Part 26-1. The Endocrine System

내분비 p1567-1577

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 

  somatotropes -- produce GH 

  lactotrops -- produce prolactin 

  thyrotrops -- make thyrotropin or TSH  

           Pit-1

             ; a single transcriptional activation protein

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

    gonadtropins -- make lutropin or LH and follitropin or FSH 

    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

           / 93 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, thyrotropin 분비를 억제함.

# octreotide

    - potent, long acting somatostatin analog

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

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

    - 123I-labeled octreotide somatostatin receptor-positive tumor metastasis localization 유용.

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

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

           / 70개의 amino acid

    / chromosom 12 long arm 존재

    / insulin 상당한 구조적 상동관계를 가짐

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

           / circulating level GH 혈중 농도에 크게 관련됨. (태아기와 신생아기는 예외)

# IGF-II 

           - 67 amino acids single chain protein

           - 유전인자는 chromosom 11 short arm 위치

           - homology to IGF-I

           - bone cells에서 중요한 mitogen이지만 physiologic roles 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 acids 구성

; gene chromosome 6 위치

; dopamine

 - major prolactin inhibiting factor

 - hypothalamic dopaminergic pathway disruption하여 prolactin

      혈중농도를 상승시킴

; 혈중 prolactin 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 cell 대한 TRH 작용을 차단하여 TSH 분비를 억제

          - prolactin 분비를 자극 

          - synthetic TRH ; TSH prolactin pituitary reserve 검사하는데 유용

ACTH

; production

    - pituitary gland 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-LPH β-endorphin 상승함

; *principal pigmentary hormone in humam rather than FSH

POMC peptides

CRH

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

- median eminence에서 predominanat하게 발견되며 brain, placenta 등에서도 생성됨   

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

    / oCRH hCRH보다 작용이 크고 오래가기 때문에 choice 되며cushing syndrome DDx 유용함

Gonadotropin (LH, FSH)

; α & β subunit 구성되며, α-subunit TSH 동일함. 

    - *β-subunit 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) 일부분에 불과하다.

neuron of supraoptic and paraventricular nuclei of hypothalamus

neuronal axons

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

Hormones (AVP, Oxytocin)

; octapeptide hypothalamus 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 plasma AVP농도는 fetal stress sensitive indicator

; Desmopresin

  - synthetic analog, high potency, selectivity for ADH receptors

    - DI 치료시에 intranasal small amount 효과적

Ocytocin

; 자궁수축을 유도하고 유즙분비에 관여함

Chapter 512. Hypopituitarism

Etiology (Table 512-1)

Congenital defect

Pituitary Hypoplasia

; isolated phenomenon or association with more extensive developmental abnormalies

    anencephaly

    holoprosencephaly ; cyclopia, cebocephaly, orbial hypotelorism

    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 hypopituitarism postaxial polydactyly & bifid epiglottis 있을 경우 증후군을 의심

Cleft Lip And Palate

; 4%에서 GH deficiency 발생,  short stature 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 3-4 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 space sella turcicaherniation되어 sella remodeling되고 pituitary gland flattened

; 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

       may cause hypothalamic-hypophyseal destruction

       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 irradiation 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 schedule incidence 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)

  type I ; autosomal recessive

      - type IA ; complete deletion of GH1 gene

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

    type II ; autosomal dominant

  type III ; X-linked

; multiple pituitary hormones deficiency

    - same classification

# Type IA

    - *GH 치료시 Ab형성을 잘하여 poor response

           / PCR, southern blotting 시행하여 less antigenic biosynthetic GH 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 defect 가능성이 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

    hypopituitarism all clinical finding

           ; but *increased circulating leve of GH

    *very low level of IGF-I

  not respond to exogenous hGH

  absence of GH-binding activity

           ; confirm

           ; point to abnormality of GH receptor

  gene mutation

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

    parent of patients’ stature is normal range

Clinical Manifestation

Patients Without Demonstable Lesions Of The Pituitary 

; 93출생시 정상 체중 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. pituitary 점차 파괴되면서 spotaneously improved

; *expading tumor에의한 lesion 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

    - *22-4, 22-5(p940-941)

     GH deficiency

            ; *peak level of GH < 7 ug/L

     false negative response in any single test

                ; 20%

     false negative response in both test

                   ; 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

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

  evedence of IICP

  enlargement of sella 

        ; 특히 ballooning with erosion and calcifications within or above sella

2) MRI

    *hypopopituitarism 가진 모든 환자에게s indicated

    space occupying lesion 상세히 알수있음

  ant. & post. pituitary lobe pituitary stalk size 명확하게 알수있슴

  empty sella turcica로부터 differentiating하는데 C-T보다 우수함

  post. pituitary bright spot으로 쉽게 구별됨

  hypoglycemia and micropenis 가진 newborn

        ; suspected hypopituitarim에대한 conformative diagnostic technique 

3) Skeletal matration

  markedly delayed in longstanding GH deficiency

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

    fontanell ; 2 이후까지 open

  found intersutural warmian born

  long born ; slender & osteopanic

4) Dual photon x-ray absorptiometry

    newer method of assessing body composition

  deficient bone mineralization

  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 state 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 puberty 경우

    - short course testosterone therapy 하면 puberty 앞당길수 있슴

; DDx

    - *genetic short stature skeletal maturation chronological age 일치함

Genetic Short Stature

; found in other family members

; growth 관련된 hormon study - 정상

Primary Hypothyroidism

; easily diagnosed on clinical grounds

; GH provocative test - subnormal

; enlargement of sella 나타날수 있슴

; low T4, elevated TSH levels

    - estabilsh the diagnosis

; thyroid hormone으로 치료하는 동안에 pituitary hyperplasia 호전됨

Emotional Deprivation

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

; growth retardation important cause hypothyroidism 유사함

; mechanism

    - not fully understood, sensory and emotional deprivation 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 practices 바뀐다던지, abuse 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 weight 분만력이 있슴

; short term treatment with GH

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

Treatment

# classic GH deficiency

  치료는 가능한 조기에 시행하며, 치료시기가 빠를수록 long term expectation 좋음

  recommended dose of hGH

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

  *치료는 더이상 반응이 없을 때까지 혹은 epiphyseal closure 될때까지 계속

  치료도중 효과가 떨어질 경우 용량을 올리기 전에 compliance부터 평가

  치료반응

    ; *max. response 치료 1 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-I 유용한 경우

    Laron syndrome

    GH1 gene deletion with high titer of antibodies

# GH 사용되어질수 있는 다른 경우 

    children with IUGR

    chronic renal failure

    Noonan syndrome

    Turner syndrome ; untreated 비교할때 final height cm 더커짐

# other hormonal deficiencies should be replaced

  TSH deficient subjects

         ; thyroid hormone full replacement dose 투여 

  ACTH-dependent patient

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

    ; 수술 등의 stress 상황시에는 증량

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

   gonadotropins deficiencies

           ; gonadal steroid puberty 일어날 때까지 혹은 골연령에 도달할때까지 투여

   microphallus 가진 infant

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

            - osseous maturation에대한 지나친 영향없이 penis normal size 성장시켜줌 

Chapt. 513. Diabetes Insipidus (Arginine Vasopressin deficiency)

 ; lack of the antidiuretic hormone, arginine vasopressin (AVP)으로 인해 polyuria, polydipsia 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 eminence 유리되는 AVP 때문에 DI 발생하지 않음

# AVP

  ; V2 recepor 결합함으로써 kidney distal tubules collecting duct 직접 작용  

    ; V2 receptor is responsible for

     vasodilator effect of the hormone

     increasing for VIII activity

     increasing the concentration of von Willebrand factor

Etiology

1) tumor of the suprasellar and chiasmatic regions

    ; craniopharyngioma, optic glioma, germinoma common causes

2) Langerhans cell histiocytosis

  ; *25%에서 hypothalamus pituitary histiocytic infiltration 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 decades 감소

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

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

                   --> * 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 degenerative process

7) septo-optic dysplasia

8) idiopathic

    ; 초기에 진단이 원인이 모르는 경우로서 20% 차지

    ; *그러나 이러한 환자들의 반이상이 intracranial tumor

           - DI 나타난 1년까지 no clinical, neuroradiologic sign

           - 25% 4세까지 no clinical, neurologic sign

           --> ★그러므로 idiopathic DI 적어도 4 동안의 periodic reevaluation 필요함

    ; ⅓에서  AVP-producing cell 대한 antibody 가짐

9) autoimmune

10) 82 newborn에서 DI 일으키는 경우

    asphyxia

    intraventricular hemorrhage

    intravascular coagulopathy

    Listeria monocytogenes

    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 severity 증가하는 수도 있고, 어떤 경우는 사춘기까지 무증상으로 지낼수도 있슴

    ; *acquired bladder control 가진 children에서 enuresis 증상일수 있다.

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

    ; 땀이 나지 않고 피부는 차고 건조하고 창백함

  ; anorexia 흔하게 나타남

# primary lesion 따른 sx and sg

    ; hypothalamus tumor

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

  ; *initial DI 일으킨 lesion ant. pituitary 파괴하는 경우

        - *DI 자체는 milder 해지거나 혹은 완전히 사라질수도 있슴

Loboratory data

; daily 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.G 1.010까지 상승 있으며, urine osmolality 300까지 상승 할수 있슴

; serum osmolality 적절한 수분섭취 시에는 *정상을 유지함

; water deprition tests

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

    - 경우 ADH 투여하면 urine osmolality 상승함

; radioimmunoassy of vasopressin

    - severe neurognic DI

           / plasma levels 지속적으로 0.5 pg/mL 이하임

    - partial neurogenic DI

           / hyperosmolality & subnormal AVP levels

    - *partial DI primary polydypsia 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. 구분

           / *autosomal dominant DI시에 mutant AVP-NP II complex 축적으로 bright spot hypothalamic-neurohypophyseal tract lesion 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

  mimic DI

  elevated plasma urea and creatinine

  anemia

  isotonic rather than hypotonic urine

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

  rare but, easily confused with DI

  수분의 섭취를 제한하면 소변의 농축이 일어남

    지속적인 polydipsia 있을 때는 maximal urine concentration 저하되지만, hypertonic saline solution 투여 혹은 dehydration후에는 농축이 일어남

  urine osmolality AVP 투여시보다 dehydration 후에 더욱 상승

5) Adipsia or Hypodipsia

  isolated defect of the thirst center, extremely rare

  AVP thirst 대한 osmoreceptor ant. hypothalamus에서 인접하기 때문에 hypodipsic hypernatremia antidiuretic function defect 관계됨

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

Å요붕증의 세가지 감별진단을 위한 방법과 차이점.

# Water deprivation test

    ;

Prognosis

DI 자체는 rarely threatens life이며, serious underlying condition 중요함  

hypothalamus or pituitary lesion trauma surgical intervention후에 초래된 DI 대개 일시적임 

Langerhans cell reticuloendothelioses 가진 일부 환자에서는 spontaneous remission         일어남  그러나 나머지는 pri condition remission후에도 only long residuum으로           남을 수도 있슴  

clinical DI 개선이 ant. pituitary insufficiency 발생에 선행할수도 있슴

brain tumor ; lesion site neoplastic cell type 따라 예후가 결정됨

84 Treatment

1) causative factors 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 avtivity 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

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

  ; parenteral preparation

           - *0.03-0.15 ug/kg

           - useful postoperatively

            / 특히 transsphenoidal surgery후에 nasal packing 하고 있는 경우

  ; polyuria 다시 나타나거나 effect 사라진 경우에는 effective dose 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 clearance 증가하기 때문

  - hyponatremia 동반한 hypouricemia SIADH 진단적 단서가

; renal & adrenal function 정상

92 Treatment

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

    ; 원인치료를 하면 없어짐

2) *fluids restriction

  ; sodium 소실한 양만큼 보충

3) hypertonic saline solution

    ; little benefit 

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

    ; *furosemide with 300 ml/m2 of 1.5% sodium chloride 투여로 sodium level 올리고 diuresis 유도함

4) demeclocycline

    ; AVP renal tubule 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

      develop a distintive syndrome of salt wasting

      associated with head trauma, CNS surgery, tumor or meningitis

 2) SIADH와의 차이점     

       hypovolemia

      maintenance fluids 투여 받는데도 excessive urine flow rate 

      large net loss of sodium

      혈장 ADH 농도 감소

 3) increased ADH & decreased plasma renin and aldosteron level

    ; 원인이 ANH 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 tumor 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)

     pituitary adenoma

     hypothalamic tumor ; GHRH secretion

     other tumors particulary in the pancreas

          ; somatotroph hypersecretion & large amount GHRH 분비하는 경우

           - pancreatic tumor

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

Clinical manifestations

  rapid linear growth

  coarse facial features, enlarging hands and feets, young children에서는 linear growth 선행하여 head rapid growth 나타남

  일부 환자에서는 behavioral or visual problems 일으킴

  대부분의 환자에서 abnormal growth 사춘기에 현저해짐

  body distal part 비대가 주로 나타남

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

       턱이 과도하게 커지고 치아가 서로 벌어지며 손가락과 발가락이 두꺼워짐

  dosal kyposis ; fatigue & lassitude early sx으로 나타남

  delayed sexual maturation 혹은 hypogonadism 나타날수 있슴

  나중에 IICP signs 나타남

Laboratory Data

     elevated growth hormone (400 ng/ml)

     glucose tolerance test시의 hyperglycemia 의해서도 GH level 감소되지 않음

     L-dopa에의해 GH level paradoxic하게 감소될수 있슴

     일부의 환자에서는 thyrotropin-releasing hormone 투여시 GH level 상승이 나타남

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

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

     plurihormonal adenomas (secrete GH & prolactin)

         ; marked hyperprolactinemia보임

     impaired secretion of gonadotropin, thyrotropin or corticotropin

     radiologic finding

        (skull x-ray)

             enlargement of sella turcica and paranasal sinuses

        (CT or MRI)

             delineates the tumor

     tufting the pharanges, increased heel pad thickness

     normal osseous maturation

Differential Diagnosis

     hereditary tall stature

          ; 대개 가족이나 친척 중에 abnormal height 있슴

            tall person well proportioned, free of IICP

     excessive growth during preadolescence in obese children

          ; temporary state 키가 giant 도달하지는 않음

     precocious puberty

          ; 대개 tall stature 보임

            epiphysis 조기에 closure되고

            성장이 조기에 끝나기 때문에 giant 도달하지는 않음

     hypogonadism  or Marfan syndrome

          ; 임상적으로쉽게 구분되며 정상 GH level 가짐

     lipodystrophy

          ; 일부에서 GH level 상승과 gigantism보임 

            그러나 subcutaneous fat 발달하지 않음

            hypothalamic function disorder 보임

     sotos syndrome

          ; pituitary gigantism보다 more common

Treatment

     surgery

     irradiation

     medical therapy 

         octreotide

            ; long acting analog of somatostatin

              native peptide보다 GH 억압효과가 45 정도됨 

              acromegaly 가진 성인에서 지속적으로 GH IGF-I 농도를

                          낮추며 tumor size 감소시킴  

Sotos Syndome (Cerebral Gigantism)

; characterized by rapid growth, but *not endocrine disorder

Cause

  ; unknown

    ; hypothalamic defect suggested

    ; 대부분 sporadic하게 발생

Clinical Manifestation

  birth weight and length ; above 90 percentile, macrocrania

  rapid growth

           ; *1세경 affected infant height 97 percentile 이상임

  *4-5 세까지는 accelerated growth, 이후 normal rate 돌아옴

    usually normal but may slightly early puberty

  large hand & feet, thickened subcutaneous tissue

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

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

  some degree of mental retardation, and predominately perceptual defficiency

Laboratory finding

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

  oseous maturation ; compatable with height

  normal level of GH and other endocrine hormones

  *abnormal EEG 흔함

  *dilated ventricular system 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

  *headache, amenorrhea, galactorrhea

           ; *common

  여아에서 2 높은 발생빈도

  type I multiple endocrine neoplasm에서 prolactinoma adolescence시에 나타남

  prolactin level

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

  chileren

           ; macroadenomas

           ; may be visual defect

         ; *⅓에서 hypopituitarism, GH deficiency

3) DDx

  primary hypothyroidism

        ; hyperprolactinemia due to pituitary hyperplasia

  variety of medications

  pituitary stalk dysfunction (eg, craniopharyngioma)

  other benign conditions

4) Treatment

   surgical resection by transfrontal or transsphenoidal approach

   bromocryptine ; standard drug for treating hyperprolactinemia

Chapter 516. Physiology of Puberty   

1. puberty 발현단계

 1) prepubetal stage

  (1) early childhood에서 8-9 사이

  (2) hypothalamic-pituitary-gonadal axis dormant state

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

  (3) hypothalamus pituitary actiavity 억압되어 있슴

     by neuronal restraint pathways

        negative feedback

        minute amounts of circulating gonadal steroids

 2) pubety onset 1-3년전

    sleep동안에 low serum LH level secretion 변화가 와서 sleep-entrained LH

       secretion pulsatile fashion으로 변하며 이것은 hypothalamic GnRH

       endogenous episodic discharge 반영함

    gonadotrpin pulsatile secretion으로 gonads 성숙과 sex hormine분비가 일어남

 3) early puberty

    2 성징이 나타남

    hypothalamus, pituitary and gonads 사이에 지속적이고 활발한 상호 작용이 극대화됨

 4) midpuberty

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

 5) middle or late adolescence

    cyclicity and ovulation 발생

    positive feedback mechanism 발생 ; midcycle 동안 상승된 estrogen levels LH

       현저한 상승을 일으킴

2. GnRH

   pubety onset progression 관여하는 major factor

   (간접증거) sexually immature animal GnRH 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 mo pubic hair 나타난다.

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

                   / mean age of menarche ; 12.75 yr (미국)

       - 미국의 경우 ; 12세까지 95%, 13세까지 99%에서 puberty sign 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 spurt 여아보다 2 정도 늦으며 18 이후까지도 계속 성장할수 있슴

# 사춘기 발현에 영향을 미치는 요소

   genetic and environmental factors

       ; menarche age 낮아지고 있으며,

        이것은 better nutrition 개선된 genital health 반영함

   미국흑인이 백인보다 빠름

   ballet dancers, gymnasts, runners, and other girl athletes

       ; early childhood부터의 leanness and strenous physical activity puberty

        혹은 menarche 현저히 감소시키며, 성인이 되어서도 oligomenorrhea 혹은

         amenorrhea 보일수 있슴

   adrenal cortical androgens

       ; LH 혹은 sex hormone 상승

        그리고 puberty 초기변화가 있기전 6-8 경에 상승하는 경우 (adrenarche)

Chapter 517. Disorder of Pubertal Development

# Precocious Puberty

  ; puberty 시작하는 시기가 variation 심하기 때문에 정의하기가 어렵다.

    ; 대개 성징의 출현이 여아에서는 8 이전, 남아는 9 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 pseudopuberty 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 scan MRI 발달로 현재는 idiopathic sexual precocity빈도가 감소

; *여아에서 10 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

        - *6 이전 onset

           - rapid physical and osseous maturation

           - *height potential loss

    ; slowly progressive variant

        - 6 이후에 onset

           - *osseous maturation linear growth 병행하여 height potential 유지됨

    ; unsustained central precocious puberty

           - spontaneously regression

Laboratory Data

 1) immunoradiometric, immunofluorimetric and chemiluminescent assy for LH

    ; great diagnostic sensitivity using random blood samples

      LH prepubertal children에서는 undetectable,

      그러나 central sexual precocity 때는 50-70%에서 detectable

 2) 수면시의 serial blood sample에서 LH 측정

    ; great diagnostic power

      -- LH well-defined pulsatile secretion 나타남

 3) GnRH stimulation test

    ; helpful diagnostic tool  particulary for boys

     여아에서는 sexual development early phase시에는 LH 반응이 낮음

 4) LH : FSH ratio

    ; midpubertal 까지는 low

 5) 여아에서 초기에는 estrogen농도가 낮거나 undectable

    남아에서 s-testosterone levels detectable

 6) both sex에서 sex hormone농도는 puberty stage 일치

 7) osseous maturation ; variable advanced

 8) pelvic ultrasonography

    ; 여아에서 ovaries progressive enlargement

      뒤따라 uterus pubertal size 커짐

 9) CT, MRI scan

    ; 정상 puberty에서처럼 pituitary gland physiologic하게 enlargement

Differential Diagnosis

 1) organic central nervous system causes of central sexual precocity

 2) gonadotropin-independent causes of isosexual precocious puberty

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

                  tumors, McCune-Albright syndrome, exogenous source of estrogen

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

                chorionic-gonadotropin-producing hepatoma, familial male precocious puberty

Treatment

# GnRH analog

    ; stimulatory effect pituitary gonadotropic cells desensitization

    ; rapidly progressive precocious puberty 대상이

    ; *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

     대부분 breast size 변화가 없으며 stage III-V 정도이며, 점차적인 adipose tissue

        침착으로 약간커질수도 있다

     pubic hair does not progress

     pelvic ultrasonography  ; decrease of the ovarian and uterus size

   (4) in boys

     decrease of testicular size

     variable regression of pubic hair

     decrease in the frequeny of erections

   (5) serum sex hormone concentrations

     testosterone < 20 ng/dl in boys

     estradiol < 10 pg/ml in girls

     LH concentration< 1 IU/L

      GnRH stimulation 대한 FSH LH 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

     most common brain lesion causing precocious puberty

     ectopically located neural tissue containing GnRH secretory neurons

     functions as an accessory GnRH pulse generator

     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 manifestation tumor 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 hamartoma 일어날수 있음

       증가된 sex hormone level growth-promoting effect 때문에 masked

Treatment

   (1) neurosurgical intervention

      ; hypothalamic harmartoma때는 indication 되지 않으며

        드물게 intractable seizure 적용

   (2) 치료는 pathogenic process 성상과 위치에 따라서 시행

   (3) GnRH analog

       central precocious puberty 일으키는 organic brain lesion 효과적

                                     ( idiopathic sexual precocity 효과 비슷 )

       choice to halt premature sexual development

 

   (4) combined growth hormone therapy

      ; associated growth hormone deficiency 있는 경우

517.3 Syndrome of Precocious Puberty and Hypothyroidism

# untreated hypothyroidism에서 unphysiologic precocious pubery & prepubertal bone age 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 profile 빠르게 정상으로 돌아옴       

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

517.4 Gonadotropin-Secreting Tumor

Hepatic Tumor

   (1) hepatoblastoma 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

       ; HCG 생산하여 testes Leydig cell 있는 LH receptor 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

         survival 대개 진단시부터 1 이하

Other Tumor

   (1) 종류

       chorionic gonadotropin-secreting choriocarcinomas

        teratocarcinoma

       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 age usual pubertal age 도달했을때

           - gonadotropin serecretion

                   --> pubertal response to GnRH

                   --> *true precocious puberty 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

       often disappear spontaneiusly

       aspiration or surgical excision of cyst ; rarely indicated

 2) persistent estradiol secretion

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

       -- estrogen production normalize 시키지는 못함

 3) long-acting agonist of GnRH

     ; puberty 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. compression bony lesion으로 인해 올수 있음

517.6 Familial Male Gonadotropin - Independent Precocious Puberty

1. male-limited autosomal dominant sexual precoicity

      gonadotropin independent

      transmitted through affected males,

         unaffected female carriers of the gene

      sign of puberty ; 2-3 yr of age 

      testis ; slight enalrged

                 biopsy상에서 Leidig cell matuartion 일부에서는

                 marked hyperplasia 소견보이며 seminiferous tubule matuartion

      testosterone levels

               ; marked elevated

      LH baseline levels

               ; prepubertal state, pulstile secretion 없으며,

                GnRH stimulation no response

      osseous maturation

               ; markedly advanced

      sexual precoicity gonadotropin independent이지만,

         점차 gonadotropin dependent

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 testosterone  prepubertal 농도로 낮추지 못하거나,

       testosterone effect 완전 차단하지는 못함

517.7 Incomplate (Partial) Precoicous Development

 * puberty 다른 signs 나타나지 않고 precoicity isolated manifestation 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 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 & reproduction normal

   (7) LH estriol

         ; below the limit of the assay

   (8) basal FSH GnRH stimulation 대한 LH 반응

         ; normal controls경우 보다 greater

 cf) true precocious puberty때는 LH 현저하게 상승

   (9) ultrasound examination  of ovaries

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

  (10) 일부에서는 breast develpoment 명백하게 systemic estrogen effect

      관련이 있으며 초음파상 ovaries or uterus enlarged

                                      (exaggerated or atipical thelarche)

      spontaneously regression 점에서 central precocity 다름

  (11) premature thelarche benign condition이지만 true or pseudoprecocious puberty

      1st sg이거나, exogeneous estrogen 효과일 있으므로 상세한 history 하고

      bone age 측정한다.

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

      continued observation 중요함

  3 이후의 thelarche

        ; 대부분에서 precocious thelrache보다는 다른 원인을 생각

  regression & recurrence thelarche

        ; functioning of follicular cyst 암시

Premature Adrenarche

   (1) sexual hair 여아에서 8,

                 남아에서 9 이전에 나는 경우로 다른 성숙의 증거가 없다

   (2) 남아보다 여아에서 흔함

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

      마지막에 axilla 나타나면서  성인형의 axillary oder 흔하게 동반됨

   (4) height & osseous maturation

        ; sl advanced

   (5) adrenal androgen production early matuartion event  zona reticular

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

      C-17, 20-lyase activity 증가함

      결과적으로 basal and ACTH-stimulated 5 _ steroid (17-hydroxypregnenolne and             DHEA) 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 effect 특징이

         1가지 혹은 이상 나타남    

       -  ACTH stimulation test 하여 17-hydroxyprogesteron 측정함으로써

          nonclassic congenital adrenal hyperplasia rule out

   (7) 성인이 되었을때 hyperadrenalism polysystic ovarian syndrome high risk

Premature Menarche

   (1) premature thelarche, or adrenarche보다 less frequent

   (2) affected girls 대부분은 1-3 bleeding episode 있음

   (3) plasma gonadotropin 정상이며, estradiol level 상승

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

       sarcoma botryoides 등이 있음

517.8 Medicatinal Precoicity

   (1) sex hormone expose되거나 ingestion Hx 있음

       estrogen in cosmetics

       hair cream

       breast augmentation cream

   (2) vitamin tablet sex hormone으로 contamination 경우

   (3) exogenous estrogen

         ; breast areolar intense, dark, brown color

   (4) precocious hormone exposure 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.

    40-50ug/24h for infants

    70-120ug/24h for children

    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) T3  T4보다 3-4 정도 대사성 역가를 가짐

  2) adult : T4 100 ug

            T3 20  ug 매일 생성

  3) 생성

     20% : thyroid 에서 생성

     나머지 : T4 deiodination으로 생성

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

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

                                             T4 부터 생성.

  4) T3 생리학적 작용의 대부분을

# T4

  1) T4 양은 많으나  nuclear receptor 약하게 결합되어 있고 T3 전환하여 생물학적

      활성을 나타냄

  2) 혈액 T3 level T4 1/50

# 작용

  1)  increase oxygen consumption 

  2)  stimulate protein synthesis

  3)  influence growth & differentiation

  4)  affect carbohydrate, lipid, & vitamin metabolism

# 작용 기전

  1) intracellular T3 nucleus 내로 들어가 thyroid hormone receptor 결합하는데,

     receptor steroid hormone receptor ( glucocorticoid, estrogen, progesterone,

        Vit D, retinoids ) 계열이다.

     4가지 type α1 & 2 , β1 & 2

  2) circulating T4 70% thyroxine-binding globulin (TBG) 결합해 있고,

     나머지는 thyroxine-binding prealbumin 결합되어 있다

     단지 0.03%만이 free thyroxine (FT4) 구성한다.

  3) circulating T3 50% TBG 결합하고 50% albumin, 0.3%만이 unbound or

      free T3 존재함.

# Regulation

  1) TSH (thyroid - stimulating hormone)

     glycoprotein으로 ant. pituitary에서 생성 분비됨

     thyroid gland adenylate cyclase 활성화 시킴

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

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

        (ii) β-subunit : hormone 특이성을 부여

  2) TRH (thyroid - releasing hormone )

     hypothalamus에서 합성되어 pituitary 분비

     tripeptide

     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

  ; thyrocyte apical surf. 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

           - 30 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 10-12 fetal thyroid : iodine conc.--> iodothyronine합성 능력을 가짐

                fetal pituitary : TRH 함유

2) fetus   

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

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

   (3) reverse T3 : fetus 매우 높다가 (250ng/dl at 30), term 150ng/dl까지 떨어짐.

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

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

                   (특히 brain) 역할을 .

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

   (2) hypothyroid fetus --> 분만 전까지 maternal T4 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

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

Serum Thyroxine-Binding Globulin

; liver에서 생성되는 glycoprotein.

; T4 70%, T3 50% 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 level 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

      lower radiation exposure

      high-quality scintigram

Chapter 519. Defects of Thyroxine-Binding Globulin

; *clinical ds 관련이 없고 치료할 필요가 없다

TBG deficiecy

  1) *X-linked dorminant disorder

  2) 종종 neonatal hypothyroidism screening 발견됨

Laboratory Finding  

    ; *T4(), RT3U(), freeT4(), TSH()    

Diagnosis

    ; TBG (-) or low level

Pathogenesis

    ; codon mutation(leucine to proline), point mutation

Epidermiology

     male > female

     1/2400 newborn males

     36 % : TBG < 1mg/l

     mild TBG deficiency

        1/42000 heterozygous females

     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

     pregnancy

     estrogen Tx

     hepatitis

Familial Dysalbuminemic Hyperthyroxinemia

  1) autosomal dominant disorder

  2) DDx : hyperthyroidism

  3) Lab

     T4 : abnormal albumin variant 결합하는 T4

     free T4, free T3, TSH n'l

     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 : rudiments 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 )

  수년 동안 충분한 양의 thyroid hormone 공급되거나 유아 초기에 부족해짐

  임상적으로 tongue base 또는 neck midline ( hyoid ) growing mass 인지됨

  때로 thyroglossal duct cyst 관련되기도

  euthyroid 환아에서 ectopic thyroid tissue surgical removal hypothyroidism 초래하기도

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

      1/3 : consanguinity ( Japan )

      과거에는 goiter동반 유무와 관계없이 clinical hypothyroidism 생후 몇달

         내에 생겼지만, 최근 neonatal screening program에서 detect

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

          --> 10 goiter hypothyroidism으로 발생

      thyroid & salivary gl.에서 iodine concentration 능력이 부족함

      uptake of radioiodine & pertechnetate 감소

      saliva ; serum ratio of 123I : 진단에 도움

      Tx ;  과량의  potassium iodine 치료에도 반응하지만 thyroxine으로

                치료하는것이 바람직함   

Thyroid Peroxidase Defects Of Organifiaction & Coupling

      most common defect

      iodide thyroid trap되고 oxidation되어 reactive iodine으로 된후

          tyrosine units 포함됨

            ; 과정은 H2O2, thyroid peroxidase hematin생성이 요구됨

      Dx

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

              thyroid radioactivity marked decrease

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

               40-90% radioiodine 방출함

      Pendred syndrome

          (i) sensorineuronal defness & goityer

          (ii) (+) perchlorate discharge

Defects Of Thyroglobulin Synthesis

      goiter

      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

      thyroid ca. 또는  hyperthyroidism 치료를 위해 임신시 radioiodine

         부적절하게 투여한 경우 hypothyroidism 유발됨

      fetal thyroid 70-75 쯤에 iodine trapping 할수 있음

      가임기 여성에 radioiodine투여할 때는 투여전  pregnancy test 반드시

         시행하며, 수유 여성에게 radioactive iodine투여는 금기임

Thyrotropin defeciency

# developmental defect of pitiutary or hypothalamus

    (2) TSH - deficient hypothyroidism

       1/30000 - 1/50000

       neonatal thyroid screening 에서 30-40% detect

       대부분 multiple pituitary deficiency

       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

         Lab

             ; TSH 증가, T4 정상

       autosomal recessive

       TSH 대한 resistance 보임에도 불구하고 치료없이도 euthyroid

          남는 경우도 있고, severe hypothyroidism으로 치료한 경우도 있음

# Isolated deficiency of TSH

       rare autosomal recessive

       different point mutations in TSH β- subunit gene

Thyrotropin hormone Unresponsiveness

    (1) mild congenital hypothyroidism으로 detect newborn infant 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

       T4 감소

       TSH 증가

       no response to exogenous TSH administration

Thyroid hormone unresponsiveness

    (1)대부분의 환자는 goiter 가지고 있슴

    (2) Lab

        T4, T3 free T4 , free T3 증가

                  ( DDx; graves ds)

    (3) Sx

       mild mental retadation

       growth retadation

       delayed skeletal maturation

        attention - deficit hyperactivity disorder ( ADHD )

    (4) Dx

       TSH ; diagnostic

                 not- suppressed (as in graves ds)

                 mod. 증가 혹은 정상  

       TSH  response to TRH (+)

       failure of TSH suppression

           ; resistance generalized하고, peripheral tissues 뿐만아니라 pituitary까지 손상.

    (5) autosomal dorminant

    (6) neonatal thyroid screening T4 상승시 의심할수 있고, growth & skeletal retardation

         없으면 치료는 필요하지 않음.

    (7) autosomal recessive form of thyroid resistance

       hypothyroidism early in life

       DNA study, major deletion of β-thyroid receptor

    (8) selectively resistance to thyroid hormone

       pituitary gl.에만 영향

       peripheral tissue thyroid hormone resistant 하지 않으므로 환아는 goiter &

           hyperthyroidism 양상을 보인다

       DDx : pituitary TSH-secreting tumor

Other Cauce of Hypothyroidism

 (goiter 동반)

      fetal exposure to excessive or antithyroid drugs

            ; transient

      topical iodine-containing antiseptics

            ; transient

             특히 low birthweight infant

              --> neonatal screening test abnormal result 야기

      asthma Tx drug

      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

  eyes : far apart

  bridge of broad nose : depressed

  narrow palpebral fissure.

  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

  lethargic

  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

    ; *Tgin 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 99mTc-sodium pertechnetate보다 우수함

  ; thyroid tissue 보이지 않는 경우

       thyroid aplasia

       neonate /c TRBAb

       infant /c the iodide - trapping defect

       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

      low voltage P & T

      diminished amplitude of QRS complex

          poor left ventricular function & pericardial effusion

# EEG

       low voltage

# 2 이상에서 serum cholesterol 증가.

Prognosis

; neonatal screenig program 보급후 congenital hypothyroidism 예후는 매우 좋아짐

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

; thyroid hormone 생후 초기 동안의 정상적인 cerebral development 중요하므로 irreversible brin damage 방지하기 위해 적절한 치료가 즉시 시작되어야

; 2 이후 hypothyroidism onset 경우 예후가 더욱 좋은 것으로 보아 thyroid hormone brain growth 대한 역활이 중요함을 있음

Treatment

# *sodium L- thyroxine

    ; drug of choice

  1) circulating T3 80% T4  monodeiodination 의해 형성되므로 치료한 경우

     T3, T4 정상 범위

    ; Dosage

        - neonate 10-15 ug/kg/day

       - children 4 ug/kg/day

       - adult 2 ug/kg/24hrs

  ; 치료효과 :  T4 & TSH 정상범위 유지해야

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

      매우 증가함

  ; side effects : 대부분 용량과 관계 있음

     pseudotumor cerebri : 치료 4개월

                              8-13세의 acquied hypothyroidism환아에서 수있음

     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 detect.

3) subtotal thyroidectomy for thyrotoxicosis or cancer

4) removal of ectopic thyroid tissue.

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

   subhyoid gl. thyroglossal duct cyst 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 irradiation

      thyroid damage

    ; 1/3 : 치료 1 이내 TSH

      15 - 20 % ; 5-7 hypothyroidism으로 진행

8) protracted ingestion of mediations containg iodides

    ; accompanied by a goiter

  ; amiodarone

     cardiac arrhythmia 사용

     37% iodine 함유

     *치료환아의 20%에서 hypothyroidism

     high iodine content

     inhibition of 5-deiodinase (T4T3)

     T4, T3, TSH serial measurement 필요

Clinical Manifestation

  1) Sx

     deceleration of growth ( 1st Sg )

     myxedematons changes of skin.

     constipation

     cold intolerance

     decreased energy

     increased need for sleep

     school work & grades ; not suffer

     delayed osseous maturation

            : Ix of duration of hypothyroidism.

     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 atrophy 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.

          ; 질병이 동시에 나타남

    (5) 다른 autoimmune disorder와의 관계

       type l polygrandular autoimmune syndrome

           +- hypoparathyroidism

           |  Addison ds

           +- mucocutaneous candidiasis 

               ; 10%에서 autoimmune thyroiditis 동반

       Schmitt syndrome or type II polyglandular autoimmune disease

          Addison ds c IDDM or autoimmune thyroid ds or both

       pernicious anemia, vitiligo, alopecia 연관

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

       congenital rubella 환아에서 발생율 증가

       Turner synd & Down synd과도 연관이 있음

Laboratory Data

1) definitive Dx ; thyroid biopsy

2) thyroid function

    ; slightly or moderately TSH

           - often normal

                   --> *goiter lymphocytic infiltration 의하여 발생한 것이 아니고, thyroid growth- stimulating immunoglobulin 의한 발생함을 시사

  ; progressive thyroid failure 되면

           - T4감소, T3감소, TSH증가

3) thyroid scan

   50% ; irregular & patchy distribution of radio isotope

   > 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

   환아 형제의 1/2에서 (+)

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

      없이도 (+)

   DM 환아의 20%에서 (+)

   congenital rubella syndrome 환아의 23%에서(+)

Treatment

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

  1) hypothyroidism증상이 있을때

  2) goiter size 줄어드나 몇년간 지속됨

  3) antibody level  fluctuation하면서 몇년간 지속됨

  4) suppressive Tx에도 불구하고 prominent nodule 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 lobe 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

     exquisite tenderness of gland

     swelling

      erythema

     dysphagia

     limitation of head motion

     leukocytosis

  8) scintigram of thyroid

        ; complex echogenic mass

  9) thyroid function test :  normal

     thyrotoxicosis <- aspergillus 의한 suppurative thyroiditis

  10) Tx

     I & D

     antibiotics 투여

     infection사라진 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

     vague tenderness over the thyroid

     low- grade fever

        또는 severe pain in thyroid 

     high fever & chill

        inflammation 이미 형성된 thyroid hormone 순환내로 leakage때문

  5) Lab

       T3, T4 상승

  6) mild hyperthyroidism sx

  7) radioiodine uptake

  8) ESR 상승

  9) course

     variable

     euthyroid -> hypothyroid

     수개월 이후 remission   

Chap. 522. Goiter

# Enlargement Of The Thyroid Gland

  euthryroidism : normal function of gland

  hypothyroidism : thyroid deficiency

  hyperthyroidism : overproduction of hormone

# 분류

    congenital or acquired

    endemic or sporadic

# 원인

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

infiltrative process <- inflammatory or neoplastic

with thyrotoxicosis   <- TRS Ab

552.1 Congenital Goiter

; usually sporadic

Etiology

Administration Of Antithyroid Drug Or Iodides

     during pregnancy for Tx of thyrotoxicosis

     goitrogenic drugs이나 iodides 태반을 통과하여 고용량시 thyroid hormone 합성을 방해하여 태아의 goiter & hypothyroidism 유발함

     goitrogen thyroid hormone 동시 투여시에도 불충분한 양의 T4 태반을

        통과하므로 효과 없음

Asthma Tx

Amiodarone

     37% iodine content

     euthyroid

     retardation of osseous maturation

     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

     --> 상태가 계속 지속되지는 않으므로 thyroid hormone 달후에 중단가능

4. enlargement of thyroid at birth

  1) respiratory distress --> nursing difficulty & death

  2) head extreme hyperextension

  3) respiratory obstruction 심한 경우 tracheostomy보다 partial thyroidectomy 적응증이

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 infant 때는 thyroid hormone으로 즉각 치료하고 정밀 검사는 연기시킴

  3) recessive gene으로 유전되므로 genetic counselling 중요

     다음 임신시 ultrasound fetal goiter detect

Iodine Deficiency

  1) rare cause of congenital goiter

  2)임신 초기 심한 iodine deficiency goiter 없더라도 neurologic damage 야기할수 있고,       maternal & fetal hypothyroidism 유발하여 maternal thyroid hormone protective 

     transfer 일부 방지

  3) lobulated, asymmetric, firm large goiter

      ; thyroid 또는 근처의  teratoma 고려

522.2 Endemic goiter & Cretinism

1. moderate deficiency of iodine

    : compensatory hypertrophy & hyperplasia

      +- thyroid hormone 합성증가

      +- hormone return 속도 증가

       --> 조직의 thyroid hormone demand 충족

2.  sea water, fish, shellfish에는 iodine 풍부

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

   권장량 infant 40-50 /24hr

Clinical Manifestations

  1) mild iodine deficiency

    (1) adolescence & pregnancy같은 rapid growth period외에는 thyroid enlargement

        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 

       neurologic type

       myxedematous type

    (3) neurologic syndrome

       mental retardation

       deaf -- mutism

       disturbances in standing & gait

       pyramidal sg

             ; clonus of foot, Babinski sg., patellar hyperreflexia

       goitrous, euthyroid

       normal purpertal development & adult stature

       little or no impaired thyroid function

    (4) myxedematous syndrome

       mental retardation

       deaf

       neurologic sx

       delayed sexual development & growth

       myxedema

       absence of goiter

               -> T4

                   TSH markedly

           ultrasonography : thyroid atrophy

    (5) Pathogenesis of neurologic syndrome

       iodine deficiency & hypothyroxinemia during pregnancy

           --> fetal & postnatal hypothyroidism

       fetal thyroid 발달전 fetal brain에는 thyroid hormone 대한 receptor존재

       태반을 통과한 모체의 thyroid hormone nervous system발달에 도움을

    (6) Myxedematous syndrome

       thyroid autoimmunity : TGBI ( ? )

       environmental factors

           +- selenium deficiency

           |  goitrogenic foods

           |  thiocyanates

           +- Yersinia

4. Tx

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

    치료는 4세이전 myxedematous cretinism환아에서는 5개월 euthyroid state

  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 Tx iodide 함유

  2) firm & diffuse enlarged

  3) Wolff-Chaikoff effect

     과량의 iodidine 투여시 iodine organification & thyroid hormone synthesis방해

     short - lived

     hypothyroidism 유발시키지는 못함

     iodide투여가 계속 되면 autoregulatory mechanism 의해 iodine trapping제한되고 thyroid iodine level 감소하고 organification 정상적으로 진행됨

     iodide-induced goiter 환아에서는 thyroid hormone biosynthesis defect 인해

        escape 일어나지 못함   

         +- lymphocytic thyroiditis

         |  subclinical inborn error in thyroid hormone synthessi

         +- partial thyroidectomy

  4) Lithium carbonate

     psychotherapy drug

     iodide 경쟁적으로 작용

     lithium iodide synergistic effect 있으므로 혼용은 피함

  5) Amiodarone

     antiarrhythmic drug

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

     underlying autoimmune disease 가진 환아에서는 hypothyroidism 일으키고 외는 hyperthyroidism 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) scintiscan 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 Tx nodule 없어지지 않으면 malignancy 배제위해 op 

522.4 Intratrachel Goiter

1. intraluminal thyroid beneath the tracheal mucosa.

   continuous /c normal extratracheal thyroid

   airway obstruction 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

    toxic uninodular goiter(Plummer ds)

    hyperfunctioning thyroid Ca.

    thyrotoxicosis factitia

    acute suppurative thyroiditis

    subacute thyroiditis

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

 * 대부분 thyroid hormone 대한 pituitary unresponsiveness

    TSH secreting pituitary tumors. only in adults

    infants born to mothers with Graves ds.

    transitory phenomenon

    classic Graves ds. during neonatal period

    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

     T  helper cell (CD4+) in dense lymphoid aggregates

        cytotoxic T cells (CD8+) in lower dense area

     failure of T suppressor cells

        expression of T helper cells      

        sensitized to the TSH Ag

         interact with β cell

               ( plsma cell 분화.

           thyrotropin receptor-stimulating Ab ( TRSAb ) 생성

        TRSAb + receptor for TSH

        c AMP

     TRBAb 생성되어 보통 clinical course TRSAb & TRBAb 비에 관계있음

  3) ophthalmopathy

     thyroid & eye muscle 있는 antibody