Download REVIEW Viral Infections and Diseases of the Endocrine System

THE JOURNAL OF INFECTIOUS DISEASES • VOL 124, NO.1· JULY 1971
© 1971 by the University of Chicago. All rights reserved.
REVIEW
Viral Infections and Diseases of the Endocrine System
From the Virology Section, Laboratory of Microbiology,
National Institute of Dental Research,
National Institutes of Health,
Bethesda, Maryland
The etiology of most endocrine disorders remains
unknown. Although viruses have been suggested
as possible etiologic agents, this area has received
relatively little attention. Scattered throughout
the literature, however, are a number of case
reports which contain clinical and pathological
evidence of endocrine involvement during and
after certain viral infections. The purpose of this
report is to review the clinical and experimental
literature, critically examine the relationship between viral infections and endocrine disease, and
discuss experimental approaches which might aid
in studying the effect of viruses on endocrine
function.
that acute infections would simply bring the patient under the care of a physician, whereupon
unrecognized diabetes might be discovered.
Recently, Gamble et al. [11] used serologic
techniques to study the relationship between
newly diagnosed diabetes and a variety of viral
infections. Serum was collected from a large number of patients with newly diagnosed diabetes
and appropriate control subjects. Antibody was
measured against mumps (S and V antigens),
influenza A, Band C, parainfluenza, respiratory
syncytial virus, measles, herpes simplex, adenovirus, and coxsackie (A and B). Gamble and coworkers failed to find any relationship between
antibody against mumps and diabetes. Only neutralizing antibody to coxsackie B, particularly
type 4, appeared more often and in higher titer
in the diabetics than in the controls. Furthermore,
the titer of antibody bore an inverse relationship
to the duration of the diabetes. Since infections
with coxsackie virus are relatively common, the
possibility that the rise in antibody may have
represented an anamnestic response or that the
"latent diabetics" may simply have developed a
more severe viral infection, which in turn resuIted in a greater antibody response, cannot be
excluded.
Several other viral infections, including measles, polio, influenza, rubella and tick-borne encephalitis, have been associated temporally with
the onset of diabetes, but the number of cases
are few and the evidence is weak [5, 12-15].
Viral hepatitis also has been associated with the
onset of diabetes [16, 17], but the effect of hepatic dysfunction and steroid therapy on glucose
metabolism makes the etiology of the diabetes
unclear. Severe cytomegalic inclusion disease [18,
19], coxsackie B infection [20], and the hemorrhagic fevers [21, 22] produced lesions in the
islets of Langerhans, but there was no information
Pancreas
The role of infectious agents in the pathogenesis
of diabetes mellitus has been the subject of considerable controversy [1]. Many case reports have
appeared in the literature showing a temporal
relationship between certain viral infections and
the onset of diabetes. In a number of these cases,
diabetic symptoms appeared within 1-8 weeks
after infection, and persistent diabetes, rather
than a transient alteration in metabolism of glucose, ensued. Of all the viral infections, mumps
has been most frequently associated with diabetes [2-9]. However, many of the cases were
reported before 1940 and did not contain laboratory data to confirm the diagnosis of mumps, nor
any real proof that the viral infection had caused
diabetes. In fact, it was argued by Marble [10]
Received for publication February 1, 1971, and in
revised form April 1, 1971.
Please address requests for reprints to Dr. A. L.
Notkins, Virology Section, Laboratory of Microbiology,
National Institute of Dental Research, National Institutes of Health, Bethesda, Md. 20014.
94
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Nelson L. Lcvy and Abner Louis Notkins
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Viruses and Endocrine Disease
Investigators from Italy also have some evidence that a viral infection can produce diabetes
in animals [27-30]. These workers noted that a
few days to weeks after an epizootic of foot-andmouth disease in Perugia, a number of cattle developed severe emaciation, anorexia, and polyuria. Laboratory tests revealed hyperglycemia
and glycosuria. Examination of the pancreas
from four animals revealed almost total absence of the islets of Langerhans with infiltration of round cells and some acinar and ductal
necrosis. Lesions in the pituitary and adrenals
were noted, but the extent of the lesions and the
functional state of these organs were not described. A virus was isolated from these animals
and passaged in tissue culture [30]. Inoculation
of this virus into normal cattle resulted in some
evidence of hyperglycemia in about 25 % of the
animals. Since a very small number of animals
were used and rigorous controls were not included, the ability of foot-and-mouth disease to
produce diabetes awaits confirmation. Pancreatic
lesions also have been observed in other viral
infections (e.g., foot-and-mouth disease in guinea
pigs and mice [31, 32], coxsackie B in mice [33,
34], and infectious pancreatic necrosis virus in fish
[35]), but the lesions did not always involve the
islets of Langerhans and the reports contained
little or no information on metabolism of glucose.
The possibility that at least some cases of diabetes mellitus may have a viral etiology merits
serious consideration. In humans, attempts should
be made to identify viral antigens and recover
latent or persistent viruses from the pancreas of
known diabetics. Few, if any, experiments of this
type have been reported in the literature. In animals, efforts should be made to study the effect
of a variety of known viruses on the functional
state of the beta cells. These experiments might
prove useful in uncovering new models for diabetes.
Thyroid
A number of investigators have suggested that
subacute thyroiditis may be of viral origin. This
disease frequently is preceded by a nonbacterial
infection of the upper respiratory tract and clusters of thyroiditis have been reported during certain epidemics of viruslike diseases [36-40].
Several viruses have been implicated in the patho-
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as to whether these patients developed clinical
symptoms of diabetes. In some infections, especially mumps, insular damage might be secondary
to diffuse virus-induced pancreatitis. Since only
a few beta cells are needed to maintain glucose
metabolism [13], extensive destruction of the
islets of Langerhans must occur before clinical
diabetes would appear.
Experiments in animals provide the best evidence for virus-induced diabetes. Craighead and
coworkers [23-24a] found that infection of mice
with the M variant of encephalomyocarditis virus
resulted in a syndrome similar to diabetes in over
40% of the surviving mice. Within four to eight
days after infection, the immunoreactive insulin in the pancreas had decreased to onefourth the control value and the immunoreactive insulin in the plasma had increased approximately threefold. Shortly thereafter, insulin
in the plasma decreased markedly and hyperglycemia and glycosuria followed. The glucose in
blood from fasting infected mice was two- to
threefold above the uninfected controls ( 117
mg/ 100 ml). Infectious virus was recovered from
the pancreas during the acute phase of the infection. Although a certain percentage of the animals recovered, abnormal metabolism of glucose
and hyperglycemia persisted in some mice for as
long as 11 months. Histologic examination of the
pancreas during the hyperglycemic phase revealed
a decrease in the number and size of the islets of
Langerhans, focal necrosis, and marked degranulation of the beta cells. The exocrine portion of
the pancreas appeared intact, the level of amylase in serum was not elevated, and lesions were
not found in the liver, adrenals, or pituitary.
Genetic factors seem to play a role in the development of this diabeteslike syndrome. Craighead and Steinke [24a] found that the incidence of
diabetes was substantially lower in females than
males and that the severity of the diabetes was
dependent upon the strain of the mouse. It often
has been suggested that a specific genetic predisposition might be involved in the development
of diabetes in humans. If, in fact, such a predisposition does exist, it might be due to such factors
as genetically determined receptor sites for a specific virus or altered immunologic responsiveness
to a particular viral antigen. Differences in the
genetic susceptibility of the host have been reported with other viral infections [25, 26].
96
with cytomegalic inclusion disease [18, 19, 56],
hemorrhagic fever with renal syndrome [57], and
Marburg virus infection [58]. Myxedema has been
reported in patients following infection with
mumps [59-61], but a coincidental association
cannot be excluded. Only in rare cases [37, 62]
are reports found in the literature of attempts to
identify viral antigens or isolate virus from diseased human thyroid tissue. Experiments in animals also have received little attention. Recently,
Lungu and coworkers [63, 64] reported that infection of rats with influenza virus resulted in hypertrophy of the thyroid and an increase in both
uptake of iodine and basal metabolism. Infection
of rats with pseudorabies virus, however, inhibited
uptake of iodine and depressed basal metabolism.
Data were obtained only during the first three days
after infection, hormone levels were not measured,
and whether these viruses acted directly on the
thyroid gland or through the central nervous system was not determined. Efforts should be made
to develop additional animal models and to rigorously evaluate the effect of viral infections on thyroid function.
AdrenaJs
Although it has been known for years that adrenocortical hormones could affect the susceptibility
of the host to viral infections [65], the effect of
viral infections on the functional capacity of the
adrenals has received relatively little attention. In
fact, viral infections of the adrenals were thought
to be rare [66]. However, there are a number of
case reports in which adrenal lesions were associated with severe generalized viral infections.
Adrenalcortical necrosis has been observed in
generalized infection with herpes simplex virus
[67-70]. This form of the disease is particularly
severe in patients with underlying immunologic
disorders or eczema. Shock and electrolyte imbalance have been reported in fatal cases, presumably on the basis of adrenal insufficiency. Hemorrhage, necrosis, and inclusion bodies have been
reported in the adrenals of patients with cytomegalic inclusion disease, particularly in those with
chronic debilitating illnesses [18, 19, 56, 71-73].
Adrenal lesions also have been observed in severe
cases of coxsackie B infection [74-76] and in
overwhelming infections with varicella [77-80]
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genesis of subacute thyroiditis. In 1957, Eylan
and coworkers [37] reported 15 cases of thyroiditis during an epidemic of mumps in Israel.
Ten out of the 11 patients tested had complement fixation titers of at least 1: 80 for antibody
to mumps, while only eight out of 87 controls
had titers as high as 1: 20. A virus thought to be
identical with mumps was recovered from two
out of four thyroid biopsies but was not recovered from the blood or feces. Although these
results were encouraging, the rise in antibody
might have represented a subclinical infection
unrelated to the etiology of the thyroiditis, or a
nonspecific anamnestic response provoked by the
inflammatory thyroid lesions. Moreover, except
for several case reports [41-43], there has been
little additional evidence over the last 14 years
linking mumps to subacute thyroiditis. Recently,
it was suggested that infection with mumps virus
might initiate an autoimmune reaction to thyroid
tissue [44, 44a] and that relapses of thyroiditis
might be produced by a second attack of mumps
[44]. Similarly, it has been postulated that the
immune response of the host to virus-induced antigens on the surface of infected thyroid cells might
playa role in the pathogenesis of thyroiditis [45].
Serologic evidence of recent coxsackie [46, 47],
ECHO [46], and adenovirus [39, 43, 46, 48] infections also has been reported in association with
subacute thyroiditis. As in the case of mumps, the
rise in antibody might represent a subclinical
infection unrelated to the thyroiditis. Other investigators have reported cases of subacute thyroiditis following clinical cat-scratch fever [49],
measles [50, 51], influenza [52, 53], parainfluenza
[43, 53], and infectious mononucleosis [40, 54,
55]. However, in many of the cases, identification
of the virus and the diagnosis of thyroiditis was
not clearly established. Volpe et aI. [46] hypothesized that subacute thyroiditis might represent the
stereotypical response of the thyroid gland to any
one of several viral infections. Although the data
summarized here suggest that under certain conditions viral infections might result in subacute
thyroiditis, additional clinical and experimental
studies are needed to confirm this hypothesis.
Thyroid lesions have been observed in other
viral infections but the number of cases are relatively small. Edema, focal necrosis, and giant cells
have been noted in the thyroid gland of patients
Levy and Notkins
Viruses and Endocrine Disease
Pituitary
There are relatively few reports of pituitary lesions
in viral diseases. However, examination of the
pituitary from severe cases of hemorrhagic fever
with renal syndrome, Dengue hemorrhagic fever,
and infection with Marburg virus revealed petechial hemorrhages, endothelial damage, infiltration
of mononuclear cells, and necrosis [22, 57, 58,
83-86]. On rare occasions, hemorrhage and necrosis also have been reported in the pituitary of
patients with rubella, varicella, coxsackie B, and
cytomegalovirus [18-20, 91, 92]. MacKay and
Margaretten [86] postulated that disseminated intravascular coagulation might be responsible for
both the adrenal and pituitary lesions associated
with these viral infections. Very little is known,
however, about the effect of these virus-induced
lesions on the functional capacity of the pituitary.
Endocrine dysfunction also might be produced
by any process which irritates the basilar region
of the brain or meninges, presumably by disrupting the hypothalamo-neurohypophysial tract [93].
Abnormal secretion of antidiuretic hormone and
the development of diabetes insipidus have been
reported during acute viral encephalitis [93, 94].
Lederer reported two cases of thyroid insufficiency
following infection with poliovirus [95]. Since
these patients responded positively to thyroidstimulating hormone and showed no other clinical
signs of endocrine dysfunction, he suggested that
the primary lesion was in the "thyroid-regulating
capacity" of the hypothalamus. Other investigators
also reported prominent hypothalamic syndromes
following poliomyelitis [96, 97]. Clinical and laboratory data indicated varying degrees of adrenal,
gonadal, thyroidal, and hypophyseal dysfunction.
Since inflammation and necrosis in the supraoptic
and paraventricular areas of the hypothalamus
can occur during the acute phase of poliomyelitis,
endocrine dysfunction might be a sequela of these
lesions. Lesions in the hypothalamus with subsequent symptoms of endocrine dysfunction have
been reported on rare occasions following other
viral encephalitides including smallpox and varicella [93, 98, 99].
Perhaps the best evidence for virus-induced
disease of the hypothalamo-neurohypophysial system comes from the field of "slow" viruses. Infection of sheep with scrapie virus results in emaciation, obesity, thirst, craving for salt, intolerance
to cold, and fluctuations in body temperature.
This clinical picture is consistent with the reported
degeneration and gliosis of the hypothalamus and
the decreased neurosecretory material in the posterior pituitary [l Ou]. The anterior pituitary remained essentially normal. Infection of mice with
scrapie resulted in less striking lesions, but there
was a decrease in the number of Gomori-positive
astrocytes around the ventricular walls [101]. It
has been suggested that these cells might play a
role in the transport of neurosecretory material
and that the effect of scrapie on these cells might
affect indirectly the neuroendocrine system. Another "slow" virus, Kuru, produced degenerative
changes in the hypothalamo-neurohypophysial
tract, but the lesions were less severe than in sheep
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and vaccinia viruses [81, 82]. Congestion, hemorrhage, and necrosis of the adrenal cortex and medulla have been reported in fatal cases of hemorrhagic fever with renal syndrome and in Dengue
hemorrhagic fever [21, 22, 83-85]. The clinical
picture and laboratory data were consistent with
adrenal insufficiency. Several investigators have
suggested that disseminated intravascular coagulation, triggered directly or indirectly by viral infections, might be the principal cause of the adrenal hemorrhage and necrosis [86, 87]. In Dengue
hemorrhagic fever, it has been postulated that the
immune response of the host (especially to a subsequent infection with a related strain of virus)
may somehow be involved in the pathogenesis of
this disease [88].
In general there is very little quantitative information on the relationship between the severity
of virus-induced adrenal lesions and the functional capacity of the adrenal glands. Increased
levels of cortisol have been reported in patients
with encephalitis associated with rubella, varicella,
and mumps [89, 90], but it is not known whether
the increased secretion of cortisol was a direct
effect of the virus on the adrenals or an indirect
effect through the central nervous system. Tests
of adrenal function should be used to evaluate the
status of the adrenal glands during and after clinical and experimental viral infections, and the possible role of low grade, persistent viral infections
in the pathogenesis of adrenal disease (e.g., Addison's disease) should be explored.
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infected with scrapie, and signs of hypothalamic
dysfunction were minimal [102].
Levy and Notkins
thymus [109, 110]. However, the effect of these
viruses on the production of thymosin [111] is
not known.
Gonads
Parathyroids, Pineal Glands, and Thymus
There is virtually no information on the effect of
viral infections on the parathyroid or pineal glands.
Wilkins [93] speculated that a virus might be involved in the etiology of chronic idiopathic hypoparathyroidism, but there is little evidence to support this speculation. The pineal gland seldom is
examined in routine autopsies, and pineal dysfunction rarely is recognized on the clinical level.
Although it is known that viruses can replicate
and produce lesions in the thymus, the effect of
these lesions on thymic function has not been adequately studied [l08]. Several investigators have
suggested that the murine leukemia viruses might
exert their immunosuppressive effect through the
Discussion
The information summarized above shows that
certain viral infections can produce gross and microscopic lesions in the endocrine glands. In many
cases, however, the pathology in the endocrine
glands was only one aspect of a severe and often
overwhelming viral infection. Furthermore, most
of the reports contain little or no information on
the relationship between the endocrine lesions and
the functional state of the endocrine glands. In
fact, it is not certain whether the lesions in the
endocrine glands were due to replication of the
virus in hormone-producing cells or were secondary to pathologic processes resulting from replication of virus in other cells. The literature also contains a number of case reports purporting to show
a temporal relationship between certain viral infections (e.g., mumps) and the onset of endocrine
disease (e.g., diabetes mellitus or subacute thyroiditis). Many of these reports, however, represent isolated cases and are not well documented
or appropriately controlled.
In order to evaluate the role of viruses in endocrine disorders, a systematic approach involving
rigorous epidemiological, clinical, and laboratory
studies is needed. Tests of endocrine function must
be performed during and after documented viral
infections. On the experimental level, in-vivo and
in-vitro models should be established. Recent reports from several laboratories suggest that animal
models are potentially available. Craighead and
coworkers [23-24a] produced a syndrome similar
to diabetes mellitus in mice with a variant of encephalomyocarditis virus, investigators from Italy
[27-30] claim they have produced diabetes mellitus in cattle with foot-and-mouth disease virus, and
Beck et al. [100] produced hypothalamic dysfunction in sheep with scrapie virus. Viruses also can
produce tumors of the endocrine glands. Adrenal,
thyroidal, and ovarian tumors have been reported
in animals infected with polyoma virus [112, 113],
thyroidal tumors have been found in animals infected with Moloney sarcoma virus [114], and
cells from endocrine glands have been transformed
in vitro by oncogenic viruses [115,116]. Although
hormone-producing cell lines are available (e.g.,
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A number of viral infections can produce lesions
in the gonads, but involvement of the hormoneproducing portion of the gland has not been documented. Although close to 20 % of postpubertal
males infected with mumps developed orchitis and
one-third to one-half of these patients showed
signs of testicular atrophy, neither impotence nor
feminization was observed [80]. In fact, Coppage
and Cooner [103] reported normal levels of testosterone in plasma of three patients with postmumps azoospermia. Orchitis also has been reported as a complication of coxsackie infection,
particularly in association with Bornholm disease
[104]. Craighead et al. [105], in fact, isolated a
coxsackie virus (group B, type 5) from the testis
of a patient with orchitis, but no mention was
made of endocrine function. Focal testicular hemorrhage, mononuclear infiltration, and depressed
spermatogenesis were reported in cases of smallpox [80], hemorrhagic fever with renal syndrome
[22], and infection with Marburg virus [58]. Hemorrhagic and necrotic foci also were observed in
the testes and ovaries of infants with fatal cases
of varicella [79] and cytomegalic inclusion disease
[19], but histologic evidence of involvement of
interstitial cells was not detected. Under certain
circumstances, severe viral hepatitis might lead to
gonadal atrophy by interfering with the liver's
ability to metabolize estrogens [106-107a].
99
Viruses and Endocrine Disease
of the host [125]. If these antigens come from
hormone-producing cells, the resulting immune
reaction might damage these cells and lead to endocrine dysfunction. This, in part, might account
for the autoantibodies found in certain endocrine
disorders [45]. Moreover, it is known from studies
in mice that under certain conditions viruses can
act as immunologic adjuvants, prevent the development of immunologic tolerance, and accelerate
the appearance of immunologic disease [126-128].
Thus, viral infections might initiate or enhance
the autoimmune process. Second, a picture resembling autoimmune disease could be produced
as a result of the host's immune response to virusinduced antigens [129, 130]. If viral antigens are
located on the surface of hormone-producing cells,
the interaction of sensitized lymphocytes, or viral
antibody plus complement, with these neo-antigens
might lead to cell destruction and endocrine dysfunction. Third, circulating virus-antibody complexes [131] might playa role in the pathogenesis
of endocrine disease. Since deposition of virusantibody complexes in the kidneys can result in
glomerulonephritis [132, 133], the possibility
exists that these complexes also might become
lodged in the endocrine organs and cause injury
to cells. In fact, endocrine lesions resulting from
disseminated intravascular coagulation might be
triggered by complexes of virus and antibody [86,
87].
In summary, there are a number of provocative
observations and several promising leads which
suggest that under certain circumstances viruses
might be involved in disorders of the endocrine
system. In general, however, the relationship between viral infections and endocrine disease has
been inadequately studied. On the clinical level, a
more rigorous approach is needed. On the experimental level, in-vivo and in-vitro models must be
established. In view of recent developments and
current concepts, the role of persistent viral infections and virus-induced immunopathology merit
further consideration in the etiology and pathogenesis of endocrine disease.
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The search for a viral etiology of the endocrinopathies has centered primarily around clinically
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