Download Effects of Thyroid Function on Blood Pressure

Effects of Thyroid Function on Blood Pressure
Recognition of Hypothyroid Hypertension
DAVID H. P. STREETEN, GUNNAR H. ANDERSON, J R . , TIMOTHY HOWLAND,
RICHARD CHIANG, AND HAROLD SMULYAN
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SUMMARY Hypothyroid ism has been known to be associated, at times, with diastolic hypertension. We have found in 40 thyrotoxic patients that the induction of hypothyroid ism by radioiodine
therapy significantly increased diastolic blood pressure, raising it above 90 mm Hg in 16 (40%) of the
patients. Restoration of euthyroidism with thyroxine administration significantly reduced the systolic
and diastolic blood pressures in these patients, with a fall in diastolic pressure below 90 mm Hg in nine
of 16 patients. The prevalence of hypothyroid ism was determined by measurements of serum thyroxine and thyrotropin concentrations in 688 consecutive hypertensive patients, referred for evaluation
and therapy of their hypertension. Hypothyroidism was found in 25 (3.6%) of the patients. Restoration of normal serum thyroxine and thyrotropin levels with thyroid hormone replacement therapy
lowered diastolic blood pressure to levels below 90 mm Hg in 32% of these patients who could be
followed up after withdrawal of all antihypertensive drug therapy when euthyroidism had been
restored (i.e., 1.2% of the 688 patients). It is concluded that diastolic hypertension resulting from
hypothyroidism is a relatively common disorder, present in 1.2% of our referred hypertensive
patients, that should be sought and treated. (Hypertension 11: 78-83, 1988)
KEY WORDS • hypothyroid hypertension
• endocrine hypertension
H
• thyroid in hypertension
were reported by Fuller et al. 2 However, in a comparison of BP measurements in 80 hypothyroid patients
and 73 euthyroid subjects, Endo et al.8 found no evidence that hypothyroidism predisposed to hypertension. Apart from this negative study, there have been
no recent attempts to determine the frequency with
which hypertension may be associated with and caused
by hypothyroidism, the treatment of which will restore
the BP to normal. We have sought to obtain this information 1) by studying the BP responses of a series of
patients with thyrotoxicosis to therapy with radioiodine as they became euthyroid and, frequently, hypothyroid and during correction of the iatrogenic hypothyroidism with thyroxine therapy and 2) by measuring
the prevalence of hypothyroidism in 688 consecutive,
referred patients with hypertension and, in those found
to be hypothyroid, by determining the effect of thyroxine replacement therapy on the BP. Some of these data
have been published previously in abstract form.9
YPERTHYROIDISM is usually associated
with peripheral vasodilatation and reduction
of the diastolic blood pressure (BP) and
sometimes with systolic hypertension, while hypothyroidism may be accompanied by diastolic hypertension, as many clinicians are aware. Elevation of the
diastolic BP was found to be common in patients with
hypothyroidism1 and has been reported in small groups
of patients with hypothyroidism and myxedema by
several investigators,2"6 who have all found a fall in
diastolic BP when the hypothyroidism was corrected
with thyroid replacement therapy. The latter observations were preceded by a report that desiccated thyroid
administration lowered the BP to normal levels in 14%
of 334 patients with essential hypertension, at a time
(in 1950) when virtually no effective forms of antihypertensive therapy were available.7 Similar findings
From the Endocrine and Cardiology Sections, Department of
Medicine, SUNY-Health Science Center, Syracuse, New York.
Supported by a research grant (HL 26748) from the National
Heart, Lung, and Blood Institute and a Clinical Research Center
grant (RR 229) from the Division of Research Facilities and Resources, U.S. Public Health Service.
Address for reprints: Dr. D.H.P. Streeten, Department of Medicine, SUNY Health Science Center, 750 E. Adams Street, Syracuse, NY 13210.
Received February 11, 1987; accepted August 13, 1987.
Patients and Methods
Serial BP measurements were made with an aneroid
sphygmomanometer in a series of 40 patients who
were referred for hyperthyroidism. The patients were
aged 30 to 65 years, of both sexes (35 women, 5 men),
and almost all were of normal weight when first seen.
78
HYPOTHYROIDISM CAUSING HYPERTENSION/S/reefen et al.
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BP was measured in the sitting posture, at each office
visit, before treatment with iodine-131 (80 /iCi/g of
estimated thyroid weight); 3 to 6 months later when
euthyroidism had been restored; during the subsequent
development of hypothyroidism, which commonly
follows radioiodine treatment; and after the restoration
of euthyroidism by replacement therapy with sufficient
L-thyroxine or desiccated thyroid to restore serum thyroxine (T4) and thyrotropin or thyroid stimulating hormone (TSH) concentrations to normal. Measurements
of serum T4 and TSH levels were made by radioimmunoassay at each visit.
In 688 consecutive, untreated patients referred for
study and management of their hypertension, we measured BP in the recumbent and standing postures with
an aneroid sphygmomanometer; serum T4, TSH, and
electrolyte concentrations, as well as plasma renin activity (PRA),10 after furosemide, 40 mg i.v., and
standing for 2 hours; BP response to the angiotensin II
antagonist saralasin; and plasma aldosterone concentration after an intravenous infusion of 2 L of 0.9%
NaCl given over 3.5 hours." 112 The patients varied in
age from 15 to 70 years, were evenly divided between
female and male (55:45) patients, and had a mean
body weight of 79.6 kg. Only in three of the five
patients whose serum TSH exceeded 30 /ilU/ml was
the diagnosis of hypothyroidism suspected on clinical
grounds. Female patients predominated (75:25)
among those patients who were found to be hypothyroid. Mean body weight in the hypothyroid patients
was 81.5 ± 2 . 9 kg, and mean age was 49.8 ± 2.5
years. Patients who were found to be hypothyroid were
given L-thyroxine in addition to their usual antihypertensive drugs in increasing doses until serum T4 and
TSH concentrations were restored to normal. When
this had been accomplished, their hypotensive medications were tapered and stopped to determine whether
the BP would remain in the normal range during treatment with thyroid replacement only.
All of these studies were approved in advance by the
Institutional Review Board for the Protection of Human Subjects at the SUNY Health Science Center
(Syracuse, NY, USA).
Results
Figure 1 shows the results of the systolic and diastolic BP measurements in the 40 patients with hyperthyroidism. Before radioiodine therapy, eight of the patients had systolic hypertension and five had diastolic
pressures above 90 mm Hg; the mean ± SEM values
for the 40 patients were 138.2 ± 3.2/77.7 ± 2.0 mm
Hg. When they had become euthyroid after I3II treatment, mean systolic BP fell to 132.6 ± 3.7 mm Hg
while diastolic pressure rose to 81.2 ± 1.9 mm Hg.
The subsequent fall in serum T4 concentration to hypothyroid levels was associated with a change in mean
BP to 141.4 ±4.6/88.4 ± 2 . 4 mm Hg. When they
were hypothyroid, 16 of the 40 patients had diastolic
BPs above 90 mm Hg. Restoration of euthyroidism (T4
and TSH both within normal limits) by replacement
therapy, reduced the diastolic BP below 90 mm Hg in
79
all except seven of the patients (five of whom also had
had diastolic hypertension when thyrotoxic), while the
BP in the entire group averaged 130.6 ± 1.9/80.8 ±
1.9 mm Hg. The changes in diastolic BP from the
thyrotoxic to the hypothyroid and euthyroid states
were highly significant by analysis of variance
(/><0.0001). The changes in systolic BP were not
significant. No clinical or laboratory differences were
found between the patients whose diastolic BP rose
above 90 mm Hg during hypothyroidism and those
whose diastolic BP remained below 90 mm Hg. However, there were significant correlations between the
diastolic BPs during hyperthyroidism and hypothyroidism ( r = +0.576, p < 0 . 0 0 1 ) , during hyperthyroidism and euthyroidism (r = +0.476, p < 0 . 0 0 5 ) ,
and during hypothyroidism and euthyroidism (r =
+ 0.653, p<0.00l).
A computer printout of the serum T4 and TSH concentrations jn the 688 untreated hypertensive patients
is shown in Figure 2. It is evident that serum T4 was
elevated ( > 12 /ig/dl) in 26 (3.8%) of the patients,
while hypothyroidism (serum T 4 < 5 fig/d\ or serum
T S H > 7 /ilU/ml, or both) was present in 25 (3.6%) of
the patients. Only three of these patients had clinical
features suggesting hypothyroidism.
Figure 3 shows the results of various functional
measurements in the 25 hypertensive patients who
were found to have hypothyroidism. Plasma renin activity, stimulated by furosemide diuresis and orthostasis, was subnormal (below 1.7 ng/ml/hr) in 13 of 25
(52%) patients. Plasma aldosterone fell into the normal
range (1.7-8.5 ng/dl) in all but one of the 22 patients in
whom it was measured after the 2-L saline infusion.
Intravenous infusion of saralasin, at 0.05 to 20 /Ltg/kg/
min, lowered the diastolic BP more than normally
(i.e., by > 8 mm Hg) in three, raised it to some extent
in 17 patients, and raised diastolic BP by more than 8
mm Hg in six of these 17 patients. Cardiac index,
measured in two patients, was high-normal in one and
low-normal in the other patient, while systemic vascular resistance was elevated in both patients studied.
Follow-up was incomplete in five of the hypothyroid patients because of death (one), loss to follow-up
(two), and departure of the patient from this area
(two). Figure 4 shows BP responses to the restoration
of euthyroidism in the remaining 20 hypothyroid patients. In eight, diastolic BP fell below 90 mm Hg
when they became euthyroid and remained below 90
mm Hg when all antihypertensive medications had
been stopped for at least 6 months. In the other 12
patients diastolic BP remained above 90 mm Hg when
euthyroidism had been restored unless antihypertensive drugs were administered. Four of the patients in
this group had severe renal insufficiency, with one of
the four requiring chronic hemodialysis. Female patients predominated both in those whose BP fell to
normal levels on thyroxine therapy alone (6 female, 2
male patients) and in those who continued to require
other antihypertensive therapy after they had become
euthyroid (9 female, 3 male patients); both groups
reflected the preponderance of women among hypo-
HYPERTENSION
FIGURE 1. Systolic and diastolic BP
readings related to serum thyroxine (T4)
or protein-bound iodine (PBl) concentrations in 40 patients during their conversion from thyrotoxicosis (T4> 12
y^gldl) to euthyroidism (T4 = 5-12
fj.g/dl) to hypothyroidism (T4 < 5 y.gldl)
and finally to euthyroidism during T4
replacement therapy. Diastolic BP was
above 90 mm Hg in five patients during
thyrotoxicosis, in 16 patients during hypothyroidism, and in seven patients during subsequent euthyroidism restored by
T4 replacement therapy.
VOL 11, No 1, JANUARY
1988
250,
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40
BEFORE
I
131
1 THERAPY
AFTER
HYPOEUTHYROID ON
EUTHYROID[ r H Y R O I D
REPLACEMENT R«
THERAPY
HYPERTHYROID
20
32
24
16
SERUM
thyroid patients in general. There was a significant age
difference (p< 0.025) between these two groups of
patients: the mean age of those whose hypertension
was corrected by thyroxine alone was 41.3 ± 6 . 0
(SEM) years (range, 21-67 years), while in the second
group mean age was 57.1 ± 3.2 years (range, 28-68
years).
Discussion
It is evident from this study that diastolic BP rose
significantly during the change from hyperthyroidism
to hypothyroidism and fell significantly when euthyroidism was restored in the 40 originally thyrotoxic
patients. These observations confirm the similar findings described by Davis and Davis4 in some of the
elderly thyrotoxic patients whose clinical responses to
radioactive iodine therapy they reported. No less than
40% of our patients had diastolic BPs over 90 mm Hg
when they were hypothyroid, and in most of these the
blood pressure fell below 90 mm Hg after adequate
replacement therapy. These data certainly substantiate
the theoretical possibility that some patients who are
seen with hypertension might have unrecognized hypothyroidism and could be restored to normotension
with thyroxine replacement therapy alone.
THYROXINE
8
0
or
PBl,
4
pg/dl
The serum T4 and TSH measurements in the 688
hypertensive patients revealed the presence of unrecognized hypothyroidism in 3.6%. Although serum T4
concentration was normal in several of these patients,
the elevation of serum TSH levels was assumed to
indicate the presence of primary hypothyroidism, in
accordance with current views.13 Among the hypothyroid patients, there was a higher prevalence (52%) of
low renin hypertension (associated with subnormal
stimulated PRA levels and an agonistic BP response to
saralasin14) than in euthyroid hypertensive patients of
whom 30% had low PRA levels." The suppressed
level of PRA did not result from autonomously and
unsuppressibly elevated plasma aldosterone concentrations, except in one patient, who did not have evidence of an adrenal adenoma by computed tomographic scanning. The hemodynamic measurements in two
of these patients disclosed elevation of the systemic
vascular resistance, as is found in most patients with
sustained hypertension.
It was of interest to find that in no less than eight
patients with unrecognized hypothyroidism, or 1.2%
of the 688 patients studied, therapeutic restoration of
euthyroidism was associated with a fall in diastolic BP
below 90 mm Hg. It is possible that the fall in BP
HYPOTHYROIDISM CAUSING HYPERTENSION/5/reeren et al.
81
FIGURE 2. Serum thyroxine and thyrotropin (TSH) concentrations in 688 untreated hypertensive patients referred for refractoriness to therapy. In 25 patients (large dots) hypothyroidism was evident from subnormal serum
thyroxine (in 11) or elevated serum TSH (in 19) concentrations or both.
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represented a placebo response, though the lack of an
adequate reduction of BP during treatment given before the initiation of T4 replacement therapy would
argue against that possibility. Thus, in these individuals, 1.2% of the 688 patients studied, it is reasonable
to attribute their hypertension to the demonstrated hypothyroidism and it was possible to control the hypertension with thyroxine alone, without the variety of
antihypertensive drugs that they had been given before
cessation of the therapy for the diagnostic studies. The
hypothyroid patients whose diastolic BP fell below 90
mm Hg on L-thyroxine therapy alone were younger
than those who continued to require other antihypertensive therapy after becoming euthyroid. Our recent
observations in patients with primary aldosteronism
and renal arterial stenosis (D. H. P. Streeten, G. H. An-
PRA
Plasma Aldosterone Change m Diastolic
after Furosemide
after 0 9 % NoCI B P during SorokJSin
and standing 2 h
Infusion
(ng/mL/h)
(mmHg)
o a
8
'¥•'
Cordioc Index
(L/mm/M 2 )
derson, Jr., S. Wagner, unpublished observations,
1987) have confirmed the general principle that hypertension in older persons frequently persists when the
initiating cause has been removed. It is possible, therefore, that if hypothyroidism had been discovered and
treated at an earlier age, more of our patients would
have been responsive to T4 alone.
Although the prevalence of hypothyroidism in our
hypertensive patients cannot be taken to indicate its
prevalence in the entire hypertensive population, it is
likely that a large number of hypertensive patients are
being given a vast array of modern antihypertensive
drugs instead of the one hormone, T4, which they really need both to correct their hypertension and to overcome their hypothyroidism. Since hypothyroidism is
mild and usually not clinically recognizable and since
Systemic Vosculor
Resistance
(dyn s)/crr.5
2200 O
FIGURE 3. Measurements of PRA (after
furosemide and standing for 2 hours), plasma aldosterone concentration (after 2 L of
0.9% NaCl i.v.), change in diastolic BP
during saralasin infusion, cardiac index,
and systemic vascular resistance in 25 hypertensive patients with hypothyroidism.
Normal ranges are shown by crosshatching. Data from patients who subsequently
became normotensive during thyroxine (T4)
therapy are shown with circles, and the
findings in those whose hypertension persisted during subsequent euthyroidism are
shown with squares.
82
FIGURE 4.
HYPERTENSION
Measurements
of
VOL 11, No 1, JANUARY 1988
serum
tkyrotropin (TSH) and thyroxine (T4)
concentrations and BP in 20 patients
during hypothyroidism (*) and therapeutically restored euthyroidism (m).
Restoration of euthyroidism was associated with a fall in diastolic BP to or
below 90 mm Hg in eight of the 20 patients.
Before Ounng
ThyroKim Rx
in in
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NORMCTTENSIVE ON L-THYRCKINE ALONE
most of these patients can be diagnosed with a serum
TSH measurement alone, the desirability of performing this determination routinely on hypertensive patients is worthy of consideration.
The mechanism of hypertension in patients with hypothyroidism is not known. Ourfindingof low stimulated PRA levels in 52% of these patients confirms
previous reports of low PRA levels in patients with
hypothyroid hypertension.5' " Thyroidectomy reduced
PRA in rats.16 These results might indicate that fluid
retention and extracellular fluid volume expansion in
hypothyroidism17'18 might be the mechanism of the
hypertension. There is also evidence for a potential
role of norepinephrine in the hypertension of patients
with hypothyroidism, both urinary excretion19 and
plasma concentration of norepinephrine3'M being elevated in hypothyroid patients. However, interpretation
of the relevance of these findings to the pathogenesis
of hypertension is complicated by the observations of
Schneckloth et al. ,21 who found reduction of the pressor responsiveness to norepinephrine in a patient with
myxedema and excessive norepinephrine responsiveness in four thyrotoxic patients.
The effects of changes in thyroid function on the BP
have been studied in spontaneously hypertensive rats
(SHR). Fregly22 reported that SHR had lower l3lI-uptake by the thyroid gland than normotensive control
animals. However, thyroidectomy or administration of
propylthiouracil prevented the expected rise in BP,
both in renal hypertension23 and in NaCl-induced hypertension in rats.24 Serum T4 concentrations are lower
in the prehypertensive stage of SHR, but thyroidectomy at this stage prevents the later development of
hypertension.23 These observations in SHR were made
in relation to the systolic BP. If they have any bearing
on the pathogenesis of hypertension in humans, they
may be more related to isolated systolic hypertension,
such as that seen in 20% of our thyrotoxic patients,
than to diastolic hypertension.
r,l
T
s
;
-
REQUIRING OTHER THERAPY + L'THYROXINE
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Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension.
D H Streeten, G H Anderson, Jr, T Howland, R Chiang and H Smulyan
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Hypertension. 1988;11:78-83
doi: 10.1161/01.HYP.11.1.78
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1988 American Heart Association, Inc. All rights reserved.
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