Unusual Manifestations of Hypothyroidism
Irwin Klein, MD, Gerald S. Levey, MD
\s=b\ Thyroid hormone exerts direct effects on essentially all of
the organ systems of the body. Hypothyroidism is a frequently
diagnosed endocrine disorder that has characteristic clinical
signs and symptoms. In addition to these common manifesta-
tions, however, there are many additional manifestations of
hypothyroidism that are less commonly acknowledged and
Include involvement of the hematologic, muscular, cardiac,
and rheumatologic systems. It is important to recognize that
these other organ systems may be involved and that the
resulting disease states can dominate the clinical picture. As
with the classic manifestations of hypothyroidism, these un-
usual manifestations respond to thyroid hormone replace-
ment therapy. Thus, the importance of recognizing these signs
and symptoms, as a result of hypothyroidism, is evident. This
article emphasizes these less common manifestations of the
patient with hypothyroidism, and, in addition, discusses the
possible pathophysiologic mechanisms by which thyroid hor-
mone deficiency can lead to organ system dysfunction.
(Arch Intern Med 1984;144:123-128)
"LJypothyroidism due to failure of the thyroid gland (pri-
* *
mary hypothyroidism) is a relatively common endo¬
crine disorder seen under ordinary circumstances with
characteristic clinical signs and symptoms, including cool,
dry skin, puffy features, cold intolerance, constipation,
hoarse voice, dryness of the hair, brittleness of the finger
nails, nonpitting peripheral edema, slow return of reflexes,
and bradycardia.1·2 Diagnosis is readily confirmed by the
determination of the serum levels of thyroxine (T4) and
thyroid-stimulating hormone (TSH).3,4 It is perhaps not as
well appreciated that the general nature of the effects of
thyroid hormone result in abnormalities in many organ
systems producing a complex and diverse array of signs and
symptoms in addition to those noted earlier. Thus, primary
hypothyroidism is associated with hématologie (anemia and
coagulopathy), muscular (myopathy), cardiac (cardiomeg-
aly), and rheumatologic abnormalities (arthralgias, joint
effusion, hyperuricemia, and associated autoimmune dis¬
ease), which may dominate the clinical picture and serve as
the manifesting sign or symptom of the disorder. When this
Accepted for publication July 1, 1983.
From the Division of Endocrinology and Metabolism and the Department
of Medicine, University of Pittsburgh School of Medicine (Drs Klein and
Levey); and the Veteran's Administration Hospital (Dr Klein), Pittsburgh.
Reprint requests to the Division of Endocrinology and Metabolism,
University of Pittsburgh School of Medicine, 961B Scaife Hall, Pittsburgh,
PA 15261 (Dr Klein).
Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015
occurs and is not recognized by the examining physician,
errors in diagnosis can be made with potentially serious
consequences for the patient. The purpose of this review is
to describe selected manifestations that, although not usu¬
ally recognized as classic manifestations of hypothyroidism
per se, can be the major manifestation of the disease.
HEMATOLOGIC MANIFESTATIONS
Anemia
Anemia is a common finding in the laboratory evaluation
of hypothyroidism and may be normochromic normocytic,
hypochromic microcytic, or macrocytic.6 It has been esti¬
mated that one third to half of the patients with hypothy¬
roidism have some decrease in the normal RBC mass.6 The
degree of anemia is most often modest with hemoglobin
concentrations of approximately 11 g/dL, but, occasionally,
the hemoglobin concentration may be as low as 6 to 7 g/dL.
The normochromic normocytic anemias may be secondary
to decreased erythropoietin production, which results in
decreased erythrocyte synthesis.7 Hypochromic microcytic
anemias are more commonly observed in women and are
ascribed to the menorrhagia that can accompany hypothy¬
roidism. The coexistence of iron deficiency in patients with
hypothyroidism may lead to a more severe degree of ane¬
mia.5-6 Approximately one third of the patients with hypo¬
thyroidism and anemia will have a macrocytic anemia
suggestive of vitamin B12 deficiency.8,9 Although there is an
increased incidence of pernicious anemia in patients with
autoimmune thyroid disease (see "Associated Autoimmune
Diseases" section), these patients constitute only a portion
of the entire group of patients with hypothyroidism and
macrocytosis. Deficiencies of serum (or RBC) folate simi¬
larly do not explain the changes observed.9
When examining the peripheral blood smear of a patient
with hypothyroidism and macrocytic anemia, it is impor¬
tant to search for associated changes in WBCs and platelets
(multilobed polymorphonuclear leukocytes and enlarged
platelets) before assuming that a vitamin BI2 (pernicious or
folate-deficient) anemia is present. The findings of an iso¬
lated increase in RBC size suggests the presence of a macro¬
cytic anemia due to thyroid hormone deficiency rather than
a true megaloblastic anemia. This macrocytic alteration in
the RBC membrane may possibly derive from the associ¬
ated secondary serum lipid alterations10 and will resolve
with thyroid hormone replacement therapy alone. In the
presence of true megaloblastic changes and a serum hemo¬
globin less than 9.0 g/dL, the likelihood of an accompanying
 vitamin B12 or folate deficiency is greater.910 Persistence of a
macrocytic anemia after adequate thyroid hormone re¬
placement therapy would constitute the need for further
studies to establish a diagnosis of pernicious anemia.
There is a relatively high percentage of the overall popu¬
lation with organ-specific antithyroid antibodies in their
serum.11 This frequency increases with age and is especially
common in women older than the age of 40 years.12 It is well
established that the causative basis for most cases of both
hypothyroidism and pernicious anemia is an autoimmune
disease.1213 This is supported by the finding of antithyroid
antibodies in 80% of the patients with spontaneous hypo¬
thyroidism. In addition, there is an increased frequency of
other organ-specific immune-mediated diseases in patients
who are known to have autoimmune thyroiditis.14 Thus, it is
not surprising that as many as 30% of the patients with
hypothyroidism will have antiparietal cell antibodies in
their serum (an approximate threefold increase over the
general population) and that 4% of this population will
demonstrate antibodies to the vitamin B12-binding pro¬
tein.11 Overall pernicious anemia is at least 20 times more
common in patients with hypothyroidism.
Coagulopathy
Patients with hypothyroidism have been observed to have
minor bleeding tendencies, including easy bruising and
menorrhagia.1516 There are additional reports of more se¬
vere hemorrhagic diathesis in patients with myxedema.16 In
studies of platelet adhesiveness, there was a demonstrable
abnormality in 12 of the 16 patients with hypothyroidism
that was corrected with thyroid hormone replacement ther¬
apy. Platelet counts and fibrinogen levels were normal in
that study. While bleeding times were occasionally pro¬
longed, these did not correlate with the decreased platelet
adhesiveness. Rogers et al16 have shown a positive correla¬
tion between factor VIII coagulant activity and the serum
levels of T4. Thus, patients with hypothyroidism exhibit an
acquired coagulation defect that is reversible with thyroid
hormone replacement therapy and, in some ways, is similar
to the abnormalities observed in von Willebrand's disease.16
MUSCULOSKELETAL FEATURES
Myopathy
There is a spectrum of muscle disorders that can occur in
a patient with hypothyroidism,1720 ranging from the com¬
monly observed delay in deep-tendon reflexes to the much
less frequent development of muscle hypertrophy and pseu-
domyotonia (Hoffmann's syndrome18·19). The former occurs
in as many as 85% of the patients, while the latter has been
reported in less than 10% of the patients. An intermediate
symptom complex, including muscular stiffness, pain, and
cramps, may be noted by as many as half ofthe patients with
myxedema who were the patients specifically queried.19
We have recently reported the clinical features of two
patients with severe hypothyroid myopathy and their re¬
sponse to therapy.19·21 Figure 1 illustrates the physical
appearance of one patient with hypothyroid myopathy. At
the time of the initial examination, there was an increased
mass of many of the muscle groups, including the trapezius,
deltoids, rectus capitus, and gastrocnemius. This was ac¬
companied by firmness to palpation, increased muscle
definition, and mild-to-moderate objective muscle weak¬
ness.19 While some muscle dysfunction was observed, true
myotonia was absent. There was percussion myoedema and
a severe delay in deep-tendon reflexes. Characteristic of the
history obtained from our patients was the occurrence of
muscle cramps, especially severe at night and low back pain
of long duration. Most patients described their muscle
Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015
weakness as fatigue and an inability to perform repetitive or
prolonged muscular activity, rather than difficulty with
completing a single, short, muscular feat.
Table 1 is the summary of the laboratory and electro-
myographic (EMG) findings in six patients with severe hy-
pothyroid myopathy, including muscular hypertrophy and
muscle stiffness. All six patients had thyroid function study
results diagnostic of primary hypothyroidism with a low T4
level and an elevated TSH level. In addition, all patients had
mild to marked elevation of serum creatine kinase (CK).
Electromyographic recordings in five of the patients dis¬
closed multiple abnormal findings. Most consistent was the
presence of repetitive, positive waves recorded from the
gastrocnemius and lumbar paraspinal muscles.19 Other
changes, including increased insertional activity and occa¬
sional fibrillations, were also recorded. Studies of nerve
conduction velocity were not consistently abnormal and,
occasionally, showed slowing of the distal median nerve
suggestive of carpal tunnel compression.20
The finding of increased serum levels of CK, as well as
that of aldolase, SGOT, and lactic dehydrogenase (LDH)
were not surprising in view of the previous reports of these
abnormalities in as many as 80% of the patients with hypo¬
thyroidism.21 The magnitude of CK rise was marked in five
of the six patients. Determinations of normal percentages of
CK-MB isozyme confirmed the musculoskeletal origin for
these elevations.21 It has not been establisehd whether the
serum enzyme levels reflect an increased release from
muscle (or liver in the case of SGOT and LDH), a decreased
clearance of these enzymes, or both.
There are multiple reports of muscle biopsies performed
in patients with hypothyroid myopathy.19,24,25 Biopsy speci¬
mens were obtained in three of our patients and similar to
prior reports, no consistent changes were observed. How¬
ever, in one patient (patient 5) a biopsy specimen of the left
vastus lateralis demonstrated severe variation in fiber
shape and size (Fig 2). Enzyme histochemistry results
showed that there was hypertrophy of type 1 fibers, ranging
in size from 100 to 150 µ , as well as predominance (70%) of
type 2 fibers. As with previous articles, no additional
information was obtained by study with electronmicro-
scopy.
We and others have previously stressed the importance of
demonstrating a predictable response to thyroid hormone
replacement therapy in establishing the diagnosis of hy¬
pothyroid myopathy.1725 Figure 1 illustrates the appearance
of the muscles of patient 3 before and five months after
levothyroxine replacement. In chronologic order, therapy
was followed by a mild worsening of muscular cramps and
stiffness (lasting one to two weeks) with a subsequent
improvement in those complaints and also an increase in
subjective and objective muscle strength. This was accom¬
panied by an improvement in muscle function with de¬
creased fatigue and increased ability to perform repetitive
muscular activity. Muscle mass and the abnormally firm
muscle consistency was improved in most cases by two to
three months and resolved in all cases by eight months. This
clinical response to treatment occurred with a predictable
decline in the serum levels of CK and the other measured
enzyme abnormalities.21 Repeated EMG studies in three of
our patients showed a decrease or total absence of previ¬
ously observed changes.21,26
Hypothyroid myopathy has been observed accompanying
varying degrees of thyroid hypofunction. While the more
severe forms of muscle dysfunction are usually associated
with recognizably low levels of T4 and elevated levels of
TSH, Wilson and Walton20 have suggested that the onset of
myopathy may precede the development of abnormal thy-
 Fig 1.—Appearance of patient 3 before (left, top and bottom) and five months after (right, top and bottom) institution of
treatment with levothyroxine, 0.15 mg/day. Note decrease in muscle mass especially prominent in trapezius and
deltoid muscles. This change was associated with improved muscle function and return to normal consistency as
judged by palpation.

roid function test values. The patients studied by those Cardiomegaly

authors were examined before the availability of measure¬
ments of TSH, the most sensitive test for the presence of hy¬
pothyroidism. We have recently observed normal levels of
T4 and estimated free thyroxine (calculated from T4 and
triidothyronine [T3] resin uptake) in a 52-year-old man with
complaints of myalgias, muscle cramps, fatigue, and ele¬
vated serum levels of CK. Serum TSH was 7 mU/mL (nor¬
mal, <6 mU/mL), which increased to 48 mU/mL after the
administration of 400 µg of thyrotropin-releasing hormone.
The hyperresponsiveness of TSH to thyrotropin-releasing
hormone administration is consistent with primary hypo¬
thyroidism. After treatment with 0.15 mg/day levothyrox¬
ine, the patient had complete resolution of his muscular
symptoms. Thus, it seems that in certain patients hypothy¬
roid myopathy may be an early manifestation of mild thy¬
roid dysfunction.
The clear demonstration that hypothyroidism is capable
of producing a wide spectrum of muscle dysfunction in both
adults (Hoffmann's syndrome)1819 and in children (Kocher-
Debré-Sémélaigne syndrome)17·19·25 justifies the routine
screening of thyroid function in any patient with a secon¬
dary myopathy. It has been suggested that anywhere from
5% to 10% of acquired muscle disease may be due to thyroid
dysfunction.1719 In children, there is muscle weakness with¬
out the stiffness and pseudomyotonia observed in adults.
The extreme degree of muscle hypertrophy has given rise to
the descriptive term the infant Hercules syndrome." The
adult and childhood forms of myopathy seem to share a
common pathophysiology and response to treatment.26
Hypothyroidism has been shown to be accompanied by a
reversible decrease in cardiac contractility.27,28 Multiple
measures of cardiac performance are uniformly altered in
the patient with hypothyroidism and respond promptly to
thyroid hormone replacement therapy. Prior clinical stud¬
ies have suggested that cardiomegaly is one manifestation
of an underlying cardiac dysfunction; however, overt signs
of congestive heart failure are uncommon in uncomplicated
hypothyroidism. A recent study by Khaleeli and Menon29
found that pericardial effusions detected by echocardiogra¬
phy were common in a group of unselected patients with hy¬
pothyroidism. The resolution of these effusions can be
expected promptly after the institution of thyroid hormone
replacement therapy; rarely are they a cause for tamponade
or hemodynamic compromise.29,30
The mechanism of action of thyroid hormone at the cel¬
lular level has been fairly well established.31,32 Studies by
Samuels et al32 have demonstrated the ability of T3 to bind
to cell nuclear receptors and to stimulate the transcription
of messenger RNA that codes for specific proteins. One
of these proteins is the enzyme that hydrolyzes adenosine
triphosphate (ATP) in response to changes in sodium
and potassium adenosine triphosphatase concentrations
(Na/K ATPase). The enzyme Na/K ATPase accounts for
much of the energy consumed by the body during basal
metabolic conditions.33,34 This relationship accounts for in¬
creased tissue enzyme levels and increased oxygen con¬
sumption in the patient with hyperthyroidism, with the

Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015

 Table 1.—Evaluation of the Condition of Patients With
Hypothyroid Myopathy
Serum Levels

Thyroid-
Patient Stimulating Creatine
No./Sex/ Thyroxlne, Hormone, Klnase, Electromyogram
Age, yr ^g/dL* µ /mLt mU/mLt Recordings
1/F/56 2.9 100 943 Positive waves
and fibrillation
2/M/54 1.4 64 2,500 Not performed
3/F/57 2.3 110 1,210 Positive waves
and increased
insertional
activity
4/M/43 3.2 37 5,760 Positive waves
and increased
insertional
activity
5/M/58 1.2 74 353 Positive waves
6/M/38 1.8 82 3,950 Positive waves

*Normal value, 5.5 to 12.5 µg/dL.

fNormal value, less than 10 µ /mL.
¿Normal value, 0 to 90 mU/mL. Fig 2.—Muscle biopsy specimen obtained from vastus lateralis
muscle of patient 5. There is severe variation in fiber shape and size.
Type 1 fibers are hypertrophie, with size ranging up to 150 pm. Type
2 fibers were quantitatively predominant and appeared angulated
Table 2.—Characteristics of Effusions in Patients and occasionally atrophie (hematoxylin-eosin, 320).
With Hypothyroidism

Parameter Finding
RHEUMATOLOGIC FINDINGS
Appearance Straw colored
Volume Often large In a large referral rheumatic disease clinic, hypothyroid¬
Specific gravity 1.012-1.025
ism was a commonly encountered cause for a variety of
Protein Elevated with same elactrophoretic protein
as serum musculoskeletal complaints.40,41 These included arthralgia,
Cells Variable but almost always <1,500/cu mm stiffness, paraesthesias, joint swelling, and pseudogout.
Cholesterol Greater than or equal to serum concentrations,
may have crystals with bilirubin Physical findings included synovial effusions and synovial
Viscosity* Normal to increased thickening, but true inflammatory changes were unusual.
When the test results for rheumatoid factor were normal,
^^^^^^

Culture Sterile
*As reported for synovial fluid by Dorwart and Schumacher.42
reverse situation in the hypothyroid state.34
In cardiac muscle, Na/K ATPase plays an important role
in the regulation of contractility. Schwartz et al35 have
studied the effects of digitalis and the digitalis glycosides on
cardiac muscle, and they have shown that the action of the
drug is mediated through the inhibition of Na/K ATPase. It
seems reasonable to postulate that in patients with hypo¬
thyroidism the decreased levels of Na/K ATPase in heart
muscle account for the long-recognized increased sensitiv¬
ity to digitalis.36 A decrease in the metabolic clearance of
digitalis with resulting increases in serum levels may also
play an important role in mediating the effects of drug ther¬
apy.
Recent experiments with animals with hypothyroidism
have shown that thyroid hormone is capable of altering the
amount and type of myosin in cardiac muscle.37 Animals
with hypothyroidism synthesize an isozyme of myosin that
has less ATPase activity (V3) than does a euthyroid or hy-
perthyroid heart (V, predominance). Similarly, when levo-
thyroxine is administered to a hypothyroid rat, there is an
increase in myosin ATPase activity and a return to the V,
myosin isozyme.38 Thus, thyroid hormone via its ability to
alter the synthesis of specific proteins may be an important
humoral regulator of myocardial metabolism. These pri¬
mary alterations in contractile proteins may, in part, ex¬
plain the observed changes in cardiac contractility of the
hypothyroid heart.39
the patients' conditions were often diagnosed as having
either seronegative rheumatoid arthritis or fibrositis. In
addition, carpal tunnel syndrome and intervertebral disc
disease were suspected or diagnosed in patients later found
to be hypothyroid.40
Dorwart and Schumacher42 studied 12 patients with
hypothyroidism to evaluate rheumatic complaints. Synovial
effusions, most commonly involving the knee, were demon¬
strated in eight patients. The fluid analyses were remark¬
able for increased viscosity and increased concentrations of
hyaluronic acid and for the lack of true inflammatory
changes (Table 2). It has not been clearly established why
synovial thickening and effusions occur in the joints of
patients with myxedema. Abnormal lymphatic drainage
may be important,43 but results of studies in our laboratory
suggest that increased serum levels of TSH may be causa¬
tive.44 It has been reported that TSH is capable of stimulat¬
ing the adenylate cyclase activity in synovial membranes.
This stimulation may increase the cellular production of
hyaluronic acid and synovial fluid.44 If, in fact, TSH is an
important mediator of synovial changes, this may explain
the observation that joint effusions are a less common
finding in secondary hypothyroidism.
All previous articles stress the dramatic symptomatic im¬
provement experienced by this group of patients in re¬
sponse to thyroid hormone replacement therapy.40-12 Thus,
Bland and Frymore40 have suggested that the diagnosis of
"myxedema-derived" rheumatic disease due to myxedema
is not established unless the patient responds to therapy
and remains asymptomatic for at least one year after

Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015

 treatment. Similar to the response of hypothyroid myopa¬
thy, this response to therapy should occur during a predict¬
able period.
Serous Effusions
Accumulation of abnormal amounts of protein-rich fluid
in the synovium, pleura pericardium, and peritoneum often
suggests causative diagnoses other than hypothyroidism.
In the evaluation of both exudative and transudative effu¬
sions, especially when there is no coexistent arthritis,
cardiac, hepatic, or renal disease, hypothyroidism becomes
an important consideration.29·43·45 As with some of the other
unusual manifestations of hypothyroidism, the effusions
may antedate other more typical symptoms or they can
occur with relatively mild degrees of thyroid dysfunction.45
Recent evidence confirms the earlier suggestion of an
abnormality in lymphatic function43 as an important cause of
the increased serous fluid accumulation. The lymphatic
dysfunction is most likely a combination of increased mem¬
brane permeability to protein and mucopolysaccharides, as
well as a decreased rate of lymph flow.43 In addition to an
accumulation of proteinaceous effusions in the serious cav¬
ities, myxedema may also yield increased fluid in other
anatomic areas, including the scrotum, the middle ear, and
the subarachnoid space.46 The characteristics of serous
effusions in the patient with hypothyroidism are listed in
Table 2. The demonstration of chemical evidence of hypo¬
thyroidism and a resolution of these effusions with thyroid
hormone replacement therapy confirm the suspected un¬
derlying disorder.
Hyperuricemia
Alterations of uric acid metabolism have been reported in
a number of endocrine disease states. While controversy ex¬
ists as to the frequency of hyperuricemia in hypothyroid¬
ism, it appears that serum levels of uric acid in men with hy¬
pothyroidism are higher than those observed in age-
matched normal control subjects,46 whereas in women they
are similar. In addition, there is a suggestion of an inverse
correlation between the values ofthe levels of serum thyroid
hormone and serum uric acid. Two studies have implicated
abnormal renal excretion of uric acid to account for these
changes.46·47
Prior studies of the relationship among hypothyroidism,
hyperuricemia, and gout have included too few patients to
allow any firm conclusions concerning potential cause-and-
effect relationships.47 The most reproducible observation is
the ability of thyroid hormone replacement therapy to
decrease serum uric acid levels and increase the urinary
uric acid levels in patients with hypothyroidism.46·47 In a
susceptible person, hypothyroidism may alter uric acid
clearance sufficiently to precipitate an acute attack of gout,
and conversely thyroid hormone treatment may reverse or
improve this abnormality. The overall frequency of hypo-
thyroidism-related hyperuricemia and gout remains to be
determined.
In contrast to true gout, joint effusions containing cal¬
cium pyrophosphate crystals (pseudogout) have been re¬
ported to be frequent in hypothyroidism. In a study of
12 patients with severe myxedema, aspiration of synovial
fluid demonstrated calcium pyrophosphate crystals in six
patients, and this was associated with roentgenographic
evidence of pseudogout. None of these patients had experi¬
enced acute attacks with pseudogoutlike pain before thy¬
roid hormone treatment; synovial fluid cell counts were
usually less than 1,000/cu mm.42
Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015
Associated Autoimmune Diseases
Both the connective tissue diseases associated with poly-
articular arthritis as well as hypothyroidism due to chronic
lymphocytic thyroiditis (Hashimoto's disease) have been
shown to have various autoimmune markers and an autoim¬
mune etiology.1214·48'49 There is a well-documented increased
frequency of coexistent autoimmune diseases14,49 and the
association of chronic lymphocytic thyroiditis (Hashimoto's
disease) with rheumatoid arthritis has been previously
described.49 To further explore the relationship between
connective tissue diseases and thyroid disease, we retro¬
spectively studied 62 cases of fatal progressive systemic
sclerosis (PSS, scleroderma) for the presence of patholog¬
ical or chemical evidence of thyroid gland dysfunction. In
patients with PSS, histopathologic evidence of severe fibro¬
sis of the thyroid gland was significantly more frequent than
in age-matched control subjects. Seven (25%) of the 27 pa¬
tients studied had chemical evidence of hypothyroidism,
and 14 patients (50%) had significant titers of antithyroid
antibodies.14
Therefore, while it is important to consider the possibil¬
ity that certain rheumatic symptoms may be a manifesta¬
tion of hypothyroidism, in the setting of a true inflamma¬
tory arthritis, the physician must also be alerted to the
occurrence of a coexistent of the following autoimmune
connective tissue diseases: pernicious anemia, vitíligo,
rheumatoid arthritis, Sjögrens syndrome, systemic lupus.
erythematosus, chronic active hepatitis, and progressive
systemic sclerosis. Conversely, the presence of antithyroid
antibodies in a patient with a collagen vascular disease
should not be unexpected. As has been previously demon¬
strated, complete thyroid function testing may well demon¬
strate treatable abnormalities in this group of patients.14
Julio Martinez, MD, performed the histologie studies of the muscle biopsy
specimens. Mitchell Parker, MD, D. R. Ayyar, MD, and Robert Shebert,
MD, participated in the evaluation of the condition of the patients with
myopathy. Mary McAleavey typed the manuscript.
Dr Klein is a clinical investigator of the Veterans Administration.
References
1. Watanakunakorn C, Hodges RE, Evans TC: Myxedema: A study of
400 cases. Arch Intern Med 1965;116:183-190.
2. Hall R, Scanlon MF: Hypothyroidism: Clinical features and complica-
tions. Clin Endocrinol Metabol 1979;8:29-38.
3. Larsen PR: Thyroid pituitary interaction: Feedback regulation of
thyrotropin secretion by thyroid hormones. N Engl J Med 1982;306:23-32.
4. Lawrence AM, Wilbur JF, Hagen TC: The pituitary and primary
hypothyroidism: Enlargement and unusual growth hormone secretory
responses. Arch Intern Med 1973;132:327-333.
5. Tudhope GR, Wilson GM: Anemia in hypothyroidism. Q J Med
1960;29:513-537.
6. Fein HG, Rivlin RS: Anemia in thyroid diseases. Med Clin North Am
1975;59:1133-1145.
7. Das KC, Mukherjie M, Sarkar TK, et al: Erythropoiesis and erythro-
pietin in hypo- and hyperthyroidism. J Clin Endocrinol Metabol 1975;40:
211-220.
8. Hines JD, Halstead CH, Griggs RC, et al: Megaloblastic anemia
secondary to folate deficiency associated with hypothyroidism. Ann Intern
Med 1968;68:792-805.
9. Caplan RH, Davis K, Bengston B, et al: Serum folate and vitamin B12
levels in hypothyroid and hyperthyroid patients. Arch Intern Med 1975;135:
701-704.
10. Cooper RA: Lipids of the human red cell membrane: Normal composi-
tion and variability in disease. Semin Hematol 1970;7:296-322.
11. Herbert V: Hypothyroidism; blood, in Werner S, Ingbar S (eds):
Diseases of the Thyroid. Hagerstown, Md, Harper & Row Publishers Inc,
1978, p 925.
12. Doniach D: Humoral and genetic aspects of thyroid autoimmunity.
Clin Endocrinol Metabol 1975;4:267-284.
13. Volpe R: The role of autoimmunity in hypoendocrine and hyperen-
docrine function. Ann Intern Med 1977;87:86-99.
14. Gordon MB, Klein I, Dekker A: Thyroid disease in progressive
systemic sclerosis: Increased frequency of glandular fibrosis and hypothy-
roidism. Ann Intern Med 1981;95:431-435.
 15. Edson JR, Fecher DR, Doe RP: Low platelet adhesiveness and other
hemostatic abnormalities in hypothyroidism. Ann Intern Med 1975;82:342\x=req-\
346.
16. Rogers JS, Shane SR, Jencks FS: Factor VIII activity and thyroid
function. Ann Intern Med 1982;97:713-716.
17. Ramsey I: Muscular abnormalities of hypothyroidism, in Thyroid
Disease and Muscle Dysfunction. London, Heinemann Medical 1974,
pp 126-174.
18. Hoffmann J: Weiteaer beitrag zur lehre von der Tetanie. Dtsch
Z Nervenheilkd 1897;9:278-280.
19. Klein I, Parker M, Shebert R, et al: Hypothyroidism presenting as
muscle stiffness and pseudohypertrophy: Hoffmann's syndrome. Am J Med
1981;70:891-894.
20. Wilson J, Walton JN: Some muscular manifestations of hypothyroid-
ism. J Neurol Neurosurg Psychiatry 1959;22:320-324.
21. Klein I, Mantel P, Parker M: Resolution of abnormal muscle enzyme
studies in hypothyroidism. Am J Med Sci 1980;279:159-162.
22. Griffiths PD: Serum enzymes in diseases of the thyroid gland. J Clin
Pathol 1965;18:660-663.
23. Goldman J, Matz R, Mortimer R, et al: High elevations of creatine
phosphokinase in hypothyroidism. JAMA 1977;238:325-326.
24. Salick AI, Choachis SD Jr, Pearson CM: Myxedema myopathy:
Clinical electrodiagnostic and pathologic findings in advanced cases. Arch
Phys Med Rehabil 1968;49:230-237.
25. Norris FH, Panner BJ: Hypothyroid myopathy. Arch Neurol 1966;14:
547-589.
26. Waldstein SS, Bronsky D, Shrifter HB, et al: The electromyogram in
myxedema. Arch Intern Med 1958;101:97-102.
27. Amidi M, Leon DF, DeGroot WJ, et al: Effect of the thyroid state on
myocardial contractility and ventricular ejection rate in man. Circulation
1968;38:229-239.
28. Crowley WF, Ridgway EC, Bough EW, et al: Non-invasive evaluation
of cardiac function in hypothyroidism: Response to gradual thyroxine
replacement. N Engl J Med 1974;296:1-6.
29. Khaleeli AA, Menon N: Factors effecting resolution of pericardial
effusions in primary hypothyroidism: A clinical, biochemical and echocar-
diographic study. Postgrad Med 1982;53:473-476.
30. Davis PJ, Jacobson S: Myxedema with cardiac tamponade and peri-
cardial effusion of 'gold paint' appearance. Arch Intern Med 1967;120:615\x=req-\
619.
31. Sterling F: Thyroid hormone action at the cell level. N Engl J Med
1979;300:117-123.
32. Samuels HH, Stanley F, Shapiro LE: Dose-dependent depletion of
nuclear receptors by L-triiodothyronine: Evidence for a role in induction of
Downloaded From: http://archinte.jamanetwork.com/ by a University of British Columbia Library User on 06/19/2015
growth hormone synthesis in cultured GH1 cell. Proc Natl Acad Sci USA
1976;73:3877-3881.
33. Katz AK, Lindheimer MD: Renal sodium and potassium-activated
adenosine triphosphatase and sodium reabsorption in the hypothyroid rat.
J Clin Invest 1973;52:796-804.
34. Edelman IS, Ismail-Beigi F: Thyroid thermogenesis and active
sodium transport. Recent Prog Hormone Res 1974;30:235-243.
35. Schwartz A, Lindemayer GE, Allen JC: The sodium potassium
adenosine triphosphatase: Pharmacological, physiological and biochemical
aspects. Pharmacol Rev 1975;27:3-134.
36. Buccino RA, Spann JF, Pool PE, et al: Influence of the thyroid state
on the intrinsic contractile properties and energy stores of the myocardium.
J Clin Invest 1967;46:1669-1682.
37. Hoh JF, McGrath PA, Hale PT: Electrophoretic analysis of multiple
forms of rat cardiac myosin: Effects of hypophysectomy and thyroxine
replacement. J Mol Cell Cardiol 1977;10:1053-1076.
38. Dillmann W: Thyroid hormone and the heart. Thyroid Today 1983;6:
1-6.
39. Morkin E, Flink IL, Goldman S: Biochemical and physiological
effects of thyroid hormone on cardiac performance. Prog Cardiovasc Dis
1983;15:435-464.
40. Bland JH, Frymore JW: Rheumatic syndromes of myxedema. N Engl
J Med 1970;282:1171-1174.
41. Golding GN: Hypothyroidism presenting with musculoskeletal symp-
toms. Ann Rheum Dis 1970;29:10-14.
42. Dorwart BB, Schumacher HR: Joint effusions, chondrocalcinosis and
other rheumatic manifestations in hypothyroidism. Am J Med 1975;59:
780-790.
43. Parving HH, Hansen JM, Nielsen SL, et al: Mechanism of edema
formation in myxedema. N Engl J Med 1979;301:460-465.
44. Newcombe DS, Ortel RW, Levey GS: Activation of human synovial
membrane adenylate cyclase by thyroid-stimulating hormone. Biochem
Biophys Res Comm 1972;48:201-204.
45. Sachdev Y, Hall R: Effusions into body cavities in hypothyroidism.
Lancet 1975;1:564-565.
46. Leeper RD, Benua RS, Brener JL, et al: Hyperuricemia in myx-
edema. J Clin Endocrinol Metabol 1960;20:1457-1466.
47. Newcombe DS: Endocrinopathies and uric acid metabolism. Semin
Arthritis Rheum 1973;2:281-300.
48. Becker KL, Ferguson RH, McConahey WM: The connective tissue
diseases and symptoms associated with Hashimoto's thyroiditis. N Engl
J Med 1963;268:277-280.
49. Mulhern LJ, Masi AT, Shulman LE: Hashimoto's disease: A search
associated disorders in 170 clinically detected cases. Lancet 1966;2:508-511.