Re:Re Hashi's and Graves

[Guest guest]

Val, You wrote: However, since?anti-thyroid? drugs (Methimazole and PTU)?reduce TRab antibodies (all kinds) you could use a dose of?antithyroid? drugs?*PLUS* replacement hormone to keep your levels stable, until TRab are gone. This therapy is a form of another therapy called "Block and Replace".? Please provide links with info and/or studies that point out ATD's like Methimazole or PTU reduces TSH receptor antibodies. I have somewhat looked for info and haven't found anything (yet). My DD's Dr has told us that she needs

the block and replacement treatment. But, we decided to put it off until absolutely necessary. Now that you have mentioned the benefits we may need to rethink our strategy. Also, are you familiar with how TBG (Thyroid Binding Globulin) fits into the autoimmune thyroid picture. If so, I would welcome your comments as well as anyone else's! Dr wants to run a TBG on DD to see if the FreeT4 is as low as it looks and the FreeT3 is as high as it looks - to see if the TBG is impacting test results. The TBG test should eliminate all binding protein related interferences. He has warned the test is time consuming and expensive. Just curious if anyone has had this test done? All I ran across is that interferences are rarely seen in Free T tests. However, the old obsolete Total T3/T4 tests are always affected

and essentially that's why they are of no medical worth, but many Dr's don't realize that and still use them. Thanks, Bj

Sick sense of humor? Visit Yahoo! TV's Comedy with an Edge to see what's on, when.

[Guest guest]

It's interesting you mention TBG, as I'm just gotten curious about

this subject - wondering what impact this may have on some Hashi's

folks. I'll also be interested in any comments too.

Also, this article may be of interest to some Hashi's folks..this is

a guy on the 's yahoo group who has a great 's site:

http://mysite.wanadoo-members.co.uk/addisons_network/enter.html

under the section " High Cortisol Binding Globulin as cause of

's " :

I am a retired Chief Biomedical Scientist with over 36 years

experience in pathology

and I believe these results from patients who were clinically

suffering from symptoms of

adrenal insufficiency suggest that something else was interfering, in

those patients'

blood stream, with their cortisol levels. I had already noticed that

most of this group

of patients were female and that many had reported they also suffered

from an established

diagnosis of hypothyroidism or Hashimoto's disease. One female

patient in the group who

also had Hashimoto's disease reported that her replacement dose of

thyroxine had at one time

required increasing over a period of several months from 200µg/day

(often recognised

as full replacement dose) to 400µg/day at the time of an apparently

unrelated medical

condition. This required increase had been investigated by her

endocrinologist and discovered

to be the result of an elevated level of thyroid binding globulin

(TBG).

From research on the Internet, I discovered a paper by Wyeth Lederle,

a well known drug

company, in which they related the fact that patients with increased

TBG levels also

were often found to also have elevated levels of both sex hormone

binding globulins (SHBG)

and cortisol binding globulins (CBG). I also uncovered another report

by the Department of

Chemical Pathology at Hong Kong University Hospital in which they

mentioned in a ward manual

that high CBG could affect cortisol response to ACTH, 'often from a

normal baseline'.

Cindi

>

> > > Also, are you familiar with how TBG (Thyroid Binding

Globulin) fits into the autoimmune thyroid picture. If so, I would

welcome your comments as well as anyone else's! Dr wants to run a

TBG on DD to see if the FreeT4 is as low as it looks and the FreeT3

is as high as it looks - to see if the TBG is impacting test

results. The TBG test should eliminate all binding protein related

interferences.

[Guest guest]

> Please provide links with info and/or studies that point out

ATD's like Methimazole or PTU reduces TSH receptor antibodies. I

have somewhat looked for info and haven't found anything (yet).

>

Hi Becky,

These effects on autoantibodies have been known for a long time.

I'll post some of the latest ones and then links to the older

references:

First, here's the link to Thyroid Disease Manager, which is writen

by top endos in the country as a teaching tool for other endos:

http://www.thyroidmanager.org/Chapter11/11-frame.htm

" ...A most exciting new idea regarding their [antithyroid drugs]

action stems from observations that antithyroid therapy is

associated with a prompt reduction in circulating antithyroid

antibody titers (TPOab TGab), [101]and anti-receptor antibodies

(TRab). [77, 78, 102] Studies by MacGregor and colleagues [103]

indicate that antibody reduction also occurs during antithyroid

therapy in patients with thyroiditis maintained in a euthyroid

state, thus indicating that the effect is not due only to lowering

of the FTI in Graves' disease. These authors also found a direct

inhibitory effect of PTU and carbimazole [methimazole] on

antithyroid antibody synthesis in vitro and postulate that this is

the mechanism for diminished antibody levels. [104]Other data argue

against this hypothesis. [105, 105.1]

Antithyroid drug therapy is also associated with a prompt reduction

in the abnormally high levels of activated T lymphocytes in the

circulation. [106]Totterman and co-workers have shown this therapy

causes a prompt and transient elevation of activated T suppressor

lymphocytes in blood. [107]We and others [106, 108] have shown that

during antithyroid drug treatment the reduced numbers of T

suppressor cells present in most thyrotoxic patients return to

normal. Antithyroid drugs do not directly inhibit T cell function.

[109]All of these data argue that antithyroid drugs exert a powerful

beneficial immunosuppressive effect on patients with Graves'

disease. While much has been learned about this process, the exact

mechanism remains uncertain. Evidence that antithyroid drugs exert

their immunosuppressive effect by a direct inhibition of thyroid

cell production of hormones has been reviewed recently by Volpe.

[109]

101. Marcocci C, Chiovato L, tti S, Pinchera A: Changes of

circulating thyroid autoantibody levels during and after therapy

with methimazole in patients with Graves' disease. J Endocrinol

Invest 5:13, 1982.

102. Pinchera A, Liberti P, o E, Fenzi GF, Grasso L, Rovis I,

Baschieri L: Effects of antithyroid therapy on the long-acting

thyroid stimulator and the antithyroglobulin (TGab)antibodies. J

Clin Endocrinol Metab 29:231, 1969.

103. MacGregor AM, Ibbertson HK, BR, Hall R: Carbimazole and

autoantibody synthesis in Hashimoto's thyroiditis. Br Med J 281:968,

1980.

104. McGregor AM, sen MM, McLachlan SM, Rooke P, BR, Hall

R: Carbimazole and the autoimmune response in Graves' disease. N

Engl J Med 303:302, 1980.

105. Hallengren B, Forsgren A, Melander A: Effects of antithyroid

drugs on lymphocyte function in vitro. J Clin Endocrinol Metab

51:298, 1980.

105.1. Weetman AP. The immunomodulatory effects of antithyroid

drugs. Thyroid 4:145-146, 1994.

106. Ludgate ME, McGregor AM, Weetman AP, Ratanachaiyavong S,

Lazarus JH, Hall R, Middleton GW: Analysis of T cell subsets in

Graves' disease: alterations associated with carbimazole. Br Med J

288:526, 1984.

107. Totterman TH, Karlsson FA, Bengtsson M, Mendel-Hartvig IB:

Induction of circulating activated suppressor-like T cells by

methimazole therapy for Graves' disease. N Engl J Med 316:15, 1987.

108. Sridama V, Pacini F, DeGroot LJ: Decreased suppressor T-

lymphocytes in autoimmune thyroid diseases detected by monoclonal

antibodies. J Clin Endocrinol Metab 54:316, 1982.

109. Volpe R. Evidence that the immunosuppressive effects of

antithyroid drugs are mediated through actions on the thyroid cell,

modulating thyrocyte-immunocyte signaling: A review. Thyroid 4:217-

223, 1994.

-------------------------------------------------------

These below talk about Carbimazole which is the UK version of

Methimazole. I actually found the one from 1980 that used

Carbimazole for Hashi's too --- read on....

Carbimazole and the autoimmune response in Graves' disease.

McGregor AM, sen MM, McLachlan SM, Rooke P, BR, Hall R.

Microsomal antibodies (TPOabs and TGabs) and antibodies directed

toward the receptor for thyroid-stimulating hormone (TSH-Receptor

ab) decreased in parallel while patients with Graves' disease were

taking carbimazole, whereas no significant changes were observed

during treatment with placebo or propranolol. The changes in

autoantibody levels during carbimazole treatment were independent of

changes in serum thyroxine and could have been due to a direct

effect of the drug on autoantibody synthesis. Evidence for this

suggestion was provided when low doses of methimazole (the active

metabolite of carbimazole) were found to inhibit thyroid-

autoantibody production in cultured lymphocytes. Since thyroid

lymphocytes are probably a major site of thyroid-antibody synthesis

in Graves' disease and methimazole is concentrated in the thyroid

during treatment, a local action of the drug on antibody production

seems likely. This possibility could be important in the use of

carbimazole to control hyperthyroidism.

PMID: 6247656 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entrez?

Db=PubMed & Cmd=ShowDetailView & TermToSearch=6893563 & ordinalpos=1 & itool=

EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlu

s

Carbimazole and autoantibody synthesis in Hashimoto's

thyroiditis.

McGregor AM, Ibbertson HK, BR, Hall R.

Serum thyroxine (T4), thyrotrophin (TSH), and thyroid microsomal

antibody levels (TPOab and TGab) were measured in 20 patients with

Hashimoto's thyroiditis and hypothyroidism before, during, and after

treatment with carbimazole or placebo. Thyroid microsomal antibody

levels fell during treatment in the 10 patients who received

carbimazole, while serum thyroxine and thyrotrophin levels did not

change. There were no changes in the placebo group. The study proves

support for the concept that carbimazole may act directly on

autoantibody synthesising lymphocytes localised in the thyroid. Such

an effect might be valuable in influencing the autoimmune process in

autoimmune thyroid disease.

PMID: 6893563 [PubMed - indexed for MEDLINE]

[Guest guest]

> Also, are you familiar with how TBG (Thyroid Binding Globulin)

fits into the autoimmune thyroid picture. If so, I would welcome

your comments as well as anyone else's! Dr wants to run a TBG on

DD to see if the FreeT4 is as low as it looks and the FreeT3 is as

high as it looks - to see if the TBG is impacting test results. The

TBG test should eliminate all binding protein related interferences.

>>>

Hi again,

I don't know anything about the TBG other than it binds to T4 and T3

and that's why we use Free T4 and Free T3 testing instead.

I did find this on Thyroidmanager.org - you may want to visit this

link since there's is a lot more there on how to use these tests.

Take care!

Val

http://www.thyroidmanager.org/FunctionTests/assay-frame.htm

• Clinical Performance of Total Hormone Methods:

The diagnostic accuracy of total hormone measurements would equal

that of free hormone if all patients had similar binding protein

concentrations 5. Unfortunately, serum TBG abnormalities that

distort the total:free hormone relationship, are commonly

encountered in clinical practice (Table 2). Additionally, some

patients have abnormal thyroid hormone binding proteins or

autoantibodies that render total hormone measurements diagnostically

unreliable [Table 1 & section 5(] 30,31. Consequently, TT4 and TT3

measurements are rarely used as stand-alone tests, but are employed

in conjunction with a binding protein estimate test [i.e. thyroid

hormone binding ratio, THBR, see section 3A(] to form a free

hormone index (FT4I or FT3I). The index approach corrects for common

abnormalities in the proteins that bind thyroid hormones in the

circulation (see section 3A) 32,33.

Total T4 reference ranges vary to some extent between methods but in

general have approximated 58 to 160 nmol/L (4.5-12.6 µg/dL) for more

than two decades. There is a new trend to use TT4 measurements in

preference to FT4 estimate tests to monitor pregnancy, provided that

the TT4 reference range is adjusted by a factor of 1.5 to

accommodate the effects of the predictable TBG elevation

261,354,355. Likewise, serum TT3 reference values are also method

dependent, with ranges approximating to 1.2 - 2.7 nmol/L (80 –180

ng/dL) 26.

.....

A. Two-Test Index Methods (FT4I and FT3I)

Free Hormone Indexes (FT4I and FT3I) are based on simple

calculations that modify the total hormone value to provide an

approximation of the free hormone concentration in the presence of

abnormal binding proteins. These indexes have been used to estimate

free hormone concentrations for 40 years and require two separate

measurements. One test is a measurement of total hormone

concentration (TT4 or TT3) [section 2], the other, an assessment of

binding protein concentration using either (a) a TBG immunoassay,

( a Thyroid Hormone Binding Ratio (THBR) or " Uptake' test, or ©

an estimate of the free hormone fraction determined by isotopic

dialysis or ultrafiltration. The purity of the hormone tracer

critically impacts the diagnostic accuracy of indexes calculated

using isotopic THBR tests or free fraction assessments 53-55.

Current THBR tests are usually able to produce normal FT4I and FT3I

values when TBG abnormalities are mild (i.e. pregnancy and estrogen

therapy). However, these tests often fail to normalize FT4I and FT3I

values in euthyroid patients with grossly abnormal binding proteins

(congenital TBG extremes, familial dysalbuminemic hyperthyroxinemia

(FDH), thyroid hormone autoantibodies and NTI) 56-58. These tests

also have impaired diagnostic accuracy in the presence of certain

drugs that influence thyroid hormone protein binding 59.

(a) TBG Immunoassays

There is no improvement in diagnostic accuracy of free hormone

indexes (TT4/TBG) calculated using direct TBG measurement in

preference to a THBR ( " uptake " ) test (Table 2). Further, the TT4/TBG

index approach is not independent of the TBG concentration, nor does

it correct for non TBG-related binding protein abnormalities (Table

1) 32,33,60-62. Thus, despite the theoretical advantages of using

direct TBG measurements, indexes employing THBR ( " uptake tests " )

appear to be diagnostically superior to the TT4/TBG index approach

that is now rarely used 63.

( Thyroid Hormone Binding Ratio (THBR) / " Uptake " Tests

The first " T3 uptake " tests developed in the 1950s employed the

partitioning of T3-I131 tracer between the plasma proteins in the

specimen and an inert scavenger (red cell membranes, talc, charcoal,

ion-exchange resin or antibody) 64-66. The scavenger " uptake " of T3

tracer was an indirect, reciprocal estimate of the TBG concentration

of the specimen. Initially, T3 uptake tests were reported as percent

uptakes (free/total tracer). Sera with normal TBG concentrations

typically exhibited uptakes that were 30 ± 5 percent of the T3

tracer. Subsequently, T3-I125 replaced T3-I131 tracers and the

American Thyroid Association recommended that the calculation should

be based on the ratio between absorbant counts divided by the total,

minus absorbant counts, rather than the ratio between absorbant

counts and total counts 54,67. Further, it was recommended that

uptake methods be renamed Thyroid Hormone Binding Ratio (THBR) tests

and expressed as a ratio with normal sera, having an assigned value

of 1.00 54,67. Historically, the use of T3 tracer, as opposed to T4

tracer, was made for practical reasons. Specifically, T3 binding to

TBG is ten-fold lower than T4-TBG binding, resulting in a greater

percentage of unbound T3 tracer being available for scavenger pick

up, and consequently required shorter gamma counting times. As non-

isotopic technology became more widely used, labeled T4 became the

preferred hormone for the THBR testing because a T4 " uptake " more

appropriately correct for T4-binding protein effects 68. Current

THBR tests usually produce normal FT4I and FT3I values when TBG

abnormalities are mild (i.e. pregnancy). However, these tests may

not produce normal index values when patients have congenital TBG

extremes, familial dysalbuminemic hyperthyroxinemia (FDH), thyroid

hormone autoantibodies, nonthyroidal illness or medications that

directly or indirectly influence thyroid hormone binding to plasma

proteins 69-72.

[Guest guest]

I may be missing something here...but wouldn't TSH suppressive therapy

have the same effect as the anti-thyroid drugs?

cindi

>

>

> These effects on autoantibodies have been known for a long time.

> I'll post some of the latest ones and then links to the older

> references:

>

[Guest guest]

clarification - to get the entire article, go to the " breaking news " ,

link to the left.

cindi

>

> It's interesting you mention TBG, as I'm just gotten curious about

> this subject - wondering what impact this may have on some Hashi's

> folks. I'll also be interested in any comments too.

>

> Also, this article may be of interest to some Hashi's folks..this is

> a guy on the 's yahoo group who has a great 's site:

>

> http://mysite.wanadoo-members.co.uk/addisons_network/enter.html

[Guest guest]

Both excessive TSH and positive titres of TRab have negative effects

on us. So we need to do both: Reduce TRab *And* keep TSH low.

> >

> >

> > These effects on autoantibodies have been known for a long time.

> > I'll post some of the latest ones and then links to the older

> > references:

> >

>