Thyroid status, old age, disability/brain function and survival

[Guest guest]

Hi All,

CR seems to involve lower thyroid functions. To me this

suggested that thyroid status, old age, disability/brain function

and survival may describe the pdf-available, not yet in Medline

below.

Related to this is the remainder of the post.

For definitions, is:

Thyrotropin: Thyroid stimulating hormone.

Polypeptide hormone (28 kD), secreted by the anterior

pituitary gland, that activates cyclic AMP production in thyroid

cells

leading to production and release of the thyroid hormones (T4 and

T3). T4 and T3 blood levels feedback on the pituitary gland and

decrease thyroid stimulating hormone production when T3 and

T4 levels are high.

Thyroxine: Thyroid hormone.

First, is the abstract of the pdf-available not yet in Medline

central paper.

Thyroid Status, Disability and Cognitive Function, and Survival in

Old Age

ijn Gussekloo; van Exel; Anton J. M. de Craen; Arend E.

Meinders; Marijke Frölich; Rudi G. J. Westendorp

JAMA. 2004;292:2591-2599.

... A prospective, observational, population-based

follow-up study within the Leiden 85-Plus Study of 87% of a 2-year

birth co-hort

(1912-1914) in the municipality of Leiden, the Netherlands. A total

of 599 par-ticipants

were followed up from age 85 years through age 89 years (mean [sD]

follow-up,

3.7 [1.4] years).

Main Outcome Measures Complete thyroid status at baseline; disability

in daily

life, depressive symptoms, cognitive function, and mortality from age

85 years through

89 years.

Results Plasma levels of thyrotropin and free thyroxine were not

associated with dis-ability

in daily life, depressive symptoms, and cognitive impairment at

baseline or dur-ing

follow-up. Increasing levels of thyrotropin were associated with a

lower mortality

rate that remained after adjustments were made for baseline

disability and health sta-tus.

The hazard ratio (HR) for mortality per SD increase of 2.71 mIU/L of

thyrotropin

was 0.77 (95% confidence interval [CI], 0.63-0.94; P=.009). The HR

for mortality

per SD increase of 0.21 ng/dL (2.67 pmol/L) of free thyroxine

increased 1.16-fold (95%

CI, 1.04-1.30; P=.009).

Conclusions In the general population of the oldest old, elderly

individuals with ab-normally

high levels of thyrotropin do not experience adverse effects and may

have a

prolonged life span. However, evidence for not treating elderly

individuals can only

come from a well-designed, randomized placebo-controlled clinical

trial.

Now, below, is the review in this latest JAMA issue,

that is also pdf-available and not yet in Medline.

Thyroid Disease in the Oldest Old: The Exception to the Rule

S.

JAMA. 2004;292:2651-2654.

See also pp 2591, 2600, and 2632.

Thyroid Neoplasia, Autoimmune Thyroiditis, and Hypothyroidism

in Persons Exposed to Iodine 131 From the Hanford Nuclear Site

; J. Kopecky; E. Hamilton; Lynn Onstad;

and the Hanford Thyroid Disease Study Team

JAMA. 2004;292:2600-2613.

Clinical Crossroads

A 64-Year-Old Woman With a Thyroid Nodule

J. Mandel

JAMA. 2004;292:2632-2642.

And, here is the review, from which I very much enjoyed to read:

" Gussekloo et al 24 cite data in animal

studies showing that hypothyroidism is associated with a

longer life span, possibly related to a lower metabolic rate.

Whether this might also be the case in humans with sub-clinical

hypothyroidism or overt hypothyroidism remains

speculative. There is a large body of work comparing thy-roid

physiology in older and younger individuals,33 which

demonstrates decreased thyroid hormone action at the tis-

sue level, decreased thyroid hormone metabolism, and al-terations

in the hypothalamic-pituitary-thyroid axis in the

elderly " .

The young man knows the rules, but the old man knows the excep-

tions.1

Oliver Wendell Holmes

ALMOST 4 DECADES AGO,BASTENIE AND COL-leagues

2 used the term subclinical hypothyroidism

to describe, for the first time, a group of clinically

euthyroid individuals with circulating antithy-roid

antibodies, low normal plasma protein–bound iodine

levels, and, using a mouse bioassay, elevated serum thyro-tropin

levels. Evered and colleagues 3 subsequently de-scribed

a similar group of asymptomatic individuals in whom

" conventional tests of thyroid function showed nothing

abnormal ...butthey were all found to have a raised se-rum

thyrotropin concentration. " They also used subclini-cal

hypothyroidism to describe this constellation of clini-cal

and laboratory data. Since then, hundreds of articles have

been published on this topic, but physicians are no closer

to understanding whether this mild, usually asymptomatic

form of hypothyroidism presents a clinical risk, requiring

screening for detection and thyroid hormone treatment, or

whether screening and therapy are unnecessary and possi-bly

even counterproductive.4

Subclinical hypothyroidism is most often detected in older

women (age 60 years), in whom the prevalence may be

as high as 20%.5 The majority of affected individuals have

circulating antithyroid antibodies,2 establishing the auto-immune

etiology of subclinical hypothyroidism. Most pa-tients

have only slightly elevated serum thyrotropin levels

(usually between 5 and 10 mIU/L), emphasizing the mini-mal

nature of the biochemical abnormality.5,6 Given the de-mographics

of subclinical hypothyroidism, it is not surpris-ing

that symptoms consistent with mild hypothyroidism,

including cold intolerance, dry skin, constipation, and de-pressed

mood, are frequently seen in older patients with sub-clinical

hypothyroidism.5,7 However, whether these and other

nonspecific symptoms are more prevalent or more severe

than they are in an age-matched healthy control popula-tion

remains to be established.

Starting with Bastenie et al,8 some investigators have ob-served

an association between subclinical hypothyroidism

and atherosclerotic cardiovascular disease,9,10 whereas oth-ers

have been unable to establish an unambiguous link.11,12

If an association does exist, it has been postulated to be me-diated

by dyslipidemia, long known to be present in overt

hypothyroidism, or via nontraditional risk factors such as

C-reactive protein, homocysteine, and lipoprotein(a).13 How-ever,

the link between subclinical hypothyroidism and these

putative risk factors is rather tenuous. For example, while

some epidemiological studies have demonstrated a higher

frequency of cardiovascular disease in individuals with sub-clinical

hypothyroidism, they do not necessarily show al-tered

serum lipid levels in affected individuals.9 Further-more,

only a handful of controlled trials of thyroxine therapy

have demonstrated improvement in serum lipid levels 14 or

other putative risk factors 15 in patients with minimal se-rum

thyrotropin elevations (ie, 5-10 mIU/L), with the ma-jority

of studies showing no effect.16,17 More recent small trials

of thyroxine therapy in subclinical hypothyroidism have

shown improvements in other surrogate end points, includ-ing

increased endothelium-dependent vasodilatation 18 and

a decrease in carotid intimal thickness,19 lending support

to the hypothesis that subclinical hypothyroidism may be

associated with atherosclerosis.

Just as an unequivocal relationship between subclinical

hypothyroidism and prevalent cardiovascular disease or car-diovascular

risk factors has been difficult to document in

cross-sectional studies, until recently no study had shown

an increase in overall or cardiovascular mortality in indi-viduals

with subclinical hypothyroidism followed up lon-gitudinally.

In fact, 2 long-term follow-up studies showed

that patients with thyrotropin levels higher than 5 mIU/L

had 10- and 20-year survival times comparable with euthy-roid

controls.20,21 In a study published more recently, an in-crease

in all-cause mortality was seen in men with subclini-cal

hypothyroidism who were followed up for 12 years.10

These data are difficult to interpret because the increase in

all-cause mortality was observed only in years 3 through 6

of follow-up and was no longer present after 10 years, the

causes of death were not available to the investigators, and

the effect was limited to men.

Because of its high prevalence in older persons and a pos-sible

association with cardiovascular disease, subclinical hy-pothyroidism

has become a public health issue of some

prominence. For example, the Institute of Medicine evalu-ated

the advisability of covering thyrotropin screening among

the Medicare population. After analyzing the available evi-dence

and performing a cost-benefit analysis, the Institute

of Medicine found the evidence for a benefit of screening

to be lacking, and consequently determined that coverage

for screening should not be provided as a Medicare ben-efit.

22 A similar conclusion against screening for mild hy-pothyroidism

in the adult population was reached by a con-sensus

development panel sponsored by the 3 major

professional societies published earlier this year in JAMA.23

The panel also recommended against routine treatment of

subclinical hypothyroidism. The panel's recommenda-tions

were so contentious that the 3 sponsoring societies (the

American Thyroid Association, the American Association

of Clinical Endocrinologists, and the Endocrine Society) have

declined to endorse the statement.

The article by Gussekloo et al 24 in this issue of JAMA must

be assessed against this background. The authors used a

population-based, prospective study of all 85-year-olds liv-ing

in Leiden, the Netherlands, who were invited to par-ticipate

between 1997 and 1999 during the month of their

85th birthday. Of the individuals who were approached, 87%

or 599 agreed to participate in the study. Their thyroid sta-tus

was assessed at baseline, and individuals who were found

to have overt thyroid disease (hyperthyroidism or hypothy-roidism)

were referred to their primary care physicians for

possible treatment. Individuals with subclinical hypothy-roidism

(elevated serum thyrotropin, normal free thyrox-ine)

and subclinical hyperthyroidism (subnormal serum thy-rotropin,

normal free thyroxine) were followed up without

therapy. Through annual personal follow-up visits in the in-dividuals'

homes, the investigators assessed activities of daily

living, cognitive performance, and depressive mood using

a battery of validated rating scales. Survival was prospec-tively

monitored.

At baseline, the prevalence of hypothyroidism in this el-derly

cohort was 12%, and somewhat surprisingly, subclini-cal

and overt hypothyroidism occurred with equal fre-quency.

Astonishingly, none of the patients who had been

found to have overt thyroid disease was prescribed treat-ment

by their physicians. Consequently, at the end of the

4-year follow-up period at age 89 years, the only patients

who were taking thyroid medications were those few who

had been taking it when the study began. This is important

because prior cohort studies that have followed up indi-viduals

with subclinical hypothyroidism prospectively have

not ascertained whether they had been given thyroid hor-mone

replacement during the follow-up period.20,21

At the start of the follow-up period, individuals who had

elevated serum thyrotropin levels at baseline had compa-rable

activity, cognitive function, and depressive feelings com-

pared with individuals with normal thyroid function. Thus,

there was no evidence that overt or subclinical hypothy-roidism

affected elderly individuals' performance status or

mood. After 3 years, none of the individuals with subclini-cal

hypothyroidism had progressed to overt hypothyroid-ism.

Furthermore, during the annual follow-up examina-tion,

those participants with increased serum thyrotropin

levels actually had a similar or less rapid decline in specific

disability measures compared with individuals with nor-mal

thyroid function. Most surprising, perhaps, was the ob-servation

that individuals with both overt and subclinical

hypothyroidism had lower all-cause and cardiovascular mor-tality

than clinically euthyroid individuals. Lower mortal-ity

rates were seen in both men and women, and this oc-curred

even though serum cholesterol levels were higher in

this group at baseline. In contrast, increasing serum levels

of free thyroxine and low serum thyrotropin levels (ie, overt

or subclinical hyperthyroidism) were associated with an in-creased

risk of cardiovascular mortality.

These data seem to be at odds with the preconceived no-tions

of the effects of hypothyroidism on functioning, cog-nitive

ability, mood, and cardiovascular outcomes. Several

intervention trials have suggested that subclinical hypothy-roidism

is associated with memory deficits in younger in-dividuals

25-27 that are reversible to some extent with thy-roid

hormone therapy. On the other hand, cross-sectional

studies of geriatric populations have not shown differences

in cognitive function between euthyroid individuals and those

with mild hypothyroidism.28,29 Although one prospective

study did show an increase in cognitive decline in individu-als

with below normal serum thyroxine levels.30 Data on

mood in younger individuals with subclinical hypothyroid-ism

are similarly inconsistent, with some studies showing

depressed mood 26,31 that improves with thyroxine,26 while

other studies have not documented any change after treat-ment.

27 In cross-sectional studies focusing on depression in

geriatric populations, some found a possible relationship be-tween

depression and elevated serum thyrotropin levels,32

while others did not.29 And although one might have thought

that the investigators in the present study would have found

a higher cardiovascular mortality in patients with subclini-cal

hypothyroidism, they did not, and this is at odds with

the most recent prospective study,10 but similar to the 2 other

studies.20,21

In summary, it appears that neither subclinical hypothy-roidism

nor overt hypothyroidism is a cause of decline in

performance, altered cognition or mood, or long-term sur-vival

in the oldest old. Gussekloo et al 24 cite data in animal

studies showing that hypothyroidism is associated with a

longer life span, possibly related to a lower metabolic rate.

Whether this might also be the case in humans with sub-clinical

hypothyroidism or overt hypothyroidism remains

speculative. There is a large body of work comparing thy-roid

physiology in older and younger individuals,33 which

demonstrates decreased thyroid hormone action at the tis-

sue level, decreased thyroid hormone metabolism, and al-terations

in the hypothalamic-pituitary-thyroid axis in the

elderly; whether these changes or others might be respon-sible

for some of these observations is not known. The re-sults

from the study by Gussekloo et al should not be ex-trapolated

to young or middle-aged individuals with

hypothyroidism who may experience adverse health con-sequences

if not treated.9,10

From a clinician's point of view, the data presented by

Gussekloo et al 24 need to be replicated by other groups. If

these results can be confirmed, they would strongly imply

that thyroid hormone therapy could have adverse effects on

mortality in the oldest old with subclinical hypothyroid-ism

or overt hypothyroidism, particularly when the thy-roid

disease is diagnosed by screening. Without long-term,

prospective randomized controlled trials of treatment for sub-clinical

hypothyroidism, it is hard to recommend for or

against treatment, and clinicians must rely on imperfect evi-dence

from observational studies, such as the one by Gusse-kloo

et al.24 Currently, there is little debate among endo-crinologists

regarding thyroxine treatment of individuals with

overt hypothyroidism or subclinical hypothyroidism with

serum thyrotropin levels higher than 10 mIU/L.23 This is

based on the likelihood of reversible dyslipidemia 34 and its

known link with adverse cardiovascular outcomes, as well

as the relatively high likelihood of progression of subclini-cal

hypothyroidism to overt hypothyroidism over a 10- to

20-year period.35

It may be that individuals with hypothyroidism who are

older than 85 years are being protected from adverse out-comes

by a lower metabolic rate or other factors, and that

current clinical guidelines and recommendations should not

apply to this select group. However, one study should not

challenge clinical practice so radically that more than a cen-tury

of successful treatment of hypothyroidism would be

called into question. However, given the totality of evi-dence,

22,23 combined with data from the study by Gusse-kloo

et al,24 it is reasonable to recommend against screen-ing

for thyroid disease in asymptomatic elderly individuals.

If an elderly individual is found by screening or case find-ing

to have overt hypothyroidism, it would be reasonable

to initiate thyroxine treatment, although the serum thyro-tropin

target might be 4 to 6 mIU/L, rather than the target

of less than 3.0 mIU/L that has been recommended by some

groups.36 If subclinical hypothyroidism is identified in an

individual aged 80 years or older, and the serum thyrotro-pin

level is between 5 and 10 mIU/L, initiation of thyrox-ine

therapy probably is not necessary. If the serum thyro-tropin

level were higher than 10 mIU/L, initiating thyroxine

therapy would be appropriate as has been recommended,23

but again, the target serum thyrotropin level would be rela-tively

high (eg, 4 to 6 mIU/L).

The provocative data presented by Gussekloo et al 24

prompt a number of questions and speculations. First, a ma-jor

clinical concern is whether treatment of subclinical hy-

perthyroidism would improve survival because both Gusse-kloo

et al 24 and others 20 have shown increased mortality in

affected individuals. Current recommendations support

therapy in patients with serum thyrotropin levels of less than

0.1 mIU/L,23 but no randomized controlled trials have been

performed and they are sorely needed. Second, is there a

survival advantage to having autoimmune thyroiditis, the

likely cause of the thyroid disease in this cohort of older in-

dividuals?

Third, if the data on a possible protective effect

of hypothyroidism are correct, what is the mechanism? The

answers to this more fundamental question must await ad-ditional

research into the relationship between the aging pro-cess

and thyroid hormone action at the cellular level.

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Cheers, Alan Pater