Download thyroid iodine - UMF IASI 2015

THE THYROID
The Thyroid Gland
• The thyroid is a small (25 grams) butterfly-shaped gland
located at the base of the throat. The largest of the
endocrine glands, it consists of two lobes joined by the
isthmus. The thyroid hugs the trachea on either side at
the second and third tracheal ring, opposite of the 5th,
6th and 7th cervical vertebrae. It is composed of many
functional units called follicles, which are separated by
connective tissue.
• Thyroid follicles are spherical and vary in size. Each
follicle is lined with epithelial cells which encircle the
inner colloid space (colloid lumen). Cell surfaces facing
the lumen are made up of microvilli and surfaces distal to
the lumen lie in close proximity to capillaries.
The Thyroid Gland
•
•
•
•
•
•
Formation of the thyroid gland occurs during weeks 7-9 of gestation as an
epithelial proliferation of the floor of the pharinx at the site of foramen cecum
linque. The gland riches its final position by week 9 descending along the
thyro-glosal duct.
Weeks 7-9 : thyroid formation begins
Week 10 : TSH and T4 are detectable
Week 17 : structural maturity of the thryoid gland
Week 20 : type 2 and type 3 deiodinase are present
Weeks 18 – 40 :
– TRH present
– TSH is present and controls thyroid hormone production
– Fetal thyroid response to TSH - thyroid hormone to TRH and TSH
hormone feed established
Thyroid anatomy
Microscopic appearance of thyroid
follicles
Thyroid hormones in the body
Thyroid hormones synthesis
The thyroid is stimulated by the pituitary hormone TSH to produce two
hormones, Thyroxine (T4) and triiodothyronine (T3) in the presence
of iodide. Hormone production proceeds by six steps:
1.
Dietary iodine is transported from the capillary through the
epithelial cell into the lumen NIS and Pendrin.
2.
Iodine is oxidized to iodide by the thyroid peroxidase enzyme (TPO)
and is bound to tyrosine residues on the thyroglobulin molecule to
yield monoiodotyrosine (MIT) and diiodotyrosine (DIT).
3.
TPO further catalyzes the coupling of MIT and DIT moieties to form
T4 and/or T3.
4.
The thyroglobulin molecules carrying the hormones are taken into
the epithelial cells via endocytosis in the form of colloid drops.
5.
Proteolysis of the iodinated hormones from thyroglobulin takes
place via protease/peptidase action in lysosomes and the hormones
are released to the capillaries.
6.
Any remaining uncoupled MIT or DIT is deiodinated to regenerate
iodide and tyrosine residues.
Iodine metabolism in normal thyroid cells
TSH signaling via the TSH receptor (which is shown at the bottom of the thyrocyte on the left) controls
thyroid hormone synthesis, and it can increase expression of NIS in the basolateral membrane of
thyrocytes. As shown in the thyrocyte on the right, NIS takes up iodide from the blood. The proteins
involved in efflux of iodide at the apical membrane are not known, and the roles of AIT and pendrin are
unclear. As shown in the left-hand thyrocyte, iodide is organified in the tyrosyl residues of Tg in a
reaction catalyzed by TPO, in the presence of H2O2, which is produced by DUOX. Tg contains MIT,
DIT, T3, and T4 and is stored in colloid until T3 and T4 need to be released into the blood.
ION TRANSPORT BY THE
THYROID FOLLICULAR CELL
ClO4-, SCNBLOOD
I-
I-
organification
NaI symporter (NIS) and pendrine
Thyroid peroxidase (TPO)
COLLOID
Propylthiouracil (PTU)
blocks iodination of
thyroglobulin
THYROGLOBULIN SYNTHESIS IN THE
THYROID FOLLICULAR CELL
Iodination of
Tyr residues of Tg
COLLOID
TSH
TSH receptor
TPO
THYROID HORMONE SECRETION BY THE
THYROID FOLLICULAR CELL
T4
T3
COLLOID
DIT
MIT
TSH
TSH receptor
I-
THYROID HORMONES
OH
OH
I
I
I
I
I
O
O
NH2
I
O
OH
Thyroxine (T4)
NH2
I
O
OH
3,5,3’-Triiodothyronine (T3)
Thyroid hormone transport
• bound to thyroxine-binding globulin (TBG):
70%
• bound to transthyretin or "thyroxinebinding prealbumin" (TTR or TBPA):1015%
• Paralbumin: 15-20%
• unbound T4 (fT4): 0.03%
• unbound T3 (fT3): 0.3%
FEEDBACK REGULATION
THE HYPOTHALAMIC-PITUITARY-THYROID AXIS
Hormones derived from the pituitary that regulate
the synthesis and/or secretion of other hormones
are known as trophic hormones.
Key players for the thyroid include:
TRH - Thyrophin Releasing Hormone
TSH - Thyroid Stimulating Hormone
T4/T3 - Thyroid hormones
Control of thyroid function
TRH
Thyrotropin releasing hormone is produced by the
hypothalamus and functions to stimulate the anterior
pituitary to release TSH. TRH is a small tripeptide that
acts in conjunction with somatostatin and dopamine to
regulate the synthesis and release of TSH in a dose
dependent manner. Dysfunction at this stage in the
stimulatory cascade results in decreased TSH
production and hence hypothyroidism, termed a tertiary
thyroid disorder. While thyroid hormones T4 and T3
down-regulate TSH in a classic feedback inhibition
scheme, TRH production is also inhibited the these
thyroid hormones, albeit to a lesser degree, in the
hypothalamus.
Control of thyroid function
TSH
Thyroid stimulating hormone (TSH) or thyrotropin is a glycoprotein with
a molecular weight of approximately 28,000 daltons, synthesized by
the basophilic cells (thyrotropes) of the anterior piyuitary TSH is
composed of two noncovalently linked subunits designated alpha
and beta. Although the alpha subunit of TSH is common to
luteinizing hormone (LH), follicle stimulating hormone (FSH) and
human chorionic gonadotropin (hCG), the beta subunits of these
glycoproteins are hormone specific and confer biological as well as
immunological specificity. Both alpha and beta subunits are required
for biological activity. TSH stimulates the production and secretion of
the metabolically active thyroid hormones, thyroxine (T4) and
triiodothyronine (T3), by interacting with a specific receptor on the
thyroid cell surface. T3 and T4 are responsible for regulating diverse
biochemical processes throughout the body which are essential for
normal development and metabolic and neural activity.
THYROID HORMONES ACTIONS
THYROID HORMONE METABOLISM
“Step up”
“Step down”
T4
R
R
T3
rT3
R
3,3’-T2
R=
THYROID HORMONE
DEIODINASES
• Three deiodinases (D1, D2 & D3) catalyze
the generation and/disposal of bioactive
thyroid hormone.
• D1 & D2 “bioactivate” thyroid hormone by
removing a single “outer-ring” iodine atom.
• D3 “inactivates” thyroid hormone by
removing a single “inner-ring”iodine atom.
• All family members contain the novel
amino acid selenocysteine (SeC) in their
catalytic center.
BASIC ORGANIZATION OF THE
SELENODEIODINASES
extracellular domain
NH2
intracellular domain
COOH
EXISTS AS A
DIMER
BASICS OF THYROID HORMONE
ACTION IN THE CELL
SPECIFIC ACTIONS OF THYROID
HORMONE: METABOLIC
• Regulates of Basal Metabolic Rate (BMR).
• Increases oxygen consumption in most
target tissues.
• Permissive actions: TH increases
sensitivity of target tissues to
catecholamines, thereby elevating
lipolysis, glycogenolysis, and
gluconeogenesis.
SPECIFIC ACTIONS OF THYROID
HORMONE: DEVELOPMENT
• TH is critical for normal development of the
skeletal system and musculature.
• TH is also essential for normal brain
development and regulates synaptogenesis,
neuronal integration, myelination and cell
migration.
• CRETINISM is the term for the constellation of
defects resulting from untreated neonatal
hypothyroidism.
THYROID HORMONES MECHANISM OF
ACTIONS
•
•
•
•
Passive diffusion or active transport?
Deiodination of T4 to T3
T3 binds to specific nuclear receptor
Nuclear receptor activation increases RNA and protein
synthesis
• Increased Na/K aATP-ase and ATP turn-over
• Increased oxigen consumption in mitochondrias
• Calorigenic effects
THYROID HORMONES ACTIONS
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•
Increase basal metabolic rate
Increase heat production through stimulation of Na/K ATP-ase
Stimulate protein synthesis
Regulate long bone growth synergistic with GH
Stimulate neuronal maturation
Increase number of cathecolamine receptors
TH are essential for normal development and differentiation of
all cells of the human body
• Increase lipid catabolism / lypolisis
• Increase glucose uptake and metabolism
• Growth, development, body temperature, energy metabolism
regulation
Thyroid hormones are responsible for neuronal mielinization
EXAMPLES OF THYROID DISEASES
Hypothyroidism
Hyperthyroidism
EXAMPLES OF THYROID DISEASES
Juvenile Hypothyroidism
Congenital Hypothyroidism
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
skin -appendages
warm, moist skin;
sweating; fine, thin hair;
Plumber's nails; pretibial
dermopathy (Graves'
disease)
pale, cool, puffy skin;
brittle hair and nails
Eyes, face
Upper lid retraction (wide
stare); periorbital edema;
exophthalmos, diplopia
(Graves' disease)
Eyelid drooping;
periorbital edema; puffy,
nonpitting facies; large
tongue
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
Cardiovascular
decreased peripheral
resistance, increased
cardiac output, stroke
volume, heart rate, pulse
pressure; congestive
heart failure (high-output);
increased contractility,.
arrhythmogenic; angina
increased peripheral
resistance, decreased
cardiac output, stroke
volume, heart rate, pulse
pressure; congestive
heart failure (low output);
bradycardia (low voltage
ECG with prolonged PR
interval, flat T wave);
pericardial effusion
Respiratory
dyspnea; reduced vital
capacity
hypoventilation (CO2
retention) pleural
effusions
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
CNS
Nervousness,
hyperkinesia, variable
emotional states
lethargy, neuropathy
Gastrointestinal
increased appetite;
increased bowel
movement frequency;
hypoproteinemia
decreased appetite,
decreased bowel
movement frequency;
ascites
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
Musculoskeletal
Weakness; fatigue;
hypercalcemia,
osteoporosis, increased
deep tendon reflex
muscle fatigue, reduced
deep tendon reflex,
increased alkaline
phosphatase, LDH, AST
Renal
Increased renal blood
flow; increased GFR; mild
polyuria
Decreased renal blood
flow; decreased GFR;
reduced water excretion
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
Hematopoietic
anemia (increased RBC
turnover); increased
erythropoiesis
anemia (decrease
production rate,
decreased iron
absorption, decreased
folate acid absorption,
autoimmune pernicious
anemia),decreased
erythropoiesis
Reproductive
decreased fertility;
menstrual irregularity;
enhanced gonadal steroid
metabolism
infertility;hypermenorrhea
decreased libido;
impotence, decreased
gonadal steroid
metabolism
Physiological system
Hyperthyroidism
(thyrotoxicosis)
Hypothyroidism
Metabolic
increased basal rate;
negative nitrogen
balance, hyperglycemia;
increased free fatty acids,
decreased cholesterol
and triglycerides;
increased hormone
degradation; increased
requirement for fat-and
water-soluble vitamins;
enhanced drug
detoxification
decreased basal rate;
delayed insulin
degradation, with
increased sensitivity;
enhanced cholesterol and
triglyceride levels;
decreased hormone
degradation; decreased
requirements for fat-and
water-soluble vitamins;
decreased drug
detoxification.
Normal ultrasound appearence of
the thyroid gland
Calculation of thyroid volume
Formula of a rotationg elipsoid
a = AP diameter AP
b = Transverse diameter
c = longitudinal diameter
I
axbxcx/6
II a x b x c x 0.479
III a x b x c x 0.53
IV a x b x c x 0.5
Malignant thyroid nodule
Thyroid scintigraph
Thyroid scintigraph with 123I
The nodule on the right lobe appears to be hypofunctioning (cold
nodule).
Magnetic resonance imaging:
large goiter and anaplastic carcinoma of the thyroid
Thyroid computed tomography multiple malignant nodules
Thyroid computed tomography – large multinodular goiter
TSH, T4 and T4 assessment and their values in thyroid diseases
Thyroid function tests – decisional algorithm
ENDEMIC GOITER
Iodine Deficiency Disorders
Role of iodine and sources
• Fetal body and brain development
• Hearing system development
• Normal prenatal body function
• Animal products: meet, milk
• Water
• Factors that interfere with iodine metabolism:
goitrogens: cassava, cabage, tiocyanates,
fluoride, selenium deficiency
Iodine Deficiency
• Goiter in children and adults / increased volume
of thyroid gland
• Severe mental retardation
• Growth failure
• Speech and hearing defects
• Low intelectual capacity even in mild iodine
deficiency
• Cretinism: neurologic or mixedematous ( when
iodine deficiency and selenium coexist)
IDDs
• Prenatal: mental retardation, low birth weight, increased
prenatal death
• Newborn: goiter, transient hypothyroidism, definitive
hypothyroidism, increased frequency of congenital
mixedema
• Childhood and adolescence: goiter, growth and mental
retardation, hypothyroidism: clinical or subclinical
• Adulthood :
– goiter and complications, including thyroid nodules and
aggressive follicular cancer
– Endemic mental retardation
– Hypothyroidism
– Reduces fertility
IDDs – normal iodine supply
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•
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50 μg for infants less than 12 month
90 μg for children ( 2-6 years of age)
120 μg for scholl children (7-12 years of age)
150 μg for adult beyond 12 years of age
200-250 μg for lactating women
IDDs – a worldwide health problem
1.
2.
3.
•
1.6 billion people at risk
50 millions of children at risk
100,000 cretins are borned each year
Africa
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–
–
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•
Population at risk: 220 million
Fetal death: 15,000
Cretins: 30,000
Brain- demaged children: 1 million
China
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Endemic goiter prevalence: 8.4-85 %
Endemic cretinism: 0.63-11.4 %
IDDs – evalution
1. Clinically: O – normal, I – palpable, II – visible in
normal position of the neck
2. Calculation of thyroid volume
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•
Normal for adult men: up to 25 mL
Normal for adult women: up to 18 mL
3. Biochemical :
•
•
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•
urinary iodine :10 μg / dL
Serum TSH slightly increased > 5 mIU/L
Serum thyroglobuline: less than 10 ng/mL in adults
Maternal milk: 9 μg / dL
IDDs severity of iodine deficiency
Assessed variable
Normal
Mild
Moderate
Severe
Goiter adults %
Thyroid volume over normal %
Urinary iodine μg/dl
Serum thyroglobuline ng/mL
<5
<5
>10
>10
5 - 19.9
5 - 19.9
5 - 9.9
10 - 19.9
20 - 29.9
20- 29.9
2 - 4.9
20 – 39.9
> 30
> 30
<2
>40
Newborns
TSH in serum > 5 mIU/L
Urinary iodine ng/mL
<3
> 10
3 – 19.9
3.5 – 9.9
20 – 39.9
1.5 – 3.4
> 40
< 1.5
“historical” huge endemic goiter
Histology in endemci goiter: Inequal follicles
Large intrathoracic goiter
Endemic cretinism with goiter mixedematous:
short stature, hipothyroidism, mental retardation
Endemic cretins – neurologic
Spastic paresis, severe mental retardation, deafness
Most effected areas by IDDs
• Himalaya
• Central Africa
• South America – Andine areas
Urinary iodine excretion per liter after
Universal Salt Iodization program
implementation
Goiter prevalence varies inversely with iodine
excretion which is the witness of iodine intake
Endemic goiter prevalence before and after iodine replacement
Goiter prevalence in South America
In spite of iodine replacement programs goiter prevalence still
increases due to increase population at risk and discontinous survey
of results
IDDs profilaxis
• Iodine given as:
– Iodisyzed salt
– Iodizyzed oil, injectable
– Universal Salt Iodization Program: advocacy,
implementation, continuous survey
Goiter was practically eradicated in Europe but small
areas with borderline deficiency still exist
First country in which goiter was eradicated was
Switzerland
In our country still exist areas with mild endemic goiter
HYPOTHYROIDISM
HYPOTHYROIDISM
Clinical and biochemical syndrome that results from thyroid
hormone defiency and slow metabolic rate
In chiledrean and adolescents hypothyroidism results in slow
growth rate and mental retardation
In all cases hypothyroidism results:
• in reduced basal metabolic rate
• Reduced oxigen consumption
• Deposition of glycosamino glicans in the extracell space
especially in muscles and skin with water infiltration that may
be severe in untreated hypothyroidism and classic aspect of
MIXOEDEMA
Signs and symptoms of hypothyroidism are all reversible under
treatment except for untreated congenital hypothyroidism
ADULT HYPOTHYROIDISM INCLUDING
CHILDHOOD AND ADOLESCENCEND CAUSES
PRIMARY HYPOTHYROIDISM:
1.
Hashimoto’s thyroiditis
a. with goiter
b. without goiter late stage of autoimmune thyroiditis with thyroid fybrosis
2.
Radioactive iodine treatment for Graves’ disease
3.
Thyroidectomy for Graves’ disease, nodular goiter or thyroid cancer
4.
Excessive iodine ingestion, including contrast media (effect Wolf – Chaikoff
5.
Subacute thyroiditis transient
6.
Severe iodine deficiency
7.
Drugs: litium, interpheron alpha, amiodarone
SECONDARY HYPOTHYROIDISM
•
MULTIPLE PITUITARY HORMONE DEFICIENCY OR ISOLATED
TERTIARY hypothyroidism – hypothalamic dysfunction
SYNDROME OF GENERALISED THYROID HORMONE RESISTANCE
HYPOTHYROIDISM: pathogeny
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Reduction of basal metabolic rate
Reduced oxigen consumption
Deposition of glycosamino glicans in the
extracell space especially in muscles and
skin with water infiltration that may be
severe in untreated hypothyroidism and
classic aspect of MIXOEDEMA
Slow function of neurons
HYPOTHYROIDIS IN ADULT
SIGNS AND SYMPTOMS
COMMON FEATURES FOR SEVERE AND MODERATE
HYPOTHYROIDISM:
• Fatigability
• Cold intolerance
• Moderate increase in weight
• Constipation
• Menstrual abnormalities, heavy menstrual bleeding
• Muscle cramps
Physical examination:
• Cold, dry skin
• Undepresible edema of hands and feet
• Voce răguşită
• Reflexe lente
• Carotenodermie
HYPOTHYROIDIS IN ADULT
SIGNS AND SYMPTOMS
Cardio vascular system:
•
•
•
•
Bradicardia
Abnormal contractility of ventricular walls (Ultrasound)
Pericardial effusion (ultrasound)
Incresed vascular resistance
ECG:
• Hypovoltage of QRS waves
• Increased cholesterol, LDL-cholesteron, lypprotein A and
Homocisteine which act as atherogenic factors
• Low basal meabolic rate in hypothyroid old patients may be
protective for angina
HYPOTHYROIDIS IN ADULT
SIGNS AND SYMPTOMS
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•
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Lung function:
Slow respiratory rate
Abnormal response to hypoxia and hypercapnia wich
may be involved with onset of mixoedema coma
Digestive system:
Chronic constipation Marcat redusă cu constipaţie
cronică şi eventual ileus
Kidney function
Reduces glomerular rate filtration
Inability to excrete free water with secondary water
intoxication and severe hyponatremia
HYPOTHYROIDIS IN ADULT
SIGNS AND SYMPTOMS
Anemia:
• Iron deficency
• Anability to have normal folate absorbtion
• Vitamin B12 and megaloblastic anemia
• Association with autoimmune anemia in patients with
Hashimoto’s thyroiditis
Nervous and muscular system:
• Severe muscle cramps
• Paresthesias
• Muscle weakness
HYPOTHYROIDIS IN ADULT
SIGNS AND SYMPTOMS
Reproductive system:
• Anovulaţion şi infertility
• Heavy menstrual bleeding
Central nervous system:
• Chronic weakness
• Letargy
• Inability ot concentrate
• Slow speech
• Loss of memory
• Depression
• Extreme agitation (“mixoedema meadness)
HYPOTHYROIDISM IN ADULTS
RARE FEATURES
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•
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Neurastenia
Paresthesias
Persistent weakness
Infertility
Precocious or delayed puberty
Idiopatic edema or pericardial efusion
Chronic rhinitis and hoarse voice due to
infiltration of vocal cards
• Severe depression or emotional instability
HIPOTIROIDISMUL LA ADULT
SEMNE ŞI SIMPTOME
Anemia:
• Deficit de fier şi sinteza anormală a hemoglobine
• Deficit de folat datorită tulburărilor de absorbţie
• Deficit de vitamina B12 şi anemie megaloblastică
• Tiroidita hashimoto ca maladie autoimună se poate asocia cu
anemia megaloblastică, altă afecţiune autoimună
Neuromuscular system:
• Crampe musculare severe
• Paresezii
• Astenie musculară
HYPOTIROIDISM - DIAGNOSIS
Patient takes thyroid
hormonesi
Patients does not take thyroid
hormones
Stop medication
for 6 weeks
TSH and fT4
fT4 normal
TSH normal
EUTIROIDISM
fT4 low
Ft4 low
TSH increased
TSH normal or
decreased
PRIMARY
HYPOTHYROIDISM
SECONDARY
HYPOTHYROIDISM
US, antiTPO, anti Tg
antibodies
Assess pituitary
Subclinical hypothyroidism
TSH
Increased TSH Low T4 and T3
Primary hypothyroidism
Low TSH Low T4 and T3
Secondary hypothyroidism
Increased
Antithyroid
antibodies
Low urinary
iodine,
Increased I
uptake
TRH test
History of
thyroid surgery,
antithyroid
drugs
Negative
Positive
Pituitary failure
Hypothalamic
disease
Radioiodine
for
hyperthyroidism
Iodine
deficiency
Autoimmune
thyroiditis
Increased iodine
excretion: iodine
excess
Subclinical hypothyroidism: increased TSH,
low or normal fT4
•
•
•
•
Risk factor for atherosclerosis
Adverse effect on hearth function
Abnormal lipid profile
Adverse effects on fetal development if subclinical
hypothyroidism is ignored during pregnancy
• Increased prevalence of depression
• Abnormal coagulability
Prevalence of suclinical hypothyroidism
increases with age
HYPOTYROIDISM COMPLCATIONS
• ATEROSCLEROSIS: major risk factor for
atherosclerosis
• Reduced vascular compliance and fluxendothelial mediated vascular dilataiton
• Hearth function abnormalities (ultrasound)
– Increased vascular resistance
– Decreased left ventricular ejction fraction
– Decreased vascular compliance
HYPOTYROIDISM COMPLCATIONS
Mixoedema coma
is a very rare complication which occurs in untreated hypothyroidism in
certain favoring conditions: winter time, untreated hearth or lung
disease, stroke, sedatives given to untreated patients
Clinical features:
• Pregressive weakness
• hypotermia
• hypoventilation
• hypoglicaemia
• hyponatremia
• Shock
• Death in more than 50 % (to 80% of cases)
Mixoedema coma clinical characteristics
History: hypothyroidism known by relatives, radioiodine treatment for
Graves disease, post thyroidectomy scar
The development of coma is slow and progressive to gradual
development of letargy and coma
Clinical examination:
• Frequently the patient is an old woman with hypotermia, pale and
yeloww skin, hoarse voice
• Large tonque, edema of the face and extremities, ileus
• Slow reflexes
• Signs of other diseases: stroke, myocardial infarction, digestive
hemorrhage, hypocalcemia, seizures
• other:
• pleural effusion, peritoneal or pericardic effusion
Mixoedema coma – pathophysiology
CO2 retention
• Hypoxia este determed by reduced sensitivity of respiratory
centers to oxigen deficiency and hyper CO2, reduced
respiratory muscles efficiency, obesity. It need assisted
ventilation
• Reduced kidney perfusion with water retention, hyponatremia
and cerebral edema.
• Hypotermia due to TH deficiency central body temperature may
drop to 340C
Treatment
•
•
•
High doses of glucocorticoides : hydrocortisone acetate100mg. i.v.
followed by 50 mg. every 6 h
T4 in high dose: 300-400μg i.v. followed by 80 % of substitution
dosage every day
These high doses may worsen angina or precicpitate arrhitmias
Mortalitaty may be up to 80 %
HYPOTHYROIDIS - TREATMENT
LEVOTIROXINE – T4
• Has a half life of 7 days and this allows to be taken once a day
• Has a good absorbtion which allows to maintain a stable concentration
during the day
• All dose must be taken in the morning on an empty stomach
• Monitoring treatment: serum TSH and fT4 every 3 month
• Serum T4 may be increased 4 h after T4 is taken but without clinical
problems
• The dose for complete subsittution in an adult is 2.2 μg/kg.bw/d
• The full dose must be done from the beginning of treatment in patients
under 45 (50) years
• In older patients treatment begin with low dose of 25 μg day for 7 -14
daysdays with increase in dosage with 25 μg every 7-14 days till full
replacement dose is reached
• The dosage is adhusted every 4-6 week in order to maintain THS in the
normal limits:0.4-4 mIU/L
CONGENITAL HYPOTHYROIDISM - CAUSES
1. PRIMARY HYPOTHYROIDISM IN THE NEWBORN:
a. WITH GOITER:
• Imborn erors in thyroid hormone synthesis
• Severe iodine deficiency (mixedematous endemic cretinism)
• Transient hypothyroidism in arias with severe iodine deficiency
b. Without goiter
• Thyroid agenesis or hypogenesis
• Due to trans placental passage of thyroid bloking antibodies from
mother with autoimmune thyroiditis (transient)
2. SECONDARY HYPOTHYRIIDISM IN THE NEWBORN
Congenital TSH deficiency usually associated with other pituitary
hormone deficiency
Classification and etiology of congenital hypothyroidism
Primary hypothyroidism
Thyroid dysgenesis: hypothyroidism due to a developmental anomaly
(Thyroid ectopia, athyreosis, hypoplasia, hemiagenesis)
Associated mutations: (these account for only 2% of thyroid dysgenesis cases; 98%
unknown)
TTF-2,
NKX2.1,
NKX2.5
PAX-9
Thyroid dyshormonogenesis: hypothyroidism due to impaired hormone production
Associated mutations:
Sodium-iodide symporter defect
Thyroid peroxidase defects
Hydrogen peroxide generation defects (DUOX2, DUOXA2 gene mutations)
Pendrin defect (Pendred syndrome)
Thyroglobulin defect
Iodotyrosine deiododinase defect (DEHAL1, SECISBP2 gene mutations)
Resistance to TSH binding or signaling
Associated mutations:
TSH receptor defect
G-protein mutation: pseudohypoparathyroidism type 1a
Syndromic hypothyroidism
Pendred syndrome - (hypothyroidism- deafness - goiter) Pendrin mutation
Bamforth-Lazarus syndrome - (hypothyroidism - cleft palate - spiky hair) TTF-2
mutation
Ectodermal dysplasia - (hypohidrotic - hypothyroidism - ciliary dyskinesia)
Hypothyroidism - (dysmorphism - postaxial polydactyly - intellectual deficit)
Kocher - Deber - Semilange syndrome - (muscular pseudohypertrophyhypothyroidism)
Benign chorea - hypothyroidism
Choreoathetosis - (hypothyroidism - neonatal respiratory distress) NKX2.1 /TTF-1
mutation
Obesity - colitis - (hypothyroidism - cardiac hypertrophy - developmental delay)
Transient congenital hypothyroidism
Maternal intake of antithyroid drugs
Transplacental passage of maternal TSH receptor blocking antibodies
Maternal and neonatal iodine deficiency or excess
Heterozygous mutations of THOX2 or DUOXA2
Congenital hepatic hemangioma/hemangioendothelioma
Central hypothyroidism (syn: Secondary hypothyroidism)
Isolated TSH deficiency (TSH b subunit gene mutation)
Thyrotropin-releasing hormone deficiency
Isolated, pituitary stalk interruption syndrome (PSIS), hypothalamic
lesion, e.g. hamartoma
Thyrotropin-releasing hormone resistance
TRH receptor gene mutation
Hypothyroidism due to deficient transcription factors involved in pituitary
development or function
HESX1, LHX3, LHX4, PIT1, PROP1 gene mutations
Peripheral hypothyroidism
Resistance to thyroid hormone
Thyroid receptor b mutation
Abnormalities of thyroid hormone transport
Allan-Herndon-Dudley syndrome (monocarboxylase transporter 8
[MCT8] gene mutation)
Transcription factor gene mutations resulting in
thyroid dysgenesis and associated clinical findings
Mutated Gene Associated clinical findings
Thyroid transcription factor 2 (TTF2):thyroid dysgenesis, choanal atresia, cleft
palate, and spiky hair
NKX2.1 congenital hypothyroidism, respiratory distress, ataxia and benign
chorea
NKX2.5 Congenital hypothyroidism and cardiac malformations
PAX-8 Thyroid dysgenesis, kidney and ureteral malformations
Rastogi and LaFranchi Orphanet Journal of Rare Diseases 2010, 5:17
http://www.ojrd.com/content/5/1/17
Etiology of congenital hypothyroidism in 148 patients
diagnosed in the Quebec Newborn Screening, program from
1990-2004. (modified from: Eugene et al.
J Clin Endocrinol Metab 90:2696-2700, 2005 [111])
Female
Male
Athyreosis 14 10
24
Ectopic
78 24
102
Orthotopic/dyshormonogenesis
9 13
22
Totals
101 47
148
Total
Percentage
16
68
15
100
Incidence of congenital
hypothyroidism: Selected
demographics from New York State
(2000-2003)
(modified from: Harris & Pass,
Molec Genet Metab
91:268-277, 2007 [5])
Demographic Incidence
Overall 1:1681
Gender
Male 1:1763
Female 1:1601
Ethnicity
White 1:1815
Black 1:1902
Asian 1:1016
Hispanic 1:1559
Birth weight
Classic :1/4000-1/5000
Birth weight
< 1500 g 1:1396
1500 - 2500 g 1:851
> 2500 g 1:1843
Single vs. multiple births
Single 1:1765
Twin 1:876
Multiple 1:575
Mother’s age
< 20 years 1:1703
20-29 years 1:1608
30-39 years 1:1677
> 39 years 1:1328
Rastogi and LaFranchi Orphanet
Journal of Rare Diseases 2010,
5:17
http://www.ojrd.com/content/5/1/17
Page 2 of 22
Prevalence of individual symptoms
of
hypothyroidism at the time of
diagnosis.
(modified from:
Alm et al. Brit Med J 289:1171-175,
1984
Prolonged Jaundice 59 vs 33**
Feeding Difficulty 35 vs 16**
Lethargy 34 vs 14**
Umbilical Hernia 32 vs18*
Macroglossia 25 vs12*
Constipation 18 vs10
Cold or mottled skin 18 vs 10
Hypothermia 3 vs 3
No symptoms 16 vs 33**
Other clinical features
reported:
Abnormal cry 7 vs 6
Edema 5 vs 3
Hypothyroid appearance 6 vs 2
Hypotonia 3 vs 3
• TSHb mutations
• TSH receptor inactivating mutations
• Thyroid dysgenesis
◦ TTF-2 mutations
◦ NKX2.1 mutations
◦ PAX-8 mutations
• Thyroid dyshormonegenesis
◦ Sodium-iodide symporter mutations
◦ Hydrogen peroxide mutations
▪ DUOX2 mutations
▪ DUOX2A mutations
◦ Thyroid peroxidase mutations
▪ Pendred syndrome (PDS): pendrin gene
mutations
◦ Thyroglobulin mutations
◦ Deiodinase mutations
• Defects in thyroid hormone transport
◦ MCT8 mutation
Infant with congenital hypothyroidism. A - 3 month old infant with untreated
CH; picture demonstrates hypotonic posture,
myxedematous facies, macroglossia, and umbilical hernia. B - Same infant,
close up of face, showing myxedematous facies, macroglossia, and
skin mottling. C - Same infant, close up showing abdominal distension and
umbilical hernia.
Radiograph of the left lower extremity of two infants, showing absence of the distal femoral
epiphysis on left. Radiograph of the left lower extremity of two infants. The infant on the left with
congenital hypothyroidism demonstrates absence of the distal femoral and proximal tibial
epiphyses, while in the normal infant on the right the distal femoral epiphysis is present.
Defect
Radionuclide image
Ultrasonography
Serum
thyroglobulin Maternal TRab
Aplasia
Hypoplasia
Ectopia
TSHb
mutations
No uptake gland
↓ uptake
↓ uptake,
No uptake
Absent gland
Low
Negative
Intermediate
Intermediate
Intermediate
Negative
Negative
Negative
TSH receptor
inactivating
mutation
↓ uptake
Small, eutopic
Ectopic gland
(hypoplastic)
Eutopic gland
(hypoplastic)
Eutopic gland
TSH receptor
inactivating
mutation
Trapping
error
Beyond
trapping error
Maternal
TRB-Ab
↓ uptake
Eutopic gland
Intermediate-high Negative
↓ or no uptake
Eutopic gland
↑ uptake
Eutopic, large gland
Low-intermediate Negative
High Exception: Tg gene mutations
Negative
↓ or no uptake
Eutopic gland
Low-intermediate Positive
Intermediate-high Negative
Technetium 99 m scan findings in congenital hypothyroidism.
A-Technetium 99 m scan, showing a large gland (approximately
twice normal size) in eutopic location, consistent with dyshormonogenesis.
B-Technetium 99 m scan, showing uptake in ectopic location, i.e.
ectopic gland.
C-Minimal uptake, consistent with aplasia or severe hypoplasia.
Treatment of CH
Term as well as preterm infants with low T4 and elevated TSH should be
started on L-thyroxine as soon as the diagnosis is made.
Age
0 – 6 mo
7 – 11 mo
1 – 5 yr
6 – 10 yr
11 – 20 yr
Adults
Dose of T4 in
μg/kg/day
10 – 15
6–8
5- 6
4- 5
1–3
1–2
The initial doseof L-thyroxine should be 10-15μg/ kg/ day with the aim to
normalize the T4 level at the earliest.
Those infants with severe hypothyroidism (very low T4, very high TSH and
absence of distal femoral and proximal tibial epiphyses on radiograph of knee)
should be started with the highest
dose of 15μg/ kg/ day.
Tratamentul hipotiroidismului
congenital
Age
0 – 6 mo
7 – 11 mo
1 – 5 yr
6 – 10 yr
11 – 20 yr
Adults
Dose of T4 in μg/kg/day
10 – 15
6–8
5- 6
4- 5
1–3
1–2
Monitoring of therapy:
T4 should be kept in the upper half of normal range (10-16 μg/dL) or free
T4 in the 1.4 - 2.3 ng/dl range with the TSH suppressed in the normal
range.
T4 and TSH levels should be checked according to the following
schedule:
0-6 months: every 6 weeks
6 months-3 years: every 3 months
> 3 years: 6 monthly
T4 and TSH should also be checked 6-8 weeks after any dosage change.
It is equally important to avoid over treatment. Adverse effects of over
treatment include premature fusion of cranial sutures, acceleration of
skeletal maturation and problems with temperament and behavior.