she is hypothyroid based on TSH and low freeT4, but not terribly so because T3 is near bottom normal. The cause of the hypothyroidism is not yet clear, but it is either primary thyroid disease or loss of T4. Presumably she would need a TBG leak out of the body to cause low TBG/T4, as in the nephrotic syndrome. I believe leak into a chylothorax would initially be recirculated. However since this is being drained each day, it may constitute a serious loss of thyroid hormone. If your therapy is satisfactory her T4 should respond promptly to the administered hormone, but if she is loosing much into the chylothorax the dosage will need to be increased. Possibly the chylothorax is telling you that something is aberrant in her gut, in which case absorption might be a problem. So far as I know the absorption of T4 and T3 from the gut is via the mesenteric vessels and portal vein. The dopamine may also be worsening thyroid function by lowering TSH from an even higher level. Best regards, Leslie J De Groot, MD

WHAT TO DO WITH AN INCIDENTAL 1MM PAPILLARY CANCER?16 Dec 2002
What is the appropriate workup and treatment plan for a 41 yo female who underwent right total thyroidectomy for what was initially felt to be a single hot nodule with symptoms of hoarseness, localized pain and enlargement? Path report revealed 1 large encapsulated adenoma as well as several smaller nodules. An incidental finding unrelated to any nodule and without vascular involvement was a 1 mm papillary carcinoma, follicular variant. Should this patient be evaluated and treated as stage 1 papillary cancer with total thyroidectomy plus minus RAI, with hormone suppression or should the finding be considered incidental and followed annually?
Thank you. Mark J. Krzyston, MD, 1175 Cook Rd. Ste 225, Orangeburg, SC 29118

RESPONSE-If the contralateral side was normal at operation and normal by US, and careful review of pathology reveals no evidence of malignancy in any of the nodules, I believe following the patient on T4 replacement with periodic US exams is sufficient. If the contralateral side was abnormal at op or on US, the abnormality would have to be evaluated independently "de novo" by appropriate studies such as US and FNA. Tiny (1-4mm) papillary cancer foci are found in 6% or more of autopsy series, and clearly in most cases carry a benign prognosis. But there are occasional reports of metastases from tiny primary foci, and obviously larger tumors must have grown from such small foci originally. Leslie J De Groot,MD

THERAPY OF THYROID CANCER WITH KNOW POSITIVE NECK NODES, ELEVATED TG, AND NEGATIVE SCAN? 1 Nov 02
I am writing to seek your opinion on a patient who has been treated and followed up by one of my colleagues and recently I was involved in his management. A detailed medical report is attached but briefly he is a 33-year-old man who had papillary thyroid cancer of 4.5 cm size with lymph node mets. He underwent total thyroidectomy and bilateral modified neck dissection in May 1999. He was subsequently treated with 136 mci iodine-131 for local neck uptake and unsuppressed Tg of 0.7 mcg/l. His follow up was marked by slightly elevated unsuppressed Tg levels ( 2.7 and 3.5 mcg/l) but negative diagnostic WBS and essentially negative US examinations. In June 2002, his Tg rose to 1.4 mcg/l while he was on 0.2 mg L-thyroxine. In October 2002, Tg was 29 mcg/l off treatment. Radioiodine Whole body scan is negative but US showed 5 and 8 mm right cervical lymph nodes and FNA from one of them was positive. PET scan showed uptake in the lower neck but no other uptake. CT chest showed no lung mets. The question basically is what would you recommend at this stage? Thank you in advance for your help.
Ali Alzahrani, M.D.,King Faisal Specialist Hospital & Research Center,MBC-46, P.O. BOX 3354, Riyadh 11211, Saudi Arabia.

RESPONSE-Your patient has residual tumor at least in neck node(?s). Possibly the nodes would take up RAI and be treated to some extent by a large RAI dose at this point. This approach is followed by some physicians when the source of the TG is unknown. However I would favor first removal of the known positive node (or more likely nodes) by surgery. The stimulated TG of 29 indicates a significant amount of functioning tumor, so the neck nodes may be only part of the problem. If the TG remains signficantly elevated after node resection, and no other source can be identified by neck MRI and US, and his chest CAT is negative, RAI therapy may then be appropriate. You may also want to do abdominal CAT and bone scan in your survey for mets. Of course the value of treating such TG levels "blindly" with large doses of RAI is still debated, but your patient is young and thus aggressive therapy is reasonable.
Leslie J De Groot,MD

HASHIMOTOSTRANSIENTHYPOTHYROIDISMELEVATEDRAIUHASHIMOTO’S, TRANSIENT HYPOTHYROIDISM, AND AN ELEVATED RAIU
Sent: Monday, September 16, 2002 8:54 PM
May I get your opinion on the following case:
22 year old woman with presents to her primary provider with complaints of amenorrhea times 6 months. Additional concerns include cold intolerance, dry skin, hair loss and an 18lb weight gain over the past year. In March of this year TSH 2.54.. On 8/14/02 TSH 52.43, Free T4 0.62 (nl .68-1.76).
On 9/9/02 TSH 30.61, free T4 0.69, T3 118, TPO ab 972.
Primary provider orders thyroid uptake and scan which are completed on 9/12/02, prior to her evaluation in the endocrine clinic 9/16/02. The scan shows a diffuse goiter. The 6 hour uptake is 32%. In endocrine clinic the above history is obtained.

Physical examination is notable only for a diffuse goiter about 2 times normal size, which is non-tender.
Can we explain this mixture of findings based on an acquired defect > of iodide organification secondary to TPO ab inhibition of thyroid peroxidase? If not, what might be the cause of the high uptake at the same time as the high TSH and low free T4 levels. Would you not just go ahead and put her on L-T4 replacement therapy?
Thank-you so much for your assistance,
Karen Kartun, M.D., Kaiser Permanente
Division of Endocrinology, 9985 Sierra Avenue’> Fontana, CA 92335
email: kkartun@pol.net

ANSWER BY DR ANTHONY WEETMAN
This patient clearly has autoimmune thyroid disease as shown by the
positive TPO antibodies. There has been a very rapid change in thyroid
function, from a normal TSH to a value of 50 in 6 months and then a
rapid fall, with only barely reduced T4 levels at the peak of TSH and a
normal T4 on the last value we are given.

Although TPO antibodies may inhibit TPO enzyme activity in vitro, these
data are controversial and there is no in vivo evidence to support this
type of action. For instance TPO antibodies are transferred across the
placenta yet the babies of such mothers with high TPO antibodies have
normal thyroid function.

Goitrous autoimmune hypothyroidism with an elevated TSH is a known cause
of increased radioiodine uptake (1). I suspect that this is the
diagnosis here and the pattern of thyroid function fits with a
recovering phase of silent thyoiditis in such a gland. Whether the
increased uptake is solely mediated by the elevated TSH or is due to
coincidental thyroid stimulating antibodies, which occur in some
patients, could only be assessed by measuring these antibodies but I do
not think this test is strictly necessary. I would simply ensure that
the patient is not taking iodine supplements intermittently, and monitor
thyroid function regularly, say every 3- 4 weeks; the latest T4 level is
normal and therefore there is no need to start thyroxine until the
pattern of illness shows this is needed. If normal thyroid function
resumes, regular followup will be required.
1. McDougall IR, Cavalieri RR. In vivo radionuclide tests and imaging.
In Werner and Ingbar's The Thyroid. 8th edition Eds Braverman LE,
Utiger RD, Lippincott, Philadelphia pp355-375

P.S.-May another contributor note that the last values fit with subclinical hypothyroidism, and some practitioners - (including this one) would feel safer starting replacement T4 at this time. L De Groot,MD

IS THIS GRAVES’ DISEASE? 1 Oct 02
I recently saw a 25 year old male law student with hyperthyroidism. He came with a diagnosis of Graves disease made about 3 years previously (solely on clinical grounds as far as I can tell). He was treated with PTU with control of symptoms for about 1 and 1/2 year after which he stopped the drug. His hyperthyroidism returned over the course of several weeks to a few months. When he presented 2 months ago, he had been of the PTU about a year and was symptomatically hyperthyroid. The hyperthyroidism was interfering with his law studies. He was tachycardic, diaphoretic and tremulous on exam. His thyroid was twice enlarged and diffusely so. No nodules were appreciated, although on serial exams there does appear to be some inhomogeneity in the texture of the gland. His thyroid function tests showed and undetectable TSH <0.01 and and elevated FT4 of 3.2 and a elevated Total T3 of 250. I discussed options with him regarding treatment and he decided to consider I131 but wanted to restart PTU for now. I convinced him to obtain a I123 study to calculate a dose for I131 and confirm the Graves diagnosis. He delayed and only did the I123 after 2 to 3 weeks of PTU therapy and improvement in his symptoms. I took him off the PTU for 2 weeks (after the 3 week therapy) and obtained the I123 scan. His 6 and 24 hour uptakes were at the upper limits of normal. 33% or so at 24 hours. The scan showed heterogeneous uptake. Antimicrosomal (antiTPO) antibodies were strongly positive but a TSI assay was negative.
I thus have two questions-
1. Diagnoisis - is this patient's diagnosis atypical Graves, a variant of toxic multinodular goiter, Graves with in a multinodular goiter, transition from Hashimoto's to Graves?
2. What would be the best course of therapy? Would I-131 be beneficial?
Thanks very much for any insight.
Coleman Gross, MD
Specialty Clinics, University Health Service,Tang Center,2222 Bancroft Way, Berkeley, CA 94720
ANSWER- by Leslie J De Groot,MD
The clinical picture is certainly most compatible with Graves, in view of the rapid relapse, youth, male sex, non-lumpy gland, and + TPO-Ab. I suppose a toxic multinodular goiter might present this way, but it would be unusual. A non-homogenous scan is not rare, probably because of the variable extent of coexistent thyroiditis in various parts of the gland. Obviously an US might be informative, but I do not think you really need it if you can feel the gland and do not feel lumps. Since he relapsed from one course of ATD, he probably would do so again. Thus I believe most thyroidologists would offer RAI as the next therapy, and I do not see any contraindication from what you report. If you have a capable surgeon available, surgery is also reasonable to consider, especially if he has significant ophthalmopathy.

Yours, L. David Roper: roperld@vt.edu
RESPONSE from Dr Furio Pacini-Dear Dr. Roper- I received your question about the utility of pentagastrin test in patients with C609Y ret mutation. This mutation has been reported in association with familial isolated medullary thyroid cancer (FMTC). As is the case with mutations in other codons associated with FMTC, the consensus agreement proposed in several congress of the MEN 2 study group is that pentagastrin test it is always advise in gene carriers of FMTC to ascertain whether some minimal disease is already present. If a significant response of calcitonin to pentagastrin stimulation is present (or if some other clinical features are suspicious) thyroidectomy is advise. If not, thyroidectomy may be delayed, although some authors prefer to propose surgery even if pentagastrin test is negative. I hope that this clarification may answer your question.
Sincerely F. Pacini MD

HOW TO TREAT SUB-CLINICAL HYPOTHYROIDISM?
Hello. One of my patients is a lady aged 48 years. She has most signs and symptoms that correlate with hypothyroidism. Her TSH is 9.7 mlu/L ( range 0.27-4.2), T4 is 13 pmol/L (range 12-22), T3 is 4.7 pmol/L (range 2.8-7.1) . There is no relevant history. She is having menorrhagia (severe) , shortness of breath, iron deficiency anemia, obesity, lemon yellow color, flushing of checks, BP= 170/90, diabetic since one year (type 2) , had rough skin, complain always of somnolence , general weakness and sweating. Please send for me your opinion and plan for management and should we consider it as a case of overt hypothyroidism or a subclinical one. Thanks for your cooperation. Dr.Moh'd Attallah, Mohammed_attallah@yahoo.com
RESP0NSE-Dear Dr Attallah, your patient has still a T4 and T3 within the normal range and should therefore be classified as subclinically hypothyroid. It is difficult to assess if her complaints are due to hypothyroidism and/or to her diabetes in combination with obesity. On the other hand the level of TSH and free T4 are at the border of overt hypothyroidism and my advise to you is to determine her thyroid auto-antibodies and to treat her with thyroid hormone such that her final TSH finally drops between 0.27 and maximally 2.0 mU/l. If antibodies are present in the serum, than it is almost certain that she will eventually develop full blown hypothyroidism and in that case treatment should be continued irrespective of any immediate effect. If antibodies are absent and T4 substitution has no effect discontinuation of T4 could be considered but the patient should be frequently seen in follow up.
Georg Hennemann, MD, PhD, FRCP, FRCP(E)
E mail: g@hennemann.demon.nl

QUESTION- How to manage existing hypothyroidism perioperatively in a patient NPO ?
I was called to evaluate a 82 year old female with cholecystitis who had hypothyroidism and has been taking levothyroxine 125 mcg/day. Her last TFT was fT4- 1.3; TSH - 6.1 three days ago. Patient is NPO. Suction tube is in place. It is on constant suction. There is a plan for surgery in 5-7 days. Should be levothyroxine be given IV or withheld for a short period of time. Thank you for your service. I always read all your Q&A section. It is very useful. Feel free to publish my question if you find it interesting enough for physicians. Sincerely yours, Dmitri Kirpichnikov kirpidi@yahoo.com
Dmitri Kirpichnikov, MD, 9711 Third Ave, Brooklyn, NY 11209
RESPONSE-No problem to withhold it for a few days. Regards, Georg Hennemann, MD,

QUESTION- HOW LONG TO WAIT AFTER OPERATION BEFORE RAI ABLATION?
Dear experts -In the literature it is always suggested that the radio iodine abalation is administered approx 4-6 weeks post operatively after total /near total thyroidectomy for ca. One of the reasonS is for stimulation of TSH so it is at least above 30 mIU/L, but if this level of TSH is reached before this period( by end of first week? ) can RAI be
administered sooner ? Thanks
Hamda Saleh, Registrar,The Children's Hospital at Westmead,NSW,Australia
612-98452905 Nasir Kahlon <nasirk@bigpond.net.au> 6/16/2002
ANSWER-I am not aware of any reason that one needs to wait longer than the interval required to raise the TSH, or of a study on the question. Note that the TSH may go up slowly or never reach 30 if a large amount of thyroid is left in place. The prior approach involved allowing patients to recover from the operation, and then preparing for ablation. Probably either way is acceptable.
Leslie J De Groot,MD

QUESTION - DO WE REALLY NEED TO DO BOTH fT4 AND TSH IN EVALUATING PATIENTS?
Dear Sir,
Sincere admiration for your great website. Regarding evaluation of
thyroxine replacement therapy, it is always suggested to evaluate TSH
and free T4. However except in the situation of pregnancy (where only
depending on TSH could result in a retarded action), I don' t see much reason to
determine both values. Is it wrong to check only TSH ?
Dr. Henri Maex, Antwerp, Belgium Email- Henri Maex <mj7653@planetinternet.be>
6/12/2002

QUESTION- HOW TO MANAGE FETAL HYPOTHYROIDISM AND GOITER
Dear expert: Patient is a 29 yr old lady - 26 weeks intauterine pregnant. She has had an earlier miscarriage at 6 wks gestation - cause unknown. Not a consanguinous marriage. Routine ultrasound at 26 weeks revealed a fetal goiter - 3.5 x 2.5x 2.5 cms. Weeks of gestation by ultrasound corresponds to gestational age by LMP. Pregnancy is otherwise normal without any other complications. There are not from endemic areas for iodine deff.Mother's thyroid function tests are normal - TSH and Free T4 . Her Antithyroid peroxidase antibodies are negative. Cord blood TSH is > 100, Free T4 - 2.5 (4.2 - 6.2),Anti TPO is negative. IV levothyroxine is avialable with difficulty and very expensive - Rs 8000/ per 100 Ucg. These are mothers and my concerns :
1) Will the baby's IQ be completely normal with treatment with intra-amniotic LT4?
2) What are the chances of a similar problem in subsequent pregnancies - as she is considering an MTP if the chance of normalization OF IQ of the child is not high.
Other queries are:
1) What would be the dose of IV levothyroxine -intra-amniotic - would a loading dose be required?
2) How soon would the goiter shrink and will it shrink completely???
3) Would oral LT4 in high doses be of any use at all, since cost is a factor?
4) Would u recommend an MTP to this patient?
We would appreciate a prompt response so that a decision can be made soon.
Regards,
Radha Reddy MD (Endocrinology and Diabetes, USA), Consultant Endocrinologist,
Mallya Hospital, Bangalore, India
"radha reddy" <radreddy@yahoo.com>, Thursday, June 06, 2002 8:58 PM

ANSWER BY DR ROSALIND BROWN
Dear Dr. Reddy: I find your case most unique and perplexing since the baby appears to have quite severe fetal hypothyroidism despite the apparent absence of either thyroid disease or medication in the mother. Therefore, one would need to hypothesize both fetal thyroid disease (presumably due to an abnormality of thyroid hormonogesis) as well as the absence of adequate maternal thyroid hormone to at least partially compensate for the severe fetal hypothyroidism. I would therefore think that before embarking on intraamniotic T4, it is most important to be absolutely sure that the mother is not taking something (e.g., a homeopathic remedy, or iodine-containing medicine for asthma, etc.) that might preferentially affect the baby's thyroid function.
in answer to your questions:
1)Although there are no guarantees in medicine, the baby's IQ should be normal with intramniotic T4. By analogy, babies with no thyroid gland at all have normal cognitive development even with POSTnatal treatment as long as treatment is sufficiently early and adequate. I personally have never advocated intraamniotic T4 since usually my preference would be to reduce the dosage of antithyroid medication in the mother (in cases of maternal Graves' disease). I would, however, in your case due to the severity of the hypothyroidism, not to mention the presence of fetal goiter which, if sufficiently large, can cause respiratory obstruction and distress.
2) Most cases of thyroid dyshormonogenesis are autosomal recessive and therefore carry with them a 1/4 chance of recurrence in each pregnancy. It is now possible to determine the molecular etiology of many of these cases although this is usually only done in research laboratories and clearly, if the molecular etiology were known one could even do fetal diagnosis.
3) The doses of L-T4 that have been used in the literature are 250-500 micrograms, given every 1-2 weeks as necessary. Improvement in the TFT's and shrinkage of the goiter are observed within a few weeks. (cf: Perelman AH et al, JCEM 71:618, 1989;Davidson KM et al, NEJM 324:543, 1991;Vicens-Calvet E et al, J Pediatr 133: 147,1998).
4) Yes (see (1)
Sincerely, Rosalind S. Brown, MD,Professor of Pediatrics,
University of Massachusetts Medical School,
Director, Division of Pediatric Endocrinology/Diabetes
UMass Memorial Health Care <Rosalind.Brown@umassmed.edu>

QUESTION- PATIENT SEEKS COUNSELING ABOUT THE POSSIBILITY OF FUTURE THYROID EXACERBATIONS

In brief he is a 40 year old male who presented in his early 30s with hypothyroid symptoms and a modest goiter of several month's duration. A family history of transient hypothyroidism, possibly in the setting of pregnancy, was reported. An elevated TSH and low total T4 were found and corrected with Synthroid. His symptoms completely resolved. No other testing was performed at that time.
In the intervening years he experienced increasing sinus and rhinitis symptoms and he failed medication therapy. He underwnet endoscopic surgery, which alleviated his sinus symptoms but his rhinitis persisted. Annual TSH testing was normal on a steady dose of Synthroid.
In mid-2001 he suffered a severe, persistent URI with intermittent low-grade temperatures for several months (another family member had a similar URI course). After six weeks of URI symptoms and severe rhinitis he began experiencing what in retrospect appear to be hyperthyroid symptoms (sweating and tachycardia). TSH was in the mid-normal range in mid-2001 but fell to just beneath the normal range by fall 2001. Unfortunately free T4 was not measured. Synthroid was held and beta blockade introduced until TSH returned to normal. Steroid was not administered because of ongoing URI symptoms.
His low-grade fever from the previous illness had resolved in the interim, but when sharing new household viral illnesses in late 2001, intermittent sweating and hyperdynamic symptoms recurred for brief durations when acutely ill. By spring 2002 his hyperdynamic symptoms slowly abated and his TSH rose (and hypothyroid symptoms recurred). As of mid 2002 he is on his baseline dose of Synthroid with normal TSH, normal free T4, and normal free T3.
Immunological testing performed before his TSH was found to have fallen was unremarkable except for a modest IgE spike. His ESR was never elevated. Viral testing was negative. A bone marrow (performed because of the combination of low-grade fevers and sweating) had a gross appearance remininscent of pernicious anemia but testing was unremarkable (felt to be "reactive", consistent with either an autoimmune state or viral illness).
A thyroid ultrasound was consistent with Hashimoto's thyroiditis of uncertain duration. Thyroid antibodies were moderately elevated, also consistent with thyroiditis of unclear duration. Of note is that a PET scan, done as part of the work-up prior to frank TSH changes, showed intense thyroid uptake.
He now returns concerned about the possibility of future recurrence. At present he is euthyroid but has ongoing rhinitis symptoms. Other findings have resolved.
Thanks, C. L. Etheridge, MD cle.md@verizon.net

ANSWER BY LESLIE J DE GROOT, MD
I believe you describe one of the more unusual, but not unique, presentations of autoimmune thyroid disease. Probably this is best classified as "Hashimoto'sThyrodiitis". The course, with periods of hyperthyroidism and hypothyroidism, is occasionally seen. Presumably this is related to changes in the types of antibodies being produced (stimulatory vs inhibitory) or the intensity of the T cell response. The relation to sinusitis (or another infection) is probably real, and has been reported by Amino and co-workers, along with the elevation of IgE. One presumes that the release of cytokines into the circulation (IL-1, IL-2, Il-L-6, IFN gamma, TNF alpha) is the actual cause of the changes in the thyroid inflammatory process. Sometimes the process seems to have a mixture with SAT, with thyroid pain and tenderness, but in your case the low sed rate rules out that process as the primary diagnosis. I think there is a strong likelihood of recurrence. While use of steroids might control the process temporarily, the only "solution" I know of, if the problem is severe enough to merit such , would be to remove the thyroid by either RAI or surgery, and I would favor the latter if a good surgeon is available.
Leslie J De Groot, Univ of Chicago, Chicago, IL 60637 ldegroot@medicine.bsd.uchicago.edu

QUESTION- "HASHIMOTO'S ENCEPHALITIS" ?
Dear Thyroid experts :I had a patient who was admitted to hospital with confusion. she is 39 yo with known Hashimotos found last month to present with tonic-clonic seizure. Not doing well for one month and problems with word finding. ct at outlying hospital reported as cerebral edema. EEG revealed bifrontal rhythms and polymorphic slowing. Had a ventriculostomy placed due to CSF pressure of 20. Pt discharged and then represented with confusion ...Further investigations showed questionable cerebritis around ventriculostomy site on MRI . Other w/u at outside hospital neg HSV/PCR, transthoracic echo neg, CT angiogram positive for PE with positive anticardiolipin antibody. Pt then anticoagulated prior to transfer to our institution--- Found to have elevated microsomal ab 1:6400, and anti TPO 2517. Patient was seen by rheumatologist with negative workup at our institution (neg for ANA, anti DNA , anti RNA, SSA, SSB, SCL70 and chromatin antibodies negative, c3 208 ). Underwent plasmapheresis and steroids. She was then place on prednisone 100mg /d. No other residual neurological problems. No other explanation by rheum who felt the original antibodies for anticardiolipn was negligible (am trying to get records).
I had seen her one year ago with a goiter about 120g and placed her on thyroid hormone for biopsy positive autoimmune thyroid Hashimotos.
Other complicating history--with PE dx on coumadin, not optimal surgical candidate at this time.
Is there some information /references on Hashimoto's encephalopathy/cerebritis as that is the suspected diagnosis by the rheumatologist. . If this is true -optimal treatment? Ablation with I-131 vs surgical resection of goiter?....Should I be worried about thyroid lymphoma ? Re bx ? Re-ultrasound thyroid for size pending.
Appreciate any input or recommendations for further history or investigations.
anne marie lee
annemarielee@earthlink.net
anne.m.lee@healthpartners.com
2220 riverside ave s
mpls, mn 55454
612-373-5540
univ of mn clinical asst professor

RESPONSE BY LESLIE J DE GROOT,MD-- Surely your case fits into the category of "Hashimoto's encephalitis". By now there have been more than 50 similar patients reported.-(Neurology 1991:41:223-233, Neurol 1996;243:585-593, Neurology 1997;49:623-626, Euro Neurol 1999;41:79-84, and many others on Medline). The manifestations are typically confusion, obtundation, dementia, seizures, sometimes psychosis, movement disorders, stroke-like episodes with abnormal EEG, variable minor abnormalities on CAT or MRI, sometimes elevated CSF protein, and typical findings of Hashimoto's with high antibodies. Usually the patients respond to prednisone, and some have been given other therapies including IV IgG and cyclophosphamide. Some do not respond totally. I am not aware that removal of the thyroid by surgery and 131-I has been reported or attempted, although it obviously is an interesting idea. If the patient fails to respond to immuno-suppressive therapy , one could make a case for total removal of thyroid antigens. However I must immediately point out that there is absolutely no published support or experience with this approach, so far as I know.
There is as yet no consensus that this is "due to " Hashimoto's thyroiditis and its autoimmunity. Some observers believe this is the case, and others contend that it is simply the combination of some yet undiagnosed unusual encephalitis, and a fairly common thyroid disease. My bias is that it will be found to be tied in some way to autoimmunity to CNS antigens that somehow overlap with antigens in the thyroid.
Leslie J De Groot, MD Univ of Chicago/Endocrinology

RESPONSE BY DR. NOBUYUKI AMINO - Your case is compatible with so called Hashimoto’s encephalopathy or encephalitis, although the existence of such a specific disease is not completely established. As you know Hashimoto’s thyroiditis is very common. Around 10 % of adult women in the general population have positive anti-thyroid microsomal antibodies. Thus I speculate that an autoimmune encephalitis is coincidentally associated with Hashimoto’s thyroiditis. It is well known that Hashimoto’s thyroiditis frequently aggravates during the postpartum period, but development of associated encephalopathy has not been reported. Therefore I believe that encephalopathy in your patient might occurred independently from Hashimoto’s thyroiditis. Therefore total thyroidectomy may not release the patient’s symptoms. We need more definitive evidence that encephalopathy is really causatively associated with autoimmune thyroid disease. In your case, the patient is suffered from PE, and has positive anticardiolipin antibodies. It is strongly suggested that encephalopathy might be related to a vascular problem induced by an autoimmune mechanism, such as lupus anticoagulant and/or other antibodies to various coagulation factors. As reported in other patients, steroid therapy would be preferable, if patient relapses.

QUESTION- PRIMARY VS SECONDARY HYPOTHYROIDISM ?- AND FINANCIAL PROBLEMS.
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

ANSWER BY DR. WILMAR WIERSINGA
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.)

QUESTION-DOES THIS PERSON HAVE “THYROID HORMONE RESISTANCE”? (12/7/01)
Case submitted by Dr Karen Kartun.
History: This 54-year-old woman is referred for a thyroid evaluation. She was originally diagnosed as hyperthyroid about 20 years ago when she presented with complaints of irritability, feeling "hyper" and general malaise. That had been present for many years before her presentation to this physician. She was treated with radioactive iodine at that time at another facility. Those records are not available. She was subsequently given L-T4 replacement therapy but has never been able to get her levels balanced out since that time. She has persistently had an elevated TSH level with an elevated free T4 level on varying doses of thyroid hormone. She is currently treated with Levothroid 212 mcg daily. She has been consistent in taking her medication everyday. Currently she has some complaints of heat intolerance. She has irritable bowel syndrome and some complaints of hair loss. Weight loss has been difficult for her and she maintains the weight in the mid 170s. She has had some increased blotchiness of the skin recently. She has no complaints of edema, muscle cramps, nervousness, palpitations, or tremor. She is troubled by depression which is treated with Effexor. Her mother had a goiter which was resected. She does not know of any other family with thyroid dysfunction.
Past Medical/Surgical History: (1) Thyroid disease as above. (2) Depression. (3) Irritable bowel syndrome. (4) Status post hysterectomy. (5) History of hand and foot surgeries. (6) Hypertension.
Medications: (1) Levothroid 212 mcg q.d. (2) Premarin 0.9 mg q.d., (3) Effexor 150 mg b.i.d. (4) Atenolol 25 mg q.d.
Allergies: None.
Family History: Mother died at 62 with history of thyroid and heart disease. Father died at 68 with a CVA in his history.
Siblings - she has a brother who committed suicide and a sister who died of a brain tumor. She has 4 children, one who has had cerebral palsy, the others are healthy.
Social History: She does not smoke cigarettes, drinks alcohol occasionally.
Review of systems: negative except as above
.
Examination: Blood Pressure: 118/66. Height: 5 feet 3.5 inches. Weight: 176 pounds. Pulse: 59. Temperature: 96.4°. She was alert and oriented x 3 and well appearing. HEENT: Extraocular movements were intact. Pupils are equal and round. There was no lid lag, there was no proptosis. Visual fields were intact to confrontation. Neck: Supple. No lymph nodes are palpated. Thyroid did not show a goiter. Lungs: Clear to auscultation. Cardiac Exam: Normal S1/S2. Abdomen: Soft and nontender. Back: Negative for CVA or spinal tenderness. Extremities: Negative for edema. Neuro Exam: Shows 2+ deep tendon reflexes and a tremor was noted.
Laboratory studies were reviewed. In 11/99 her TSH was 18.23(0.35-6) with a free T4 of 1.79(0.68-1.76), 7/9/01 her TSH was 15.13, free T4 2.09,
8/14/01 TSH 10.62 (0.35-6), free T4 1.87(0.68-1.76), total T3 210 (58-184)with an FSH level of 29.9, LH of 24.3, prolactin 65.8 (1.6- 27.1), and am cortisol 16.8,
8/20/01 TSH 4.98, free T4 2.55, T3 211. All of those laboratory studies were done on doses of thyroid hormone replacement greater than 200 mcg daily.
Dr Kartun,s evaluation: This is a very strange story and group of laboratory results. It would be extremely helpful to see the original thyroid function tests and Nuclear Medicine scan report from the time of her initial diagnosis 20 years ago even though her symptoms date back even further than that. There are several possible explanations for her levels; (a) patients who do not take their Levothroid regularly as prescribed can get an elevated TSH level. Sometimes if they take a large number of tablets right before their laboratory tests are done in hopes of normalizing their levels you can see the high free T4 level with an elevated TSH, (b) patients with thyroid hormone resistance can have similar levels. This is a genetic disease which is inherited as an autosomal dominant trait. Therefore, we would expect other family members to have been similarly affected. We do not have a definite history of other affected family members though Ms. James suspects that her daughter may have similar problems, or (c) patients' with TSH secreting pituitary adenomas could have similar laboratory values. It seems as if it would be unlikely that a patient with a TSH secreting adenoma would not be made even more hyperthyroid than baseline levels by the addition of the very high doses of L-T4 she is already receiving. Although this has been going on for 20 years it seems hard to imagine that a TSH secreting adenoma could be missed for that many years. However, in reviewing the literature, there are reports that note the length of time from the onset of symptoms to the time of diagnosis varies from 1-27 years. Many of these patients have received I-131 therapy in the past. Bonnie does not have a goiter and she does not have visual field defects that are obvious. Her FSH and LH are appropriately elevated for a menopausal woman. Her prolactin is moderately elevated and TSH secreting adenomas can co-secrete prolactin or possibly a pituitary tumor can cause stalk compression leading to an elevated prolactin level. Hypothyroidism can also cause prolactin levels to go up because TRH is a prolactin secretagogue. Her cortisol levels are reasonable.
Assuming that the patient is honest and her compliance with her therapy has been good we need to differentiate between the latter 2 possibilities. An SHBG is elevated in patients with adenomas and normal in those with thyroid hormone resistance. An alpha subunit is elevated in adenomas and normal in resistance to thyroid hormone. If this were an adenoma the patient theoretically would not require L-T4 therapy and if we decrease it or stop it she should still have an elevated free T4 level unless her prior radioactive iodine therapy did knock out her endogenous thyroid function and her TSH is not suppressible by the overdosage of L-T4 therapy she is currently receiving. We do need to tease these things out.

The plan is as follows: (1) Decrease L-T4 to 150 mcg daily and repeat thyroid function tests in 6 weeks. (2) Will check a TSH, a free T4, a total T3, a prolactin, an IGF-1 level today and an SHBG and an alpha subunit. (3) It is okay to go ahead with the pituitary MRI scheduled for 10/23 but no therapy should be instituted prior to obtaining the results of the above laboratory studies.

Additional results since the date of the initial consultation--
10/12/01 SHBG 49.1 (18-114) , PROLACTIN 50.0 (1.6-27.1) , T3 165 (58-184) ,FREE T4 1.80 (0.68-1.76) ,TSH 10.55 (0.3506)
IGF-1 138 (90-360) ,ALPHA SUB UNIT 0.2
10/23/01 MRI-vague hypodensity (<1cm) in the right inferolateral pituitary which persists with contrast enhancement.
Stalk and chiasm normal. There was mild sloping of the sellar floor.
On 150mcg L-T4 QD: 11/28/01 T3 143 (58-184) ,FREE T4 1.29 (0.68-1.76) ,TSH 43.98 (0.35-6)

(12/15/01)I just got back another interesting piece of information. I had the case patient's daughter tested. Her TSH is 1.92 (0.35-6), her free T4 is 2.08 (0.68-1.76) and her total T3 is 236 (58-184). She is not on any thyroid hormone and has never had any form of thyroid treatment. This looks to me like thyroid hormone resistance in this family. Would you agree? If so how do I determine the appropriate levels of free T4/TSH at which to keep the case patient?
Karen Kartun, M.D. Department of Medicine , Division of Endocrinology, Kaiser Permanente ,9985 Sierra Avenue ,Fontana, CA 92335 ,(909)427-3334 email: kkartun@pol.net

ANSWER BY DR SAMUEL REFETOFF – (12/20/01) From the follow-up on this case, it is obvious that Dr. Kartun does not need the help of "an expert". Short of demonstrating a mutation in the thyroid hormone receptor (TR) beta gene, the diagnosis of resistance to thyroid hormone (RTH) is almost certain. I would like, however, to take this opportunity to make a few comment that may be helpful to practicing physicians. 1. Because RTH is inherited, a simple and direct approach to the diagnosis is to test family members. This always proves to be cost effective, considering the additional tests, such as MRI, often used to rule out alternative diagnosis, are quite pricey. Testing family members is particularly helpful when the study of the key case is complicated by prior ablative therapy and the requirement of hormone replacement. The fact that RTH is inherited as a dominant trait reduces the number of individuals that need to be examined, since, one of the parents must be affected and 50% of siblings and progeny would manifest the phenotype (high serum free T4 and T3 levels with normal TSH).
2. Having said that study of family members is the cornerstone in the diagnosis, it is important to note that 10% of TR beta gene mutation occur de novo. Thus, the key case may be the first family member carrying the TR beta gene mutation. Furthermore, in another 10% of individuals with RTH, the phenotype is not caused by mutations in the TR beta gene. In such instances, additional tests are required to establish the diagnosis.
3. A solid clinical proof that elevated serum free T4 and free T3 levels with non-suppressed TSH is due to RTH is the measurement of responses to exogenous thyroid hormone given in incremental doses. A relatively simple and established protocol is the administration of graded doses of T3 (50, 100, and 200 micrograms/day) each given in two divided doses for three days. The baseline and following each dose central and peripheral parameters of thyroid hormone action are measured and the changes compared to data available from unaffected controls.
Baseline measurements of peripheral markers of thyroid hormone action, such as, cholesterol, SHBG (measured in this case), ferritin, and creatine kinase are of little value because of the broad normal range and unrelated conditions that could affect their levels. It is the change in their response to thyroid hormone administration that is valuable for the diagnosis of RTH.
4. Finally, I would like to point out several findings in Dr. Kartun's case that are of interest or important in the differential diagnosis as well as additional simple tests that could have been of diagnostic value.
a. Slight elevation of the serum free T4 concentration without TSH suppression is not uncommon in individuals on L-T4 replacement. However, in such instances, T3 remains in the normal range. Similarly, patients with familial dysalbuminemic hyperthyroxinemia (FDH) present with high T4 and even high free T4 levels (measured by direct methods) and non-suppressed TSH. With only rare exceptions, also these individuals have normal serum T3 levels. Thus, in considering the diagnosis of RTH, both free T4 and free T3 must be measured.
b. Since RTH is most commonly mistaken as autoimmune thyroid disease (Graves'), the absence of thyroid peroxidase, thyroglobulin and TSH receptor antibodies could point towards the proper diagnosis. c. When goiter is absent and in patients who have not received prior ablative therapy, measurement of the thyroidal radioiodide uptake could be of help. It should be high in RTH but normal in thyroid hormone transport defects, such as FDH.
d. Serum prolactin is occasionally high in individuals with hypothyroidism. This is also the case in individuals with RTH who are inadequately replaced with thyroid hormone following ablative therapy.
e. A normal alpha subunit and a normal response of TSH to TRH should be sufficient as preliminary tests for TSH producing adenoma. MRI of the pituitary which can be often abnormal due to incidentalomas, should be reserved for those patients who have no living relatives available for testing or when thyroid function tests in family members have proven to be normal.
. Recommendations regarding Dr. Kartun's case:
a. The patient should be placed on sufficient amount of thyroid hormone to maintain a normal TSH level. If sinus tachycardia develops, Atenolol should be added to the treatment regiment.
b. The remainder of the patient's children should be tested. Those with abnormal thyroid function tests should be informed and given letters explaining the cause. They should be instructed to provide this letter to any physician who proposes treatment for their thyroid tests abnormalities.
c. Identification of the genetic defect is not mandatory. However, in families in whom RTH is associated with growth retardation, mental retardation or severe attention deficit disorder, identification of the mutation could aid in providing future prenatal diagnosis.

THYROID HORMONE TREATMENT AND URIC ACID LEVEL
Dear Doctor
I have a patient with benign thyroid cyst on suppressive therapy with 150 micrograms thyroxine . Her thyroid function tests on this are :
Free T 4 23.2pmol/l range10-25
freeT3 6.8pmol/l range 3.3-7.2
S-TSH <0.01 0.2-0.4
Her uric acid is very low at 86micromols/l, range 140-390.
She also has a hip bursitis and shoulder capsulitis, but ESR is normal, RF normal, and ANF normal. Her diet is apparently normal. Using a MIRENA coil.
Is there any relation of the low uric acid to the thyroid treatment
Regards
Dr Tom Scade, MbChBBSC(Hons)FRCP(G)MRCGP(UK)
Emirates Clinic , PO Box 26777, Dubai , UAE
e-mail tom.scade@emirates.com

Answer by Dr Jim Stockigt

There is no description that I can find of subnormal serum uric acid
associated with thyroid hormone excess. There is a useful section on
hypouricemia in the Harrison text, 14th Edn, p2165. Can you be sure that
none of the medications used for the shoulder complaint have a uricosuric
component ?
One other comment. I wonder about the wisdom of using suppressive T4
therapy in a woman who may be at risk of osteoporosis, when the benefit of
such therapy in managing benign cysts is less than convincing. Subclinical
thyrotoxicosis as a result of suppressive T4 certainly seems to decrease
bone density ( see Wesche et al J Clin Endocrinol Metab 2001; 86:998-1005)
Regards, Jim Stockigt

THYROXINE REQUIREMENT DURING PREGNANCY
Friday, October 26, 2001 7:14 AM
One of my patients underwent total thyroidectomy because of failure of drug treatment of Graves disease. One month postoperative she was pregnant. Under 150 mcg T4 the TSH was 3.6 mU/L in the first trimester. After 2 months it rose to 26 mU/L (under 170 mcg/d) and it was necessary to give more T4: The TSH normalised at the 6 month of pregnancy under 250 mcg/d (TSH 4.2 , fT4 18.6 pmol/l, fT3 3.5 pmol/l).
Today, around term, she needs 5.8 mcg/kg effectve weight/d, or 7 mcg/kg prepartum weight/d) in order to achieve a TSH of 1.4 I have no doubt about compliance (the pharmacy confirms the correct amount of tablets). Normal weight, no symptoms, fetal growth normal. (P.S.-Prepartum weight 50 Kg and during pregnancy 57Kg).Is is an extreme form of physiological THR in pregnancy?
Many thanks for your answer.
Dr. Fabio Cattaneo, Lugano, Switzerland

ANSWER Wednesday, October 31, 2001 3:32 AM.It is estimated that in almost all patients with thyroid deficiency (previously having received radioiodine, or operated, or with autoimmune thyroid disorders), the replacement dosage of l-T4 needs to be increased during pregnancy. The guidelines to carry out this dosage increment are as follows :1) it has to be done relatively rapidly during early gestation, and certainly within the first trimester;2) the dosage increment needs to be closely monitored during gestation, in order to avoid a rise in serum TSH. In our experience, changes in l-T4 dosages occurred until mid-gestation (5-6 months), and rarely in the last trimester (a platteau is reached at this stage); 3) percentage-wise, the dosage increment is approximately 30-60 % above baseline (preconception) daily doses. However, this is an average, but does not tell us anything about individual cases. Individually, l-T4 doses may have to be doubled (and even higher); in our own experience, one compliant patient required above 300 mcg/d during pregnancy; 4) the final dosage increment depends upon several factors that are difficult to predict:
- The functional reserve of the thyroidal machinery : see the paper by Mike Kaplan, comparing pregnant patients with Hashimoto (requiring a lesser increase) and thyroid ablation for cancer, etc (requiring proportionally more);
- The rise in TSH (when it has occurred, like in your case) is an additional difficulty, because then one often runs "behind" the actual events taking place and it is sometimes difficult to bring the TSH back to normal before the end of gestation (it seems that you succeeded);
- Iodine deprivation : because of increased needs for iodine during pregnancy, and its reduced availability in the pregnant state, this may constitute an additional factor to complicate matters. Obviously, this factor will only play a role when the iodine nutritional status is limited, restricted, or deficient. Also, iodine deficiency will obviously play no role (as in your patient) when a total thyroidectomy has been performed previously;
- Thyroxine absorption by the digestive tract : this has not been investigated so far, but we believe that some pregnant women may have "malabsorption" of thyroxine;
- Changes in weight. I hope to have brought some light to your clinical problem, which is frequently encountered, and requires particular attention given the possibility that hypothyroxinemia in expecting mothers may have a deleterious role for the progeny's final IQ (see Haddow, Pop, etc). Furthermore, the fact your patient already had a serum TSH of 3.6 mU/L in the first trimester (while taking 150 mcg) is an indication that she was slightly undertreated for this stage of early pregancy. It is therefore not surprizing that a few weeks later the TSH rose to 26 mU/L. As I indicated above, you "ran behind the cat", and this can be shown by the fact that, at 6 months of gestation, the serum TSH was still too high (4.6 mU/L), despite giving 250 mcg/day.
Prof Daniel GLINOER<Daniel_GLINOER@stpierre-bru.be>