Part 26-1. The Endocrine System

PART 26.  The Endocrine System

Section 1. Disorder of the Hypothalamus and Pituitary Gland   

# Ant. pituitary gland

1. origin

    ; Rathke pouch as invagination of the oral endoderm

2. 5 cell types

    ; produce six peptide hormones 

  ① somatotropes -- produce GH 

  ② lactotrops -- produce prolactin 

  ③ thyrotrops -- make thyrotropin or TSH  

           ♥ Pit-1

             ; a single transcriptional activation protein

             ; contribute to embryologic development & differentiated function of above 3 cell types 

    ④ gonadtropins -- make lutropin or LH and follitropin or FSH 

    ⑤ orticotropin -- produce corticotropin (ACTH)

Ant. Lobe Hormones 

; act on other endocrine gland, certain body cell

; controlled by neuropeptide releasing and release-inhibiting hormones by hypothalamic neuron

    --> capillaries of median eminance

    --> ant. pituitary through portal vein

Human GH 

; protein with 191 amino acid

; genes (GH1)

    - *long arm of chromosome 17 (q22-24)

    - expressed in pituitary somatotropes

; ★Other 4 Genes Identiying More Than 90%

    - CS1 & CS2 genes

           / ※93객 encode human chorionic somatomammotropin (hCS)

    - GH2(placental GH gene)

    - CSP(partly disabled pseudogene)

; pulstile secretion

    - *highest level during sleep

; measured by standard radioimmunoassay(RIA) or ultrasensitive immunoradiometric assay(IRMA)

; regulation

    - GHRH & somatostatin

; action mechanism

    - binding to receptor molecules on the surface of target cells

           --> induces receptor dimerization and activation of recptor-associated *Janus kinase(Jak2)

           --> nuclear gene transcription

           --> IGF-I, IGF-II

# somatostatin

    ; not limited 14- and 28- amino acid form으로 존재 

        - 췌장의 D cell에서 분비되며

     - insulin, glucagon, secretin, gastrin, VIP, GH, thyrotropin의 분비를 억제함.

# octreotide

    - potent, long acting somatostatin analog

  - insulin 보다도 우선적으로 GH 분비를 억제, 따라서 GH-secreting tumor 환자에 사용되며

    - 그 이외에 gastrinoma, insulinoma, glucagonoma, VIPnoma, carcinoid 등의 치료에 사용됨.

    - ¹²³I-labeled octreotide는 somatostatin receptor-positive tumor와 metastasis의 localization에 유용.

; *mitogenic action은 increase synthesis of IGF-I에의해서 일어난다.

    - IGF-I (insulin-like growth factor-I, formly somatomedin C)

           / 70개의 amino acid

    / chromosom 12의 long arm에 존재

    / insulin과 상당한 구조적 상동관계를 가짐

    / 생성은 일차적으로 liver에서 일어나며 국소적으로 mesoderm과 ectodermal cells에서 일어남 (특히 소아의 growth plate)

           / circulating level은 GH의 혈중 농도에 크게 관련됨. (태아기와 신생아기는 예외)

# IGF-II 

           - 67 amino acids로 된 single chain protein

           - 유전인자는 chromosom 11의 short arm에 위치

           - homology to IGF-I

           - bone cells에서 중요한 mitogen이지만 physiologic roles은 잘알려져 있지 않음 

# ★several disorder of growth

    ; caused by abnormalites of the gene encoding GHRH receptor, Pit-1, GH1, GH receptor

    ; *no growth disorders in genes encoding GHRH, IGF-I, IGF-I receptor or IGF-II

Prolactin

; 199 amino acids로 구성

; gene은 chromosome 6에 위치

; dopamine

 - major prolactin inhibiting factor

 - hypothalamic dopaminergic pathway를 disruption하여 prolactin의

      혈중농도를 상승시킴

; 혈중 prolactin 이 상승하는 경우

 - administration of TRH

 - primary hypothyroidism

 - disruption of pituitary stalk ( <-- craniopharyngioma )

; main established role

    - *initiation and maintenance of lactation

; mean serum level

 - child and fasting adult ; 5 - 20 ug/L

 - fetus and neonate during 1st wk ; > 200 ug/L 

TSH

; two glycoprotein chains linked by hydrogen bonding

    α-chain ; identical to FSH, LH, hCG

  β-chain ; unique & specific 

; mapped on chromosome 6

; ♥ Functions : Increase of

    - iodine uptake

    - iodide clearance from the plasma

    - iodotyrosine & iodothyronine formation

    - thyroglobulin proteolysis

    - release of thyroxine (T4) and triiodothyronine (T3) from the thyroid

; action mechanism mediated by cyclic adenosine monophosphate

; deficiency of TSH ; atrophy of thyroid

; excess of TSH --> hypertrphy, hyperplasia of thyroid

# TRH

          - 1st isolated tripeptide

          - T4, T3 ; pituitary cell에 대한 TRH의 작용을 차단하여 TSH의 분비를 억제

          - prolactin 분비를 자극 

          - synthetic TRH ; TSH와 prolactin의 pituitary reserve를 검사하는데 유용

ACTH

; production

    - pituitary gland의 large precusor glycoprotein product (POMC)로부터 proteolytic cleavage에의해 생성

           POMC --cleavage--> ACTH + β-lipotropin (β-LPH)

              ACTH --cleavage--> α-melanocyte-stimulating hormone

                                      ; first 13 amino acids of ACTH

                                        no corticotropic activity

              β-LPH +-cleavage--> neurotropic peptides

                     |                ; morphinomimetic activity

                     |                  fragment 61-91, β-endorphin

                     +------------> β-melanocyte-stimulating hormone

                                      ; 17-amino acid fragment of β-LPH

; ★Secretion

    - diurnal rhythm

    - *lowest level between 10 PM and 2 AM

  - *peak levels at 8 AM

  - regulation by CRH

; *ACTH 상승시 β-LPH와 β-endorphin 이 상승함

; *principal pigmentary hormone in humam rather than FSH

POMC peptides

CRH

- ACTH, β-endorphin, other POMC related peptides의 분비를 조절

- median eminence에서 predominanat하게 발견되며 brain, placenta 등에서도 생성됨   

- synthetic ovine (oCRH)과 human CRH (hCRH)가 임상적으로 사용됨

    / oCRH가 hCRH보다 작용이 크고 오래가기 때문에 choice가 되며cushing syndrome의 DDx에 유용함

Gonadotropin (LH, FSH)

; α & β subunit로 구성되며, α-subunit는 TSH와 동일함. 

    - *β-subunit가 specific hormonal action

; FSH

    - mediated by receptors on ovarian granulosa cell & testicular sertoli cells

    - follicualr develpment & gametogenesis

  - *suppressed by inhibin

    - ♣★ Activin(β-β dimer)

           / stimulate FSH stimulation

           / paracrine effect in the testis

; LH

    - mediated by receptors on ovarian theca cells & testicular Leydig cell

    - luteinization & Leydig cell function

  - *suppressed by androgen, estrogen

Post lobe hormones

Post Lobe Of Pituitary

; *functional unit(=neurohypophysis)의 일부분에 불과하다.

① neuron of supraoptic and paraventricular nuclei of hypothalamus

② neuronal axons

③ neuronal terminals in the median eninence or in the post. pituitary

Hormones (AVP, Oxytocin)

; octapeptide로 hypothalamus의 supraoptic & paraventricular nuclei에서 neurosecretion으로 생성, 분비됨

AVP

; *affect blood pressure, intestinal contractility, hepatic glycogenolysis, platelet aggragation, release of coagulation factor VIII

; *permeability of the renal tubular cell membrane through cAMP

; stimuli for AVP release

    - increased plasma osmolality perceived by osmoreceptor in hypothalamus

  - decreased blood volume perceived by baroreceptor in carotid sinus of aotic arch        

; *umbilical cord plasma의 AVP농도는 fetal stress의 sensitive indicator

; Desmopresin

  - synthetic analog, high potency, selectivity for ADH receptors

    - DI 치료시에 intranasal small amount가 효과적

Ocytocin

; 자궁수축을 유도하고 유즙분비에 관여함

Chapter 512. Hypopituitarism

ÅEtiology (Table 512-1)

Congenital defect

Pituitary Hypoplasia

; isolated phenomenon or association with more extensive developmental abnormalies

    ① anencephaly

    ② holoprosencephaly ; cyclopia, cebocephaly, orbial hypotelorism

    ③ septo-optic dysplasia (de Morsier syndrome)

; hypoplastic optic discs with typical double rims and sparse retinal vessels, absence of septum pallucidum

★Hall Pallister Syndrome

; absence of pituitary gland associated with

    - *hypothalamic hamartoblastoma, postaxial polydactyly, nail dysplasia, bifid epiglottis, imperporated anus, anomalies of heart, lungs, kidneys

; *neonate에서 hypopituitarism과 postaxial polydactyly & bifid epiglottis가 있을 경우 이 증후군을 의심

Cleft Lip And Palate

; 4%에서 GH deficiency 발생,  short stature가 있으면 32%에서 나타남

Midfacial Anomalies Or Solitary Maxillary Central Incisor

; high likelihood of GH deficiency

Unilateral Or Bilateral Optic Nerve Hypoplasia 

; endocrine abnormalities

    - extremely variable from only GH to multiple pituitary deficiencies

; delay in linear growth

    - 빠르게는 3mo부터 시작되지만 대개 3-4세 전에는 발견이 잘안됨

; ★affected newborn

    - *apnea, hypotonia, seizures, prolonged jaundice, hypoglycemia without hyperinsulinism, microphallus (in males)

Aplasia Of Pituitary Without Brain Or Skull Abnomalies

; affected infant

  - early hypoglycemia & microphallus in males

; some infants

  - evidence of neonatal hepatitis syndrome

; suggested autosomal recessive inheritance

Empty-Sella Syndrome (Enlarged Sella & Hypopituitarism)

; deficient sella diaphragm으로 인해 suprasella subarachnoid space가 sella turcica로herniation되어 sella가 remodeling되고 pituitary gland가 flattened됨

; 수술이나 방사선치료 후에 발생하며 idiopathic하게도 생김

Other Syndromes with Prominant Short Stature

; *Turner, Fanconi, Russell-Silver, Rieger, Williams, CHARGE syndromes

Destructive Lesions

; usually multiple hormonal deficiencies

Craniopharyngioma

; *▲common lesion

CNS Gerninoma, Eosinophilic Granuloma, Tuberculosis, Sarcoidosis, Toxoplasmosis, And Aneurism

       ① may cause hypothalamic-hypophyseal destruction

       ② 종종 skull에서 방사선적 변화를 일으킴 

 ※ indications of tumor of roentgenogram 

   - enlargement of sella

   - deformation or destruction of clinoid process

   - intrasella or suprasella calcification (craniopharyngioma)

Histiocytosis

특히, cranial irradiation을 받은 경우

Truma Including Child Abuse, Traction At Delivery, Anoxia, And Hemorrhagic Infarction

; may damage pituitary, stalk, or hypothalamus

Radiotherapy for malignancy of CNS or other cranial structure and ALL with prophylactic cranial irradiation

    ; slow growth during radiation therapy or chemotherapy

           --> improved growth for a yr or two

           --> and then declined growth & develop hypopituitarism

    ; *dose & fractional schedule이 incidence에 중요

    ; total dose of *35-45GY

           - *mostly GH deficiency 5yr after treatment

    ; *20GY doses

           - *subtler defects

Spinal Irradiation

    ; disproportionally poor growth of the trunk

Idiopathic Hypopituitarism

; no demonstrable lesion of pituitary or hypothalamus

; ▲common

; ★in most, functional defect of hypothalamus

; GH only or multiple hormones deficiency

; most often sporadic

; asso. /c breech birth, forceps delivery, intrapartum & maternal bleeding

    --> *pathologic factor is birth traum & anoxia

Genetic Forms Of Hypopituitarism (5%) 

; GH deficiency only or several other ant. hornone deficiency

; ♣McKusik Classification Of Isolated GH Deficiency (IGHD)

  ① type I ; autosomal recessive

      - type IA ; complete deletion of GH1 gene

      - type 1B ; heterogenous with respect to severity and sites of mutations

    ② type II ; autosomal dominant

  ③ type III ; X-linked

; multiple pituitary hormones deficiency

    - same classification

# Type IA

    - *GH 치료시 Ab형성을 잘하여 poor response

           / PCR, southern blotting을 시행하여 less antigenic biosynthetic GH을 만들어 투여

    - differnt size deletion

           / *▲common & smallest deletions : 6.7kb long

           / other deletion : 7.0, 7.6, greater than 45kb

    - extreme postnatal growth failure, failure to release GH after stimulation with GHRH

# Type IB

    - genetic defect 종류

           / 1- or 2-bp deletions in GH1 gene

           / mutations within 4th and last intron of GH1 gene

                   : comprimise normal pre-mRNA splicing at the usual exon 3 to 4 splice boundary

           / mutations in GHRH receptor gene

# Type II

    - singe-base substitutions in intron 3

           --> omission of exon 3 from spliced mRNA

           --> proteins lacking amino acids 32 to 71 & lacking one of cysteine residues

# Type III

    - not identified

    - transmitted along with immunoglobulin deficiency

# ★multiple pituitary hormone deficiency in Type I & Type III

    - underproduction of GH, TSH, ACTH, LH, FSH

    - prolactin tend to normal or high

    - hypothalamus defect의 가능성이 더 높은 것으로 생각되고 있다.

    - gene defects

           / *defect in gene for Pit-1

                   : gene deletion

                   : nonsense and missense muation

                   : substitutioning tryphtophan for rginine at position 271

Growth Hormone Receptor Defects

※87 Laron syndrome

    ① hypopituitarism의 all clinical finding

           ; but *increased circulating leve of GH

    ② *very low level of IGF-I

  ③ not respond to exogenous hGH

  ④ absence of GH-binding activity

           ; confirm

           ; point to abnormality of GH receptor

  ⑤ gene mutation

        --> *loss of GH-binding activity in membrane receptor

    ⑥ parent of patients’ stature is normal range

Clinical Manifestation

Patients Without Demonstable Lesions Of The Pituitary 

; ※93출생시 정상 체중 및 신장

; delayed epiphyseal clusure

    - growth beyond age

    - without treatment, 4-12SD below the mean

;   ★infant with congenital defects of the pituitary or hypothalamus

    - neonatal emergency

           / apnea, cyanosis, severe hypoglycemia

    - *microphallus - additional diagnostic clue

    - accom. with hypoadrenalism, hypothyroidism

    - prolonged neonatal jaundice

; ★round head, short & broad face, promiment frontal bone, depressed nasal bridge & saddle shaped small nose with well developed nasolabial folds, late eruption of teeth, short neck

; small larynx, high pitched voice & remains after puberty

; well proportioned extremities with small hands & feet

; underdeveloped genitalia for the child's age, delayed or absent sexual maturation, usually lack of facial, axillary & pubic hair, fine scalf hair

; symptomatic hypoglycemia usually after fasting

; usually normal intelligence

Patient With Demostrable Lesions Of The Pituitary

; initially normal, simialr to idophathic pituitary growth failure or growth ceases

; *atrophy of the adrenal cortex, thyroid, and gonads

    - loss of weight, asthenia, senstive to cold, mental torpor, and absence of sweating

; failure of sexual maturation

  - atrophy of gonads and genital tract, amenorrhea and loss of pubic hair and axillary hair

; tendency to hypoglycemia and coma

; 초기에 DI 발생

    - *ant. pituitary가 점차 파괴되면서 spotaneously improved

; *expading tumor에의한 lesion일 경우

    - headache, vomiting, visual disturbance, pathologic sleep, decreased school performance, seizures, polyuria, and growth failure 등이 나타남

    - craniopharyngioma

        / visual field defects, optic atrophy, papilledema, and cranial nerve palsy 등이 흔함              

※95 Laboratory Data

; profound postnatal growth failure ( < 3SD mean for age and gender)

    - suspection of classic GH dediciency

; low serum levels of IGF-I & GH dependent IGF-BP3

; low or absent response of GH for stimulation

    --> *definitive diagnosis

;   ※88, 95 Provocative Tests

    - 20 min period of strenous exercise or administration of L-dopa, insulin, arginine, clonidine, glucagon

    - *표22-4, 22-5(p940-941)

     ① GH deficiency

            ; *peak level of GH < 7 ug/L

     ② false negative response in any single test

                ; 20%

     ③ false negative response in both test

                   ; 4%

           ④ majority of prepubertal children

                   ; fail to achieve GH value above 7ug/L with two test

                   --> *3days of estrogen priming recommand

; ※95 measuring the spontaneous secretion of GH level

  - every 20 min during a 24- or 12-hr (8P.M. -- 8 A.M.) period 

; ※96 GH neurosecretory dysfunction

    - normal porvocation tests

    - little spontaneous GH secretions

    - *GH replacement 치료시 가장 좋은 효과

; exam other pituitary functions

    - levels of TSH, T4, ACTH, cortisol, dehydroepiandrosterone sulfate, gonadotropins, gonadal steroids

; hypothalamic lesion

    - hypothalamic-releasing hormones stimulations

    - *TRH administration

           --> normal rise in TSH, PRL

           --> hypothalamic defect

    - *elevated PRL level

           --> strong evidence of hypothalamus lesion

Rentgenographic Examination

1) skull x-ray

    ① destructive or space-occupying lesion causing hypopituitarism (most helpful)

  ② evedence of IICP

  ③ enlargement of sella 

        ; 특히 ballooning with erosion and calcifications within or above sella

2) MRI

    ① *hypopopituitarism을 가진 모든 환자에게s indicated

    ② space occupying lesion을 상세히 알수있음

  ③ ant. & post. pituitary lobe와 pituitary stalk의 size를 명확하게 알수있슴

  ④ empty sella turcica로부터 differentiating하는데 C-T보다 우수함

  ⑤ post. pituitary가 bright spot으로 쉽게 구별됨

  ⑥ hypoglycemia and micropenis를 가진 newborn

        ; suspected hypopituitarim에대한 conformative diagnostic technique 

3) Skeletal matration

  ① markedly delayed in longstanding GH deficiency

  ② bone age ; approximately 75% of chromological age, TSH & GH  deficiency시에 더현저하게 delay 

    ③ fontanell ; 2세 이후까지 open

  ④ found intersutural warmian born

  ⑤ long born ; slender & osteopanic

4) Dual photon x-ray absorptiometry

    ① newer method of assessing body composition

  ② deficient bone mineralization

  ③ deficincy in lean body mass and corresponding increased in adiposity

Differential Diagnosis

Legion : systemic conditions

    ; Inflammatory Bowel Disease, Occult Renal Disease, Turner Syndrome, Theoretical Defects of Molecular Structure

㉿Constitutional Growth Delay

; one of variants of normal growth

; 원인 - 상대적인 hypogonadotropic state의 지속

; normal length & weight at birth

; *normal growth for first 4-12mo

    --> *and then decelerated growth below the 3percentile

    --> *growth rate of 5cm/yr or more by 2-3yr

; GH secretion or other study

    - within normal limit

; bone age

    - ★closer to height age than to chronological age

; other family members

    - history of short stature in childhood, delayed puberty, and eventual normal stature     

; prognosis

    - *good 결국 정상성인의 키에 도달함

; *남아에서 unusal degree of delayed puberty인 경우

    - short course testosterone therapy를 하면 puberty를 앞당길수 있슴

; DDx

    - *genetic short stature 은 skeletal maturation 이 chronological age와 일치함

Genetic Short Stature

; found in other family members

; growth에 관련된 hormon study - 정상

Primary Hypothyroidism

; easily diagnosed on clinical grounds

; GH provocative test - subnormal

; enlargement of sella가 나타날수 있슴

; low T4, elevated TSH levels

    - estabilsh the diagnosis

; thyroid hormone으로 치료하는 동안에 pituitary hyperplasia가 호전됨

Emotional Deprivation

(=psychologic dwalfism, deprivation dwarfism, or reversible hyposomatotropism)

; growth retardation의 important cause로 hypothyroidism과 유사함

; mechanism

    - not fully understood, sensory and emotional deprivation 이 성장을 방해

; funtional hypopituitarism

    - *low levels of IGF-I, inadequate response of GH to provocative stimuli, delayed puberty

; clue the diagnosis

    - history of disturbed mother-child or family relations

    - 부모가 상황을 감추거나 아이도 드러내지 않아 진단이 힘들다.

; ※89 Clinical Manifestation

    - perverted or voracious appetites, enuresis, encoporesis, insomnia, crying spasmus, sudden tantrums

    - excessively passive or aggressive

  - boderline or dull-normal intelligence

; child-rearing practices가 바뀐다던지, abuse가 제거되면 성장이 현저하게 호전됨

; period of catch up growth

    - *seperation of cranial stuture, other evidence of pseudotumor cerebri 등이 일어나 sign of mass lesion 으로 오인할수 있슴

Silver-Russell Syndrome

; *short stature, frontal bossing, small triangular facies, sparse subcutaneous tissue, shortened and incurved 5th fingers, asymmetry(hemihypertrophy)

; low birth weight의 분만력이 있슴

; short term treatment with GH

    - often increased rate of growth but, long term benefits는 unknown

♣Treatment

# classic GH deficiency

 ① 치료는 가능한 조기에 시행하며, 치료시기가 빠를수록 long term expectation은 좋음

 ② recommended dose of hGH

    ; *0.18-0.3mg/kg/wk, SC in six or seven divided doses

 ③ *치료는 더이상 반응이 없을 때까지 혹은 epiphyseal closure 될때까지 계속

 ④ 치료도중 효과가 떨어질 경우 용량을 올리기 전에 compliance부터 평가

 ⑤ 치료반응

    ; *max. response는 치료 첫 1년 동안 일어나며, 계속 사용하면서 반응도가 떨어짐

# ♥Side Effect Of GH

    ; leukemia

           - double risk than general population

  ; pseudotumor cerebri

  ; slipped capital femoral epiphysis

  ; worsening of scoliosis

    ; *increased total body water during first 2wks

    ; Creutzfeldt-Jakob disease

  ; *development of reversible hypothyroidism

           - due to enhanced converseion T4 to T3 & decreased TSH level

    ; change in fasting and postprandial insulin level

           - before treatment : characteristically low

         - during GH treatment : normalize

           - DM 가능성 있지만 실제로는 드물다

# ★Recombinant IGF-I가 유용한 경우

    ① Laron syndrome

    ② GH1 gene deletion with high titer of antibodies

# GH 이 사용되어질수 있는 다른 경우 

    ① children with IUGR

    ② chronic renal failure

    ③ Noonan syndrome

    ④ Turner syndrome ; untreated와 비교할때 final height가 수cm 더커짐

# other hormonal deficiencies should be replaced

  ① TSH deficient subjects

         ; thyroid hormone을 full replacement dose로 투여 

  ② ACTH-dependent patient

    ; optimal dose of hydrocortison 투여 (should not exceed 10mg/m2/24hr)

    ; 수술 등의 stress 상황시에는 증량

    ; 만약 partial deficiency가 있는 경우에는 성장이 완전히 끝날때까지 치료를 미룰수도 있슴

   ③ gonadotropins deficiencies

           ; gonadal steroid는 puberty가 일어날 때까지 혹은 골연령에 도달할때까지 투여

   ④ microphallus를 가진 infant

       ; one or two 3-mo courses of monthly injection of 25mg of testosterone enanthate

            - osseous maturation에대한 지나친 영향없이 penis를 normal size로 성장시켜줌 

Chapt. 513. Diabetes Insipidus (Arginine Vasopressin deficiency)

 ; lack of the antidiuretic hormone, arginine vasopressin (AVP)으로 인해 polyuria, polydipsia을 보이는 경우

# Permanent DI

    ; due to destruction of supraoptic and paraventricular neuclei, division of supraoptic-hypophyseal tract above median eminence

# Transitory Polyuria

    ; due to transection of tract below median eminence, removal of just post. lobe

    ; median eminence로 유리되는 AVP 때문에 DI는 발생하지 않음

# AVP

  ; V2 recepor에 결합함으로써 kidney의 distal tubules과 collecting duct에 직접 작용  

    ; ★V2 receptor is responsible for

     ① vasodilator effect of the hormone

     ② increasing for VIII activity

     ③ increasing the concentration of von Willebrand factor

Etiology

1) tumor of the suprasellar and chiasmatic regions

    ; craniopharyngioma, optic glioma, germinoma가 common causes

2) Langerhans cell histiocytosis

  ; *25%에서 hypothalamus와 pituitary histiocytic infiltration의 결과로 DI 발생

    ; *4-5년이내에 거의 발생

    ; cytoplasmic Ab to AVP-producing cells

3) *encephlitis, sarcoidosis, tuberculosis, actinomycosis, leukemia

4) injuries to the head

    ; esp. skull base fractures

           - *즉시 혹은 수개월 후에도 발생

5) operative procedures near pituitary or hypothalamus

    ; transitory or permanent DI

6) hereditary

    ; autosomal dominant form

        - 출생시부터 수년 사이에 발생 

    - *증상은 3rd-5th decades에 감소

       - AVP level ; absent (< 0.5 pg/ml) 혹은 variable

       - AVP & neurophysin II(NP II) gene in chromosome 20

                   --> *본 질환은 neruophysin II mutation

                   --> mutant AVP-NPII complex

    ; ★Wolfram syndrome (acronym DIDMOD)

    - consist of DI, DM, optic atrophy, deafness

    - autosomal recessive inheritance pattern

    - gene on chromosome 4p

    - pathology

           / *β-cells, supraoptic and paraventriculare nuclei, optic nerve, cranial nerve VIII 에 degenerative process

7) septo-optic dysplasia

8) idiopathic

    ; 초기에 진단이 원인이 모르는 경우로서 약 20% 를 차지

    ; *그러나 이러한 환자들의 반이상이 intracranial tumor

           - DI 나타난 후 1년까지 no clinical, neuroradiologic sign

           - 25%는 4세까지 no clinical, neurologic sign

           --> ★그러므로 idiopathic DI는 적어도 4년 동안의 periodic reevaluation 이 필요함

    ; ⅓에서  AVP-producing cell에 대한 antibody를 가짐

9) autoimmune

10) ※82 newborn에서 DI를 일으키는 경우

    ① asphyxia

    ② intraventricular hemorrhage

    ③ intravascular coagulopathy

    ④ Listeria monocytogenes

    ⑤ group B β-hemolytic streptococcal meningitis  

Clinical Manifestations

; polyuria & polydypsia - outstanding features

# Infancy

    ; *매우 보채며 우유를 먹이면 만족하지 않고 물을 주면 조용해짐

  ; *hyperthermia, rapid loss of weight, collapse are common

  ; dehydration으로 brain damage 받아서 *mental impairment 올수 있슴

    ; *vomiting, constipation, & growth failure

# Children 

  ; wide variationin of the manifestations

         - 나이와 함께 severity가 증가하는 수도 있고, 어떤 경우는 사춘기까지 무증상으로 지낼수도 있슴

    ; *acquired bladder control을 가진 children에서 enuresis가 첫 증상일수 있다.

    ; 심한 갈증 때문에 play, learning, sleep 등을 방해 받기도함

    ; 땀이 나지 않고 피부는 차고 건조하고 창백함

  ; anorexia가 흔하게 나타남

# primary lesion에 따른 sx and sg

    ; hypothalamus tumor

           - growth disturbance, progressive cachexia or obesity, hyperpyrexia, sleep disturbance, sexual precoccity, emotional disorder

  ; *initial로 DI를 일으킨 lesion 이 ant. pituitary를 파괴하는 경우

        - *DI 자체는 milder 해지거나 혹은 완전히 사라질수도 있슴

Loboratory data

; Ådaily urine volume - 4-10 L or more, urine color - 엷거나 무색, S.G - 1.001~1.005, urine osmolality - 50~200 mOsm/kg water

; severe dehydration 시에는 S.G가 1.010까지 상승 할 수 있으며, urine osmolality는 300까지 상승 할수 있슴

; serum osmolality는 적절한 수분섭취 시에는 *정상을 유지함

; water deprition tests

    - 3hr-period of dehydration (water deprivation test) 시에 plasma osmolality 상승, 반면에 urine osmolality는 plasma level 이하로 유지됨.

    - 이 경우 ADH를 투여하면 urine osmolality가 상승함

; radioimmunoassy of vasopressin

    - severe neurognic DI

           / plasma levels은 지속적으로 0.5 pg/mL 이하임

    - partial neurogenic DI

           / hyperosmolality & subnormal AVP levels

    - *partial DI와 primary polydypsia의 감별에 유용

; skull x-ray

  - reveal evidence of intracranial tumor

       / calcification, enlargement of sella turcica, erosion of clinoid process, increased width of suture lines

; MRI

    - indicated for all patients suspected DI

  - T1-weighted image

           / hyperintense signal (=bright signal or bright spot)

                   : post. pituitary에서 나타나므로 ant. 와 구분

           / *autosomal dominant DI시에 mutant AVP-NP II complex의 축적으로 bright spot이 hypothalamic-neurohypophyseal tract lesion에 나타나지 않는다.

           / thickening of pituitary stalk

           : DI and *Langerhans cell histiocytosis or lymphocytic infiltration

Differential Diagnosis

1) Hypercalcemia or Potassim Deficiency

2) Nephrogenic DI

    ; male infant에서 감별요

3) Familial Nephronophthisis

  ① mimic DI

  ② elevated plasma urea and creatinine

  ③ anemia

  ④ isotonic rather than hypotonic urine

4) Compulsive Water Drinking (Psychogenic Polydypsia, Primary Polydypsia)

  ① rare but, easily confused with DI

  ② 수분의 섭취를 제한하면 소변의 농축이 일어남

    ③ 지속적인 polydipsia가 있을 때는 maximal urine concentration이 저하되지만, hypertonic saline solution을 투여 혹은 dehydration후에는 농축이 일어남

  ④ urine osmolality가 AVP 투여시보다 dehydration 후에 더욱 상승

5) Adipsia or Hypodipsia

  ① isolated defect of the thirst center, extremely rare

  ② AVP와 thirst에 대한 osmoreceptor가 ant. hypothalamus에서 인접하기 때문에 hypodipsic hypernatremia가 antidiuretic function defect에 관계됨

  ③ hypothalamic tumor 때에 흔하며, 특히 gerninoma, gliomas, histiocytosis, congenital malfomation, microcephaly 때 잘옴

Å요붕증의 세가지 형 및 감별진단을 위한 방법과 차이점.

# Water deprivation test

    ;

Prognosis

① DI 자체는 rarely threatens life이며, serious underlying condition 이 중요함  

② hypothalamus or pituitary lesion의 trauma나 surgical intervention후에 초래된 DI는 대개 일시적임 

③ Langerhans cell reticuloendothelioses를 가진 일부 환자에서는 spontaneous remission         이 일어남  그러나 나머지는 pri condition의 remission후에도 only long residuum으로           남을 수도 있슴  

④ clinical DI의 개선이 ant. pituitary insufficiency의 발생에 선행할수도 있슴

⑤ brain tumor ; lesion site와 neoplastic cell type에 따라 예후가 결정됨

※84 Treatment

1) causative factors을 먼저 고려

2) desmopressin (1-desamino-8-D-arginine vasopressin ; DDAVP)

  ; drug of choice

  ; highly effective analog of AVP

  ; more resistant to degradation by peptidase than native AVP

  ; antidiuretic activity of DDAVP

        - *2000-3000 times greater than its pressor activity

  ; 1ug ; antidiuretic avtivity가 8-10 hr 동안 지속 (native AVP ; 2-3 hr )

  ; nasal tube delivery system으로 투여 (nasal spray)

        - 5-15 ug, single dose or divided into two doses

    - *2세 이하에서는 small doses로 투여 (0.15-0.5 ug/kg/24hr)

  ; parenteral preparation

           - *0.03-0.15 ug/kg

           - useful postoperatively

            / 특히 transsphenoidal surgery후에 nasal packing을 하고 있는 경우

  ; polyuria가 다시 나타나거나 effect가 사라진 경우에는 effective dose를 repeat

    ; ★DI 이외에 투여하는 경우

           - hemophilia A or von Willebrand disease

                   / 15 times

           - Enuresis

                   / slightly higher dose (20-40ug)

513.1 Nephrogenic Diabetes Insipidus(Vasopressin Receptor Defect)

Chapter 514. Inappropriate Secretion Of Antidiuretic Hormone (=Hypersecretion Of Vasopressin)

# Å특징

    - one of most common aberrations of AVP secretion

    - inapproate high plasma AVP level 

    - not suppresed by further dilation of body fluids

Etiology

# conditions involved CNS

  ; meningitis, encephalitis, brain tumor and abscess, *subarchnoid hemorrhage, Guillain-Barre syndrome, head trauma, after transsphenoidal surgery for pituitary tumors

# pneumonia, tuberculosis, *acute intermittened porphyria, cystic fibrosis, infant botulism, perinatal asphyxia, use of positive-pressure respirators, *drugs(vincristin, vinblastine)

# *Ewing sarcoma, malignant tumor of pancreas, duodenum, thymus, oat cell carcinoma of the lung

# chloropropamide theray for DM

# antidiuretic preparation으로 치료 받는 DI환자에서 IV fluid therapy 혹은 excessive ingestion of fluids

Clinical Manifestations

; *most often latent and asymptomatic

; hypotonicity & water intoxication으로 인한 증상

    - s-Na > 120 meq/L maybe normal

           / *loss of appetite, nausea, vomiting : early

           / irritability, personality change(hostility, confusion)

    - s-Na < 110 meq/L

           / *neurologic abormalities : stupor, convulsive seizure

; *normal skin turgor & BP, no dehydration

Laboratory Data

; low serum sodium & chloride

    - normal serum bicarbonate level

; *continued renal sodium excretion

; hypo-osmolar serum, urine is less than maximally dilute

; urine osmolality is greater than appropriate for serum osmolality

; hypouricermia

    - common

    - volume expansion에대한 2차적인 반응으로 urate clearance가 증가하기 때문

  - ★hyponatremia를 동반한 hypouricemia가 SIADH의 진단적 단서가 됨

; renal & adrenal function은 정상

※92 Treatment

1) underlying disorder의 치료 (eg. meningitis, pneumonia)

    ; 원인치료를 하면 없어짐

2) *fluids restriction

  ; sodium은 소실한 양만큼 보충

3) hypertonic saline solution

    ; little benefit 

  ; severe water intoxication으로 convulsion, coma 등이 있을 때는 osmolality를 증가시켜서 CNS 증상을 완화

    ; *furosemide with 300 ml/m² of 1.5% sodium chloride의 투여로 sodium level을 올리고 diuresis를 유도함

4) demeclocycline

    ; AVP의 renal tubule에 대한 작용을 interfere

  ; *성인의 SIADH 치료에 유용하며, 소아에서의 역할은 확립되어 있지 않음

5) Chronic SIADH

    ; single daily dose of furosemide

514.1 Cerebral Salt Wasting

 1) acute or chronic CNS damage

      ① develop a distintive syndrome of salt wasting

      ② associated with head trauma, CNS surgery, tumor or meningitis

 2) SIADH와의 차이점     

      ① hypovolemia

      ② maintenance fluids를 투여 받는데도 excessive urine flow rate 

      ③ large net loss of sodium

      ④ 혈장 ADH의 농도 감소

 3) increased ADH & decreased plasma renin and aldosteron level

    ; 원인이 ANH의 inappropriate secretion임을 암시

 4) therapy

    ; volume-for-volume replacement of urine loss with 0.9% or 3% sodium chloride

Chapter 515. Hyperpituitarism

; primary hypersecretion of pituitary hormones ; adenoma에의한 경우는 소아에서는 rare

; 가장 흔히 발생하는 pituitary tumor는 corticotropin, prolactin or growth hormone 등을 분비하는 경우들임

; hypothalamic harmartomas

    - secrete gonadotropin-releasing hormone

  - cause precoccious puberty

Pituitary Gigantism And Acromegaly

; open epiphyses, overproduction of GH --> gigantism

; closed epiphyses, overproduction of GH --> acromegaly

Etiology

(소아에서는 rare)

     ① pituitary adenoma

     ② hypothalamic tumor ; GHRH secretion

     ③ other tumors particulary in the pancreas

          ; somatotroph의 hypersecretion & large amount의 GHRH를 분비하는 경우

           - pancreatic tumor

           - McCune-Albright syndrome ; GH secreting adenoma와 연관이 있는 경우

Clinical manifestations

 ① rapid linear growth

 ② coarse facial features, enlarging hands and feets, young children에서는 linear growth에 선행하여 head의 rapid growth가 나타남

 ③ 일부 환자에서는 behavioral or visual problems을 일으킴

 ④ 대부분의 환자에서 abnormal growth는 사춘기에 현저해짐

 ⑤ body의 distal part의 비대가 주로 나타남

     ; 두개골의 둘레가 증가, 코가 넓어지고 혀가 커지면서 얼굴의 형태가 거칠어짐

       턱이 과도하게 커지고 치아가 서로 벌어지며 손가락과 발가락이 두꺼워짐

 ⑥ dosal kyposis ; fatigue & lassitude가 early sx으로 나타남

 ⑦ delayed sexual maturation 혹은 hypogonadism 이 나타날수 있슴

 ⑧ 나중에 IICP signs 이 나타남

Laboratory Data

     ① elevated growth hormone (400 ng/ml)

     ② glucose tolerance test시의 hyperglycemia에 의해서도 GH level 이 감소되지 않음

     ③ L-dopa에의해 GH level 이 paradoxic하게 감소될수 있슴

     ④ 일부의 환자에서는 thyrotropin-releasing hormone 투여시 GH level의 상승이 나타남

     ⑤ insulin-like growth factor-I (IGF-1) level은 지속적으로 상승되어 있슴

         ; 대개 2.6-21.7 u/ml,  normal 0.3-1.4 ul/ml

     ⑥ plurihormonal adenomas (secrete GH & prolactin)

         ; marked hyperprolactinemia보임

     ⑦ impaired secretion of gonadotropin, thyrotropin or corticotropin

     ⑧ radiologic finding

        (skull x-ray)

             enlargement of sella turcica and paranasal sinuses

        (CT or MRI)

             delineates the tumor

     ⑨ tufting the pharanges, increased heel pad thickness

     ⑩ normal osseous maturation

Differential Diagnosis

     ① hereditary tall stature

          ; 대개 가족이나 친척 중에 abnormal height가 있슴

            tall person은 well proportioned, free of IICP

     ② excessive growth during preadolescence in obese children

          ; temporary state로 키가 giant에 도달하지는 않음

     ③ precocious puberty

          ; 대개 tall stature를 보임

            epiphysis가 조기에 closure되고

            성장이 조기에 끝나기 때문에 giant에 도달하지는 않음

     ④ hypogonadism  or Marfan syndrome

          ; 임상적으로쉽게 구분되며 정상 GH level을 가짐

     ⑤ lipodystrophy

          ; 일부에서 GH level 상승과 gigantism보임 

            그러나 subcutaneous fat는 발달하지 않음

            hypothalamic function disorder를 보임

     ⑥ sotos syndrome

          ; pituitary gigantism보다 more common

Treatment

     ① surgery

     ② irradiation

     ③ medical therapy 

         octreotide

            ; long acting analog of somatostatin

              native peptide보다 GH 억압효과가 약 45배 정도됨 

              acromegaly를 가진 성인에서 지속적으로 GH과 IGF-I의 농도를

                          낮추며 tumor size도 감소시킴  

Sotos Syndome (Cerebral Gigantism)

; characterized by rapid growth, but *not endocrine disorder

Cause

  ; unknown

    ; hypothalamic defect가 suggested

    ; 대부분 sporadic하게 발생

Clinical Manifestation

  ① birth weight and length ; above 90 percentile, macrocrania

  ② rapid growth

           ; *1세경 affected infant의 height가 97 percentile 이상임

  ③ *4-5 세까지는 accelerated growth, 그 이후 normal rate로 돌아옴

    ④ usually normal but may slightly early puberty

  ⑤ large hand & feet, thickened subcutaneous tissue

  ⑥ large & dolichocephalic head and prominent jaw, hypertelorism, antimongoloid slant eyes

  ⑦ clumsiness and awkward gait , great difficulty in sports, riding bicycle, other tasks requiring coordination

  ⑧ some degree of mental retardation, and predominately perceptual defficiency

Laboratory finding

    ① lagre skull, high orbital roof, normal sized sella but slightly post. inclination,                   and increased interorbital distance

  ② oseous maturation ; compatable with height

  ③ normal level of GH and other endocrine hormones

  ④ *abnormal EEG가 흔함

  ⑤ *dilated ventricular system 이 종종 나타남

5) increased risk of neoplasia

  ; hepatic carcinoma and wilms, ovarian and parotid tumor

Prolactinoma

1) *▲common pituitary tumor in adolescents

    ; esp. microadenoma (<1cm)

2) Clinical Manifestation

 ① *headache, amenorrhea, galactorrhea

           ; *▲common

 ② 여아에서 2배 높은 발생빈도

 ③ type I multiple endocrine neoplasm에서 prolactinoma가 adolescence시에 나타남

 ④ prolactin level

        ; moderately (40-50 ng/ml) or *markedly (10000-15000 mg/ml) elevation

 ⑤ chileren

           ; macroadenomas

           ; may be visual defect

         ; *⅓에서 hypopituitarism, GH deficiency

3) DDx

 ① primary hypothyroidism

        ; hyperprolactinemia due to pituitary hyperplasia

 ② variety of medications

 ③ pituitary stalk dysfunction (eg, craniopharyngioma)

 ④ other benign conditions

4) Treatment

   ① surgical resection by transfrontal or transsphenoidal approach

   ② bromocryptine ; standard drug for treating hyperprolactinemia

Chapter 516. Physiology of Puberty   

1. puberty의 발현단계

 1) prepubetal stage

  (1) early childhood에서 8-9세 사이

  (2) hypothalamic-pituitary-gonadal axis는 dormant state

      ; LH와 sex hormone (estradiol in girls, testosterone in bosy)의 혈중농도는 variable

  (3) hypothalamus와 pituitary actiavity는 억압되어 있슴

     by ① neuronal restraint pathways

        ② negative feedback

        ③ minute amounts of circulating gonadal steroids

 2) pubety onset 1-3년전

    ① sleep동안에 low serum LH level secretion의 변화가 와서 sleep-entrained LH

       secretion 이 pulsatile fashion으로 변하며 이것은 hypothalamic GnRH의

       endogenous episodic discharge룰 반영함

    ② gonadotrpin의 pulsatile secretion으로 gonads의 성숙과 sex hormine분비가 일어남

 3) early puberty

    2차 성징이 나타남

    hypothalamus, pituitary and gonads 사이에 지속적이고 활발한 상호 작용이 극대화됨

 4) midpuberty

    LH pulse가 daytime 동안에도 나타남 (90-120 min 간격으로 일어남)

 5) middle or late adolescence

    ① cyclicity and ovulation 발생

    ② positive feedback mechanism 발생 ; midcycle 동안 상승된 estrogen levels 이 LH의

       현저한 상승을 일으킴

2. GnRH

   pubety의 onset과 progression에 관여하는 major factor임

   (간접증거) sexually immature animal에 GnRH의 pulsed administration시에

              pubertal development 나타남

# age of onset of puberty

    ; variable & more closely correlated with osseous maturation

  ; in girls

       - *breast bud : usually 1st sign (10-11 yr)

       - *breast bud 6-12 mo후 pubic hair가 나타난다.

       - *2-2.5년후 menarche가 나타나며, 6년 정도까지 늦어질수 있다.

                   / mean age of menarche ; 12.75 yr (미국)

       - 미국의 경우 ; 12세까지 95%, 13세까지 99%에서 puberty sign 이 나타난다.

        - ★peak height velocity

                   / always precedes menarche

                   / *at breat stage II-III, 11-12yr

    ; in boys

       - *growth of testes (>3ml in volume or 2-5 cm in longest diameter) and thinning of penis

                   / *1st sign

        - followded by pigmentation of the scrotum and growth of penis

       - and then pubic hair

       - ★peak height velocity

         / *at maximal genital stage IV-V, 13-14yr

       - growth spurt가 여아보다 약 2년 정도 늦으며 18세 이후까지도 계속 성장할수 있슴

# 사춘기 발현에 영향을 미치는 요소

   ① genetic and environmental factors

       ; menarche의 age가 낮아지고 있으며,

        이것은 better nutrition과 개선된 genital health를 반영함

   ② 미국흑인이 백인보다 빠름

   ③ ballet dancers, gymnasts, runners, and other girl athletes

       ; early childhood부터의 leanness and strenous physical activity가 puberty

        혹은 menarche를 현저히 감소시키며, 성인이 되어서도 oligomenorrhea 혹은

         amenorrhea를 보일수 있슴

   ④ adrenal cortical androgens

       ; LH 혹은 sex hormone의 상승

        그리고 puberty의 초기변화가 있기전 약 6-8세 경에 상승하는 경우 (adrenarche)

Chapter 517. Disorder of Pubertal Development

# Precocious Puberty

  ; puberty가 시작하는 시기가 variation 이 심하기 때문에 정의하기가 어렵다.

    ; 대개 성징의 출현이 여아에서는 8세 이전, 남아는 9세 이전에 나타나는 경우임

# Classifications

    1) true or central precocious puberty

           ; gonadotropin dependent 

  2) peripheral precocious puberty or precocious pseudopuberty

           ; gonadotropin independent        

★Table 517-1

# True Precocious Puberty

  ; always isosexual 

  ; involved hypothalamic-pituitary-gonadal activation

  ; 2ndary sexual characteristics & gonadotropin-mediated increase in size & activity of gonads

# Precocious Pseudopuberty

  ; some of 2ndary sexual characteristics

    ; no activation of normal hypothalamic pituitary gonadal interplay

    ; isosexual or heterosexual

# Mixed Type Of Precocious Puberty

    ; precocious pseudopuberty가 maturation of hypothalamic-pituitary-gonadal axis & trigger onset of true precocious puberty

    ; ♥흔히 일어나는 경우

       - congenital adrenal hyperplasia

       - McCune-Albright syndrome

           - familial male precocious puberty

517.1 Gonadotropin-Dependent Precocious Puberty

; 과거에는 빈도가 높았으나 CT scan과 MRI의 발달로 현재는 idiopathic sexual precocity빈도가 감소

; *여아에서 10배 이상의 발생빈도

; 대개는 sporadic하게 생기나 일부에서는 familial하게 발생

Clinical Manifestations

# advanced height, weight and osseous maturation

  --> early epiphyseal closure

    --> ultimate short stature in adults

           : less than 5 percentile in 1/3 girl, most boys

# compatible mental development

# *emotional behavior, mood swings

    ; but no serious psychologic problems

# ★Three Main Patterns Of Progression

    ; rapidly progressive sexual precocity

        - *6세 이전에 onset

           - rapid physical and osseous maturation

           - *height potential의 loss

    ; slowly progressive variant

        - 6세 이후에 onset

           - *osseous maturation과 linear growth가 병행하여 height potential은 유지됨

    ; unsustained central precocious puberty

           - spontaneously regression

Laboratory Data

 1) immunoradiometric, immunofluorimetric and chemiluminescent assy for LH

    ; great diagnostic sensitivity using random blood samples

      LH가 prepubertal children에서는 undetectable,

      그러나 central sexual precocity 때는 50-70%에서 detectable

 2) 수면시의 serial blood sample에서 LH 측정

    ; great diagnostic power

      -- LH의 well-defined pulsatile secretion이 나타남

 3) GnRH stimulation test

    ; helpful diagnostic tool  particulary for boys

     여아에서는 sexual development의 early phase시에는 LH의 반응이 낮음

 4) LH : FSH ratio

    ; midpubertal 까지는 low

 5) 여아에서 초기에는 estrogen농도가 낮거나 undectable

    남아에서 s-testosterone levels가 detectable

 6) both sex에서 sex hormone농도는 puberty stage와 일치

 7) osseous maturation ; variable advanced

 8) pelvic ultrasonography

    ; 여아에서 ovaries가 progressive enlargement

      뒤따라 uterus가 pubertal size로 커짐

 9) CT, MRI scan

    ; 정상 puberty에서처럼 pituitary gland가 physiologic하게 enlargement

Differential Diagnosis

 1) organic central nervous system causes of central sexual precocity

 2) gonadotropin-independent causes of isosexual precocious puberty

     ① in girls ; ovarian tumor, anovulatory functioning ovarian cysts, ferminizing adrenal

                  tumors, McCune-Albright syndrome, exogenous source of estrogen

     ② in boys ; congenital adrenal hyperplasia, adrenal tumors, Ledig cell tumors,

                chorionic-gonadotropin-producing hepatoma, familial male precocious puberty

Treatment

# GnRH analog

    ; stimulatory effect로 pituitary의 gonadotropic cells을 desensitization

    ; rapidly progressive precocious puberty가 대상이 됨

    ; *leuprolide acetate (Lupron Depot Ped)

    - *0.25-0.3 mg/kg IM once every 4wk

    ; other long active preparations

           - *D-Trp6-GnRH(Decapeptyl), goseretin acetate (Zoladex)

    ; side effect

           - fewer than 5%

           - *recurrent sterile fluid collection at sites of injection

                   / *▲serious

           - *change to daily s.c. injection of aqueous analog (e.g. histrelin acetate[Supprelin], 10ug/kg/24hr

Effect Of Treatment

   (1) decrease of the growth rate, and even greater decrease of the rate of

       osseous maturation

   (2) advanced (pubertal) bone age 경우

        ; marked deceleration of their growth rate

          complete arrest in the rate of osseous maturation

   (3) in girls

     ① 대부분 breast size는 변화가 없으며 stage III-V 정도이며, 점차적인 adipose tissue의

        침착으로 약간커질수도 있다

     ② pubic hair는 does not progress

     ③ pelvic ultrasonography  ; decrease of the ovarian and uterus size

   (4) in boys

     ① decrease of testicular size

     ② variable regression of pubic hair

     ③ decrease in the frequeny of erections

   (5) serum sex hormone concentrations

     ① testosterone < 20 ng/dl in boys

     ② estradiol < 10 pg/ml in girls

     ③ LH concentration< 1 IU/L

     ④ GnRH stimulation에 대한 FSH와 LH의 증가가 1-2 IU/L 이하

517.2 Precocious Puberty Resulting From Organic Brain Lesions

Etiology

 -- involve the hypothalamus by scarring, invasion, or pressure

   (1) postencephalitic scars

   (2) tuberculous meningoencephalitis

   (3) hydrocephalus

   (4) tuberous sclerosis

   (5) severe head truma

   (6) optic glyoma, astrocytoma, ependymomas, neurofibromas

   (7) irradiation of the brain (eg. children with leukemia)

   (8) hypothalamic hamartoma

     ① most common brain lesion causing precocious puberty

     ② ectopically located neural tissue containing GnRH secretory neurons

     ③ functions as an accessory GnRH pulse generator

     ④ MRI

         ; small pedunculated mass attached to the  tuber cinerium  or the floor of the third

           ventricle, less often sessile mass

    ※ intracranial hCG secreting germinomas

         ; do not produce precocious puberty in girls 

           because of complete ovarian function can not occur without FSH priming

Clinical manifestations

   (1) precocious puberty

      ; neuroendocrine manifestation은 tumor가 방사선적으로 detection되기 1-2년전에 나타남

   (2) hypothalamic signs or Sxs

      ; DI, adipsia, hyperthermia, unnatural crying or laughing (gelastic seizure),

        obesity and cachexia

   (3) growth hormone deficiency

      ; hypothalamic hamartoma때 일어날수 있음

       증가된 sex hormone level의 growth-promoting effect 때문에 masked

Treatment

   (1) neurosurgical intervention

      ; hypothalamic harmartoma때는 indication이 되지 않으며

        드물게 intractable seizure때 적용

   (2) 치료는 pathogenic process의 성상과 위치에 따라서 시행

   (3) GnRH analog

       ① central precocious puberty를 일으키는 organic brain lesion에 효과적

                                     ( idiopathic sexual precocity와 효과 비슷 )

       ② choice to halt premature sexual development

 

   (4) combined growth hormone therapy

      ; associated growth hormone deficiency가 있는 경우

517.3 Syndrome of Precocious Puberty and Hypothyroidism

# untreated hypothyroidism에서 unphysiologic precocious pubery & prepubertal bone age을 보인다.

# cause of hypothyroidism

    ; lymphocytic thyroiditis, thyroidectomy, over treatment with antithyroid drugs

Clinical Manifestation

    ; growth retardation, osseous maturation

    ; sexual development

        - breast enlargement, menstrual bleeding

           - large, multicystic ovaries in pelvic sonography

           - unlike in true precocious puberty

                   / *testicular enlargement without substantial leydig cell stimulation & testosterone secretion

                   / *ovarian estrogen production without concomitant increase androgens

Laboratory Finding

  ; skull X-ray or MRI

        - enlargement of the skull

    ; TSH level

        - markedly elevated, often over 1000 μU/ml

    ; *mildly elevated prolactin and FSH, LH

    ; ★high FSH : LH ratio due to low LH level

Pathogenesis

    ; *“specificty spillover” by greatly elevated TSH ( TSH & gonadotropin share indentical α-chain)

    ; *impaired degradation of FSH and LH

Treatment

    ; thyroid hormone투여시 biochemical profile이 빠르게 정상으로 돌아옴       

    ; macroorchidism ( testicular vol > 30 ml )은 적절한 L-thyroxine투여 후에도 지속적으로 남을수 있다

517.4 Gonadotropin-Secreting Tumor

Hepatic Tumor

   (1) hepatoblastoma의 약 30%에서 isosexual precocious puerty발생

   (2) male에서만 나타나며, 발생시기는 4mo-8yr까지 다양 ( 평균 2yr )

   (3) enlarged liver or mass in upper quadrent

       ; suggest the diagnosis

   (4) tumor cells

       ; HCG를 생산하여 testes의 Leydig cell에 있는 LH receptor를 자극

   (5) testicular histolgy

       ; interstial cell hyperplasia and absence of spermatogenesis

   (6) plasma hCG & α-fetoprotein

       ; usually markedly elevated

         useful marked for following the effect of therapy

   (7) plasma testosterone

       ; elevated

   (8) treatment

       ; same as other carcinoma of the liver

         survival은 대개 진단시부터 1년 이하

Other Tumor

   (1) 종류

       ① chorionic gonadotropin-secreting choriocarcinomas

       ② teratocarcinoma

       ③ teratomas

   (2) location

          CNS, mediastinum, gonads

   (3) 남아에서 more common

   (4) affected patients

       ; often marked elevation of hCG & α-fetoprotein

Precocious Pseudopuberty

        discussed in chapter 532       ( adrenal cause )

                    chapter 536 & 539 ( gonadal cause )

517.5 Mccune - Albright Syndrome

(=precocious puberty with polyostotic fibrous dysplasia and abnormal pigmentation)

# ★특징

 1) endocrine dysfunction ; autonomous hyperfunction of multiple glands

 2) patchy cutaneous pigmentation

 3) fibrous dysplasia of the skelatal system

Etiology

; *missense mutation in the gene encoding the α-subunit of Gs

    --> *activation of receptors (e.g. ACTH, TSH, FSH, LH)

Clinical Manifestation

# Precocious puberty

    ; predominantly in girls

        - *onset about 3yr

    - vaginal bleeding

                   / as early as 4mo

           - secondary sex characteristics

                   / as early as 6mo

           - suppressed LH, FSH

           - no response to GnRH stimulation

       - Estradiol

           / normal to markedly elevated ( > 900pg/ml ), often cyclic

           / correlate with the size of the cysts

    ; in boys

        - less common

       - testicular enlargement

           / fairly symmetric

         / fallowed by appearance of phallic enlargement, pubic hair as in normal puberty

        - testicular histology

           / large seminiferous tubules

         / no or minimal Leidig cell hyperplasia

    ; bone age가 usual pubertal age에 도달했을때

           - gonadotropin serecretion

                   --> pubertal response to GnRH

                   --> *true precocious puberty가 combined 되어 mixed type으로 된다.

# hyperthyroidism

    ; equal in male and female

    ; multinodular

    ; uncommon clinical symptoms but goiters

    ; mildly elevated T3 level but suppressed TSH level

# ★Cushing Syndromes

    ; *bilatal nodular adrenocortical hyperplasia in early infancy

    ; preceding sexual precoicity

  ; low ACTH level, not suppressed adrenal function by large dose dexamethasone

# gigantism or acromegaly

    ; elevated GH due to increased TRH

# increased serum prolactin level

# extraglandular manifastation

  ; *phosphaturia, leading to richets or osteomalacia

    ; rare cardiovascular and hepatic involvement

Treatment

 1) functioning ovarian cyst

       ① often disappear spontaneiusly

       ② aspiration or surgical excision of cyst ; rarely indicated

 2) persistent estradiol secretion

     ; testolactone, aromatase inhibitor (estrogen 생성의 마지막 단계를 차단)

       -- estrogen production을 normalize 시키지는 못함

 3) long-acting agonist of GnRH

     ; puberty가 gonadotropin-independent에서 명백하게

       gonadotropin-dependent mechnism으로 이행하는 환자에 적응

 4) cushing synd

     ; adrenalectomy

 5) hypersomatotropism

     ; octreotide, a long-acting somatostatin inhibitor

Prognosis

 1) favorable for longevity

 2) deformities, repeated fracture, pain and

    ocasional cranial n. compression이 bony lesion으로 인해 올수 있음

517.6 Familial Male Gonadotropin - Independent Precocious Puberty

1. male-limited autosomal dominant sexual precoicity

      ① gonadotropin independent

      ② transmitted through affected males,

         unaffected female carriers of the gene

      ③ sign of puberty ; 2-3 yr of age 

      ④ testis ; slight enalrged

                 biopsy상에서 Leidig cell matuartion과 일부에서는

                 marked hyperplasia 소견보이며 seminiferous tubule도 matuartion

      ⑤ testosterone levels

               ; marked elevated

      ⑥ LH의 baseline levels

               ; prepubertal state, pulstile secretion은 없으며,

                GnRH stimulation에 no response

      ⑦ osseous maturation

               ; markedly advanced

      ⑧ sexual precoicity는 gonadotropin independent이지만,

         점차 gonadotropin dependent로 됨

Treatment

 1) ketoconazole (600mg/ 24hr in # 3)

       inhibit C-17, 20- lyase and testosterone synthesis

 2) combination of spironolactone (block androgen action) &

                   testosterone (competitive inhibitor of aromatase)

     ; serum testosterone을  prepubertal 농도로 낮추지 못하거나,

       testosterone effect를 완전 차단하지는 못함

517.7 Incomplate (Partial) Precoicous Development

 * puberty의 다른 signs은 나타나지 않고 precoicity의 isolated manifestation만 있으며,

    드물지 않게 발생함

 * two most common

    (1) development of breast in girls

    (2) growth of sexual hair in both sex

Premature Thelarche

   (1) transient condition of isolated breast development,

      sporadic하게 발생하며 드물게  familial

   (2) 대부분 생후 첫 2년내에 나타나지만, 일부에서는 출생시부터 나타날수 있음

   (3) 대개 양측성이지만 unilateral or asymetric 일수도 있음

   (4) growth & ossoeus maturation

         ; normal or slight advanced

   (5) genitalia

         ; no evidence of estrogen stimulation

   (6) menarche

         ; occurs at expected age & reproduction도 normal

   (7) LH와 estriol

         ; below the limit of the assay

   (8) basal FSH와 GnRH stimulation에 대한 LH의 반응

         ; normal controls경우 보다 greater

 cf) true precocious puberty때는 LH가 현저하게 상승

   (9) ultrasound examination  of ovaries

         ; normal size, 일부에서는 small (< 9cm)  cyst가 흔함

  (10) 일부에서는 breast develpoment가 명백하게 systemic estrogen effect 와

      관련이 있으며 초음파상 ovaries or uterus가 enlarged

                                      (exaggerated or atipical thelarche)

      spontaneously regression한 점에서 central precocity와 다름

  (11) premature thelarche는 benign condition이지만 true or pseudoprecocious puberty 의

      1st sg이거나, exogeneous estrogen의 효과일 수 있으므로 상세한 history를 하고

      bone age를 측정한다.

      serum LH, FSH, estradiol 농도가 낮지만 진단적 가치는 없으며,

      continued observation 이 중요함

  ※ 3세 이후의 thelarche

        ; 대부분에서 precocious thelrache보다는 다른 원인을 생각

  ※ regression & recurrence thelarche

        ; functioning of follicular cyst를 암시

Premature Adrenarche

   (1) sexual hair가 여아에서 8세,

                 남아에서 9세 이전에 나는 경우로 다른 성숙의 증거가 없다

   (2) 남아보다 여아에서 더 흔함

   (3) hair는 labia majora에서 시작하여  점차 pubic region가지 진행되며,

      마지막에 axilla에 나타나면서  성인형의 axillary oder가 흔하게 동반됨

   (4) height & osseous maturation

        ; sl advanced

   (5) adrenal androgen production의 early matuartion event로  zona reticular의

      조기 성숙과 함께 3β-hydroxy steroid-dehydrogenase activity가 감소되고

      C-17, 20-lyase activity가 증가함

      결과적으로 basal and ACTH-stimulated △^{5 _} steroid (17-hydroxypregnenolne and             DHEA)의 혈중농도가 상승

 

   (6) benign condition으로 치료는 필요치 않다

 

 (cf) atypical premature adrenarche

       - 소수에서  marked growth acceleration, clitorial or phallic enlargement,

         cystic acne, advanced bone age등의 systemic androgen effect의 특징이

         1가지 혹은 그 이상 나타남    

       -  ACTH stimulation test를 하여 17-hydroxyprogesteron을 측정함으로써

          nonclassic congenital adrenal hyperplasia를 rule out

   (7) 성인이 되었을때 hyperadrenalism과 polysystic ovarian syndrome의 high risk임

Premature Menarche

   (1) premature thelarche, or adrenarche보다 less frequent

   (2) affected girls의 대부분은 1-3 번 bleeding episode가 있음

   (3) plasma gonadotropin은 정상이며, estradiol level은 상승

   (4) 감별진단으로는  vulvovaginitis, foreign body, urethral prolapse,

       sarcoma botryoides 등이 있음

517.8 Medicatinal Precoicity

   (1) sex hormone에 expose되거나 ingestion한 Hx 가 있음

       ① estrogen in cosmetics

       ② hair cream

       ③ breast augmentation cream

   (2) vitamin tablet가 sex hormone으로 contamination된 경우

   (3) exogenous estrogen

         ; breast의 areolar가 intense, dark, brown color

   (4) precocious는 hormone exposure가 중단되면 사라짐

Section 2. Disorders of the Thyroid Gland

Thyroid Physiology

# main function

    ; thyroxine(T4), 3, 5, 3'-triiodothyronine(T3) synthesis

# iodine

  1) recommended dietary allowance.

    ① 40-50ug/24h for infants

    ② 70-120ug/24h for children

    ③ 150ug/24h for adolescences & adults

  2) *reaches thyroid gland as iodide

# 합성 과정

  1) oxidization of iodide by thyroidal peroxidase

    2) iodination of tyrosine

        -> monoiodotyrosine, diiodotyrosine

  3) production of T3, T4

           ; diiodotyrosine + diiodotyrosine ---> T4

     ; diiodotyrosine + monoiodotyrosine ---> T3

  4) storage as thyroglobulin in lumen of the follicle

    5) liberation from thyroglobulin

           ; by activation of protease & peptidase

# T3

  1) T3가  T4보다 3-4배 정도 대사성 역가를 가짐

  2) adult : T4 100 ug

            T3 20  ug 매일 생성

  3) 생성

     ① 20% : thyroid 에서 생성

     ② 나머지 : T4의 deiodination으로 생성

                 in liver, kidney, other peripheral tissue by type I 5'-deiodinase.

                 in pituitary gl. & brain  -- 대략 80%을 type Ⅱ 5`-deiodinase에의해

                                             T4로 부터 생성.

  4) T3 가 생리학적 작용의 대부분을 함

# T4

  1) T4는 양은 많으나  nuclear receptor와 약하게 결합되어 있고 T3로 전환하여 생물학적

      활성을 나타냄

  2) 혈액 내 T3 level 은 T4의 1/50 임

# 작용

  1)  increase oxygen consumption 

  2)  stimulate protein synthesis

  3)  influence growth & differentiation

  4)  affect carbohydrate, lipid, & vitamin metabolism

# 작용 기전

  1) intracellular T3는 nucleus 내로 들어가 thyroid hormone receptor와 결합하는데,

     이 receptor도 steroid hormone receptor ( glucocorticoid, estrogen, progesterone,

        Vit D, retinoids ) 계열이다.

     4가지 type α1 & 2 , β1 & 2

  2) circulating T4의 70%는 thyroxine-binding globulin (TBG)와 결합해 있고,

     나머지는 thyroxine-binding prealbumin과 결합되어 있다

     단지 0.03%만이 free thyroxine (FT4)를 구성한다.

  3) circulating T3의 50% 가 TBG와 결합하고 50%는 albumin에, 0.3%만이 unbound or

      free T3로 존재함.

# Regulation

  1) TSH (thyroid - stimulating hormone)

     ① glycoprotein으로 ant. pituitary에서 생성 분비됨

     ② thyroid gland내 adenylate cyclase를 활성화 시킴

     ③ 2개의 noncovalently bound subunits(chain)로 구성됨. α β(hTSH-β)

        (i) α-subunit : LH, FSH, chorionic gonadotropin과 공통

        (ii) β-subunit : hormone의 특이성을 부여

  2) TRH (thyroid - releasing hormone )

     ① hypothalamus에서 합성되어 pituitary 로 분비

     ② tripeptide

     ③ endocrine function + neurotransmitter.

  3) excess TSH or TSH 과잉

      --> hypertrophy & hyperplasia of thyroid cells increased trapping iodine.

           increased synthesis of tyroid hormone.

  4) exogenous thyroid hormone or increased thyroid hormone synthesis

      --> inhibit TSH & TRH production

  5)  decreased extrathyroidal production of T3

       ( fasting, malnutriton, acute illness, drug )

       --> inhibition of thyroxine 5'-deiodinase

       --> T3 ↓

            T4 TSH  normal

Chapter 518. Thyroid Hormone Studies

Serum Thyroid Hormone

; T4, free T4, T3, free T4, diiodothyronine, reverse T3( 3, 5’3’-triiodothyronine)

# Thyroglobulin (Tg)

  ; glycoprotein dimer

  ; thyrocyte의 apical surf.를 통해 colloid내로 분비됨

  ; ↑

           - TSH stimulation

           - neonate

           - Graves’ ds.

           - endemic goiter

    - *Ca of thyroid(↑↑)

    ; ↓

           - TSH suppression

           - athyreotic infant(↓↓)

# TSH

    ; extremely sensitive indicator of primary hypothyroidism

    ; assay

           - radioimmunoassay

     - immunometeric assay

    - *chemiluminescent assay

                   / at now standard method

    ; normal level  < 6 uU/ml

※92 TRH stimulation test

    ; 7ug/kg IV

    ; normal

           - 30분 이내 TSH baseline level 증가

    ; hyperthyroidism - no rise in serum TSH level

    ; mild thyroid failure - exaggerated TSH responce

    ; pituitary or hypothalamic failure - low basal level of TSH

Fetal & Newborn Thyroid

1) 모체의 영향과는 독립적으로 hypothalamic-pituitary system발달

    임신 10-12주 fetal thyroid : iodine을 conc.--> iodothyronine합성 능력을 가짐

                fetal pituitary : TRH 함유

2) fetus   

   (1) serum T4 : 임신 중반 부터 점차 증가하여 term에 11.5ug/dl.

   (2) serum T3 : 임신 20주 이전에는 낮다가 term에 60ug/dl

   (3) reverse T3 : fetus시 매우 높다가 (250ng/dl at 30주), term에 150ng/dl까지 떨어짐.

   (4) serum TSH : 점점 증가하여 term에 10uU/ml

3) maternal T4 : 1/3정도가 태반을 통과하여 fetal thyroid H. 합성 전까지 fetal development

                   (특히 brain)에 역할을 함.

   (1) hypothyroid mother --> at risk for neurologic damage.

   (2) hypothyroid fetus --> 분만 전까지 maternal T4에 의한 partial protection

4) ♥Change at birth

    ; acute release of TSH

        - *peak serum conc. 70uU/ml in 30min in full term

           - *rapid decline in 24hr within the next 2days to 10uU/ml

  ; T4

           - dramatic rise (*16ug/dl)

           - *gradually fall during the first 2wks to 12ug/dl

    ; T3

           - *300ng/dl in about 4hr (largely peripheral conversion of T4)

           - *decline during the 1st wks to 200ng/dl

    ; reverse T3

           - 2주 동안 200ng/dl 로 유지되다가 4주때 50ng/dl 정도로 감소

Serum Thyroxine-Binding Globulin

; liver에서 생성되는 glycoprotein.

; T4의 70%, T3의 50%와 결합함

# ♥증가하는 경우

    ; pregnancy

  ; newborn period

  ; estrogen (oral contraceptives)

  ; *perphenazine

  ; heroin

# ♥감소하는 경우

    ; androgen

  ; anabolic steroid

  ; glucocorticoid

  ; *L-asparaginase

  ; ★phenytoin, phenobarbital

           - increased hepatic degradation of TBG

           - accelerated transport T4 to tissue

           - inhibition of T3, T4 binding to TBG

  ; *congenital NS

# 측정방법

    ; RT3U (resin triiodothyronine uptake test)

           - TBG level에 따른 T4 level 해석

    ; *T4-RT3U index (thyroxine-resin T3 index)

        - correlation with free T4

        - ↑ : hyperthyroidism

        - ↓ : hypothyroidism

    - normal :  euthyroid /c mild abnormal

In Vivo Radionuclide Studies

1) ¹²³I (half-life ;13hr)

    cf. ¹³¹I ; known thyroid cancer 에만 사용

2) ★^99mTc (half-life ;6hr)

  ; *특히 소아에 많이 사용

  ; trapping but *no organification

3) Thyroid scan

  ; ♥Ix

        - ectopic thyroid tissue

    - thyroid nodule

    - assess the presense of thyroid tissue in thyroid agenesis

    ; ^99mTc perechnetate 사용시 잇점

      ① lower radiation exposure

      ② high-quality scintigram

Chapter 519. Defects of Thyroxine-Binding Globulin

; *clinical ds와 관련이 없고 치료할 필요가 없다

TBG deficiecy

  1) *X-linked dorminant disorder

  2) 종종 neonatal hypothyroidism screening시 발견됨

★Laboratory Finding  

    ; *T4(↓), RT3U(↑), freeT4(→), TSH(→)    

★Diagnosis

    ; TBG (-) or low level

Pathogenesis

    ; codon mutation(leucine to proline), point mutation

Epidermiology

     ① male > female

     ② 1/2400 newborn males

     ③ 36 % : TBG < 1mg/l

     ④ mild TBG deficiency

        1/42000 heterozygous females

     ⑤ complete TBG deficiency ( < 5μg/l ) : less frequently

        3/8 : codon mutation ( leucine -> proline )

        5/8 : reduced affinity of TBG for T4

Elevated TBG

  1) *harmless X-linked dominant

  2) 1/2500

Laboratory Finding

  ; T4 ↑ ( partly due to maternal estrogen )

  ; T3 ↑

  ; *normal TSH, free T4

    ; *RT3U ↓

Diagnosis

    ; TBG ↑, free T4 n'l

  5) euthyroid

  6) acquired ↑

     ① pregnancy

     ② estrogen Tx

     ③ hepatitis

Familial Dysalbuminemic Hyperthyroxinemia

  1) autosomal dominant disorder

  2) DDx : hyperthyroidism

  3) Lab

     ① T4 ↑ : abnormal albumin variant와 결합하는 T4 ↑

     ② free T4, free T3, TSH n'l

     ③ T3 : normal or sl. ↑

  4) euthyroid

Chapter 520. Hypothyroidism

; deficient production of thyroid hormone or defect in its receptor

♥Table 520-1

Congenital Hypothyroidism

Etiology

Thyroid dysgenesis

; prevalence

    - 1/4000 worldwide

    - lower in black americans

; *90% of infant hypothyroidism

    - 1/3 : thyroid aplasia on radionuclide scan

  - 2/3 : rudiments의 ectopic location

                        - base of tongue (lingual thyroid) to normal position of neck

; *asymptomatic at birth even if complete agenesis

    - due to transplacental passage of maternal thyroxine(T4)

; Diagnosis

    - T4↓, TSH↑

    - screen으로 hypothyroid neonate 감별 가능

; *M : F = 1 : 2

; ★Pathogenesis

  1) *thyroid growth-blocking & cytotoxic antibody

    2) *maternal TSH-binding Ab

; Ectopic thyroid tissue ( lingual, sublingual, subhyoid )

 ① 수년 동안 충분한 양의 thyroid hormone이 공급되거나 유아 초기에 부족해짐

 ② 임상적으로 tongue base 또는 neck midline ( hyoid ) 의 growing mass로 인지됨

 ③ 때로 thyroglossal duct cyst와 관련되기도 됨

 ④ euthyroid 환아에서 ectopic thyroid tissue의 surgical removal로 hypothyroidism을 초래하기도 함

Thyrotropin Receptor-Blocking Antibody ( TRBAb )

; formly called thyroid-binding inhibitor immuniglobulin ( TBII )

; cause of transitory congenital hypothyroidism

; frequency   1/50000-100000

# ♥suspicion condition

    ; maternal autoimmune thyroid ds (Hashmoto thyroiditis)

    ; maternal Graves ds.

  ; maternal hypothyroidism on replacement Tx

  ; recurrent congenital hypothyroidism of a transient nature in subsequent siblings

    --> measure maternal TRBAb level

; often have thyrotropin receptor-stimulating antibody(TRS Ab), antiperoxidase(=antimicrobial) Ab

; Thyroid scan

    - *thyroid tissue (-)

    - but replacement Tx 중단후 normal thyroid gl.

; half-life of Ab

    - 7.5 days

; remission in about 3 mo

Defective Synthesis of Thyroxine

# ♥Characteristic

    ; congenital hypothyroidism

    ; incomplete defect

    ; compensation

    ; *delayed onset

    ; *almost always goiter

    ; autosomal recessive

Defect Of Iodide Transport

      ① 1/3 : consanguinity ( Japan )

      ② 과거에는 goiter동반 유무와 관계없이 clinical hypothyroidism이 생후 몇달

         내에 생겼지만, 최근 neonatal screening program에서 detect됨

      ③ 일본에서는 식사에 iodine content 함량이 매우 높다 ( 19 ng/24 hr )

          --> 10년 후 goiter와 hypothyroidism으로 발생

      ④ thyroid & salivary gl.에서 iodine concentration 능력이 부족함

      ⑤ uptake of radioiodine & pertechnetate 감소

      ⑥ saliva ; serum ratio of ¹²³I : 진단에 도움

      ⑦ Tx ;  과량의  potassium iodine 치료에도 반응하지만 thyroxine으로

                치료하는것이 더 바람직함   

Thyroid Peroxidase Defects Of Organifiaction & Coupling

      ① most common defect

      ② iodide가 thyroid에 trap되고 oxidation되어 reactive iodine으로 된후

          tyrosine units에 포함됨

            ; 이 과정은 H2O2, thyroid peroxidase hematin생성이 요구됨

      ③ Dx

          (i) radioiodine test dose투여 2시간후 perchlorate or thiocyanate 투여시

              thyroid radioactivity의 marked decrease

          (ii) perchlorate discharge가 정상에서는 10%이하에 비해  이런 환아에서는

               40-90% radioiodine을 방출함

      ④ Pendred syndrome

          (i) sensorineuronal defness & goityer

          (ii) (+) perchlorate discharge

Defects Of Thyroglobulin Synthesis

      ① goiter

      ② Lab 

            ⒜ TSH 증가

            ⒝ T4 감소

            ⒞ thyrogloburin( Tg) ; (-) or low

Defects In Deiodination

    ; *deficiency of deiodinase

           --> inhibition of deiodination of monoiodotyrosine & diiodotyrosine in thyroid & pph tissue

           --> *no recycling of iodine

           --> *urinary loss of nondeiodinated tyrosine

           --> hormonal deficiency & goiter

Radioiodine

      ① thyroid ca. 또는  hyperthyroidism의 치료를 위해 임신시 radioiodine을

         부적절하게 투여한 경우 hypothyroidism이 유발됨

      ② fetal thyroid는 70-75일 쯤에 iodine trapping을 할수 있음

      ③ 가임기 여성에 radioiodine투여할 때는 투여전  pregnancy test를 반드시

         시행하며, 수유 여성에게 radioactive iodine투여는 금기임

Thyrotropin defeciency

# developmental defect of pitiutary or hypothalamus

    (2) TSH - deficient hypothyroidism

       ① 1/30000 - 1/50000

       ② neonatal thyroid screening 에서 30-40% detect

       ③ 대부분 multiple pituitary deficiency

       ④ Sx

            +-hypoglycemia

            | persistent jaundice

            | micropenis ~c septooptic dysplasia

            | midline cleft lip

            | midface hypoplasia

            +-other midline facial anomalies

# ♣Pit-1 gene Mutations

    ; deficiency of thyrotropin, growth hormone & prolactin

    ; Pit-1

           - tissure transcription factor

    - differentiation, maintenance & proliferation of somatrophs, lactotrophs & thyrotrophs

    ; TRH stimulation test

           - *failure of prolactin response to TRH

            --> exam of Pit -1 gene

# mutation in the TSH -receptor (TSHR) gene

       ①  Lab

             ; TSH 증가, T4 정상

       ② autosomal recessive

       ③ TSH에 대한 resistance를 보임에도 불구하고 치료없이도 euthyroid로

          남는 경우도 있고, severe hypothyroidism으로 치료한 경우도 있음

# Isolated deficiency of TSH

       ① rare autosomal recessive

       ② different point mutations in TSH β- subunit gene

Thyrotropin hormone Unresponsiveness

    (1) mild congenital hypothyroidism으로 detect된 newborn infant가 후에 type Ia

        pseudohypoparathyroidism으로 증명됨

    (2) generalized impairment of cAMP activation

         by genetic deficiency of α subunit of guanine nucleotide regulating protein (G5α)

    (3) Lab

       ① T4 감소

       ② TSH 증가

       ③ no response to exogenous TSH administration

Thyroid hormone unresponsiveness

    (1)대부분의 환자는 goiter를 가지고 있슴

    (2) Lab

        T4, T3 free T4 , free T3 증가

                  ( DDx; graves ds)

    (3) Sx

       ① mild mental retadation

       ② growth retadation

       ③ delayed skeletal maturation

       ④ attention - deficit hyperactivity disorder ( ADHD )

    (4) Dx

       ① TSH ; diagnostic

                 not- suppressed (as in graves ds)

                 mod. 증가 혹은 정상  

       ② TSH  response to TRH (+)

       ③ failure of TSH suppression

           ; resistance가 generalized하고, peripheral tissues 뿐만아니라 pituitary까지 손상.

    (5) autosomal dorminant

    (6) neonatal thyroid screening시 T4 상승시 의심할수 있고, growth & skeletal retardation이

         없으면 치료는 필요하지 않음.

    (7) autosomal recessive form of thyroid resistance

       ① hypothyroidism early in life

       ② DNA study, major deletion of β-thyroid receptor

    (8) selectively resistance to thyroid hormone

       ① pituitary gl.에만 영향

       ② peripheral tissue는 thyroid hormone에 resistant 하지 않으므로 환아는 goiter &

           hyperthyroidism의 양상을 보인다

       ③ DDx : pituitary TSH-secreting tumor

Other Cauce of Hypothyroidism

 (goiter 동반)

      ① fetal exposure to excessive or antithyroid drugs

            ; transient

      ② topical iodine-containing antiseptics

            ; transient

             특히 low birthweight infant

              --> neonatal screening test상 abnormal result 야기

      ③ asthma Tx drug

      ④ amiodarone

            ; antiarrhythmic drug /c high iodine content

※객 Clinical Manifestations

; *M : F = 1 : 2

; normal birthweight & length

    - but increased head size due to myxedema of brain

; ※객prolongation of physiologic icterus

    - *earlist sign

    - due to delayed maturation of glucuronide

; feeding difficulties, sluggishness, lack of interest, somnolence, choking spells during nursing

    - during 1mo

; resp. difficulties

    - due to large tongue)

; apneic episode, noisy respiration, nasal obstruction

; typical respiratory distress syndrome

; weak crying, poor appetite

; constipation

    - not respond to Tx

; large abdomen

; umbilical hernia

; *subnormal body temperature (<35℃)

; skin (esp. extremities) - cold, mottled

; edema of genitalia & extremites

; slow pulse

; heart murmur, cardiomegaly, asymptomatic pericardial effusion

; anemia - refractory to Tx with hematonics

=> progress above Sx & Sg

=> retardation of physical and mental development

=> fully developed by 3-6mo of age

; stunted growth, short extremities

; open ant. & post. fontanel

    - initial clue of congenital hypothyroidism

; face

 ① eyes : far apart

 ② bridge of broad nose : depressed

 ③ narrow palpebral fissure.

 ④ swollen eyelids.

; short & thick neck

; deposit of fats above clavicle, neck, shoulder

; delayed dentition

; hand - broad, short fingers

; carotenemia

  - yellow discoloration of skin, white sclera

; thickened scalp, coarse, brittle, scanty hair, far down hairline

; Developmental retardation

  ① lethargic

  ② late in learning to sit & stand

; delayed sexual maturation

; hypotonic

# ★Kocher-Debré-SéMé-Laigne Syndrome

    ; generalized m. hypertrophy

  ; athletic appearance due to pseudohypertrophy

           - esp. calf muscle

  ; 치료후의 m. biopsy 소견 ; 정상으로 돌아옴.

  ; boy > girl

  ; longer duration & severity of hypothyroidism

Laboratory Data

# ♥Neonatal screening

1) measure levels of T4, and then TSH when low T4

    ; identifies primary hypothyroidism, low TBG, hypothalamic or pituirary hypothyroidism, hyperthyroxinemia

    ; *miss ectopic thyroid, thyroid dysgenesis, compensated hypothyroidism

2) measure levels of TSH

    ; detect compensated hypothyroidism

    ; *miss hyperthyroxemia, low TBG, hypothalamic or pituitary hypothyroidism

# TFT

    ; T4↓, T3 normal - not helpful

    ; TSH↑ (*> 100uU/ml) if defect primarily in the thyroid

    ; *Tg↓in thyroid dysgenesis, defects of Tg synthesis or secretion

           - Tg (-) in thyroid aplasia

    ; *prolactin↑

# Retardation Of Osseous Development On X-Ray

  ; *60% at birth

    ; intrauterine life 동안 thyroid H deprivation의미

    ; no femoral distal epiphysis

    ; untreated patients

           - discrepancy between chronological age & osseous development

         - multiple foci of ossifocation on epiphyses(=epiphyseal dysgenesis)

           - deformity (" breaking ") of the 12th thoracic or 1st or 2nd lumbar vertebra

# *skull

    ; large fontanel, wide suture, intersutural(wormian) bone, sella turnica : enlarged & round erosion & thinning

# delay in formation & eruption of teeth

# cardiac enlargement & pericardial effusion

# Scintigraphy

  ; ¹²⁵ I - sodium iodide 가 ^99mTc-sodium pertechnetate보다 우수함

  ; thyroid tissue가 보이지 않는 경우

       ① thyroid aplasia

       ② neonate /c TRBAb

       ③ infant /c the iodide - trapping defect

       ⑶ normal site thyroid gl. /c normal or avid uptake of radionuclide.

           → defect on thyroid hormone biosynthesis.

# goitrous hypothyroidism

  ; radioiodine study

  ; perchrate dischange test

  ; kinetic studies

  ; chromatography

  ; thyroid tissue study ( biochemical nature 의심시 )

# EKG

      ① low voltage P & T

      ② diminished amplitude of QRS complex

          → poor left ventricular function & pericardial effusion

# EEG

       low voltage

# 2세 이상에서 serum cholesterol 증가.

Prognosis

; neonatal screenig program 보급후 congenital hypothyroidism의 예후는 매우 좋아짐

    - 생후 몇주내의 조기진단과 적절한 치료로 거의 정상적인 linear growth & intelligence를 보임

; thyroid hormone은 생후 초기 몇 달 동안의 정상적인 cerebral development에 중요하므로 irreversible brin damage를 방지하기 위해 적절한 치료가 즉시 시작되어야 함

; 2세 이후 hypothyroidism이 onset한 경우 예후가 더욱 좋은 것으로 보아 thyroid hormone의 brain growth에 대한 역활이 중요함을 알 수 있음

Treatment

# *sodium L- thyroxine

    ; drug of choice

  1) circulating T3의 80%는 T4의  monodeiodination에 의해 형성되므로 치료한 경우

     T3, T4는 정상 범위

    ; ★Dosage

        - neonate 10-15 ug/kg/day

       - children 4 ug/kg/day

       - adult 2 ug/kg/24hrs

  ; 치료효과 :  T4 & TSH가 정상범위 유지해야 함

  4) 3세때 3-4주간 치료중단시 permanent hypothyroidism에서는 TSH level이

      매우 증가함

  ; side effects : 대부분 용량과 관계 있음

     ① pseudotumor cerebri : 치료 4개월 내

                              8-13세의 acquied hypothyroidism환아에서 볼 수있음

     ② change in behavior & activity

Acquired Hypothyroidism

Etiology

1) lymphocytic thyroiditis

    ; *▲common

2) congenital thyroid dysgenesis or with incomplete genetic defects in thyroid hormone synthesis

    ; 소아기에는 임상증상이 없어 acquired hypothyroidism으로 보이나 요즘 newborn screening program에서 detect함.

3) subtotal thyroidectomy for thyrotoxicosis or cancer

4) removal of ectopic thyroid tissue.

   ① lingual thyroid, subhyoid median thyroid, thyroid tissue in a thyroglosal duct cyst.

   ② subhyoid gl. 는 thyroglossal duct cyst와 유사해 보이므로 수술전 radionuclide scan

      반드시 시행

5) ★Nephropathic Cystinosis

    ; intralysomal storage of cystine in body tissue

         --> impaired thyroid function

    ; more common compensated form

6) *histiocytic infiltration of thyroid in children with Langerhans cell histiocytosis

7) irradiation to thyroid

  ; Hodgkin ds. 또는 기타 악성종양 치료시

      bone marrow transplantation 전 irradiation

      → thyroid damage

    ; 1/3 : 치료 1년 이내 TSH ↑

      15 - 20 % ; 5-7년 내 hypothyroidism으로 진행

8) protracted ingestion of mediations containg iodides

    ; accompanied by a goiter

  ; ★amiodarone

     ① cardiac arrhythmia에 사용

     ② 37% iodine 함유

     ③ *치료환아의 20%에서 hypothyroidism

     ④ high iodine content

     ⑤ inhibition of 5′-deiodinase (T4→T3)

     ⑥ T4, T3, TSH의 serial measurement 필요

Clinical Manifestation

  1) Sx

     ① deceleration of growth ( 1st Sg )

     ② myxedematons changes of skin.

     ③ constipation

     ④ cold intolerance

     ⑤ decreased energy

     ⑥ increased need for sleep

     ⑦ school work & grades ; not suffer

     ⑧ delayed osseous maturation

            : Ix of duration of hypothyroidism.

     ⑨ headache, visual problem, precocious puberty, galactocemia

            : hyperplastic enlargement of pituitary gl. /c suprasella extension

                    ( DDx ; pituitary tumor )

  2) T4 replacement 적절히 치료후 임상 증상 호전을 보이나, 오래된 hypothyroidism

     환아에서는 catch-up growth 불완전함 ( predicted adult height보다 7cm 정도 적음 )

Chapter. 521. Thyroiditis

Lymphocytic Thyroiditis (=Hashmoto thyroiditis ; Autoimmune thyroiditis)

; *children & adolescents에서 ▲common thyroid ds.

; *▲common cause of acquired hypothyroidism

; incidence - 1% among school children

Etiology

; *typical organ-specific autoimmune ds.

; histologic finding

    - lymphcytic infiltration of thyroid.

  - early hyperplasia

       --> infiltration of lymphocytes & plasma cells between follicles

        atrophy of follicles

    - lymphoid follicle formation /c germinal center

    - Intrathyoidal lymphocytic subset

        / *60% T cells : CD4⁺ (helper), CD8⁺ (cytotoxic)

           / 30% B cells   

; HLA type

  - HLA - DR4, HLA - DR5

       / goiter, thyroiditis  ↑

    - HLA - DR3

       / atrophic variant of thyroiditis

; ★Thyroid Antigen Autoantibodies

    1) thyroid antiperoxidase Ab (TPOAb)

           (=antimicrosomal antibody)

         - 90% in lymphocytic thyroiditis

    - many patients /c Graves ds

         - *action : inhibit enzyme activity & stimulate natural killer cell cytotoxicity

    2) antithyroglobulin antibody

         - more common in adults

    3) thyrotropin receptor-blocking Ab(TRBAb)

         - *hypothyroidism & thyroid atrophy와 관련이 있다고 생각함

Clinical Manifestations

; M : F = 1 : 4-7

; more common after 6yr

    - peak incidence during adolescencts

; growth retardation, goiter

    - *▲common symptoms

    - goiters

           / insiduous, small or large

           / mostly diffusely enlarged, firm, nontender

; *mostly euthyroid & asymptomatic

    - some pressure symptoms in the neck

    - some clinically hypothyroidism

    - some clinically euthyroid & laboratory hypothyroid

    - some clinically hyperthyroid & laboratory hypothyroid

# Clinical course

    ; variable

  ; goiter

           - smaller or disappear spontaneously

    ; nongoiterous (atrophic) hypothyroidism

# Familial tendency

    (1) 환아의 형제나 부모의 발생 : 25%

    (2) thyroglobulin Ab. human thyroid peroxidase(hTPO)

          ; autosomal dominant

    (3) reduced penetrance in males

    (4) lymphocytic thyroiditis, "idiopathic" hypothyroidism, Graves ds.

          ; 세 질병이 동시에 나타남

    (5) 다른 autoimmune disorder와의 관계

       ① type l polygrandular autoimmune syndrome

           +- hypoparathyroidism

           |  Addison ds

           +- mucocutaneous candidiasis 

               ; 10%에서 autoimmune thyroiditis 동반

       ② Schmitt syndrome or type II polyglandular autoimmune disease

          Addison ds c IDDM or autoimmune thyroid ds or both

       ③ pernicious anemia, vitiligo, alopecia도 연관

       ④ DM 환아에서 백인의 20%, 흑인의 4%에서 TPO Ab발견됨

       ⑤ congenital rubella 환아에서 발생율 증가

       ⑥ Turner synd & Down synd과도 연관이 있음

Laboratory Data

1) definitive Dx ; thyroid biopsy

2) thyroid function

    ; slightly or moderately TSH

           - often normal

                   --> *goiter가 lymphocytic infiltration에 의하여 발생한 것이 아니고, thyroid growth- stimulating immunoglobulin에 의한 발생함을 시사

  ; progressive thyroid failure가 되면

           - T4감소, T3감소, TSH증가

3) thyroid scan

   ① 50% ; irregular & patchy distribution of radio isotope

   ② > 60% ; perchlorate투여시 10% 이상의 dischrge보임

4) thyroid ultrasonography

   scattered hypoechogenecity.

5) antibody titers to thyroid peroxidase(+)

   antithyroglobulin test for thyroid Ab(+) : < 50%

           → 95% 정도 진단

6) antithyroid Ab

   ① 환아 형제의 1/2에서 (+)

   ② Down syndrome or Turner syndrome을 가진 환아의 엄마에서도 뚜렷한 thyroid ds.

      없이도 (+)

   ③ DM 환아의 20%에서 (+)

   ④ congenital rubella syndrome 환아의 23%에서(+)

Treatment

; sodium -L -thyroxine( 50-150ug daily)

  1) hypothyroidism증상이 있을때

  2) goiter는 size가 줄어드나 몇년간 지속됨

  3) antibody level은  fluctuation하면서 몇년간 지속됨

  4) suppressive Tx에도 불구하고 prominent nodule이 존재시 thyroid cancer발생 가능성이 있으므로 조직학적 검사를 시행함

Other Causes Of Thyroiditis

    :  tuberculosis, sarcoidosis, mumps, cat- scratch ds

1. acute suppurative thyroiditis

  1) uncommon

  2) respiratory infection선행

  3) left lower lobe가 흔히 침범됨

  4) abscess formation

  5) mc organism : anaerobic orgarnism

                    ( Eikenella corrodens )

  6) recurrent episodes or detection of mixed bacterial flora

       ; thyroglossal duct remnant or piriform sinus fistula ( more often ) 에서 생김

  7) Sx

     ① exquisite tenderness of gland

     ② swelling

     ③ erythema

     ④ dysphagia

     ⑤ limitation of head motion

     ⑥ leukocytosis

  8) scintigram of thyroid

        ; complex echogenic mass

  9) thyroid function test :  normal

     thyrotoxicosis <- aspergillus에 의한 suppurative thyroiditis일 때

  10) Tx

     ① I & D

     ② antibiotics 투여

     ③ infection사라진 후 fistula tract찾기위해  barium esophagogram하여 확인하고,

        존재시 exterionization

 

2. subacute nonsuppurative thyroiditis ( de Quervan ds )

  1) rare in children

  2) viral cause

  3) spontaneous remission

  4) Sx

     ① vague tenderness over the thyroid

     ② low- grade fever

        또는 severe pain in thyroid 

     ③ high fever & chill

        inflammation은 이미 형성된 thyroid hormone의 순환내로 leakage때문

  5) Lab

       T3, T4 상승

  6) mild hyperthyroidism sx

  7) radioiodine uptake ↓

  8) ESR 상승

  9) course

     ① variable

     ② euthyroid -> hypothyroid

     ③ 수개월 이후 remission   

Chap. 522. Goiter

# ★Enlargement Of The Thyroid Gland

 ① euthryroidism : normal function of gland

 ② hypothyroidism : thyroid deficiency

 ③ hyperthyroidism : overproduction of hormone

# 분류

    ① congenital or acquired

    ② endemic or sporadic

# 원인

①↑ pituitary secretion of thyrotropic hormone in response to ↓ circulating thyroid hormone

② infiltrative process <- inflammatory or neoplastic

③ with thyrotoxicosis   <- TRS Ab

552.1 Congenital Goiter

; usually sporadic

Etiology

Administration Of Antithyroid Drug Or Iodides

     ① during pregnancy for Tx of thyrotoxicosis

     ② goitrogenic drugs이나 iodides는 태반을 통과하여 고용량시 thyroid hormone 합성을 방해하여 태아의 goiter & hypothyroidism을 유발함

     ③ goitrogen과 thyroid hormone을 동시 투여시에도 불충분한 양의 T4가 태반을

        통과하므로 효과 없음

Asthma Tx

Amiodarone

     ① 37% iodine content

     ② euthyroid

     ③ retardation of osseous maturation

     ④ T4 상승, TSH 상승

Mother With Antihyperthyroid Treatment

  4) 산모가 propylthiouracil  100-200 mg/24hr 복용시에도 나타나므로 출생시 thyroid study시행

3. 환아에 thyroid hormone 투여 목적

  1) treat clincal hypothyroidism

  2) hasten the disappearance of goiter

  3) prevent brain damage

     --> 이 상태가 계속 지속되지는 않으므로 thyroid hormone은 몇 달후에 중단가능

4. enlargement of thyroid at birth

  1) respiratory distress --> nursing difficulty & death

  2) head extreme hyperextension

  3) respiratory obstruction이 심한 경우 tracheostomy보다 partial thyroidectomy가 적응증이 됨

Congenital Hyperthyroidism

    ; almost goiter

           - not large goiter

    ; symptoms of hyperthyroidism

    ; often mother with Graves dis

6.  defect in synthesis of thyroid hormone

  1) 1/30000 - 50000 in neonatal screening program

  2) hypothyroid infant일 때는 thyroid hormone으로 즉각 치료하고 정밀 검사는 연기시킴

  3) recessive gene으로 유전되므로 genetic counselling 중요

     다음 임신시 ultrasound로 fetal goiter detect

Iodine Deficiency

  1) rare cause of congenital goiter

  2)임신 초기 심한 iodine deficiency는 goiter가 없더라도 neurologic damage를 야기할수 있고,       maternal & fetal hypothyroidism을 유발하여 maternal thyroid hormone의 protective 

     transfer를 일부 방지

  3) lobulated, asymmetric, firm large goiter

      ; thyroid내 또는 근처의  teratoma 고려

522.2 Endemic goiter & Cretinism

1. moderate deficiency of iodine

    : compensatory hypertrophy & hyperplasia

      +- thyroid hormone 합성증가

      +- hormone의 return 속도 증가

       --> 조직의 thyroid hormone demand 충족

2.  sea water, fish, shellfish에는 iodine이 풍부

   미국의 potassium iodide (100㎍/g) 포함한 iodized salt는 좋은 예방 효과를 보임

   권장량 infant 40-50 ㎍/24hr

Clinical Manifestations

  1) mild iodine deficiency

    (1) adolescence & pregnancy같은 rapid growth period외에는 thyroid enlargement가

        뚜렷하지 않음

    (2) girl > boy

    (3) Lab

         ; T4↓, TSH mod. ↑

           circulating T3 ↑ in normal T4

         ; preferential secretion of T3 by the thyroid

 2) Endemic cretinism

    (1) iodine deficiency in endemic goiter

    (2) type 

       ① neurologic type

       ② myxedematous type

    (3) neurologic syndrome

       ① mental retardation

       ② deaf -- mutism

       ③ disturbances in standing & gait

       ④ pyramidal sg

             ; clonus of foot, Babinski sg., patellar hyperreflexia

       ⑤ goitrous, euthyroid

       ⑥ normal purpertal development & adult stature

       ⑦ little or no impaired thyroid function

    (4) myxedematous syndrome

       ① mental retardation

       ② deaf

       ③ neurologic sx

       ④ delayed sexual development & growth

       ⑤ myxedema

       ⑥ absence of goiter

               -> T4↓

                   TSH markedly ↑

           ultrasonography : thyroid atrophy

    (5) Pathogenesis of neurologic syndrome

       ① iodine deficiency & hypothyroxinemia during pregnancy

           --> fetal & postnatal hypothyroidism

       ② fetal thyroid 발달전 fetal brain에는 thyroid hormone에 대한 receptor존재

       ③ 태반을 통과한 모체의 thyroid hormone이 nervous system발달에 도움을 줌

    (6) Myxedematous syndrome

       ① thyroid autoimmunity : TGBI ( ? )

       ② environmental factors

           +- selenium deficiency

           |  goitrogenic foods

           |  thiocyanates

           +- Yersinia

4. Tx

  1) 5년간 임신시 iodine deficiency예방을 위해 iodinated poppy seed oil single IM

    이 치료는 4세이전 myxedematous cretinism환아에서는 5개월 내 euthyroid state로 됨

  2) older children & adults

        : T4투여

522.3 Sporadic Goiter

; lymphocytic thyroiditis

    - *▲common cause

    - ★important clue to diagnsis

           / disorder in siblings, onset in early life, possible association with hypothyroidism

Iodide Goiter

  1) cough medicines & asthma Tx에 iodide 함유

  2) firm & diffuse enlarged

  3) Wolff-Chaikoff effect

     ① 과량의 iodidine을 투여시 iodine organification & thyroid hormone synthesis방해

     ② short - lived

     ③ hypothyroidism을 유발시키지는 못함

     ④ iodide투여가 계속 되면 autoregulatory mechanism에 의해 iodine trapping제한되고 thyroid내 iodine level이 감소하고 organification은 정상적으로 진행됨

     ⑤ iodide-induced goiter 환아에서는 thyroid hormone biosynthesis defect로 인해

        escape이 일어나지 못함   

         +- lymphocytic thyroiditis

         |  subclinical inborn error in thyroid hormone synthessi

         +- partial thyroidectomy

  4) Lithium carbonate

     ① psychotherapy drug

     ② iodide와 경쟁적으로 작용

     ③ lithium과 iodide는 synergistic effect가 있으므로 혼용은 피함

  5) Amiodarone

     ① antiarrhythmic drug

     ② potent inhibitor of 5`-deiodinase ( T4->T3 )

     ③ underlying autoimmune disease 가진 환아에서는 hypothyroidism을 일으키고 그 외는 hyperthyroidism을 일으킴

Simple Goiter ( Colloid Goiter )

1) euthyroid nontoxic goiter

2) unknown etiology

  ; not associated with hypothyroidism or hyperthyriodism

  ; not caused by inflammation or neoplasia

3) *girl predominantly

4) *peak incidence before & during the pubertal years

5) Histologic examination

    ; normal

  ; varialbe follicular size, dense collid, flattened epithelium

6) goiter ; small or large

7) scintiscan ; normal

8) thyroid Ab (-)

9) DDx ; lymphocytic thyroiditis, iodide goiter, mulinodular goiter

10) Tx

    ; thyroid hormone

       - avoid progression to a large multinodular goiter

  ; 치료하지 않은 환아는 periodic re-evaluation

Multinodular Goiter

  1) firm goiter with a lobulated surface

     single or multiple palpable nodule

     cystic change, hemorrhage, fibrosis

  2) ultrasound : multiple echo-free & echogenic lesions

  3) scintiscan상 nonfuction

  4) thyroid study : normal

  5) SH↑

  6) thyroid antibody (+)

  7) McCune-Albright syndrome     --------+  에서 보고

         digital anomalies & cystic renal dis-+

 

  8) Tx : T4

         surgery

            ; T4 replacement Tx로 nodule이 없어지지 않으면 malignancy 배제위해 op 

522.4 Intratrachel Goiter

1. intraluminal thyroid beneath the tracheal mucosa.

   continuous /c normal extratracheal thyroid

   airway obstruction시 extra or endotracheal 구별필요

2. Tx ; sodium-L-thyroxine : mild

        surgical removal of endotracheal goiter : severe

Chapter 523. Hyperthyroidism

 * excessive secretion of thyroid hormone

   diffuse toxic goiter(Graves ds.) during childhood

 * rare causes

    ① toxic uninodular goiter(Plummer ds)

    ② hyperfunctioning thyroid Ca.

    ③ thyrotoxicosis factitia

    ④ acute suppurative thyroiditis

    ⑤ subacute thyroiditis

    ⑥ McCune-Albright synd.( /c autonomous thyroid adenoma )

 * 대부분 thyroid hormone에 대한 pituitary unresponsiveness

    ① TSH secreting pituitary tumors. only in adults

    ② infants born to mothers with Graves ds.

    ③ transitory phenomenon

    ④ classic Graves ds. during neonatal period

    ⑤ chorioca. hydatidiform mole, stuma ovarii in adults

523.1 Graves Disease

Etiology

  1) enlargement of thymus, splenomegaly, lymphadenopathy

     infiltration of thyroid gl. & retroorbital tissues /c lymphocytes & plasma cells

     peripheral lymphocytosis

  2) thyroid gland

     ① T  helper cell (CD4⁺) in dense lymphoid aggregates

        cytotoxic T cells (CD8⁺) in lower dense area

     ② failure of T suppressor cells

        → expression of T helper cells      

        → sensitized to the TSH Ag

        → interact with β cell

               ( plsma cell에 분화.

           thyrotropin receptor-stimulating Ab ( TRSAb ) 생성

        → TRSAb + receptor for TSH

        → c AMP↑

     ③ TRBAb도 생성되어 보통 clinical course는 TRSAb & TRBAb의 비에 관계있음

  3) ophthalmopathy

     ① thyroid & eye muscle에 있는 antibody를 공유하기 때문

     ② extraocular muscles & orbital fibroblast의 Ab가 orbital fibroblast에 의한

        glucosaminoglycan의 합성을 자극하고 m. cell의 cytotoxic effect를 가지게 함

  4) HLA type과의 연관성

     ① HLA-B8

        HLA-DR3(7 배)

             : other HLA-D3-related disorders

               ( Addison disease, IDDM, myasthenia graves, celiac ds )

     ② SLE, RA, vitiligo, ITP, pernicious anemia.

     ③ 가족력에서는 Graves ds.와 가장 연관이 있는 것도 lymphocytic thyroiditis,

        autoimmune hypothyroidism., neonatal hyperthyroidism임

Clinical Manifestations

1) Incidence

    ; 15세 이하 - 5%

    ; *peak incidence - during adolescence

    ; M : F = 1 : 5

2) Clinical Course

    ; variable

  ; *not so fulminant, gradually

  ; *발생과 진단사이에 평균 6-12개월의 interval

3) Symptoms

    ; *emotinal disturbances with motor hyperactivity - earliest Sg

    ; irritable, excitble, cry easily owing to emotional lability

  ; school work suffers as a result of short attention span  

    ; *tremor of the fingers on arm extension

    ; voracious appetite with loss of or no increase in weight

    ; variable size of thyroid

         - goiter : almost

    ; eye

           - *exophthalmos in most but mild

           - lagging of the upper eyelid

         - impairment of convergence

         - *retraction of upper eyelid & infrequent blinking

    ; skin

           - smooth & flushed, excessive sweating

    ; muscular weakness

           - uncommon

    - severe -> spell

    ; tachycardia, palpitation, dyspnea, cardiac enlargement & insufficiency

    ; atrial fibrillation ; rare

    ; mitral regurgitation due to papillary m. dysfunction<