Thyroid gland

THE THYROID GLAND

Emil Theodor Kocher
Switzerland Berne University
Berne, Switzerland
b. 1841- d. 1917
The Nobel Prize in Physiology or Medicine 1909
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.
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 the gland acts by elaborating a secretion, which reaches the various
parts of the body. It is, as the expression goes, an internal «secretion».
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. Are doctors
now making use of the newly won province of physiological
therapeutics to the extent that it deserves? 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 Knoten

The concept of radioactive tracing was developed by György Hevesy (1885-
1966), the Nobel Prize winner Hungarian scientist. According to the basic idea
the human body cannot distinguish the radioactive isotope of an element from
the non-radioactive one, thus the radioactive isotope of the element can get to all
those organs within the body where the element itself can.

Radioiodine-Scintigraphy
J 131 J 123
99mTc
Toxic multinodular
goiter
Toxic autonomous
nodule

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

Edward C. KENDALL
Kendall hat weitere wichtige Beiträge zur Endokrinologie geleistet. Für die Entdeckung des
Nebennierenhormons Cortison (Compound E) erhielt er im Jahre 1950 gemeinsam mit Tadeus Reichstein
und Philip S. Hench den Nobelpreis für Physiologie oder Medizin (2, 3).
Medizinische Kurznachrichten der Deutschen Gesellschaft für Endokrinologie
(Mediensprecher: Prof. Helmut Schatz, Bochum)

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 (ClO 4 ), THIOCYANATE (SCN - ),
PERTECHNATe (TcO 4 ), NITRATE (NO 3 ), (competition); LITHIUM.
2. IODINE-OXYDATION
Iodide leaves the cell via pendrin (anion exchanger I - /Cl - )
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
Proteolysis of thyreoglobulin in lysosomes - phagolysosomes
release of T3 [10%] und T4 [90%].
9. DEIODINATION (deiodinases)
TSH
10. SECRETION
TSH

Synthesis of thyroid hormones

Hormone transport
T3 (Half life: 24h) and T4 (Half life: 8d)
> 99.5% protein-bound
bound: T 4 =99.98%; T 3 =99.5%
Only the free hormone is biologically active!!
(prevention of filtration in the kidney,
buffer, 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
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 (β 3 -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
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
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.
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.

REGULATION OF THYROID HORMONE SECRETION
* Hypothalamo-hypophyseal-thyreoid axis
* Extrathyroid metabolism of thyroid hormones –
activation of T 4 to T 3 (inactivation to rT 3 )
Deiodase-Isoenzymes
* dietary uptake of iodine – iodine metabolism

Hypothalamo-pituitary-
Thyreoid axis
CNS
Inhibition by:
Dopamine, SOM,
Glucocorticoid
Thyreoideastimulating
hormone
T 4 T 3
Thyreotropin-Releasing-Hormon
PROLACTIN
T 3 = TRH Receptor ↓
T 3 = 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 tract and increased Zustände der hormone Follikellepithelzellen: synthesis.
High blood iodine concentration: inhibition of T 4 u. T 3 production and
decreased release from thyreoglobulin. [PLUMMER-EFFEKT]
exokriner: Sekretion des Hormons in die Schilddrüsenfollikel
absorptiver: Aufnahme des Kolloids durch Pinozytose
endokriner: Freisetzung der Hormone

pyro-Glu-His-Pro
Glykoprotein, 28 kDa
T 3 , T 4

Effects of TSH
TSH stimulates:
Iodine uptake by follicle cells
[Na/I cotransporter (symporter)]
Iodination
Conjugation (MIT, DIT → T 3 , T 4 )
Endocytosis of thyreoglobulin
Proteolysis (Thyreoglobulin → T 3 T 4 )
Secretion (T 3 , T 4 )
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?)

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)

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]
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]
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]

Celebrities with Thyroid Disorders
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
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
Deckname
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

Hyperthyreosis
Morbus Basedow-Graves
man : women = 1 : 8
Cause:
Autoimmune disease
LATS (long acting thyroid stimulator) (80% in Graves')
Thyroid stimulating immunoglobulins TSI
Symptoms:
Merseburger Trias:
Goiter, exophthalmus, tachycardia
Increased basic metabolic rate
hypocholesterinemia
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 o C), 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
Cause: iodine deficiency in most cases
Symptoms:
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)
inhibitory TSH-receptor antibodies
* Heart: cardiomegaly, bradycardia
* Weight gain hypercholesterinaemia
* Dried out hair and skin * Hoarseness (larynx edema)
* Become intolerant to cold * goiter
* Muscles aches and cramps * Depressed and irritable
* Constipation * Some loss of memory
* Decline in Sex Drive
* Irregular Periods

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 T 4 is essential.)

Cerebellar
development
Myelinization

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

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.