Autoimmune thyroiditis: Centennial jubilee of a social disease and its comorbidity

Abstract

The history of autoimmune thyroiditis (AIT) and its role in pathophysiology of transition from adolescent hypothalamic syndrome (obesity with rose striae) into early metabolic syndrome is reviewed. Marfanoid phenotype and chronic disequilibrium between local, autacoid-mediated and systemic, hormone-mediated regulation, typical for inherited connective tissue disorders, may promote this transition. Pathogenetic roles of hyperprolactinemia and cytokine misbalance are evaluated and discussed in its pathogenesis.

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Please cite this article in press as: L.P. Churilov, et al., Autoimmune thyroiditis: Centennial jubilee of a social disease and its comorbidity,
Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.002
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Review1
Autoimmune thyroiditis: Centennial jubilee of a social disease
and its comorbidity
Q1
2
3
L.P.Churilova,∗,Yu.I. Stroev a,I.Yu. Serdyuka,O.M. Kaminova-Mudzhikovaa,
Q2
I.V. Belyaevaa,A.N. Gvozdetskya,N.A. Nitsa a,b, L.R. Mikhailovab
4
5
aMedical Faculty, Saint Petersburg State University, Russia6
bResearch Institute of Phthisiopulmonology, Saint Petersburg, Russia7
Received 25 August 2012; received in revised form 1 November 2013; accepted 4 November 2013
8
Abstract
9
The history of autoimmune thyroiditis (AIT) and its role in pathophysiology of transition from adolescent hypothalamic syndrome (obesity
with rose striae) into early metabolic syndrome is reviewed. Marfanoid phenotype and chronic disequilibrium between local, autacoid-mediated
and systemic, hormone-mediated regulation, typical for inherited connective tissue disorders, may promote this transition. Pathogenetic roles
of hyperprolactinemia and cytokine misbalance are evaluated and discussed in its pathogenesis.
10
11
12
13
© 2013 Published by Elsevier Ireland Ltd.
14
Keywords: Adolescents; Autoimmune thyroiditis; Cytokines; Leptin; Marfanoid phenotype; Metabolic syndrome; Obesity; Prolactin; Transforming growth
factor
15
16
17
Contents18
1. Introduction ......................................................................................................... 0019
2. Hashimoto’s discovery: background ................................................................................... 0020
3. Hakaru Hashimoto: one article immortalized ........................................................................... 0021
4. Significance of Hashimoto’s disease in contemporary medicine........................................................... 0022
5. Comorbidity of autoimmune thyroiditis ................................................................................ 0023
6. Autoimmune thyroiditis and metabolic syndrome ....................................................................... 0024
7. Pathogenetic role of hyperprolactinemia................................................................................ 0025
8. Multi-organ autoimmunity in co-morbid and complicated AIT............................................................ 0026
9. Conclusion .......................................................................................................... 0027
References .......................................................................................................... 0028
29
1. Introduction30
It has been repeatedly noticed in medicine that a disease31
initially considered being rare or endemic appears to be
∗Corresponding author at: Department of Pathophysiology, Medical Fac-
ulty, Saint Petersburg State University, V.O. 21st Line, Bld. 8, Office 111,
Russia. Tel.: +7 904 336 3017; fax: +7 812 321 3780.
E-mail address: elpach@mail.ru (L.P. Churilov).
universally spread and socially important. One of examples is 32
HIV infection, which was proposed to call “4 H’s syndrome” 33
in 1983, when its nature was still unknown (its first victims 34
registered were Haitians, homosexuals, hemophiliacs and 35
heroin addicts only) [1].36
Autoimmune thyroiditis can be regarded as the unique 37
non-infectious example of this kind, once described as a rare 38
endemic thyroid ailment precisely 100 years ago, and nowa- 39
days appeared to be, probably, most universally spread human 40
auto-allergic disease.
0928-4680/$ – see front matter © 2013 Published by Elsevier Ireland Ltd.
http://dx.doi.org/10.1016/j.pathophys.2013.11.002

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2. Hashimoto’s discovery: background41
In 1904 J. Donath and K. Landsteiner described the first
42
proven antibody-mediated auto-allergic human disorder. It43
was paroxysmal cold hemolytic anemia in a syphilitic patient44
[2]. That time the concepts of humoral and cellular immunity45
were only just born, a role of plasma cells, recently found by46
P.G. Unna [3], as a source of antibodies was not known, the47
existence of T-lymphocytes was not known. At the same time,48
an outstanding Russian pathophysiologist, one of discoverers49
of natural autoantibodies – E.S. London (1904) already sug-50
gested the unitary theory of humoral and cellular immunity,51
postulating that both have the same source [4].52
Thyroidology of that period already had like 75 years53
of development passed as an area of clinical medicine, but54
absolutely irrelevant to immunology. Diffuse toxic goiter was55
known [5] and related to nervous disorders, although more56
than half a century still had to pass before the future discovery
57
of thyroid-stimulating antibodies [6]. Thanks to research of
58
newly (1909) Nobel-Price winner Th. Kocher, the concept of59
iodine-deficient etiology of endemic goiter, earlier suggested60
by G.A. Chatin, has got a broad recognition [7,8]. But the
61
pathologists knew colloid goiter only, resulted from thyroid62
hyperplasia in lack of iodine. Yet, goiter was common in some63
areas, where iodine deficit could not exist at all: for exam-64
ple, on Kyushu Island of Japan, famous for the birthplaces
65
of iodine-containing mineral deposits and for attraction of its66
inhabitants to sea food.
67
3. Hakaru Hashimoto: one article immortalized
68
A young surgeon, Hakaru Hashimoto (1881–1934), med-69
ical doctor in 3rd generation, the first graduate from recently70
established Kyushu Imperial University at Fukuoka, clinical71
resident of the first Japanese neurosurgeon Hayari Miyake
72
(1867–1945) – during 1907–1910 took part in histopatho-73
logical studies of partially removed thyroid glands (Fig. 1).74
In four middle aged women (two had hypothyroidism)75
he found in thyroid glands unknown pathomorphological
76
signs [9]. H. Hashimoto noticed that in difference with com-77
mon colloid goiter, these thyroid specimens contained local78
infiltrates with lymphoid cells. Formation of lymphoid folli-79
cles started from germinal centers. The author depicted the
80
changes of thyrocytes with marked diffuse fibrosis around81
the lymphoid follicles, giant eosinophilic cells and even lym-82
phatic vessels, newly structured within thyroid gland. This83
histology did not fit with the diagnoses of Graves’ disease,84
von Mikulicz disease, Riedel’s chronic thyroiditis, infectious85
thyroid involvement. Normally lymphocytes are absent in86
thyroid parenchyma [10]. Earlier such findings had never87
mentioned. Hashimoto prophetically concluded that there88
must be an exogenous factor, provoking accumulation of89
lymphocytes in thyroid. He was sure that a new disease was90
discovered. He called it “lymphomatous goiter”(lat.: struma
91
lymphomatosa) and published his observations (1912) in a
92
Fig. 1. Hakaru Hashimoto in 1912. Courtesy of Dr. Hiroshi Sato, Kyushu
University.
German journal [9]. In this paper he discussed in details (indi- 93
cating profound knowledge of a subject) all data on thyroid, 94
available to that period, and even anticipated the probable 95
kinship of a new nosological entity with Graves’ disease 96
and von Mikulicz’ disease, because “round-nucleated cells” 97
were known for their ability to infiltrate various glands. It is 98
especially valuable, because many years had to pass before 99
the recognition of autoimmune nature for all these forms of 100
pathology. 101
Later Hashimoto had to abandon scientific career, left uni- 102
versity and accepted to himself all care of family and rural 103
medical practice of his deceased father. The brilliant début 104
article, which immortalized his name, remained his sole aca- 105
demic paper. In 1934 this countryside family practitioner 106
perished from abdominal typhoid fever, caught from a patient 107
[10–13]. It was a fateful recapitulation of a previous tragedy: 108
death of a discoverer of another autoimmune thyroid disorder 109
Dr. Karl Adolph von Basedow (1799–1854), who perished 110
from epidemic typhus infected on autopsy of a patient [14].111
We believe that it was specifically Hashimoto who 112
described one hundred and one year ago, in 1912 the first 113
cell-mediated human autoimmune disease.Delayed type of 114
hypersensitivity (DTH), in fact, was medically observed as 115
early as in E. Jenner’s publications on smallpox vaccina- 116
tion [15]. But, before Hashimoto not a single DTH-mediated 117
autoimmune disease was known. Autoimmune endocrine dis- 118
orders also were not yet described to 1912, although London 119
already produced anti-sperm autoantibodies, registered their 120
presence in healthy men (1901) and came to the conclusion 121
that in enhancement of autoimmunity they can alter gonads 122
and cause infertility [4]. It means that Hashimoto can be 123
referred to as a pioneer of immunoendocrinology:indeed 124

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he has intentionally emphasized the lymphoid specifics of125
freshly discovered goiter variant, though lymphocytes in that126
epoch were not yet recognized as immunocytes!127
The true value of Hashimoto’s discovery had to wait128
for appreciation for many years. Japanese doctors were not129
German-readers, almost not aware of his publication, while130
in Germany it was already cited by Simmonds (1913) and131
Heineke (1914). A British medical graduate Williamson, who
132
described “lymphadenoid goiter” in his graduation paper of133
1925 also, did not know about Hashimoto’s article. Neither134
him, nor a Canadian surgeon Eberts who quoted Hashimoto’s135
work (1929), did not distinguish lymphomatous goiter from136
Riedel’s thyroiditis, which distinction Hashimoto did as137
early as in 1912 [13]. And there were some reasons for it.138
The majority of physicians, impressed with successful mass139
iodine prophylaxis of endemic goiter (by Marine and oth-140
ers) put goiter very close to iodine deficit in their clinical141
reasoning and did not pay any attention to its possible alter-142
native causes. Also, there was an impact of neglect among143
English and American doctors as regarded to German liter-
144
ature immediately after World War I [13]. But as soon as145
in 30ies validity triumphed: Allen Graham, a surgeon from146
Cleveland, Ohio confirmed Hashimoto’s point of view and147
priority in two papers published in English (1931–32) and148
proved that lymphomatous struma with thyroid fibrosis out-149
come was not a Riedel’s struma, but a separate nosological150
form. Moreover, he coined an eponym: “Hashimoto’s goiter”151
[16]. From thereafter papers and textbooks started to mention
152
this name regularly, first in USA, later in Britain.153
The experts of III International thyroidological congress154
in Washington D.C. (1938) dedicated special session to this155
new disease and agreed that Hasimoto discovered it. Thus it156
should be named after him. But this eponym was introduced157
into Japanese medical thesaurus much later: really, there is158
no a prophet in one’s Fatherland! The disease was recognized
159
as a separate nosological unite, but still was regarded as rare160
one, and by no means was it related to mass cases of seem-161
ingly “sporadic” hypothyroidism, observed by practitioners162
beyond the iodine-deficient regions.163
In 1956 the coryphaei of immunology E. Witebsky and164
N. Rose created a first model of Hashimoto’s disease in165
rabbits by means of immunization with marker antigen of166
thyrocytes – thyroglobulin (TG). Thus, for the first time in167
the history of Pathophysiology they proved in principle the168
very possibility of experimental modeling for autoimmune169
diseases [17,18]. Later I. Roitt and D. Doniach revealed anti-
170
tyroid autoantibodies in clinical patients with Hashimoto’s171
disease and formulated the auto-allergic concept of “struma172
lymphomatosa” [19,20]. The broadest spread of this illness,173
especially among females, finally attracted the attention of174
health professionals in 1962, and it happened beyond the175
area, where it was initially registered: I. Doniach and E.176
Williams, basing on the data of continuously performed
177
autopsies of English women perished from different reasons,178
revealed the picture of Hashimoto’s disease in thyroid glands179
of 15–25% of all cases examined [21]. In world literature the
180
disease is called Hashimoto’s chronic autoimmune thyroiditis 181
(AIT) with several synonyms: lymphomatous or lymphade- 182
noid goiter, lymphoid cell or chronic non-specific thyroiditis, 183
auto-allergic thyroiditis, chronic non-purulent thyroiditis, 184
Hashimoto’s goiter and Hashimoto’s disease [22]. Recently 185
a variant of chronic thyroiditis related to IgG4autoantibod- 186
ies was described with the predominance of fibrosis and less 187
prominent lymphoid infiltrates (“fibrotic”) [23,24]. The most 188
comprehensive global directory of medical eponyms con- 189
tains just few Japanese names equally famous worldwide, 190
besides Hashimoto’s disease: these are Takayasu’s disease, 191
Kawasaki’s disease and Aschoff-Tawara node [25].192
4. Significance of Hashimoto’s disease in 193
contemporary medicine 194
Why did ordinary family practitioner from a remote vil- 195
lage achieved global recognition? The point is that incidence 196
of AIT starting from 2nd half of 60ies in XX century con- 197
stantly increased, comprising a lion’s share of the total thyroid 198
pathology. It became not only medical, but also global social 199
problem, like diabetes mellitus. AIT is now the most impor- 200
tant reason of hypothyroidism worldwide, standing far ahead 201
of endemic goiter. According our data, the frequency of AIT 202
diagnosis on admission to hospital among St. Petersburg 203
adolescents-draftees increased more than 5-fold since 1987 204
till 2002 [26]. During 1960ies Hashimoto disease was men- 205
tioned in world literature 292 times, in 90ies – already 1792, 206
and now this request in PubMed gives 5218 references, 3028 207
of them within the last decade. 208
In our Department of Pathology the research of AIT was 209
started in fact from the moment of its foundation (1997). 210
Between Jan 1st 1998 and June 15th 2012 we had consulted 211
51 736 persons between 1 and 90 years old, suffering from 212
AIT. The majority of them stand under our dynamic observa- 213
tion during 1–14 years. As a result of research and treatment, 214
we have collected considerable clinical-pathophysiological 215
database and refined several concepts of etiology, pathogen- 216
esis and treatment of AIT, in particular: the role of Chernobyl 217
disaster sequels, roles of hyperprolactinemia, marfanoid phe- 218
notype, chronic systemic excess of some cytokines, relation 219
to early metabolic syndrome (MS), etc. These data have been 220
summarized in our 160 domestic and international papers 221
published on this topic. 222
5. Comorbidity of autoimmune thyroiditis 223
Observing the patients of different age with AIT, we have 224
noticed among them huge percentage of adolescents and 225
young adults with either juvenile dyspituitarism (Simson- 226
Page syndrome, hypothalamic syndrome of adolescence, 227
obesity with rose striae, Fig. 2), or vice versa, those with 228
obvious hypotrophy. Simpson-Page syndrome occurred in 229
24% of our cohort, compared to 1.5% in local population. 230

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Fig. 2. Habitus of a typical patient with SPS-CTD–AIT comorbidity (in left upper corner) – and content of several cytokines (TGF␤1/␤2, interferon-␥, IL-8),
hormones (prolactin, cortisol) and autoantibodies towards thyroid antigens (thyroperoxidase – Ab-TPO and thyroglobulin – Ab-TG) in blood of patients and
controls. All bioregulators determined by ELISA method. Asterisks match p< 0.05 with controls (this illustration and Fig. 3 below are published by consent of
A.B. Poletaev, editor-in-chief of the Abstract book of III Moscow International conference of autoimmunity in health and disease, 2012.
Their clinical examination brought us to curious results:231
it appeared that overwhelming majority of such patients232
(regardless of their body mass and fatness status) displayed233
the combination of various signs of non-syndromal connec-234
tive tissue dysplasia (CTD) of marfanoid phenotype (MF):235
rather tall height, long arms with the elements of arachn-236
odactyly, fairly short legs, backbone and chest deformations,237
transversal type of flat foot, benign joint hypermobility, skin
238
hyperelasticity, interdigital membranes, positive thumb and239
wrist tests (Walter symptom), mitral valve prolapse, false240
chordae in left ventricle, deformations of gallbladder, right-241
side nephroptosis, myopia with astigmatism, wrong dentition242
etc [26]. Even full Marfan syndrome, although rare in local243
population (<0.01%) occurred in this cohort in 0.74%.244
Interestingly, the adolescents of both sexes after decrease of245
their body mass (as a result of effective treatment) converted
246
into patients with typical habitus of marfanoid CTD (Fig. 2).247
At the same time, they often displayed autoantibodies248
against thyroid gland in titers, increasing with age (Fig. 3), as249
well as clinical-laboratory manifestations of hypothyroidism250
of varying severity.
251
We have separated a cohort of 195 marfanoid male 252
adolescents-draftees of the identical age [27] and 253
revealed in their blood significant increase of T3level 254
(to 2.25 ±0.06 nM/L vs 1.74 ±0.06 nM/L in controls), 255
decrease of T4(107.6 ±0.1 nM/L vs 124.4 ±3.3 nM/L) and 256
raise of TSH (2.14 ±0.13 ␮U/mL vs 0.99 ±0.06 ␮U/mL). 257
Diagnostic titers of antithyroid autoantibodies presented in 258
11. 5% of cases. Half of draftees had the ultrasonographic 259
images of thyroid typical for AIT: hypo-echogenic irregular 260
structure with micro-nodules and cysts. One third of ado- 261
lescents manifested so called “subclinical” hypothyroidism. 262
Later [28], exploring 194 persons with CTD (14–50 years 263
of age) we revealed significant decrease of T3and T4blood 264
levels, raise of TSH level, noteworthy growth of anti-TG 265
and anti-TPO autoantibody titers in their blood, compared 266
to healthy donors of the same age. In group of 40 marfanoid 267
persons with overt hypothyroidism the difference with 268
healthy donors was even sharper. 269
With aging the production of thyroid hormones by CTD 270
patients tend to decrease, with appropriate increase of 271
blood TSH, anti-TG and anti-TPO autoantibody levels. This 272

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Fig. 3. Left – content of leptin in blood of AIT-CTD patients, accompanied by either STS, or common obesity, or normal body mass. Right – age dynamics
of autoantibodies towards thyroid antigens in AIT-CTD. Asterisks match – p<0.05 with controls. Dashed line marks cut level of diagnostically significant
autoantibody titers.
tendency was accompanied by increase of thyroid gland vol-273
ume (estimated by ultrasonography). All these data may274
witness for gradual progressing of AIT in CTD patients to
275
the outcome of overt hypothyroidism [28]. Checking the276
parameters of cytokine and hormonal regulation in patients277
with combination of CTD and AIT (especially, when SPS278
presented), we registered in systemic blood significantly279
excessive concentrations of both TGF␤1 and ␤2(Fig. 2), as280
well as absolute and relative (per unite of body mass index,281
BMI) hyperleptinemia (Fig. 3)[26,28–30]. SPS and hypothy-282
roidism both are regarded by many authors as typical pseudo-283
cushingoid stress-associated disorders or diseases of over-284
stressed adaptation [31]. It is particularly right for the highly285
stressful period of adolescence, critically sensitive one in the286
ontogenesis of endocrine system [22]. Inhibiting influence of287
stress on thyroid function is well known, as well as stimulat-288
ing one – on the production of sympathetic-adrenal agonist
289
leptin (especially among the young obese persons) [31,32].290
Taking into account these influences and also the fact291
of glucocorticoid-mediated inhibition of some TGF␤effects292
(systemic excess of this cytokine is a proven central patho-293
genetic link of full Marfan syndrome [33–35]), one may294
suggest that patients with SPS have conditions for compen-295
satory hyperproduction of TGF␤, thyroid dysfunction and296
hyperleptinemia, which all were registered in our study. There297
are tight interrelations between leptin and thyroid (including
298
leptin production stimulation by TSH, thyroliberin produc-299
tion stimulation by leptin, presence of leptin receptor on300
thyroid cells, stimulation of their growth and function by lep-301
tin, suppression of leptin production by thyroid hormones302
and hyperleptinemia in hypothyroidism). Because of this303
we proposed that the excess of leptin in our patients pro-304
moted the thyroid dysfunction [36,37]. Moreover, leptin is305
a proven stimulator of Th1, macrophages of 1st type and306
autoimmune DTH reactions. These links are most impor-307
tant in AIT pathogenesis and, also they trigger inflammatory308
changes in adipose tissue [38,39]. Correlation of leptin level
309
and autoimmune thyroid disease in obese patients has been 310
already confirmed [39]. However, in a Polish study the ado- 311
lescents with AIT did not display overt elevation of leptin 312
level, although the levels of TSH and leptin correlated [40].313
Presumably, the explanation is that, unlike our patients, their 314
cohort was not selected for marfanoid habitus. It looks like 315
in marfanoid SPS adolescents, in particular, the disorders of 316
leptin regulation of autoimmunity promote the pathogenesis 317
of AIT. Hence, there must be some other factor, related to 318
CTD and able to render permissive effect on the leptin stimu- 319
lation of AIT development.It is not by chance, that comparing 320
the levels of TSH and thyroid function in marfanoid and non- 321
marfanoid SPS patients, we found that in marfanoid ones 322
TSH concentration was greater and latent hypothyroidism 323
was registered more often (52% vs 39%, respectively) [29].324
Key role may be due to another cytokine – TGF␤, which 325
systemic action is sharply excessive not only in classical full 326
Marfan syndrome [41], but also in non-syndromal CTD [29].327
We have registered weak negative correlation between TGF␤328
blood concentration and titer of antithyroid autoantibodies 329
and negative correlation between TGF␤and TSH blood con- 330
centrations [29,30]. This can be related to greater degree of 331
AIT and hypothyroidism in smaller levels of immunosuppres- 332
sive TGF␤. But, TGF␤renders unequivocal effects on the 333
course of AIT: its compensatory anti-inflammatory potential 334
does not exclude neither its ability to stimulate migration of 335
lymphocytes into thyroid, not its enhancing effect of fibrosis. 336
Also TGF␤may stimulate the development of experimen- 337
tal AIT. The induction of TGF␤production within thyroid 338
by iodides is of special significance [42–44]. Earlier many 339
authors, including us, have demonstrated that the excess of 340
iodine provokes AIT both in humans and in experimental 341
animals [45,46].342
The trend of TGF␤action over autoimmunity depends on 343
permissive context, created by other bioregulators [42].Inour 344
co-morbid patients the permissive background for excessive 345
systemic action of TGF␤1/␤2 was pro-inflammatory. Firstly, 346

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due to leptin excess (typical, for example, for post-partum347
thyroiditis and contributing into its pathogenesis) [48]. Sec-348
ondly, in SPS we have revealed hyperangiotensinogenemia349
[49], which could be very essential for marfanoid patients,350
because it was proven that via chymase activation angiotensin351
II promotes TGF␤activation and TGF␤-dependant vascu-352
lar pathology, including aneurysms, typical both for MF and353
Marfan syndrome [50]. Finally, in AIT we have revealed
354
the excess of acute phase reactant – ceruloplasmin, which is355
related to chronic systemic excess of inflammatory autacoids356
and manifestation of oxidative stress [51].357
We believe that in marfanoid SPS patients there is a “strug-358
gle” between contradictory and, in many aspects, opposite359
immunoregulation influences of leptin and TGF␤for preva-360
lence over physiological anti-thyroid autoimmunity. But,361
while these autacoids balance their effects on autoimmune362
process, at the same time they both promote the develop-363
ment and consolidation of marfanoid habitus, co-stimulating364
the axial dolichomorphic growth of mesodermal derivates365
[38,47]. Stress always means “stealing” of energetic and plas-
366
tic resources from insulin-dependent mesenchymal derivates367
on behalf of the cells holding non-insulin dependent GLUT-368
transporters [31,52]. It is highly probable that dysplastic369
connective tissue in CTD gets more prone to this deprivation370
effects of chronic stress. This link can consolidate mutually371
provocative actions of SPS and CTD. The skin striae are372
observed regularly in both disorders, as a typical manifes-373
tation of energetic and substrate deprivation of connective
374
tissue [53].375
We revealed in autoimmune thyroid disease some other376
characteristic changes in systemic action of cytokines (Figs.377
2, 4 and 5).378
It appeared that AIT (mainly – in the beginning) is379
accompanied by clear increase in systemic levels of pro-380
inflammatory TNF␣and ␥-interferon (which by the way
381
serves as an inducer of aberrant HLA-II proteins expres-382
sion on the thyrocytes, provokes autoallergy and can be in383
turn induced by leptin) [48–52]. Systemic concentration of384
pro-inflammatory IL-8 was also increased in AIT, especially385
when later combined with obesity or with SPS. At the same386
time, in combination of SPS and AIT the compensatory387
increase of anti-inflammatory IL-10, characteristic for all388
other autoimmune thyroid patient groups, was completely389
absent [54]. Similar data on the systemic excess of IL-8,390
TNF␣and ␥-interferon were reported by N.N. Tsybikov et al.391
[55].
392
The exophthalmia characteristic for the “Graves-like”393
phenotype of transgenic mice, having adiponectin excess394
[56]. Due to this we were interested in content of this auta-395
coid (known inhibitor of MS pathogenesis) in Graves’ disease396
and in various comorbidities of AIT. In AIT and, especially, in397
Graves’ disease greater relative concentrations of adiponectin398
(per unite of BMI) were revealed. But in combination of AIT
399
with SPS (in difference with AIT of common obese patients)400
there was (Fig. 4) paradoxical decrease of adiponectin level401
[54].
402
Fig. 4. Systemic action of pro-inflammatory (TNF␣) and anti-inflammatory
(adiponectin, IL-10) autacoids in AIT (in the onset and peak of disease);
AIT with CTD & SPS, AIT with common obesity, or in Graves’ disease –
compared to healthy controls (X±sx, asterisks mark p< 0.05 with controls).
Stress-associated tendency to hypoadiponectinemia in 403
adolescents also was revealed by G.P. Chrousos et al. [57].404
6. Autoimmune thyroiditis and metabolic syndrome 405
Both AIT and MS are rightfully called social diseases of 406
our century. The great prevalence of both disorders inevitably 407
causes their comorbidity, not only because of high preva- 408
lence, but also due to common pathogenetic links and close 409
clinical signs. We have examined 400 adult patients with AIT 410
and hypothyroidism of different severity (200 males and 200 411
females, between 22 and 79 years old) and in 206 of them 412
(51.5%) had manifestations typical for MS [58]. At present 413
MS is regularly reported in pediatric and adolescent patients, 414
which phenomenon was for the first time noticed as early 415
as in 1994 [59]. On the basis of many years of continuous 416
observations we suggested that most important risk factors of 417
juvenile MS (JMS) are SPS and marfanoid CTD. The main 418
mechanisms, establishing the transformation of SPS into JMS 419
in marfanoid CTD individuals, is chronic excessive systemic 420
action of the mesenchymal autacoids, mentioned above, and 421
also impact of AIT, promoted on this basis [30].422
In 2002 we were the first authors, to interprete SPS as JMS 423
or its precursor and postulated the regular transformation of 424
SPS into JMS [49,60,61]. The investigation of 250 adoles- 425
cents with SPS revealed that over 70% of them displayed 426
to the moment of examination (or developed in catamnesis) 427
4–5 signs of MS according IDF classification (i.e. arterial 428
hypertension, dyslipidemia, android obesity, intolerance to 429
glucose, hyperinsulinemia,etc.). Moreover, according mod- 430
ified Ghent criteria, practically all of them had the signs 431
of marfanoid CTD. We demonstrated (according Japanese 432
Thyroidological Association criteria) the presence of AIT 433
with all above mentioned signs of cytokine dysregulation 434

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in this group of patients [30]. Other endocrine peculiar-435
ities of them were hypercortisolism, hyperaldosteronism,436
hyperreninemia, excess of angiotensin II and, which was the437
most typical: increasing hyperprolactinemia and progressing438
hypothyroidism with raise of TSH level [30,49].439
Hypercytokinemia with involvement of mesenchymal440
autacoids: TGF␤, leptin, TNF␣, some interleukins and inter-441
ferons, acute phase reactants, as well as lack of adiponectin,
442
or hypothyroidism – all are firmly proven links of inflam-443
matory changes in adipose tissue, inducing insulin resistance444
of lipocytes, muscles, vascular walls and liver, hypothalamic445
dysfunction and thus – facilitating the formation of MS. The446
role of TGF␤is principally important, because of its ability447
to induce TAK-kinases, involved both in pro-inflammatory448
activity and in decrease of insulin sensitivity [62–65].Inco-449
morbidity of CTD, SPS and AIT we found all these signs of450
misbalance between local autacoid and systemic hormonal451
regulation.These changes, in our opinion, are responsible for452
key steps in transformation of SPS into early MS. SPS may453
fade away with aging, but AIT proceeds increasingly through
454
lifetime. Probably, it is thyroid disorder which consolidates455
this comorbidity via hypothyroidism, well proven risk factor456
of MS [66]. The adolescents with CTD and SPS have skin457
rose striae in 100% of cases. During transformation of this458
comorbidity in JMS they also frequently develop Dupuytren’s459
contracture (DC) [58]. We regard both rose striae and DC as460
the most important stigmata of comorbidity, described here.461
First of them reflects the metabolic deprivation of the dys-
462
plastic connective tissue in hypercortisolism, typical for SPS463
[30,53], second one depends on action of TGF␤[67], which464
presents in surplus in blood of our patients.465
7. Pathogenetic role of hyperprolactinemia466
The disorders of interaction between central neuroen-467
docrine and local autacoid regulation in CTD are important in468
pathogenesis of these disorders. But, as we suppose, partic-469
ular contribution belongs to noticeable hyperprolactinemia,470
observed in AIT patients (Figs. 2 and5).471
Hyperprolactinemia results from prolactoliberin action,472
caused by thyroliberin, which in turn is produced in attempt to
473
compensate for hypothyroidism developing in AIT patient. It474
causes mastalgia, mastopathy, masculine gynecomastia and475
infertility. We have a long successful experience of fertility476
re-establish in AIT patients of both sexes by means of hyper-
477
prolactinemia suppression with thyroxinotherapy [68]. The478
regular occurrence of reproductive dysfunction in autoim-479
mune thyroid disease was reported by Shoenfeld et al. [69]480
also. They related it to polyorganic autoimmune disorder,481
vitamin D deficiency, possible extrathyroid immune mediated482
effects, for example, on uterus. But, in our opinion hyperpro-483
lactinemic mechanism is most potent and plays the main part
484
in these complications of AIT. Hyperprolactinemia obviously485
alters fertility, both in males and females, suffering from AIT,486
being the significant factor of risk for fibromatosis and even
487
Fig. 5. Parameters of hormonal (prolactin, cortisol, TSH) and autoim-
mune (autoantibodies to: thyroglobulin – TG, thyroperoxidase – TPO, TSH
receptor– TSHR) regulation in controls, in onset of AIT and on the height
of AIT, in AIT combined to SPS or common obesity; and in Graves’ disease
(X±sx, asterisks mark p< 0.05 with controls).
for cancer of breast [68,70]. Besides that, the stimulating 488
influence of prolactin on immune system is very essential, 489
including its ability to promote the autoimmune processes, 490
which was shown in several non-organospecific autoimmune 491
diseases [71,72]. We demonstrated in marfanoid AIT patients 492
that the higher was the level of prolactin and lower – the level 493
of cortisolemia, the greater were the titers of anti-thyroid 494
autoantibodies [54,68].495
8. Multi-organ autoimmunity in co-morbid and 496
complicated AIT 497
We have noticed that the spectrum of autoallergy in AIT 498
patients is getting broader with the progressing of their 499
MS. We studied autoimmunity spectrum in them by mul- 500
tiparametric non-competitive solid phase ELISA assay kits 501
for simultaneous determination of different autoantibodies 502
with the panels of autoantigens attached (ELI-viscerotest 503
(Immunculus, Russia)) as described earlier [73–75]. In this 504
method the level of certain autoantibody in an individual 505
is evaluated in % compared to average one for population 506
(cumulated data from 3000 healthy donors), last is taken for 507
100% [74].508
To describe the data by groups of individuals statisti- 509
cally [76] we used the mean and standard error of the mean. 510
To check the normal distribution we applied Shapiro–Wilk 511
test. Since in each subgroup, except that of anti-adrenal 512
autoantibodies (AdrM-D/C), there was a deviation from the 513
normal distribution in one of the parameters (p< 0.05), the 514
Kruskal–Wallis test was used for the analysis with pairwise 515
comparison a posteriori. For AdrM-subgroup (distributed 516
normally) Fisher’s test with the evaluation of Levene’s 517
test followed by Bonferroni’s a posteriori comparison or 518
Tamhane’s T2 test were used. Since the Levene’s test rejects 519

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Fig. 6. Relative levels of anti-cardio/pulmo/renal autoantibodies in controls and in complicated co-morbid AIT patients (X±sx), average levels in population
were taken for 100%, *matches p< 0.05 compared to controls, all signatures and abbreviations are given in the text.
the assumption of equal variances (p=0.035), we selected520
Tamhane’s T2-test for a posteriori comparison. The study521
revealed that in many cases in plus to AIT markers these522
patients with age develop increased levels of autoantibodies523
towards heart, kidney, lung, various endocrine cells and hor-524
mone receptors, CNS antigens etc. An example is a case of525
a male patient S. who has marfanoid habitus and suffered
526
from AIT since adolescence. To the age of 25 he developed527
in plus high level of antisuprarenal antibodies with decrease528
of physiological autoimmunity against myelin.
529
We compared a group of AIT patients with obesity (I,530
n=19), a group of co-morbid AIT-CTD-SPS patients (II,531
n= 19) – both groups with similar BMI, and a control group532
without AIT-CTD-SPS co-morbidity and with normal BMI533
(III, n=31).534
In these 3 groups mentioned we tested the levels of autoan-535
tibodies against following autoantigens: Membrane antigen536
of cardiomyocytes (CoM-0.2), cardiac isoform of adrenore-537
ceptor (betaAR), membrane (KiM-0.5) and cytoplasmic538
(KiS-0.7) renal glomerular antigens, membrane (LuM-0.2)539
and cytoplasmic (LuS-0.6) lung alveolar epithelial antigens,540
insulin (Ins) and its receptor (Ins-R), thyroglobulin (TG) and541
thyrotropin receptor (TSH-R), adrenal medullar cell mem-542
brane (AdrM-D/C), myelin basic protein (MBP) and protein543
of astroglial cell filaments (GFAP). The result showed that in
544
spite of decreased average individual auto-immunoreactivity545
in AIT groups (as compared to average level in population),546
the levels of several autoantibodies were significantly ele-547
vated (Figs. 6 and 7).
548
Co-morbid AIT-CTD-SPS group II had greater levels of
549
some anti-cardiac, anti-renal and anti-lung autoantibodies
550
compared to controls, although equally obese AIT patients551
without CTD-SPS did not display significant elevation of the 552
levels of these autoantibodies (Fig. 6). This may be essen- 553
tial for involvement of kidney, heart and lungs of marfanoid 554
individuals in rapid progressing of MS. 555
Any AIT group (I either II) had greater levels of 556
anti-thyroid autoantibodies compared to controls, but AIT 557
with obesity (I) was characterized also by increased levels 558
of autoantibodies to other endocrinocytes and, especially, 559
towards insulin receptors. Levels of anti-myelin autoanti- 560
bodies and anti-adrenoreceptor ones were the same in all 561
groups, but obese AIT patients were distinguished by sig- 562
nificantly higher content of autoantibodies against astroglial 563
cells (Fig. 7). Some of this data may reflect compensatory 564
increase in autoimmunity against hyperfunctional elements 565
of neuroendocrine system, in response to hyperinsulinism 566
and hyperadrenalism, both typical for patients with MS. 567
In several cases of AIT and MS treatment of hypothy- 568
roidism with l-thyroxin provided not only substitution effect 569
and achievement of euthyroidism, but also immune modu- 570
lating action, with decrease in anti-thyroid and some other 571
(for example, anti-platelet) autoantibodies. Unlike glucocor- 572
ticoids, thyroid hormones allowed to achieve this without 573
general immune depression. We have described few cases 574
when thyroxinotherapy has been much more effective in sup- 575
pression of autoallergy, than even prednisolone treatment 576
[77].577
Zaichik [78] demonstrated that hypothyroidism inhibits 578
the programmed cell death, for example, in adrenocortical 579
apoptosis by default. We explained immunomodulation via 580
thyroid hormones taking into account that withdrawal of 581
lymphoid clones (including autoreactive ones) also requires 582
apoptosis and, moreover, thyroxin is able to accelerate it [79].583

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Fig. 7. Relative levels of anti-neuroendocrine cell autoantibodies in controls and in complicated co-morbid AIT patients (X±sx), average levels in population
were taken for 100%, *matches p< 0.05 compared to controls, ˆmatches p< 0.05 between different AIT groups, all signatures and abbreviations are given in
the text.
That is why during progressing of AIT (because of coming584
hypothyroidism) the apoptotic-mediated renewal of tissues585
will occur more slowly. This is manifested in the picture of586
hypothyroidism: for example, there is inhibition of the epi-
587
dermal stratum corneum renovation, which causes so called588
geroderma, typical for these patients. Inhibition of CNS cells589
apoptosis accounts for disorder of synaptic re-modeling in590
brain of hypothyroid cretins. We suspect that apoptotic with-591
drawal of autoreactive lymphocytes in hypothyroidism also592
slows down. This may promote the increase of anti-thyroid593
autoantibodies’ titers, cause lymphocytosis (typical for AIT)594
and facilitate the broadening of autoallergy spectrum with595
age. By the way, lymphocytosis was included into the list596
of MS manifestations from the very beginning of MS con-597
cept [80]. Thyroxinotherapy may restore the normal course598
of apoptotic cell withdrawal, thus improving not only gero-599
derma and cognitive brain functions of a patient, but also600
autoimmunity regulation [74,77]. In our practice, thyroid601
hormones display the ability to prevent autoallergy, MS and602
immunometabolic senescence [30,77,81]. We have analyzed603
100 families, where comorbidity of CTD, SPS and AIT was604
observed through several generations and demonstrated that605
auto-allergic disorders in children from those families start
606
long before overt and even before latent hypothyroidism607
[30,74]. We interpret this as an indirect witness for inherited608
basis of the comorbidity explored.609
9. Conclusion
610
We have presented data that demonstrate the existence of611
chronic conflict between central neuroendocrine (prolactin,
612
cortisol) and local autacoid (leptin, TGF␤, pro-inflammatory 613
and anti-inflammatory cytokines) forms of regulation in 614
comorbidity of marfanoid CTD, SPS and AIT. This conflict 615
serves as the main driver in the progressive course of disease 616
[82], leading to hypothyroidism, autoallergy and to early MS. 617
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