Thyroid gland

THE THYROID GLAND
The Nobel Prize in Physiology or Medicine 1909
Emil Theodor Kocher
The Nobel Medical Prize has been
awarded this year to the famous surgeon,
Professor Theodor Kocher of Bern, in
recognition of his work concerning the
physiology, pathology and surgery of the
thyroid gland.
Switzerland Berne University
Berne, Switzerland
b. 1841- d. 1917
The loss of thyroid function results in serious disturbances in this nutrition. Metabolism is
significantly diminished; growth ceases; the skin and the subcutaneous tissues are the site
of mucous infiltration; degenerative processes occur in internal organs; serious
disturbances make their appearance in the functions of the nervous system and muscles. It
became clear that
Through Kocher's exposition it became quite clear that complete extirpation of the thyroid is reprehensible. A portion
of the gland which is capable of functioning, must be left behind at operation. This very important principle of surgical
intervention has always been observed from that time onwards. With regard to the surgery of the thyroid, Kocher has
subsequently continued to occupy a leading position.
"Für seine Arbeiten über Physiologie, Pathologie und
Chirurgie der Schilddrüse"
„…no internal secretion exceeds that of the thyroid
in importance to the whole organism.
Emphatically not.
The reason for this is that, even at the present moment, the
fully developed picture of cachexia thyreopriva is still not
sufficiently well known to every doctor for him to recognize
it immediately in every case. I see a number of patients who
are treated for anaemia, chlorosis, scrofulosis, nervousness
and menstrual disorders, in which the signs of thyroid
insufficiency strike the practised eye at one glance.”
„In my student days it was still the
exception for a goitre operation to meet
with success, so that even very skilled
surgeons fully rejected it.”
(Kocher)
1875: MORTALITY 75%
1912: 0.5% (KOCHER)
Pyramidal
lappen
ULTRASOUND EXAMINATION
Doppler
SCANNING ELECTRON MICROSCOPY
Radiojod-Scintigraphie
nodules
The Nobel Prize in Chemistry 1943 was
”..awarded to George
".
de Hevesy "for his work
on the use of isotopes as tracers in the study
of chemical processes".
Born: 1 August 1885, Budapest, AustriaHungary (now Hungary)
Died: 5 July 1966, Freiburg im Breisgau, West
Germany (now Germany)
The addition of a known concentration of an isotopically labeled compound to a
sample immediately produces isotope dilution if the particular compound is
present in the sample. After thorough mixing of the isotopically labeled
compound with the sample, any technique that determines the extent of the
isotopic dilution suffices to establish the original concentration of the compound
in the mixture. For in-vivo measurement especially in human the compounds of
short half-time were applied with success.
https://www.uni-freiburg.de/universitaet/portrait/ehrungen-und-preise/Nobelpreis/vonhevesy
Radioiodine-Scintigraphy
131
J
99mTc
123
J
Toxic multinodular
goiter
Toxic autonomous
nodule
Ihre Schilddrüse in guten Händen –
Deutschland macht den Schilddrüsen-Check
Die Papillon-Studie
Ultrasound examination of 96.278 persons without
prior medical history of a thyroid disease..
http://www.schilddruese.de/
Every third person has manifestation(s) of thyroid disease.
Every fourth person has nodules in the thyroid gland.
Every second person over 45 has a thyroid disease.
Men and women are equally affected.
The most common manifestation of thyroid disease is an enlargement of
the gland, i.e. a goiter, which develops as a result of chronically low
iodine intake.
Schlucktest
Swallowing
test
another good cause
to drink for
www.forum-schilddruese.de
Thyroid gland: 15-25 g
Blood flow: 5 ml/g/min
Parafollikuläre (”C”) Zellen
(Kalzitonin)
Functional states of thyroid follicular cells
exocrine: Secretion of thyreoglobulin into the thyroid follicles
absorptive: Uptake of colloid via pinocytosis
endocrine: release of the thyroid hormones
The chemical structure
of thyroid hormones
SYNTHESIS AND RELEASE OF THYROID HORMONES
1. IODINE TRAPPING (iodine pump)
Thyroid/Serum free iodine = 25
TSH-dependent – Hypophysectomy: T/S = 5
- TSH (iodine deficiency) T/S = 250
LATS
TSH
iodine uptake - absorption
100-150 µg/day
Na/J (Na/iodine symporter [NIS]
inhibited by PERCHLORATE (ClO4), THIOCYANATE (SCN-),
PERTECHNATe (TcO4), NITRATE (NO3), (competition); LITHIUM.
2. IODINE-OXYDATION
Iodide leaves the cell aided by pendrin
Iodide oxidized to Iodine
MICROVILLI - PEROXIDASE
(Inhibited by propylthiouracil)
3. SYNTHESIS OF THYREOGLOBULIN
MW: 660 kDa, GLYCOPROTEIN
acinar cells, ribosomal synthesis
4. EXOCYTOSIS
Excytosis of thyreoglobulin into the colloid
5. Iodination
MIT, DIT
TSH
6. CONJUGATION (COUPLING)
DIT + DIT = T4 + ALANINE
MIT + DIT = T3 + ALANINE
TSH
7. PINOCYTOSIS OF THE COLLOID
Iodinated thyreoglobulin is the thyroid hormone store in the colloid.
(sufficient for 2 weeks)
1/4 MIT, 1/3 DIT, 1/3 T4, + T3
TSH stimulated process
8. PROTEOLYSIS
TSH
TSH
Proteolysis of thyreoglobulin in lysosomes - phagolysosomes
release of T3 [10%] und T4 [90%].
9. DEIODINATION (deiodinases)
10. SECRETION
TSH
Hormone transport
T3 (Half life: 24h) and T4 (Half life: 8d)
> 99.5% protein-bound
bound: T4=99.98%; T3=99.5%
Only the free hormone is biologically active!!
Significance of binding to proteins: prevention of filtration in the kidney,
hormone reserve
THYROXINE BINDING GLOBULIN (TBG, 54 kDa Glycoprotein)
THYROXINE BINDING PREALBUMIN (TBPA)
ALBUMIN
Hormone production
nmol/d
From thyroid gland
From tissue metabolismm
Plasma concentration
Total (nmol/l)
Free (pmol/l)
Biological half life (days)
Hormone binding
Biological activity
DEIODINATION
5’/3’-Deiodase Typ I : Liver, kidney, thyroid gland, etc.
5’/3’-Deiodase Typ II: Placenta, CNS, Hypophysis
EFFECTS OF THYROID HORMONES
(GENOMIC EFFECTS)
Thyroid hormones bind to specific (nuclear) receptors
(nuclear transcription factors)
Effects of thyroid hormones I
GENOMIC EFFECTS
calorigenic effect
basal metabolic rate
Oxygen consumption
synthesis of 2,3-DPG
thermogenesis
heat loss
Adult: increased production of uncoupling proteins (UPC-3)
Newborn: increased sensitivity of UPC-1 to adrenergic
stimulation (β3-receptor)
Metabolism: increased glucose absorption
Glycogenolysis, Gluconeogenesis
Insulin sensitivity (diabetogenic effect)
Lipolysis, FFA
Cholesterine
Effects of thyroid hormones II
Heart:
Permissive effect:
increased expression of β-receptors
increased catecholamine-sensitivity
positive inotropic, positive chronotropic effects
tachyarrhytmia
Increased expression: Myosin heavy chain
calcium-, Na-K-ATPase
Development: brain development
bone development
Frog metamorphosis:
from tadpole to frog
Claudia Fährenkemper
Beine einer Froschlarve
28. Februar
25. März
8. Mai
© Offwell Woodland & Wildlife Trust 1998/9 & 2000/1/2/3/4 http://www.offwell.info
8. Mai
13. Juni
9. Juli
Wenn etwas schief läuft...entsteht aus dem befruchteten Ei nie ein Frosch
Ein in Mexiko beheimateter Molch zeigt ganz natürlicherweise eine
verhinderte Entwicklung. Der Axolotl hat eine genetisch bedingte
Schilddrüsenunterfunktion und durchläuft daher keine Metamorphose.
Eigentlich wird er niemals wirklich erwachsen, trotzdem kann er sich
fortpflanzen.
Wird ein Axolotl mit Schilddrüsenhormonen gefüttert, kann er sich zum
erwachsenen Molch entwickeln. Seine Kiemen bilden sich zurück,
Lungen treten an ihre Stelle, die Beine wachsen und die Haut verändert
sich.
REGULATION OF THYROID HORMONE SECRETION
*
Hypothalamo-hypophyseal-thyreoid axis
*
Extrathyroid metabolism of thyroid hormones –
activation of T4 to T3 (inactivation to rT3)
Deiodase-Isoenzymes
*
dietary uptake of iodine – iodine metabolism
Hypothalamo-pituitaryThyreoid axis
Inhibition by:
Dopamine, SOM,
Glucocorticoid
CNS
Thyreotropin-Releasing-Hormon
Thyreoideastimulating
hormone
T4
T3
PROLACTIN
T3 = TRH Receptor ↓
T3 = TSH Synthesis ↓
THYROID
Autoregulation of the thyroid gland: role of iodine
Schilddrüse: 15-25 g
Durchblutung: 5 ml/g/min
Decreased iodine concentration in blood: uptake of iodine from the GI
Funktionelle
Zustände der
Follikellepithelzellen:
tract and increased
hormone
synthesis.
High
bloodSekretion
iodine concentration:
of T4 u. T3 production and
exokriner:
des Hormons in dieinhibition
Schilddrüsenfollikel
absorptiver: release
Aufnahme
des Kolloids
durch Pinozytose [PLUMMER-EFFECT]
decreased
from
thyreoglobulin.
endokriner: Freisetzung der Hormone
pyro-Glu-His-Pro
Glykoprotein, 28 kDa
Effects of TSH
TSH stimulates:
Iodine uptake by follicle cells
[Na/I cotransporter (symporter)]
Iodination
Conjugation (MIT, DIT → T3, T4)
Endocytosis of thyreoglobulin
Proteolysis (Thyreoglobulin → T3 T4)
Secretion (T3, T4)
Trophic effect of TSH: Hyperplasia of the thyroid gland
(increased vascularisation!)
Iodine metabolism
EFFECTS OF IODIDE
In 1948, Wolff and Chaikoff reported that high doses of iodide
block iodide organification in the rat thyroid in vivo. This
phenomenon, known as the acute Wolff-Chaikoff effect, is a
reversible process, because iodide organification resumes when the
iodide concentration in the serum decreases. The mechanisms
underlying the Wolff-Chaikoff effect are complex and involve acute
regulation of several key genes and proteins within the thyrocytes.
DISEASES OF THE THYROID GLAND
1835/1840
morbus Basedow
Henry
Plummer
(1874–1936?)
Hyperthyreosis
Die Basedow-Krankheit wurde nach dem Merseburger
Arzt Karl Adolph von Basedow (1799-1854) benannt.
Graves disease owes its name to the
Irish doctor Robert James Graves
(1796-1853)
Die Basedow-Krankheit wurde nach dem Merseburger Arzt K.
A. von Basedow (1799-1854) benannt.
Sie geht mit einer Überfunktion der Schilddrüse und typischerweise, aber nicht immer - mit den Hauptbeschwerden
der so genannten Merseburger Trias einher: Kropf, Glotzaugen
und beschleunigter Puls. (goiter, exophthalmus, tachycardia)
Nadezhda Krupskaya (1869-1939), wife of Vladimir Lenin, was believed to have
suffered from the disease, which caused her eyes to bulge and her neck to tighten.
This was the reason that her Bolshevik codename was 'Fish'. Since Graves'
disease disrupts the menstrual cycle, it is believed that this is why the couple never
Deckname
had children. (Surgery by KOCHER!)
German folk singer and musician Heino, who has since become famous for his
wearing of dark sunglasses to protect his eyes from bright sunlight.
United States President George H. W. Bush developed new atrial fibrillation and was
diagnosed in 1991 with hyperthyroidism due to the disease and was treated at Walter Reed
Army Medical Center with radioactive iodine. By coincidence (or so it is presumed, since the
ultimate cause of this disease remains unknown), the president's wife, Barbara Bush, and the Bushes'
pet dog, a springer spaniel named Millie, also developed the disease
Graves disease owes its name to the Irish doctor Robert James
Graves, who described a case of goiter with exophthalmos in 1835.
However, the German Karl Adolph von Basedow independently reported
the same constellation of symptoms in 1840. As a result, on the
European Continent the term Basedow's disease is more common than
Graves' disease.[1][2][3]
Several earlier reports exist but were not widely circulated. For example,
cases of goiter with exophthalmos were published by the Italians
Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810
respectively.[4] Prior to these, Caleb Hillier Parry, a notable provincial
physician in England of the late 18th-century (and a friend of Edward
Jenner),[5] described a case in 1786. This case was not published until
1825, but still ten years ahead of Graves![6]
However, fair credit for the first description of Graves disease ought to
go to the 12th-century Persian physician Sayyid Ismail Al-Jurjani,
who noted the association of goiter and exophthalmos in his Thesaurus
of the Shah of Khwarazm, the major medical dictionary of its time.[7]
Merseburg Trias:
Hyperthyreosis
Morbus Basedow-Graves
goiter, exophthalmus,
tachycardia
men : women = 1 : 8
Autoimmune disease
basal metabolic rate increased
goiter
exophthalmus (protrusion of the eyeball)
LATS (long acting thyroid stimulator) (80% in Graves')
Thyroid stimulating immunoglobulins TSI
shivering, restlessness, sweating, loss of weight
despite good appetite, increased body temperature,
diarrhea, hair loss, psychic changes
Thyroid storm (or thyrotoxic crisis)
is an acute, life-threatening, hypermetabolic state induced by
excessive release of thyroid hormones.
Symptoms: fever (above 39 oC), tachycardia, hypertension,
cardiac failure, psychic impairments.
Thyroid storm was commonly observed during thyroid surgery, especially
in older children and adults, but improved preoperative management has
markedly decreased the incidence of this complication. Today, thyroid
storm occurs more commonly as a medical crisis rather than a surgical
crisis.
HYPOTHYREOSIS – HYPOTHYROIDISM
The symptoms of hypothyroidism are often varied
and non-specific, weight gain and the inability to
lose weight are two of the most common symptoms
of hypothyroidism.
HYPOTHYREOSIS – HYPOTHYROIDISM
Basal metabolic rate decreased (60% ), body temperature decreased
Myxedema: impaired breakdown of hyaluronic acid, chondroitinsulphate,
and mucopolysaccharides; these accumulate in the skin and
bind fluid.
Increased TSH (due to decreased iodine availability)
* Heart: cardiomegaly, bradycardia
* Weight gain
hypercholesterinaemia
* Dried out hair and skin
Hoarseness (larynx edema)
* Hair-loss
Fatigue
* Become intolerant to cold
* Muscles aches and cramps
* Constipation
* Depressed and irritable
* Some loss of memory
* Irregular Periods
* Decline in Sex Drive
Role of the thyroid gland in the
postnatal development
Brain development
Bone development
Hypothyreosis of Newborns (1 in 3600) may cause
Cretenism: Retardation of development including severe
impairments of CNS functions and deafness.
Measurement of TSH in newborns is compulsory!
(early hormone substitution with T4 is essential.)
cortex and hippocampus after adult onset hypothyroidism, and are reversible with thyroxine treatment
[23, 24]. These morphological changes are a consequence of altered biological processes as follows.
Kleinhirnentwicklung
Fig 1. -Postnatal morphological changes in the rodent cerebellum after neonatal hypothyroidism. Upper
panel: Purkinje cells in a normal (left) and hypothyroid rat (right). Lower panel: persistence of the
external granular layer (arrow) in a hypothyroid mouse cerebellum.
Stumpen rauchender Kretine. Ein nicht kropfiger Kretine.
Anmerkung: Ein Stumpen ist im Schweizer Sprachgebrauch eine
maschinengefertigte billige Zigarre.
Nicht kropfige Kretine. Hier ist eindrücklich das damals
als "affenähnlich" beschriebene Gesicht zu erkennen.
© Abt. für Unterricht und Medien AUM, Institut für
Medizinische Lehre IML, Universität Bern
Im Bild zwei kropfige Kretine.
CliniSurf
© Universität Bern, 2013
The Kocher patient together with
her sister before the operation.
The patient was then taller than
her little sister.
Nine years after the operation
she stopped growing and
became cretinoid.
(From Kocher, T. Arch Klin Chir 29:254337,1883)
GOITROGENS
”Goitrogen" is a term used to describe any
substance that can cause enlargement of the
thyroid gland. That's because "goiter" is an
enlarged thyroid gland. Chemically, goitrogens are
isothiocyanates. These agents inhibit the uptake of
iodine into the thyroid and, consequently, the
synthesis and secretion of thyroid hormones.
Brussels sprouts, cabbage, cauliflower, kohlrabi,
radishes, etc.