The association between thyroid disease and
cardiovascular events has been established in the literature. However, recent
studies published in the Archives of Internal Medicine have highlighted
the link between subclinical thyroid disease and cardiovascular events as well
as the controversy over diagnostic testing and potential treatments. Endocrine
Today spoke with leading experts in the fields of endocrinology and
cardiology about the clinical implications and future research initiatives
surrounding this observation.
“Subclinical or mild hypothyroidism affects roughly
5% to 10% of the general population and tends to be more prevalent in women and
as one gets older. It has been controversial for a few decades whether this
needs treatment, and frequently it is not treated by a number of people, as the
evidence for any benefits is not available,” Salman Razvi, MD,
FRCP, of Gateshead Health National Health Service Foundation Trust and
Newcastle University in the United Kingdom, and a lead author on the study,
told Endocrine Today.
Salman Razvi, MD, FRCP, and colleagues published a paper on the treatment of subclinical hypothyroidism this year that has created a buzz among endocrinologists and cardiologists alike.
Photo by Mr. Gary Turner
The population prevalence of subclinical
hyperthyroidism, however, is dependent on age, sex and iodine intake, and rates
have been shown to vary among clinical studies, according to a seminal paper by
David S. Cooper, MD, of the division of endocrinology and metabolism,
and professor of medicine at The Johns Hopkins University School of Medicine,
and Bernadette Biondi, MD, of the department of clinical and molecular
endocrinology and oncology at the University of Naples Federico II in Naples,
“For most patients who have more mildly low or high
serum [thyroid-stimulating hormone] concentrations in between the extremes (ie,
0.1-0.5 mU/L and 5-10 mU/L, respectively), no firm recommendations can be made,
and the decision to treat or not to treat a patient will be based on various
clinical factors,” Cooper and Biondi wrote.
Thyroid dysfunction, CVD link
Data from a prospective cohort study published in the
Archives of Internal Medicine in May demonstrated that the association
between the risk for coronary heart disease, incident atrial fibrillation (AF)
and mortality, and subclinical hyperthyroidism is especially evident when
thyrotropin levels are lower than 0.10 mIU/L.
David S. Cooper
The study of 52,674 patients (median age, 59 years;
58.5% women) selected from 10 cohorts was conducted by Tinh-Hai Collet,
MD, of the department of ambulatory care and community medicine at the
University of Lausanne in Switzerland, and colleagues. There was a median
follow-up of 8.8 years.
Of those patients, 50,486 were euthyroid and 2,188
(4.2%) had endogenous subclinical hyperthyroidism.
CHD events were analyzed in 22,437 patients from six
cohorts (3.2% with subclinical hyperthyroidism), researchers wrote, and
incident AF was analyzed in 8,711 patients from five cohorts (9.3% with
subclinical hyperthyroidism). The researchers reported that 8,527 patients died
during follow-up, including 1,896 patients who died of CHD.
During age and sex-adjusted analyses, subclinical
hyperthyroidism was related to increased total mortality (95% CI, 1.06-1.46),
CHD mortality (95% CI, 1.02-1.62), CHD events (95% CI, 0.99-1.46) and AF (95%
CI, 1.16-2.43; see chart).
In a separate study presented at the Joint 15th
International Congress of Endocrinology and 14th European Congress of
Endocrinology meeting, Christian Selmer, MD, a research fellow at
Gentofte University Hospital in Copenhagen, Denmark, and colleagues found a
physiological relationship between all levels of thyroid dysfunction and the
risk for AF. This was substantiated with a higher risk in patients with
overactive thyroid glands, even when the condition was very mild or at the high
end of “normal,” and a lower risk in patients with underactive
Kenneth D. Burman
Selmer and colleagues identified individual-level
linkage among 525,100 patients (mean age, 51.7 years; 39.5% men) who consulted
their general practitioner from 2000 to 2009 using nationwide registries. Of
these, 504,113 (96%) patients were euthyroid, 1,474 (0.3%) had clinical
hypothyroidism, 10,679 (2%) had SCH, 3,421 (0.7%) had clinical hyperthyroidism
and 5,414 (1%) had subclinical hyperthyroidism.
The study concluded that patients with TSH levels of 0.1
mU/L and between 0.1 mU/L and 0.2 mU/L had a 1.8 (80%) and 1.5 (50%) increased
relative risk for AF, respectively. Patients who exhibited a higher range of
normal TSH levels of 0.2 mU/L to 0.4 mU/L had a 1.3 (30%) increased risk.
The researchers found clinical and SCH related to a
lower risk for AF, whereas subclinical hyperthyroidism and
“high-normal” thyroid function levels displayed a significant risk
factor for AF.
Another study led by Fen-Yu Tseng, MD, PhD, of
the department of internal medicine at National Taiwan University College of
Medicine in Taipei, Taiwan, evaluated the relationship between SCH and
all-cause and CVD mortality.
The researchers used a baseline cohort of 115,746 Taiwan
patients aged at least 20 years without a history of thyroid disease.
“Our data revealed that SCH was associated with
increased risk for all-cause and CVD mortality, especially in older
subjects,” the researchers wrote.
During the 10-year follow-up period, there were 3,669
deaths (680 due to CVD), according to data. Additional data confirmed that
compared with patients with euthyroidism, after adjustments, the RR for death
from all-cause mortality was 1.3 (95% CI, 1.02-1.66), and CVD mortality was
1.68 (95% CI, 1.02- 2.76).
“We have found that old age and female sex increase
the prevalence of SCH. Patients with SCH had higher BMIs and increased
frequency of hyperlipidemia, diabetes, and hypertension compared with euthyroid
subjects. Furthermore, SCH is independently associated with an increased risk
for all-cause and CVD mortality after adjusting for the aforementioned
confounders,” the researchers concluded.
Some data now suggest that levothyroxine could be the
solution. Retrospective information gathered by researchers in the United
Kingdom provides a glimpse into what may be the next treatment option for those
with subclinical thyroid disease.
The role of levothyroxine
In the absence of any randomized control trial data
suggesting or showing any benefit of treating subclinical thyroid disease with
levothyroxine, Razvi said he and colleagues thought it would be best to tackle
the issue from a “real-life” approach.
To do so, Razvi and colleagues obtained data for 3,093
patients aged 40 to 70 years and 1,642 patients aged older than 70 years using
the United Kingdom General Practitioner Research Database, a large primary care
database of more than 10 million patients. Patient data were recorded in 2001,
and outcomes were examined until March 2009. All patients had new SCH (serum
thyrotropin levels of 5.01-10 mIU/L).
Separate analyses were performed for younger and older
patients. HRs for fatal and nonfatal events were calculated following
adjustments for conventional ischemic heart disease risk factors, baseline
serum thyrotropin levels and initiation of levothyroxine treatment as a
Levothyroxine was used to treat 52.8% of younger
patients and 49.9% of older patients during a median follow-up period of 7.6
“My hypothesis, even before I did the analysis, was
that, based on previous meta-analyses, age may be a significant factor that
affects [CVD] and this condition. Therefore, we analyzed these two groups
separately,” Razvi said.
Sixty-eight incident ischemic heart disease events
occurred among 1,634 younger patients treated with levothyroxine vs. 97 events
in 1,459 untreated patients (HR=0.61; 95% CI, 0.39-0.95). In older patients,
however, 104 events occurred among 819 treated patients vs. 88 events in 823
untreated patients (HR=0.99; 95% CI, 0.59-1.33).
“At baseline, there wasn’t any difference
between who was treated vs. who wasn’t, with reference to the other CV
risk factors,” Razvi said. “But when we looked for a number of
surrogate risk markers, things like contact with a health professional and
number of different CV medications, they were similar in both groups.”
According to Richard Stein, MD, spokesman for the
American Heart Association and professor of medicine and director of the urban
community cardiology program at New York University School of Medicine, this is
one of the more interesting papers he has seen this year.
“It’s an impressive-looking trend in a
relatively small number of cardiac patients, but a large group of patients in a
study, and it raises an interesting question: Should we treat people with [SCH]
to reduce their risk for a cardiac event?”
Clinical implications of treatment
Although it is a topic of debate among endocrinologists
and cardiologists alike, Stein said the study does not form the basis for
“In real life, patients who are treated for this
condition seem to do well, and it is entirely safe to be treating. But,
it’s probably only worthwhile in the younger age groups, and it may not
have an impact in older individuals,” Razvi said.
However, due to the retrospective nature of the study,
Razvi said it is slightly more difficult to conclude that it could be
translated into clinical practice.
Peter A. Singer, MD, professor of clinical
medicine and chief of the clinical endocrinology department at the Keck School
of Medicine of the University of Southern California, told Endocrine Today that doctors should rely on clinical
judgment, as well as these findings.
Peter A. Singer
“There are certainly no contraindications to
treating, and people treat all the time; but I don’t think this single
article alone is enough to say you should go ahead and treat, but it is one new
piece of the puzzle,” Singer said.
According to Kenneth D. Burman, MD, chief of
endocrinology at Washington Hospital Center and professor in the department of
medicine at Georgetown University, Washington, D.C., further long-term,
prospective studies are needed to determine the relationship between SCH,
hyperthyroidism (both treated and untreated) and CV events.
“At present, levothyroxine therapy should be used
mainly with consideration of thyroid function tests, TSH and the clinical
context. I would tend to agree with the guidelines that suggest levothyroxine
treatment should be considered in patients with TSH values above the upper
normal range and less than 10 mU/L, and should be administered to patients with
TSH values greater than 10 mU/L,” Burman said.
The plan for treating SCH (serum TSH concentrations
between 5 mU/L and 9 mU/L) was published in Cooper and Biondi’s seminar.
They wrote that SCH may be associated with greater CV risk in young and
middle-aged patients compared with those aged older than 65 years, and that
levothyroxine may be justified as a form of treatment.
“If levothyroxine replacement has a beneficial
effect, treatment should be continued and serum TSH concentrations should be
assessed every 6 to 12 months to ensure that they remain within the normal
range. Patients can progress to overt hypothyroidism; therefore, increases in
levothyroxine might be needed during follow-up,” they wrote.
However, in the absence of any “clear-cut
benefits,” Cooper and Biondi wrote that levothyroxine therapy should be
stopped and serum TSH concentrations should be screened at annual visits.
Additionally, the researchers wrote that the treatment of SCH is not
recommended in elderly patients (aged older than 75 years) due to a lack of
quality-of-life and symptomatic evidence.
Age-associated TSH levels
Anne R. Cappola, MD, ScM, associate professor of
medicine at Penn Medicine and physician at Perelman Center for Advanced
Medicine in Philadelphia told Endocrine Today, older patients may not benefit
from this treatment because of an “age-associated shift in the
distribution of TSH levels toward higher levels with increasing age.”
Anne R. Cappola
Studies of older patients suggest no increase in CV risk
from leaving those with mild elevations untreated, she said.
“Not surprisingly, the older population (>70
years) had twice as many nonfatal and fatal CV events as the younger population
(aged 40 to 70 years). In the younger population, the absolute difference in
incidence of these events was 2.2% over a 7.6-year period. This is less of an
effect on CV risk than statins, but still noteworthy,” Cappola said of the
study by Razvi and colleagues.
“One of the reasons that treating an older person
with [SCH] might not help them is because there is nothing wrong with them in
the first place,” Cooper said. “The high TSH that you’re
diagnosing as being [SCH] is just the normal aging process and just the normal
level of TSH elevating, and is not necessarily indicative of an underlying
Cooper said the Razvi and colleagues paper adds some
evidence to the idea that even if patients feel healthy, treating them is
reasonable and might even benefit them in terms of CV outcomes.
“It is probably time we did a proper randomized
controlled trial of the right patient age group (younger individuals) to look
at CV disease and outcomes,” Razvi said, adding that the problem has
mainly been funding such a trial, with little to no commercial interest in
levothyroxine. However, such a trial is about to develop in Europe, he said.
Currently, Nicolas Rodondi, MD, MAS, of the
department of general internal medicine, Inselspital University of Bern in
Switzerland, is collaborating with University of Glasgow (linking with Greater
Glasgow Health Board) in Scotland; Leiden University Medical Centre in the
Netherlands; University College Cork in Ireland, and thyroid experts from the
University of California for the Thyroid Hormone Replacement for Subclinical
Hypothyroidism Trial (TRUST).
According to the TRUST website, the objective is to
determine whether there are benefits and/or drawbacks to administering
levothyroxine to older patients with SCH.
During a 5-year period, the TRUST researchers plan to
follow 3,000 patients aged older than 65 years to understand how to treat SCH.
Half of the patients will be treated with levothyroxine, and the other half
will be given placebo. Both of the groups will be monitored and evaluated on
their response to the treatments. The European Union is funding the research.
– by Samantha Costa
- Dr. Burman is deputy editor of the Journal of Clinical Endocrinology and Metabolism, editorial board member for Thyroid, consultant for Medscape and UpToDate, with clinical research protocols and support to his institution from Pfizer, Amgen, Genzyme and Eisai. Dr. Cooper is an editor for UpToDate. All other researchers report no relevant financial disclosures.
Does the study by Razvi et al provide enough evidence to encourage
routine thyroid hormone treatment in middle-aged patients with subclinical
The reason this study by Razvi and colleagues is so clinically important
is, at the present time within endocrinology, there is a major, honest
difference of opinion about whether patients with SCH should be treated.
Our basic science and clinical research work approaches this from the
cardiovascular (CV) point of view. From the cardiac perspective, subclinically
hypothyroid patients have a variety of modifiable CV risk factors. They have
elevated cholesterol, hypertension, impaired cardiac function and impaired
endothelium-derived relaxing factor, the factor that allows you to dilate your
blood vessels when you exercise.
Despite the fact that those things were known in the cardiac field,
there has never been an outcome study to establish that if you treat
hypothyroid patients, the reversal of these risk factors leads to an improved
outcome. This is the first study to demonstrate that CV mortality could be
lowered in subclinically hypothyroid patients who were treated.
Irwin L. Klein
You can criticize the study in a sense that it wasn’t a
prospective, randomized controlled trial, but it is what we call a
‘real-world study.’ These are practitioners choosing to treat or not
treat based upon existing treatment paradigms. It turns out they chose to treat
or not treat on a 1:1 ratio and there was no obvious treatment bias.
The results clearly demonstrated, in patients aged younger than 70
years, that there was a survival advantage. So that is a very relevant finding.
If I’m in the office with a 50-year-old patient with SCH, I have further
rationale to treat. Not only do I have the potential to improve the various
thyroid hormone mediated aspects of metabolism and the standard but often
subtle thyroid symptoms, but I can also potentially improve CV morbitity and
With that in mind, it is my opinion that patients with SCH should be
given levothyroxine to reduce their CV risk, with the understanding that there
is good reason to suspect you could improve their overall CV mortality.
Irwin L. Klein, MD, is a Thyroidologist and
Professor of Medicine, North Shore University Hospital, Manhasset, NY.
Disclosure: Dr. Klein reports no relevant financial disclosures.
No, it does not. The authors point out that although this is a large
observational study, it is retrospective in nature and subject to potential
bias. In addition, the authors conclude by suggesting that a randomized,
prospective trial is indicated (by their calculations, approximately 1,450
participants would be needed).
Stuart R. Chipkin
So, even the authors are not rushing to suggest widespread prescribing
of levothyroxine under these circumstances. As clinicians weigh the choice of
treating patients with similar biochemical parameters, it is worth remembering
who was excluded from this study:
- Those with a history of ischemic heart disease.
- Those with cerebrovascular disease.
- Those receiving lithium, amiodarone or steroids within the past year.
Manuscript notes the high compliance of patients treated with
levothyroxine. This may be related to improvement in some subtle symptoms
experienced by patients. In that case, it is not the CV benefit that may be the
reason to treat patients, but the presence of symptoms despite only mild
elevations in TSH and normal thyroxine concentrations. In addition, the loss in
benefit-to-risk, which occurs after age 70 raises the question of, ‘What
factors are at play?’ Are there other factors (or illnesses) that might
mitigate the benefit of levothyroxine that appears to be present at an earlier
age? Since there are several questions and insufficient answers, I would not
advocate the routine use of thyroid hormone in middle-aged patients with
SCH. Patients who do not have any of the exclusionary criteria and who have
symptoms suggestive of hypothyroidism and who are willing to accept the
addition of another medication can have the potential advantages (and
disadvantages) explained to them. Given our imperfect knowledge, a mutual
decision based on available information would seem like a reasonable course of
I would not rush to treat elderly patients with biochemical evidence of
SCH. These data do not suggest any benefit. Elderly patients are on more
medications (confirmed in this study) and the unclear benefit in clinical
outcomes would not speak toward recommending the addition of another medication
to these individuals.
Stuart R. Chipkin, MD, is a research professor
in the School of Public Health and Health Sciences at the University of
Massachusetts Amherst and an endocrinologist practicing with the Valley Medical
Group in Amherst, Mass. Disclosure: Dr. Chipkin reports no relevant