Part 26-2. The Endocrine System

부갑상선 p1605-1612

Section 3. Disorder of the Parathyroid Glands

 * parathyroid hormone (PTH) and vitamine D

        ; principal regulators of calcium homeostasis 

 * calcitonin and PTH-related peptide (PTHrP)

        ; important primarily in the fetus

1. parathyroid hormone

 1) 84 amino acid chain으로, biologic activity 34 residues 있슴

  (in the parathyroid gland)

    pre-pro-PTH ---> pro-PTH + pro-PTH ---> PTH

                                                  major secretory product of gland

                                                  rapidly cleaved in the liver and kidney                                                      into smaller COOH-terminal, midregion,

                                                      and NH2-terminal fragments.

    1-34 amino-terminal (N-terminal) fragments

       ; most useful for detecting acute secretory changes 

    carboxy-terminal (C-terminal) and midregion fragments

       ; 비록 생물학적 활성이 없지만 circulation으로부터 more slowly cleared되고,

         plasma immunoreactive PTH 80% 차지함

       ; assay primary hyperparathyroidism detection 하는데 effective

       ; glomerular filtration에의해 circulation으로부터 제거되므로 renal disease 인한

          2dary hyperparathyroidism evaluation하는데는 less useful

 2) 분비조절

     s-calcium 저하 --> PTH 분비증가 --> kidney에서 1α-hydroxylase activity

                        stimulation, 1,25-dihydroxycholecalciferol (1,25[OH]2D3) 생성을 증가

     증가된 1,25[OH]2D3 intestinal mucosa에서 calcium-binding protein (calbindin-D)

         생성을 유도하여 calcium 흡수를 일으킴

     또한 직접적으로 bone resorption 일으켜 calcium mobilization

 3) bone kidney에대한 PTH effect

     through binding to specific receptors on the membranes of target cells

             activation of a transduction pathway involving a G protein

                  coupled to the adenylate cyclase system

 

2. PTH-RELATED PEPTIDE (PTHrP)

 1) amino terminus first 13 amino acids에서 homologus to PTH,

    이중에서 8개는 PTH identical

 2) gene chromosome 12 short arm 위치

     cf) PTH chromosome 11 short arm 위치

 3) 역할 분비

      activate PTH receptors in kidney and bone cells

      increase urinary cAMP and renal production of 1,25[OH]2D3

      critical for normal fetal development

         ; essential for normal skeletal maturation of fetus, which requires 30g of calcium

          임신동안에 필요한 calcium 150 mg daily에서 400 mg during 2nd trimester  

      lactation 동안에도 분비됨

       대부분의 hormonal hypercalcemia syndrome of malignancy 증가된 PTHrP 의함

3. VIT. D

   see Chapter 43.7 and 483.1

4. CALCITONIN

 1) 32-amino acid polypeptide

 2) gene chromosome 11p 위치, PTH gene 인접하며 three peptide encode

      CT

      21-amino acid caboxy-terminal flanking peptide (katacalcin)

      CT gene related peptide

    -- CT katacalcin thyroid gland parafollicular cell (C-cell)에서 동량분비됨

 3) in fetus ; high level

      appear bone metabolism and skeletal growth

      probably stimulated by normally high fetal calcium levels

 4) children & adult ; quite low

 5) infant & children with congenital hypothyroidism (and presumed deficiency of C cells)

       ; lower level of CT than normal children

 6) action

       independent of PTH and vit D

       main biologic effect

            ; inhibition of bone resorption by decreasing number and activity of

               bone-resorbing osteoclasts

       neurotransmitter to impose a local inhibitory effect on cell function

 7) 합성

     G-I tract, pancreas, brain, and pituitary

Chapter 525 Hypoparathyroidism

Etiology

Table 525-1

 1) early neonatal hypocalcemia (see chapter 50)

     common from 12-72 hr of life

     잘오는 경우

          ; premature infants, infants with asphyxia at birth, infant of diabetic mother  

 2) late neonatal hypocalcemia  

     생후 2, 3일경부터 1주일 사이에 발생

     s-calcium level feeding of type 영향을 미침

     종종 pathogenetic factor parathyroid functional immaturity 관련되기는 하지만,               parathyroid role clarifi해야함

 3) transient idiopathic hypocalcemia  (1-8wk of age)

     serum PTH  level normal infant보다 현저히 낮음

     funtional immaturity

          ; glandular PTH secreted PTH 전환하는 효소의 deveopmental delay

 4) hyperparathyroidism during pregnancy

      transient hypocalcemia 일으킬수 있슴 

      maternal serum elevated calcium 노출됨으로써 fetal parathyroid 억압되어 발생 

      tetany 3주내에 발생하며 breast-feding 일때는 1개월 이상 delay될수 있슴

      hypocalcemia 수주 혹은 수개월 지속

      infants hypocalcemia unknown 때는 산모의 calcium, phosphorus, PTH 등을              check하며,  원인의 대부분이 parathyroid adenoma 이며 대개 무증상이다

 5) aplasia or hypoplasia of parathyroid gland

     often associated DiGeorge syndrome and

     less often velocardiofacial (Shprintzen) syndrome

        conotruncal heart defects

      thymic hypoplasia

      abnormal facies, and cleft palate

        variable phenotype, 대부분 chromosome 22q11 내에 deletion 있슴

 6) CHARGE and VATER syndrome

 7) infants of diabetic mother

 8) infants born to mother treated with retioic acid for acne early in pregnancy

 9) administration of 131 I  during pregnancy ; hypothyroidsm 함께 발생

Familial Congenital Hypoparathyroidism

   (1) transmitted by x-linked recessive gene

         ; 생후 2 - 6개월 사이에 afebrile seizure 발생

   (2) autosomal recessive syndrome

        dysmorphic features

             ; microcephaly, deep-set ear, beaked nose, micrognatha, large floppy ears 

        parental consanguinoty 

        early life profound hypocalcemia 발생

        intrauterine and postnatal growth retardation 심하고, mental retardation 흔함          원인은 불명이며, type I polyglandular autoummune disease 형태로 발생할수 있슴

   (3) autosomal dominant disorder

        가장 흔한 형태임

        gene chromosome 3q13, location of the CA2+-sensing receptor

          (cf) inactivating  mutations of this receptor

                ; familial hypocalciuric hypercalcemia and  neonatal hyperparathyroidism

        대개 mild하여 does not treatment beyond childhood

        sensorineural deafness and renal dysplasia 연관되기도함

Surgical Hypoparathyroidism 

   (1) complication of thyroidectomy

        removal or damage of parathyroid glands

        interference with blood supply or postoperative edema and fibrosis

        postoperatively sudden onset of tetany

             - temporary or permanent  

             - 어떤 경우에는 insidiously develop하기 때문에 thyroidectomy

                 수개월까지 undetected

        deposition of iron (eg, thalacemia) or copper (eg, Willson disease)

              ; may produce hypoparathyroidism

Idiopathic Hypoparathyroidism 

    ; no etiologic mechanism can be defined

      occurs after first few of life (autoimmune condition)  

      일부에서는 incomplete form of DiGeoege syndrome or autosomal dominant type나타냄

Autoimmune Hypoparathyroidism

   (1) parathyroid antibodies 종종 다른 autoimmune disorder 혹은 organ-specific antibodies          관련될때 강하게 의심 

   (2) 종종 Addison disease and chronic mucocutaneous candidiasis 관련됨

     polyglandular autoimmune disease, type I (3가지 중에서 적어도 2가지 존재시)

         환자의 ⅓은 3가지 모두를 가짐

         candidiasis ; 거의 대부분 다른 disorder 선행함

                                           (70% occur in children younger 5 yr of age)

         hypoparathyroidism (90% after 3yr of age)

                              대개 Addison disease (90% after 6yr of age) 선행함

   (3) other disorder various time 나타날수 있슴

        ; alopecia areata or totalis, malabsorptiopn disorder, pernicious qnemia,

          gonadal failure, chronic active hepatitis, vitiligo, and insulin dependent diabetes              

Clinical Manifestations 

    ; mild deficiency

           - revealed by only labiratory study

  ; muscular pain and cramps

           - early manifestation

    ; *numbness, stiffness, and tingling of the hands and feet

    ; positive Chvostek or Trousseau sign or laryngeal and carpopedal spasms

  ; convulsions with loss of consciousness

        - begin with abdominal pain followed by tonic rigidity retraction of head, and cyanosis

       - epilepsy mistaken

    ; teeth eruption ; late and irregular, teeth 흔히 soft

      skin dry and scaly, finger toes nail horizontal line 나타날수 있슴

  ; mucocutaneous candidiasis

       생기는 경우에는 hypothyroidism 선행하여 발생 

       nails, oral mucosa, mouth angle, 드물게 skin 발생

   (8) cataracts ; longstanding untreated disease에서 hypothyroidism 결과로 생김

   (9) permanent physical and mental deterioration ; 치료 하지 않고 장기간 방치시

Laboratory Data

   (1) s-calcium level ; low (5-7mg/dL)              phosphorus ; elevated (7-12mg/dL)

       ionized calcium (approximately 45% of total)

                             ; more nearly reflect physiologic adequacy

   (2) alkaline phosphate ; normal or below

      1,25[OH]2D3 ; usually normal or low,

                   but severe hypocalcemia시에는 highlevel 보일수도

      magnesium ; normal, but always should be checked

   (3) immunometric assay of PTH ; low

      synthetic 1-34 fragment of human PTH (teriparatide acetate)

                                ; increase urinary levels of cAMP and phosphate

   (4) roentgenograms

        bones ; 종종 metaphysis 국한된 증가된 density

        skull ; calcification in the basal ganglia

   (5) EKG ; prolongation of QT interval

   (6) EEG ; widespread of slow activity

   (7) Addison disease combined

            ; serum calcium level 정상을 보일수 있으며,

              adrenal insufficiency 교정후에 hypocalcemia 나타남

Treatment

; 5-10ml of 10% sodium of calcium gluconate IV at the rate of 0.5-1 mL/min

    - emergency treatment for neonatal tetany

; 1,25-dihydroxycholecalciferol (calcitrol)

    - *initial dose 0.25 ug/24hr

  - *maintenance dose 0.01-0.10 ug/kg/24hr to maximum of 1-2 ug/24hr

    - short half life 가지므로 two equal divided dose 투여

    - effect rapid onset하는 장점이 있으며 over dosage시에 중단하면 즉시 hypercalcemia reversal

; vitamin D2

    - less cost than calcitrol

  - *0.1~0.5 mg/24hr in infant and young children

  - *1.25~2.50 mg (50,000-100,000 IU)/24he once daily in old children

    - vit D slow onset of effect 치료 중단 후에 reversal of hypercalcemia markedly delayed

; adequate intake of calcium

    - calcium gluconate 혹은 calcium glubionate (Neo-Calglucon) 형태

    - 800 mg of elemental calcium daily but *rarely essential

; high content phosphorus content (eg, milk, eggs, cheese) 함유하는 diet reduction

; adrenal insufficiency 의심케 하는 소견

  - pigmentation, lowering of the blood pressure, or weight loss

        --> require specific treatment

Differential Diagnosis

   (1) magnesium deficiency ; 1.5 mg/dL (1.2 mq/L)이하일 abnormal

        familial hypomagnesemia with 2dary hypocalcemia

             ; calcium 투여는 ineffective, but magnesium 투여시에 serum calcium         

               magnesium 같이 호전됨

        hypomagnesemia due to malabsorption syndrome

             ; occur in glanulomatous colitis and cystic fibrosis

        therapy with aminoglycoside ; by increasing urinnary loss

   (2) poisoning with inorganic phosphorus

        laxative or sodium phosphate enemas

        calcium 정맥 투여로 증상이 rapidly relieved

   (3) early in the course of acute lymphoblastic leukemia

      ; usually associated with hyperphosphatemia (resulting from destruction of lymphoblast)     (4) Kenny-Caffey syndrome

        episodic symptomatic hypercalcemia 발생  

        medullary stenosis of long born, short stature, delayed closure of frontal,

           delayed bone age, eye abnormalities

Chapter 526 Pseudohypoparathyroidism (Albright Hereditary Osteodystrphy) 

# Characteristics

  ; normal or hyperplastic parathyroid

    ; endogenous or administered PTH

           - *not raises serum calcium level and decreases phosphorus

  ; genetic defects in the hormonal receptor-adenylayte cyclase system

Type IA

    ; 50%

# genetic defect

    ; *αsubunit of stimulatory guanine nucleotide-binding protein (Gsα)

           - coupling factors for PTH bound to cell surface receptors

# autosomal dominant trait

Clinical Manifestation

    ; tetany - often presenting sign

    ; short, stocky build and round face

    ; hand anomalies

           - brachydactyly with dimpling of dorsum of hand

       - longer index finger than middle finger

           - 2nd metacarpal

                   / least often involved

    ; other skeletal anomalies

        - short and wide phalanges, bowing, exostosis, and thickening of calvaria

    ; *subcutaneously calcium deposits & metaplastic bone formation

    ; *mental retardation, basal ganglia calcification, lenticular cataracts

Laboratory Finding

    ; additional resistance to TSH, gonadotropins, glucagon

           - clinical hypothyroidism

           / uncommom, but elevated balsal of TSH, exggerated response of TSH for TRH-stimulation

                   / moderated decreased levels of thyroxine and increased level of TSH

         / detected in newborn thyroid screen

       - gonadal dysfunction in adults

                   / sexual immaturity, amenorrhea, oligomenorrhea, and infertility

  ; *low serum calcium level, elevated phosphorus and alkaline phosphate, elevated immunoactive and bioactive PTH

Definitive Diagnosis

  ; synthetic 1-34 fragment of human PTH 정맥투여후 현저하게 약화된 urinary phosphate and cAMP 반응의 증명 

# pseudopseudohypoparathyroidism

    ; variant of PHP type I (Gsα의 mutation)

    ; usual anatomic stigmata of PHP 가짐 

  ; *normal serum calcium, phosphate

Type IA With Precocious Puberty

; gonadtropin-independent precocious puberty (see Chapter 517.6)

; Gsα의 single mutation으로 G protein temperature sensitive (37°C) 상태

; 정상 체온에서는 Gsα가 degrad되어 PIP 발생하며, 낮은온도 (test온도, 33° C) 에서는 LH receptor activation시키고 precocious puberty 일어남

Type IB

; normal level of G-protein activity and normal phenotype

; resistance to PTH but not other hormone

; calcium, phosphorus, immunoactive PTH type IA 동일하나, bioactive PTH not increase

Type II

; basal state PTH 투여후 모두에서 urinary excretion of cAMP 증가하나 phosphaturia 증가 않함 (type I과의차이점) 

; cAMP 정상적으로 activation되나 cell 반응하지 않아서 나타남         

Chapter 527. Hyperparathyroidism

; excessive production of parathyroid hormone (PTA)

     <- primary defect of parathyroid gl.

    +-adenoma or hyperplasia(primary hyperparathyroidism)

    +-compensatory for correcting hypocalcemic state

         (secondary hyperparathyroidism)

* Vt.D-deficient rickets & malabsorption syndrome에서 calcium intestinal

  absorption 장애가 있으나  hypocalcemia & tetany parathyroid gl.activity 증가로

  피할수 있음

* pseudohypoparathyroidism PTH  증가

* chr.renal ds.초기에 hyperphosphatemia calcium 감소 PTH증가

      renal failure 진행시 1.25[OH]2D3 합성 감소

                          ->hypocalcemia, PTH 증가

Etiology

Table 527-1

 1) primary hyperparathyroidism

   rare in children

   generalized hyperplasia of parathyroid gl.

   result of single benign adenoma

 2) Neonatal primary hyperparathyroidism

     Sx : anorexia,irritability.lethargy,constipation

             failure to thrive

     Rontgenogram

        : subperiosteal b.resorption

          osteoporosis

          pathologic fracture

   증상은 경하여 치료없이 회복되는 경우도 있고 치료가 연기되어 fatal course

      취할수도 있음

   조직학적 소견  

        : diffuse hyperplasia of parathyroi gl.

 3) familial hypocalciuric hypercalcemia (FHH)

    homozygous for mutation in the Ca2++-sensing receptor gene

    autosomal dominant

 4) Childhood hyperparathyroidism

    manifest after 10yr of age

    single adenoma 의해 생김

    familial tendency

        : asx. by careful study

          MEN syndrome 부분

 5) MEN type I

    autosomal dominant

    +-hyperplasia or neoplasia of pacreatic islet

       | (secretion of gastrin,insulin,pacreatic polypeptide,glucagon)

       | ant.pituitary(secretion of prolactin)

       + parathyroid

 

    gene:chromosome 11q13

      i) fuction as a tumor-suppressor gene

      ii)  two-hit hypothesis of tumor development

          1st mutation(germinal)

              : inherited recessive to dominant allele

               does not tumor formation

          2nd mutation(somatic)

              : eliminate the n'l allele

                -> tumor formation

 6) MEN typeII

 7) Transient neonatal hyperparathyroidism

    hypoparathyroidism(idiopathic or surgical) mother에서 태어난 아기에서 나타남

    maternal disorder 진단되지 않았거나 임신시 부적절하게 치료된경우

    cause

        : chr.intrauterine exposure to hypocalcemia

          c resultant hyperplasia of parathyroid gl.

    newborn에서 bone 먼저 침범하고 4-7개월 사이에 healing

Clinical Manifestaton

     muscular weakness

    anorexia,nausea,vomiting, constipation

    polydipsia,polyuria

    wt.loss

    fever

    nephrocalcinosis:calcium deposit in renal parenchyma

                   -> diminished renal function

    renal calculi  -> renal colic & hematuria

    osseous change -> pain in back or extremities

                          disturbance in gait

                          genu valgum, fracture, tumor             

                          Ht.decrease <- compensation of vertebrae

    abd.pain c acute pancreatitis

    parathyroid crisis

          : serum calcium > 15mg/dl

    progressive oliguria,azotemia,stupor.coma

    failure to thrive,poor feeding,hypotonia in infant

    mental retardation,convulsion,blindness as sequelae

Laboratory Data

  1) serum calcium 증가

     more severe in infants c parathyroif hyperplasia

     15-20mg/dl -> 30mg/dl

  2) ionized calcium 증가

  3) phosphorus 감소 3mg/dl

  4) magnesium 감소

  5) urine specific gravity : low

  6) serum levels of nonprotein nitrogen & uric acid( 증가 )

  7) alkaline phosphatase

     skeletal inviolvement : 증가

     hyperplasia : 정상

  8) PTH( by carboxy -terminal antisera ) :증가

  9) calcitonin : n'l

     acute hypercalciuria -> calcitonin release

     prologed hypercalciuria : hypercalcitoninemia(-)

 10) Roentgenogram

    resorption of subperiosteal b. along the margin of phalanges of hands

    skull : gross trabeculation or granular appearance from focal rarefaction

    lamina dura(-)

    진행시 generalized rarefaction,cyst,tumor.fracture,deformities

    10% : rickets

    abd : renal calculi or nephrocalcinosis

Differntial Diagnosis

# primary hyperparathyroidism

    phosphorus 감소

    calciun 증가

    PTH 증가

# corticosteroi 투여시 다른 원인으로 인한 hypercalcemia 환아에선 calcium level 영향을 미치지 않음             

Treatment

  1) surgical exploration

    모든 gl. 자세히 관찰하여 adenoma 발견시 즉시 제거함

    대부분 severe hypercalcemia 가진 신생아에는 total parathyroidectomy 시행함

    Parathyroid gl.  forearm autigraft

    수술후 hypocalcemia & tetany 발생에 대하여 계속 관찰

       몇일동안 IV calcium gluconate 투여가 필요

    대부분 calcium & phsophorus 풍부한 식사를 수술후 몇달동안 유지시킴

  2) arteriography & selective venous sampling with radioimmunoassy of PTH

    preop.localization 

    differentiation of single adenoma from hyperplasia

  3) CT. real-time US

  4) subtraction sintigraphy using 99mTc pertechnatate & 201TI

Prognosis

    good if early detection & appropriate surgical Tx

    extensive osseous lesion 존재시 permanent deformity

    renal ds. 존재시 prognosis poor

Other Causes Of Hypercalcemia

Familial Hypocalciuric Hypercalcemia (Familial Benign Hypercalcemia)

  1) usually asx

 

  2) Lab

    parathyroid gl.n'l

    PTH n'l

    subtotal parathyroidectomy hypercalcemia 교정 안됨

    magnesium usually n'l or mildly elevated

    Ca/Cr 감소

  3) autosomal dominant

     mutant gene on chromosome 3q2

  4) penetrance 100%

  5) Dx ;  serum & urine calcium concentration

  6) pathogenesis

    inactivating mutations in the Ca2+-sensing receptor gene

       -> 혈액내 free Ca2+ level 감지하여 intracellular CA2+ 증가시킴

    calcium  homeostasis in parathyroid, kidney  조절

    resistance to extracellular Ca2+ c mild to moderate hypercalcemia in heterozygote

Granulomatous Disease

  1) sarcoidosis 30-50%

  2) Lab

    PTH 감소

    1.25(OH)2D3 증가

  3) ectopic source

     : activated macrephage through stimulation by INF - a from T lymphocyte

        (granulomatous lesion 풍부)

       1a-hydroxylase in macrophage

     : unresponsive to homeostatic regulation

 4) Tx :  prs (2mg/kg/24hr PO)

           -> 1.25 (OH)2D3 감소

Hypercalcemia Of Malignancy

  1)동반되는 경우

    malignant rhabdoid tumors of kidney

    congenital mesoblastic nephroma

    neuroblastoma .meduloblastoma,leukemia

    Burkitt lymphoma

    rhabdomyosarcoma

  2) PTH : rarely elevated

  3) 대부분 malignancy 연관된 hypercalcemia   PTHrP level 증가

Miscellaneous Causes Of Hypercalcemia

  1) subcutaneous fat necrosis

      PTH n'l

  2) Hypophosphatasia

    mild to moderate hypercalcemia

    phosphorus n'l

    alkaline phosphatase subn'l

    rachitic-like lesion on roentgenogram

    urinary phosphoethanolamine inorganic pyrophosphate pyridoxal 5'-phosphate 증가

        : natural substrate to tissue-non specific ALP enzyme

           (liver,bone,kudney)

    missense mutation of gene

       -> inactive enzyme in autosomal  recessive

 

  3) Idiopathic hypercalcemia of infancy

    failure to thrive

    hypercalcemia during 1st yr

       -> spontaneous remission

    serum phosphorus & PTH : n'l

    hypercalcemia <- increased absortion of calcium

 

  4) Williams synd

    Sx

       infantile hypercalcemia

       feeding difficulties

       slow growth

       elfin face

       renovascular disorders

       gregarious personality

       IQ 50-70

       enhanced quantity & quality of vocabulary,auditory,memory,social use of language

    submicroscopic deletion at chromosome 7q11,23

         : deletion of one elastin allele

    Tx : prednisone , calcitonin

 

  5) hypervitaminosis D

    vit.D 강화 우유

    1.25 (OH)2D half-life 길기 때문에 hypervitaminosis D 진단시

       25(OH)D level   유용함

  6) prolonged immobilization

      -> +- hypercalcemia

          |  decreased renal function

          |  hypertension

          +- encephalopathy

  7) Jansen-type metaphyseal chondrodysplasia

    asymptomatic hypercalcemia

    hypophosphatemia

    active mutant PTH-PTHrP receptor

Section 4. Disorder of the Adrenal Glands

# adrenal gland

    ; two endocrine system 으로 구성, medullary and cortical system

    ; *ectoderm --> adrenal medulla, mesoderm --> adrenal cortex, gonad, liver

# 발생

    ; gestation 7th week - primordium of adrenal cortex sympathetic neural element 의해 invaded

    ; gestation 8th week - chromaffin cells 분화

  ; 2th month - adrenal gl kidney 보다 크다

  ; 4th month - kidney rapid growth

  ; 6th month - kidney adrenal gl 보다 2 정도 커짐

    ; full term - adrenal gl kidney 1/3, 무게는 7-9 g

# adrnal cortex in the fetus and newborn infant

  ; fetal cortex

           - more central portion

    - *출생시 gl 80% 차지, 2wk 50% 감소, 6mo 사라진다.

           - *DHEA(dihydroepiandrosterone) & DHEAS 생산

    ; true cortex

           - outer portion

           - zona glomerulosa , zona fasciculata , zona reticularis 구성

Fetoplacental Unit

; gestational 말기에 *fetal adrenal gl에는 3β-hydroxysteroid dehydrogenase 없으므로placental pregnenolone cortisol , aldosterone, DHEAS 합성에 사용된다

; *placenta fetal DHEAS 이용하여 estrone, estriol 합성

; estriol 임신 말기에 maternal urine 주된 estrogen 으로 fetal adrenal hypoplasia 경우 maternal urinary estriol level marked reduce

Adrenal Cortex

; zona fasciculata

    - primary stimuli : ACTH

    - cortisol, androgen 합성

; zona glomerulosa

    - primaty stimuli : RAS, potassium

    - aldosterone 합성

Å피질과 수질의 발생학적 차이점과 각각에서 생성되는 호르몬?

Glucocorticoid(17-Hydroxycorticosteroid)

; cortisol

    - compound F or hydrocortisone

    - 11β-hydroxysteroid dehydrogenase(11β- OHSD) 의해 cortisone 으로 전환

; effect

  catabolic effect

           - protein degradiation 증가

    - 주로 skin, muscle , connective , adipose and lymphoid tissue

  anabolic effect

           - 주로 liver

    - protein and glycogen content 증가

  antagonistic effect - insulin and androgen

  effect on immune and nervous system

; regulation

  ACTH ; primary

  negative feedback on ACTH secreation

; synthetic analogs

  prednisone and prednisolone

           - natural steroid 비해 antiinflammatory and carbohydrate activity 4 높다. *salt & water retention effect 적다

  *9α- fluorohydrocortisone

           - anti-inflammatory effect 15 높다. *salt & water retention effect 20 높다

  betamethasone & dexamthasone

           - anti-inflammatory effect 25 높다

    - *water & electolyte retention 효과는 적다

Aldosterone

; potent mineralcorticoid, 18-aldehyde of corticosterone 이다

; zona glomerulosa 에서 생산

; Regulation

  renin-angiotensis system

  ACTH - 정상인에서 minor effect, *anephric man 에서 보다 의미있는 효과

  potassium

  sodium

; action

  maintanance of electrolyte equilibrium

  stabilization of blood volume and blood pr

  control sodium reabsorption in the distal tubule

Androgen

  zona fasciculata zona reticularis 에서 생성

  *nitrogen, potassium, phosphorus & sulfate retension

  성장 촉진

  androgenic effect

  adrenal hyperplasia or adrenal tumor precocious growth 남성 2 성징을 일으킴

DHEAS

    ; *abundant adrenal androgen

  ; childhood low level

           -> puberty 다른 hormone 보다 먼저 증가하여 adrenarche유발

  ; marked elevation - virilizing adrenal cortical tumor

    ; lessor elevation - congenital adrenal hyperplasia

  ; modest elevation - isolated precocious adrenache

    ; not corticotropic hormone이라는 이유

           - Addison’s disease ACTH deficiency 감소되어 있으나 ACTH 줘도 증가하지 않는다.

Adrenal Medulla

; active catecholamine 생산

  - dopamine , norepinephrine , epinephrine

; biosysthetic reaction

Fig 533-1

; metabolites of catecholamine

  - VMA , metanephrine , normetanephrine

  - urine 으로 배설

; adrenal gl epi norepi

  early fetal stage ; epi 없음

  at birth ; norepi 없음

  in adult ; norepi 10-30 % 차지

; action

  mean arterial blood pressure 증가

     a. norepi ; cardiac output 증가없이 peripheral vascular resistance 증가

     b. epi ; pulse rate 증가, peripheral vascular resistance 감소, diastolic pressure 감소

  hyperglycemic and calorigenic effect ; 주로 norepi

Chapter. 528. Adrenocortical Insufficiency

Etiology

Table 528-1

Corticotropin Deficiency

1) congenital hypoplasia or aplasia of pituitary

    ; asso. disease

           - anencephaly and holoprosencephaly

2) isolated deficiency of corticotropin

3) *idiopathic hypopituitarism & destructive lesion in the pituitary

    ; *common cause of corticotropin deficiency

    ; craniopharyngioma

Adrenal Hypoplasia Congenita (AHC)

; *begins in neonatal but may be delayed to 10yr

; marked intrafamilial variablility

; pigmentation 증가, salt-losing sx, low level of all adrenal steroid 증상

; histologic exam

    - adrenal cortex disorganization & cytomegaly

; *affects boy caused by mutation of the DAX-1 gene on chromosome Xp21

; *contiguous deletion syndrome with Duchenne muscular dystrophy, glycerol kinase deficiency

Familial Glucocorticoid Deficiency

; chronic adrenal insufficiency

; 특징

    - *isolated deficiency of glucocorticoid, elevated level of ACTH, normal aldosterone production

    - *no salt-losing manifestation

; Clinical Manifestation

    - hypoglycenia, seizure & pigmentation

; M : F = 1;1

; autosomal recessive

; Histology

    - marked adrenocortical atrophy, 비교적 보존된 zona glomerulosa

; Pathogenesis

    - ACTH receptor gene mutation

           --> ACTH resistance

; *ass. syndrome - achalasia of cardia, alacrima(triple A or allgrove syndrome)

Inborn Defects Of Steroidogenesis

; *common cause of adrenal insufficiency in infancy

    - *salt-losing form of congenital adrenal hyperplasia

Isolated Deficiency Of Aldosterone

; autosomal recessive disorder

 corticosterone aldosterone 으로 전환 안됨

; manifestation

 failure to thrive , dehydration on newborn , hyponatremia , hypokalemia ,

 metabolic acidosis , hyperreninemia , hypoaldosteronism

; Treatment

  salt or 9α-fluorocortisol ( 0.05-0.3 mg daily ) renin 정상 level

  될때까지 투여

Pseudohypoaldosteronism

; neonate salt-losing syndrome 나타남

; plasma urine aldosterone level marked elevate 되고, plama renin activity elevation

    - due to target organ unresponsiveness

; 치료

    - dietary salt 공급

Addison Disease

Etiology

; tuberculosis - 과거 adrenal destruction 흔한 원인

; 93 autoimmune - common

Pathology

; no visible adrenal gland or only remnants

; medulla not destroyed with lymphocyte infiltrarion

Clinical Manifestation

; early isolated cortisol deficiency and then aldosterone deficiency symptom

; *antiadrenal cytoplasmic Ab(+)

; *autoantibodies to 21-hydroxylase

; components of two syndrome

    1) Type I Autoimmune Polyendocrinopathy

    (=*autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy)

           - AR

           - genetic defect of chromosome 21q22.3

           - *chronic mucocutaneous candidiasis : initial symptom

                   / *followed by hypoparathyroidism, Addison disease

           - asso. autoimmune disorder

                / gonadal failure, alopecia, vitiligo, keratopathy, enamel hypoplasia, nail dystrophy, intestinal malabsorption, chronic active hepatitis

           - hypothyroidism, type I DM

           - *presence of antiadrenal antibodies & steroidal-cell antibodies

    2) Type II Autoimmune Polyendocrinopathy

    - thyroid disease and IDDM 관련

Adrenoleukodystrophy (ALD)

Hemorrhagic Into Adrenal Gland

Etiology

; difficult labor or asphyxia

; Waterhouse-Friderichsen syndrome

Abrupt Cessation Of Administration Of Corticotropin Or Corticosteroid

Drug

; ketoconazol - adrenal enzyme inhibition

; rifampin, anticonvulsant (phenytoin , pb)

Clinical Manifestation

; 원인에 따라 onset 다르다.

# Onset Of Salt Loss Symptom At Birth

    ; failure to thrive, vomiting , lethargy, dehydration, circulatory collapse

    ; *adrenal hypoplasia , defect in steroidogenesis, pseudohypoaldosteronism

# Addison disease in older children

    ; onset gradual

    ; muscular weakness, lassitude , anorexia, loss of wt, general wasting, low blood pr

    ; abd pain

    ; intense craving for salt

    ; 93 Adrenal Crisis

           - sudden adrenal insufficiency aggregation

           - cyanotic, cold skin, weak rapic pulse, BP fall, rapid labored respiration

           - if no treatment, fetal

           - chronic insufficiency patients에서는 유발 인자 존재

                   / infection, trauma, excessive fatigue, drugs(e.g. morphine, barbiturates, laxatives, thyroid hormone, insulin)

# increased pigmentation of skin

    ; *occurs in cortisol deficiency with excessive secretion of corticotropin

           - primary adrenal hypoplasia, familial glucocorticoid deficiency, adrenoleukodystrophy, addison disease

    ; first on face & hands

    ; *intense in genitalia, umbilicus, axillae, nipples, joints

    ; more intense in exposed areas

# hypoglycemia

    ; congenital adrenal hypoplasia in the neonate

# deficiency of corticotropin

  ; *pigmentation (-)

  ; hypoglycemia - usually presenting manifestation

    ; salt-lossing

           - umcommon

           - *hyperkalemia 드물지만, hyponatremia 일어날 있다.

Laboratory Data

1) salt-lossing

  serum sodium and chloride ; low

  serum potassium ; 증가

  plasma renin activity ; 증가

  urimary Na, Cl 배설 증가

  urinary K ; 감소

  plasma nonprotein nitrogen level ; 증가

  blood eosinophil 증가

2) hemorrhage , adrenal cyst , tbc 원인이면 X-ray check adrenal calcification 확인

3) Plasma Cortisol Level

  *most definitive test

  *corticotropin 투여 전후 측정

           ; 투여전 낮고, 투여후 증가한다.

     a. 투여전 정상, 투여후 증가없으면 adrenocortical reserve 없는것을 의미

     b. 투여전 낮고, 투여후 증가하면 secondary adrenal insufficiency 의미

4) corticotropin level

  primary cortisol deficiency ; 높다

  secondary adrenal insufficiency ; 낮다

5) *congenital adrenal hypoplasia 의심시 plasmal cortisol precursor 측정

6) aldosterone

  low ; salt-lossing CAH, adrenal hypoplasia, Addison disease

  elevated ; pseudohypoaldosteronism

  정상 ; familial glucocorticoid deficiency

Treatment

# Acute Adrenal Insufficency

 ; 5% glucose in 0.9% saline solution ; hypoglycemia sodium loss 교정

 ; water soluble hydrocortisone (hydrocortisone hemisuccinate) iv

           - *infant 25 mg, older children 75 mg iv q 6hr 하루 투여

           - 전신상태 호전되면, 다음 24시간 동안 감량한다

           - *한글판 : 전신상태가 호전되면 매일 1/3 감량하여 유지 용량이 된후 경구 전환

    ; 48시간후 oral intake 만족스러우면 iv stop

    ; *cortisol po med.

           - 5-20 mg q 8hr

           - 24hr 동안 감량한후 48hr 전환한다.

    ; *florinef(9α-flurocortisol) add 0.05-0.3mg daily

           - *한글판 : hydrocortisone 100mg이하가 될때 추가한다.

# Chronic Replacement Therapy

  ; cortisol

           - infant 5-10 mg /24hr po #2-3

    - children , adolescent 10-20 mg/24hr po #2-3

           - ★한글판 : 15-20mg/m2/24hr

  ; florinef

           - 0.05-0.3 mg daily

           - *plasma renin activity 측정하여 monitoring

         - fluorhydrocortisone overdosage

                   / hypertension , cardiac enlargement & edema , weakness or paralysis

 ; primary corticotropin deficiency, familial glucocorticoid deficiency

           - salt-retaining hormone 필요없다

 ; primary defect in aldosterone systhesis

           - cortisol 필요없다

 ; pseudohypoaldosteronism

           - hormone 반응하지 않으므로 sodium chloride 보충

    ; *adrenal hemorrhage in newborn infant

           - *Vit K & C , whole blood transfusion 필요

Differential Diagnosis

# familial glucocorticoid deficiency

    ; absence of salt-losing symptom & presence of alacrima

# adrenoleukodystrophy

    ; elevated very long chain fatty acids

# CAH

    ; analysis to search for deletion of Xp21 region

# Duchenne muscular dystrophy

    ; elevated CPK

# glycerol kinase deficiency

    ; elevated TG

Chapter 529. Adrenogenital Syndrome

Adrenocortical Hyperfuntion

# Four Syndrome

; adrenogenital syndrome, Cushing syndrome, hyperaldosteronism, feminization           

529.1 Congenital Adrenal Hyperplasia

Pathogenesis

# autosomal recessive

# disorder of steroidogenesis

 -> cortisol 감소

 -> corticotropin 증가

 -> adrenocortical hyperplasia

 -> intermediary metabolite 증가

Deficiency Of 21-Hydroxylase

; adrenal hyperplasia 95% 차지

; 21-hydroxylase gene

    - *CYP21A & CYP21B

           / CYP21A is pseudogene

    - alternate in tandom with two genes for complements(C4A, C4B)

    - chromosome 6p between HLA-B and HLDR loci

; major mutation

    - recombination(deletions or conversions) between CYP21B & CYP21 A

; affected infant 75% - salt losing, virilizing , 25% - simple virilizing form

Deficiency Of 11β-Hydroxylase

; 5-8% 차지

; mutation in the CYP11B1 gene encoded on chromosome 8q22

; hypertension and virilization

    / *hypertension is distinctive clinical feature but absent in first few years

    / *elevated DOC cause hypertension

; plasma 11-deoxycortisol and DOC 증가

; prenatal diagnosis

    - measuring level of 11-deoxycortisol in maternal urine or in ammnionic fluid

Deficiency Of 3β-Hydroxysteroid Dehydrogenase

; 5% 차지

; *cortisol, aldosterone, androgen 합성 감소

; chromosome 1

; classic form

    - neonate / salt wasting

    - boy / incompletely virilized and hypospadias

    - girl / only mild virilized

; mild form ( non classic )

    - no salt wasting & ambiguity

    - precocious puberty or with hirsutism, menstrual disorder, infertility, polycystic ovary

; hallmark

    - 5steroid 증가

    - *elevated level of 17-hydroxyprogesterone

           / *because of extra-adrenal 3β-HSD

           / *mistaken with 21-hydroxylase deficiency

Lipoid Adrenal Hyperplasia

; *mutation of gene for steroidogenic acute regulatory protein(StAR)

; *P450 SCC(20,22-desmolase) defect

    - cholesterol pregnenolone 으로 전환 장애

; failure of cleavage of the side chain of cholesterol

    --> accumulation of cholesterol and lipid in adrenal cortex & failure of synthesis of any adrenal steroid

; manifestation

    - testicular hormone 합성장애로 male phenotypical female이며, female no genital abnormality

    - salt losing 흔하다

    - 대개 early life infancy 사망

; no elevation of steroid hormones

    - *confused with adrenal hypoplasia

17α-Hydroxylase Deficiency

; P450 17 encoded on chromosome 10

; *DOC overprocuction 으로 hypertension , hypokalemia , suppression of renin and aldosterone

; *sex hormone 합성 장애

    - male; unvirilized , phenotypic female , sexual ambiguity

    - female ; 사춘기때 sexual develop 장애

; 감별진단

    - male pseudohermaphrodism

    - testicular feminization

    - female 에서 primary hypogonadism

Clinical Manifestation

Patients Without Salt-Losing

Male

; premature isosexual develop

; normal at birth

; *6개월내 precocity 나타나 4-5 develop

    - enlargement of the penis, scrotum, prostate, pubic hair, acne , deep voice

    - muscle / well develop

    - testis / prepubertal size penis 비해 작다       

; *bone age advanced for chronologic age

  - early life 때는 크지만 epiphysis premature closure 성인시 키는 결국 작다

; normal mental develop

Female

; female pseudohermaphroditism

; musculinization 츨생시 부터 어느정도 보임

  - enlargement clitoris, labial fusion

           / mistaken with hypospadias with cryptochidism

    - common opening with urethra below clitoris(urogenital sinus)

; 출생후 musculiztion 진행되면 prematurely pubic and axillary hair, acne , tall , good muscular develop, body build of boy

; advanced ossification

11-Hydroxylase Defect

; no salt-losing manifestation

; hypertension

    - some normotensive

; gynecomastia , virilization

Patient With Salt-Losing

; 증상은 출생후 빨리 시작된다

    - failure of wt gain , progressive wt loss, dehydration, vomiting, anorexia, disturbance in cardiac rate and rhythm, cyanosis and dyspnea

; 치료하지 않으면 collapse 사망이 수주내 일어난다.

; male with normal genitalia

    - pyloric stenosis, intestinal obstruction , heart disease, cow milk intolerence, other cause of failure to thrive

3β-Hydroxysteroid Dehydrogenase

; usually salt-loser but are less virilized

; female - virilization 경도

; male - 다양한 정도의 hypospadia

Lipoid Adrenal Hyperplaia

; salt loser

; 표현형은 여성

Nonclassic 21-Hydroxylase Deficiency

; affected female - normal genitalia at birth

; male and female

    - developed symptom later life

    - precocious pubarche, early development of pubic and axillary hair, hirsutism , acne, menstrual disorder , infertility

    - some completely aymptomatic

; 75% - HLA-B14,DR1

Laboratory Data

; salt loser

    - low S-Na , Cl

    - increased S-K, nonprotein nitrogen

    - elevated plasma renin

Classic 21-Hydroxylase Deficiency

; markedly elevated 17-OHP

    - *normal baby 출생 3일까지는 높은 농도로 유지되나 그뒤 떨어짐

; blood cortisol level

    - usually low in salt losing type but often normal in simple virilizing type

; increased urinary 17-ketosteroid and pregnanetriol

Late Onset Variant Of CAH

; basal circulating 17 OHP level classic form 만큼 높지 않으며, 정상일 있다

; *진단 - ACTH iv bolus 0.25 mg 투여 60분에 17 OHP 증가

11-Hydroxylase Deficiency

; plasma DOC and 11-deoxycortisol 증가

3β-Hydroxysteroid Dehydrogenase Defect

Δ5 steroid (17-hydroxypregnenolone) marked elevation

17-OHP 증가

*21-hydroxylase defect 감별위해 ratio of 5 to 4 steroid in plasma or urine

Diagnosis

; diagnosis in later siblings

; failure to thrive female 에서 ambiguous ext. genitalia 있으면salt losing form 의심

; DDx of adrenal tumor

    - palpable

  - pyelography kidney displacement

  - US or CT 진단

; urinary 17-KS and plasma DHEAS

    - increase in CAH cortical tumor

    - very high in neoplasm

; hydrocortisone 투여시

    - CAH 에서는 steroid 정상, virilizing tumor 반응없다

; adrenal hyperplasia in male

    - *testis is small for degree of virilization

    - *Leydig cell tumor true precocious puberty 에서는 testis enlarged for age

# Detection of heterozygous carrier of 21-hydroxylase deficiency

    ; ratio of 17-OHP to 11-deoxycortisol

    ; cortisol 60min fter IV 0.25mg ACTH

    ; HLA grouping in families

96 Prenatal Diagnosis And Treatment Of 21-Hydroxylase

# Diagnosis

   1st trimester ; chorionic villi biopsy & HLA typing or DNA analysis

   2nd trimester ; 17-OHP in amniotic fluid & HLA and DNA analysis in amniotic cells

# Treatment

    ; risk pregnancy 경우 dexamethasone 임신 5주에 투여

           - 1.5 mg/24hr in # 2-3 only female

    ; 1st trimester chorionic villi biopsy 실시하여 sex & genotype결정

           --> affected female이면 치료를 계속한다.

Treatment

1) hydrocortisone 10-20mg/m2/24hr #2-3 po

    ; usually 2.5-5mg bid or tid in infantcy

    ; usually 5-10mg bid or tid in children

    ; *개인에 따라 monitoring 하면서 dose 조절한다.

2) 9α-fluorocortisone 0.05-0.10 mg daily & sodium chloride 1-3g

    ; salt-loser and elevated renin activity patients에게 투여

    ; *non-salt-losing patients라하여도 elevated plasma renin activity이면 투여한다.

3) 96 Monitoring

  plasma 17-OHP, androstenedion, testosterone , renin 9:00 AM 측정

  growth and osseous maturation monitor

4) Increased dose

    ; during periods of stress such as infection, surgery, decreased salt intake

    ; *non-salt-losing이라도 증량한다.

5) surgical correction of enlarged clitoris of female

    ; 6-12mo 시행

6) 적절한 치료를 하면 대부분의 여야는 적절한 나이에 menache 발생

7) *남아에서 적절한 치료를 하지않으면, unilateral or bilateral testicular tumors

529.2 Virilizing Adrenocortocal Tumors

; tumor resulting in musculirization in girls & precocious psedopuberty in boys

; Hepertension ; common

    cushing syndrome증상과 virilization야기

    cortical mineralcorticoid, androgen분비

3.  male ;  non-salt-losing congenital adrenal hyperplasia 증상 유사

  female ; 전에는 normal female musculirization유발

           congenital adrenal hyperplasia ; 출생시 genital abnormality 동반

; 동반 질환

  *hemihypertrophy

  *Beckwith-Widemann syndrome

  other congenital defect

           - genitourinary tract, CNS abnormalty, hamatomatous defect

; Laboratory

  1) increased urinary 17 - ketosteroid

  2) increased serum DHEA, DHEAS, androstenedione

  3) increased serum testosterone

  4) *11β- hydroxylase deficiency

           - increased deoxycorticosterone

       --> *이런 환아는 hypertensive, tumor malignacy

  5) U-S and MRI

; Treatment

  1) surgical ; transpeitoneal approach

  2) post op adrenal insufficiency방지 위해

      hydrocortisone 10-25mg q 6hr op 첫날부터 3-4일간 투여

      corticotropin c cortisol

           ; atropied gl. reactivation

      적절한 water, soidium chloride, glucose공급

  3) recurr detect 위해

     ;  adrenal androgen level check q 1 month

  4) mitotane( O,P - DDD )

      inoperable tumor

      recurrence

Chapter 530. Cushing Syndrome

# Cushing syndrome

    ; adrenal cortex hyperfunction으로 cortisol level 비정상적인 상승으로 obesity hypertension 일으키는 특징.

Etiology

# functioning adrenocortical tumor

    ; *often in infancy

    ; 대부분 malignant

    ; 3 이하에서 50% 이상, 7 이하에서 85% 발생

    ; mixed form hypercortism

# Primary Pigmented Nodular Adrenocortical Disease

    ; ACTH-dependent form

  ; adrenal gland

           - multiple small(4mm), pigmented nodule

           - cortical atrophy

    ; cause

           - circulating immunoglobulins directed toward ACTH receptors

                   --> ensuing stimulation of adrenal steroidogenesis

    ; occurs as components of *Carney complex

           - autosomal dominant

    - centofacial lentigenes, cardicac & cutaneous myxomas, sexual precocity in boy with testicular tumor, functioning pituitary tumor, pigmented melanotic schwannomas 구성

    ; occurs as components of McCune-Albright syndrome

    - ACTH-independent cushing syndrome with nodular hyperplasia and adrenal formation

           - infancy or childhood 시작

# Bilat. Adrenal Hyperplasia

    ; *7 이상 children

  ; ACTH -dependent form

  ; 20%에서 pituitary basophilic adenoma 원인

    ; *cause

           - covert pituitary adenoma (microadenoma)

    ; Nelson syndrome

  adrenalectomy pituutary tumor 발생하는

  chromophobe cell 구성

  B-lipoprotein,B - endorphin, ACTH level증가

# Ectopic Production Of ACTH

    ; 연관 질환

    islet cell carcinorma of the pancreas

    neuroblastoma or ganglioneuriblastoma

    hemangiopericytoma

    wilm's tumor

    thymic carcinoid

# Prolonged Exogeneous Administration Of ACTH or Hydrocortisone

    ; chushingoid syndrome

Clinical Manifastation

Infant

(1) girl : boy = 3:1

(2) *adrenocortical tumor(carcinoma, adrenoma, nodular hyperplasia) common lesion

(3) *older child보다 more severe

(4) Sx

  face ; round, prominent cheeks, flushed appearance (moon face)

  chin ; double

  buffalow hump, generalized obesity

  abnormal musculinization, acromegaly, hypertrichosis on face & trunk, pubic hair, acne, deepening of the voice, enlargement of the clitoris

  growth impairment

  hypertension -> heart failure

  infection 빈도 증가 -> fatal sepsis

  hemihypertrophy, other congenital defecit종종 동반

Older Children

(1) *bilat hypertroplasia of adrenal common lesion

(2) boy : girl = 1:1

(3) Sx

  *obesity, short stature

           - *common presenting features

  purplish striae on hip, abd, thigh

  delayed purbertal development, amenorrhea,

  weakness, headake, deterioration, emotional lability

  hypertension

  renal stone

Laboratory data

1) polycythemia, lymphopenia, eosinopenia

2) insulin level 높아도 diabetic glucose tolerance test

3) S- electrolyte

    ; 대개 정상, 하지만 *potassium 감소

4) *cortisol diurnal rhythm없어짐

    ; 8:00 PM cortisol level 대개 증가

    ; normal

           - 8:00A.M. 증가되어 있고, 8:00P.M. 50%정도로 감소한다.

5) urine free cortisol ; 대부분 증가

    ; urinary 17-hydroxycorticosteroids 대부분 증가

6) 96 single dose dexamethasone suppresion test

    ; 의심나는 경우에 사용

  ; 0.3 mg/m2 11:00 PM 주었을때 정상아는 다음날 8:00AM plasma cortiosol level  5ng/dL이하로 떨어짐

7) 96 Cusing syndrome 진단된 ACTH dependent인지 independent인지 결정

    ; ovine corticotrophin-releasing hormone (OCRH) stimulation test    

           - 1ug/kg IV bolus

        - ACTH dependent ; ACTH & cortisol level상승

        - adrenal tumor ; ACTH & cortisol증가 (-)

    ; High Dose Dexamethasone Suppression Test

           - dexamethasone 30, 120ug/kg/day #4 for 2days

       - ACTH dependent

                   / urinary free cortisol or 17-hydroxycorticosteroid baseline 50%이하 & serum level of cortisol 7ug/dL이하

8) other finding

    ; osseus maturation

           - usually moderate retarded but virilized children advanced

    ; osteoporosis ; spine 많다

  ; growth ; 감소

  ; muscle mass감소, adipose tissure 증가

9) Imaging studies

    ; thymic shadow absent

    ; CT scanning

           - 1.5cm이상의 adrenal tumor detect

    ; adrenal scintigraphy

           - *indicated in pigmented micronodular adrenal hyperplasia

           - more accurate than CT scan

Differential Diagnosis

1) Simple Obesity

  *대부분 키가 크다

  *oral low dose dexamethasone supression test urinary corticoseroid 분비 감소

2) generalized glucocorticoid resitance

  *cushing synd. 임상증상없이 cortisol ACTH level 증가

  무증상 혹은 hypertension,hypokalemia,precocious pseudopuberty등이 나타날수 있다.

Treatment

1) Benign cortical adenoma - unilateral adrenalectomy

  ; Bilat.cortical adenoma - subtotal adrenalectomy

2) adrenocortical carcinoma

    ; liver & lung 으로 metastasis 많다

  ; primary lesion 제거해도 예후는 나쁘다

3) Total adrenectomy

    ; op expanding pituitary tumor 30%정도에서 발생하여 최근에는 선호하지 않는다.

           - Nelson synd.

                   / intense melanosis, ACTH marked elevation, enlargemant of the sella turcica

                   / External irradiation of the pituitary으로 치료하지만 부작용이 문제

                           : hypopituitarism & behavioral change

                   / *Transsphenoidal pituitary microsurgery recommended

4) postop. 합병증

  sepsis

  thrombosis

  poor wound healing

  sudden collapse

  catch-up growth 하지만 성인키는 작다.

5) Cyproheptadine

    ; centrally acting serotonin antagonist

    ; adult에서 사용시 not sustained remission

    ; child에서 3yr remission 보고됨.

Chapter 531. Excess Mineralocorticoid Secretion

# primary hyperaldosteronism : adernal gl. defect

# secondary hyperaldosteronism : R-A system 활성

# primary hyperaldosteronism : hypertension hypokalemia 많이 발생

# secondary hyperaldosteronism 생기지 않음

# Deoxycorticosterone

    ; 1/13 sodium retaining potency

    ; overproduction hyperaldosteronism발생

           - 11β-hydroxylase & 17α-hydroxylase deficiency

Etiology

; primary hyperaldosteronism

    - rare in children

# Aldosterone-secreting adenoma

    ; unilat. 주로 여아

# Unilateral micronodular adrenocortical hyperplasia

    ; older children

    ; stimulated by circulating glycoprotein

# Glucocorticoid-suppressible aldosteronism(=glucocorticoid-remediable aldosteronism)

    ; ACTH dependent autosomal dominant trait

    ; glucocorticoid 투여로 hyperaldosteronism 급속히 억제됨.

  ; hybrid gene formation

           - crossover events between CYP11B1 gene and CYP11B2 gene

           --> *ectopic expression of aldosterone synthetase in adrenal fasciculata

Clinical Manifestation

; asymptomatic

; incidental discovery of moderate hypertension

; hypertension, headache, dizziness, visual disturbance

; chronic hypokalemia

    --> polyuria, nocturia, enuresis, polydipsia

; muscle weakness, tetany, intermittent paralysis, fatigue, growth failure

Laboratory Studies

1) *Hallmark ; hypertension, hypokalemia, suppressed plasma renin activity

2) *increased serum pH, CO2, Na, decreased serum Cl, Mg, normal serum calcium

3) urine : normal or alkaline

4) plasma urine aldosterone 증가

5) plasma renin level 감소

6) *marked elevation of 18-oxocortisol, 18-hydroxycortisol in glucocorticoid-supressible aldosteronism

Differential Diagnosis

Primary Hyperaldosteronism

; 의심되는 모든 환자에게 trial with Dexamethasone

    - 0.25mg q 6hrs

           / marked suppression of aldosterone, hypertension

                   --> glucocorticoid-suppressible aldosteronism

; 반응 없으면 CT

    - adrenal adenioma detect

; *CT 정상이면 adrenal vein catheterization

  한쪽 adernal vein 에서 높은 aldosterone 치가 나오면 aderenal adenoma             

  양쪽 높은 aldosterone 치가 나오면 bilat. hyperplasia

; 모두 실패시 explorotomy 시행

Secondary Hyperaldosteronism

; edematous disorder due to reduced effective volume

    - nephrotic synd. congestive heart failure, liver cirrhosis

; stenosis fo the renal artery

; secrete renin

    - Wilms tumor & juxtaglomerular cell tumor

Pseudohypoaldosteronism

Batter Syndrome

; hypokalemic alkalosis, hypochloremia hyperaldosteroinism,

; normal BP, high renin

; growth failure - usual presenting complaint

; primary defect - deficient reabsorption of ascending limb of loop of Henle

; hyperplasia of juxtaglomerular apparatus

; urinary secretion of PG

11B-Hyrdoxysteroid Dehydrogenase Deficiency

; 과거에 syndrome of apparent mineralcorticoid excess 불림.

; converting enzyme cortisol to cortisone

; type I mineralcorticoid receptor(kidney, parotid glands, colon) equal affinity for aldosterone, cortisol

    - 11B-Hyrdoxysteroid Dehydrogenase cortisol 대한 paracrine protector

; 질환에서는 이러한 protect 없어져 cortisol type I mineralcorticoid receptor 반응하여 aldosteronism증상을 나타낸다.

; failure to thrive, polyuria, polydipsia secondary to hypokalemia, severe hypertension

; strokes in young children

Treatment

   (1) glucocorticoid - suppressible hyperaldosternism

         ; daily administration of dexamethasone or prednisone

   (2) Bilat adrenal hyperplasia

   (3) secondary hyperaldosteronism ; 원인 치료

Chapter 532. Feminizing Adrenal Tumors

1. Boy

     ; precocious puberty

      excessive production of estrogen

      gynecomatia ; initial manifestation

      acne, deep voice, phallic enlargement

      advanced osseous maturation

      testis not enlargement

      hypertension

      urine plasma estrogen, androgen증가

2. girl

    ; 6 month - 10yr

      tumor 대부분은 adenoma

      plasma urine estrogen level 증가

      urine 17-ketosteroid 증가

      plasma   5 adrenal steroid증가

      plasma gonadotropin level감소

      CT localized tumor

Chapter 533. Pheochromcytoma

1) *chromaffin cell에서 분화된 catecholamin- secereting tumor

2) TMC siteof origin ; adrenal medullar 그외 abdominal sympathetic chain

3) tumor size  ; 1-10 cm

4) Rt > Lt

   20% ; bilateral

   30% ; both adrenal and extra-adrenal area

5) autosomal dominant trait

6) 다른 질환 혹은 syndrome 동반

   neuroblastomatosis

   islet cell adenoma

   MEN IIa & IIb

           ; medullary carcinoma of thyroid earlier age onset than pheochromocytoma

Clinical Manifestations

1) hypertension : sustained 혹은 paroxysmal

2) headache, palpitation, pallor, vomiting, sweating

3) hypertensive encephalopathy

4) severe case; pulomonary edema, cardiac & hepatic enlaregement

5) good appetite , hypermetabolism으로 wt. gain

6) DI

7) growth failure

8) ophthlamoscopic exam, papilledema, hemorragic exudate, arterial

    constiction 

Lab data

1) urine ; protein, few cast 때로 glucose나옴

2) hematuria ; bladder wall tumor의심

3) catecholamine  metabolite plsma & urine농도 증가

4) 소아에서는 norepinephrine predominent catecholamine

    total urinary catecholamine excretion : 300μg/24hr 이상

    Urine catecholamine 농도는 tumor 상관관계가 있다.

5) urinary vinillnlmandelic acid 증가

    cf. VMA 증가하는 경우

    neuroblastoma

  children 에서 age 증가에 따라

    vanilla containing food & fruit

    drug : catecholamine fluorometric determination 방해하는 .         

Differential Diagnosis

   renal or renovascular disease, coartation of aorta, acrodynia,

   thallium intoxication, hyperthyroidism, Cushing syndrome,

   11β-hydroxylase, 17-hydroxylase, 11β-hydroxysteoid dehydrogenase

   deficiency, primary aldosteronism, adrenal cortical tumor,

   essential hypertension, familial dysautonomia, cerebral disorder,         

   diabetes insipidus, DM, neurofibromatosis, neuroblastoma,

   ganglioneuroblastoma, ganglineuroma          

Treatment

; removal of tumor

# preoperative care

    ; *α- andβ-adrenergic blockade

# operative care

    ; *적절한 마취제와 volume expander

           - 술중 혹은 48시간이내에 hypotension 있기 때문

    ; transabdominal exploration

           - multiple site 있을 있기 때문

# postoperative care

    ; BP control 등이 중요

Chapter 534. Adrenal Calcification

; 주로 abd. X-ray check incidental detect     

; 출생시 anoxia trauma Hx. check

; 출생중 혹은 후에 hemorrhage adrenal gland 생겨 많이 발생

; *Neuroblastoma, ganglioneuroma, cortical carcinoma, pheochromocytoma, adrenal gland cyst

    - 이런 calcification 대개 unilat.

; tuberculosis

    - 과거 adrenal gl. calcification common factor

; Waterhouse-Friderichsen syndrome으로 회복시

; *Wolman syndrome

  - deficiency of lysosomal acid lipase

    - extensive bilateral calcification of adrenal glander

Section 5. Disorder of the gonads

Function Of Testes

Testosterone

임신 8-12

    ; hcG Leydig cell 자극하여 testosterone분비하게

  ; * 시기가 정상 virilization critical period

임신후반기 ; LH 의해 낮은 농도로 testosterone유지

*출생후 LH 증가로 testosterone peak (1-3Mo)

    ; *“minipuberty” in neonate라고 한다.

    ; 이후 감소하여 6개월경에는 low prepubertal level 감소한 puberty까지 지속된다.

testesticular torsion & atrophy in neonate

    ; testosterone 감소

        --> FSH, LH marked elevation

testosterone

    ; 5α- reductase 의해  dehydrotestosterone으로 전환 (6-8%) 

    ; *aromatase 의해 estradiol 전환 (0.3%)

circulating testosterone

    ; 1/2 sex hormone- binding globulin

  ; 1/2 albumin 결합

  ; *only 2% free form

SHBG low at birth였다가 peak during first 10 days

    ; thyroid hormone 중요한 역할을 하는 것으로 여겨지고 있다.

Mullerian-Inhibitory Substance(MIS) (=Antimullerian Hormone)

sertoli cell에서 분비

cervix, uterus,fallopian tube embrylogic precusor 성분화때 퇴화시킴

*출생후 사춘기전까지 지속하다 사춘기때 sharp decline

Inhibin

sertoli cell에서 분비

FSH secretion regulating role

# Functional integrity of pituitary-testicular axis

    ; *neonate에서는 FSH, LH, testosterone 측정만으로 평가가 가능하지만, 이후의 시기는 administering hCG 의해 testosterone 반응을 평가해야 한다.

Function Of The Ovaries

; estrogen생산

    - 주로 negative feedback으로 조절되나 midmenstration positive feedback

    - estriol -17β(E2) estrone(E1)생산되고 metabolic sustance estriol(E3)생산    

    - *estrogen adrenal gland testis에서도 androgen 전환으로 생성된다.

           / e.g. 17-ketosteroid reductase deficiency increased androstenedione

                   --> converted to estradiol & estrone

                   --> gynecomastia

    - estradiol correlate well with clinical evaluation of pubertal development, skeletal age, rising levels of FSH

; progesterone, progestational steroid생산

    - pretesterone adrenal & testicular hormone 전구 물질이다.

Diagnostic Aids

; pituitary and gonadal hormone assay발달로  pubertal development 이상에 대한 진단이 빨라졌다

; GnRH hypogonadotropic patient에서 primary pituitary, hypothalamic defect 차이를 알수 있게 됐다.

Therapeutic Aids

; estrogen 경구 투여시 파괴되므로 equine conjugated estrogen (Premarin) ethinyl estradiol 사용

; androgen long-acting esters (enanthate, cyclopenthylpropionate, phenylacetate) injection용으로 사용

Chapter 535. Hypofunction Of The Testes

# primary hypogonadism : testis이상, hypergonatropic

# secondary hypogonadism : pituitary gonadotropic H defect, hypogondotropic

535.1 Hypergonadotropic Hypogonadism In The Male

Etiology

1) congenital anorchia

  normal external genitalia

  early postnatal month low testosterone level marked elevation of LH,FSH

  hCG stimulation test :반응(-)

2) syndrome of radimentary testes

    ; autosomal or X-linked recessive trait

3) Atrophy of the testes

    ; cryptorchidism or bilat. torsion of testes surgical collection동안testes vascular damage 발생

4) Acute orchitis

    ; mumps

5) chemotheraphy & radiotherapy

    ; nitrourea 16세이전에 투여하면 permanent damage to germinal epithelium 초래한다고 하나, less vulnerable in perpubertal than in intrapubertal

Clinical Manifestation

1) primary hypogonadism

  ; *출생시 testes penis 작을시 의심할 있으나 대부분은 2 성징이 발달되지 않아 사춘기가 되어야 발견

2) facial, pubic, axillary hair 없거나 작다

3) penis, scrotum infantile형태, testes small or abscent

4) fat accumulate

    ; hip & buttock, 때로  breast & abdomen

5) *eunuchism

    ; symphysis pubis에서 feet sole까지의 길이가 symphsis pubis에서 vertex까지의 길이보다 것을 말함

Diagnosis

; serum FSH lesser extent, LH elevated above age-specific normal range

; low level of testosterone level

; attenuated rise or no rise following administration of hCG

Noonan Syndrome

; phenotypic male, female Turner syndrome 있는 anomalies 보이는 경우

; normal karyotype

    - gene mapping in chromosome 12q

# TMC abnormality

    ; short stature, webbing neck, pectus carinatum, pectus excavatum, cabitum valgum, congenital heart disease, characteristic face

# Characteristic Face

    ; hypertelorism, epicanthus, antimongloid palpabral slant, ptosis, micrognathia, ear abnormality

# other abnormality

    ; clinopathy, hernia, vertebral abnormality

; *mental retadation (25%)

; cardiac defect

    - *pulmonary valvular stenosis, ASD

; 관련질환

    - neurofibromatosis, cryptorchism, small testes, premature ovarian failure 

; puberty - 2 까지 지연

Klinefelter Syndrome

Etiology

; incidence

    - 1/1000 newborn male

; meiotic nondisjuction of X chromosome

    - 이러한 이유로 증후군은 increased maternal age incidence 증가시킬 같지만 *대부분의 경우 maternal age not advanced이다.

; chromosomal pattern

    - 47 XXY : *common

    - 그외  mosaic pattern으로 46,XY/47,XXY; 46, XY/48, XXYY; 45, X/46,XY/46,XXY; 46,XX/47, XXY

    - 드물게 48,XXXY ; 49,XXXYY; 50,XXXXYY; 47,XXY/48,XXXY; 47,XXY/49,XXXXY; 48XXYY

; 표현형은 Y chromosome으로 인해 남성형

Clinical Manifestation

; puberty되기전에는 증상 경미하여 거의 진단이 안된다.

# Children

    ; *behavioral or psychiatric disorder로만 나타나기 때문에 mental retadation, psychosocial, learning, school adjustment problems 있는 남아는 반드시 고려해야 한다.

    ; anxious, immature, exessively shy, agressive antisocial acts

    ; tall, slim underweight

# Puberty

    ; testes, phallus - small for age

    ; *delayed puberty

           - normal masculinization 되는 경우도 있지만, 상당수가 androgen deficiency 발견된다.

    ; *gynecomastia - 80%

    ; azospermia & infertility

    ; height tall

    ; *pulm. disease, varicose vein, breast cancer

    ; *mediastinal germ cell tumors

           - hCG 분비로 precocious puberty 발생

# XY/XXY Mosaicisms

    ; decreased severity and frequency

    ; better prognosis for virilization, fertility, psychosocial adjustment

# XXYY males

    ; *tend to taller than XXY patients

    ; others similar symptoms

Klinefelter Variants

    ; *exceeding 2 X chromosomes

    ; more severe      clinical manifestation

           - 특히 mental retadation, impairment of virilization

           - large malformed ears, short neck, typical faces

                   / wide set eye, mild mongloid slant, epicanthus, strabismus, wide flat upturned nose, large open mouth

    ; testes - small & undescended

    ; scrotum - hypoplastic

    ; penis - very small

    ; defects suggesting of Down syndrome

           - short in-curved terminal 5th phalanges, single palmar crease, hypotonia

    ; radiographic abnormalities

           - radioulnar synostosis or dislocation, elongated radius, pseudoepiphysis, scoliosis or kyphosis, coxa valga, retarded osseous age

Laboratory Data

# before 10yr

    ; LH, FSH정상

  ; gonadotropin-stimulating hormone hCG response 정상

  ; testes 정상 성장

# midpuberty

    ; LH, FSH 증가

  ; testicular growth 정지

  ; gonadotropin 증가, testosterone감소

  ; estradiol 증가

# testicular biopsy

  puberty ; germinal cell 감소 or 소실

  puberty ; seminiferous tubular membrane hyalinized, adenomatous clumping of leydig cell

Treatment

; long acting testosterone : 11 - 12 부터

; enanthate ester

    - starting dose 50mg every 3wk

    - 50mg increments every 6-9mo until maintenance dose for adults(200-250mg every 3-4wk)

XX Males

  1) incidence 1/20000 newborn male

  2) cl/m

      male phenotype, small testes, small phallus, no evidence of

         ovarian or mullerian duct tissue

      adult life hypogondism, gynecomastia, infertility

45 X Male

    Yp sequence translocation

XYY Males

  1/1000 newborn male

  hypogonadism (-)

  상대적으로 impulsive, antisocial

  cl/m : tall, severe nodulocytic acne, genital abnormality

  PR interval 연장, radioulnar synostosis 혼합

535.2 Hypogonadotropic Hypogonadism In The Male (Secondary Hypogonadism)

Etiology

1) hypopituitarism

    ; organic lesion - craniopharyngioma

    ; idiopathic or familial hypopituitarism

           / deficiency of GnRH

           / *microphallus(<2.5cm) in newborn male with GH defciciency

                   --> suggest GnRH deficiency

2) isolated deficiency of gonadotropin

    ; *Kallman Syndrome

           - *frequent genetic form of hypogonadotropic hypogonadism

           - ass. with anosmina or hyposmia

           - X-linked disorder caused by KAL gene at Xp22.3

           - others symptom

                   / cleft palate, hypotelorism, median facial clefts, neural hearing loss, unilateral renal aplasia

           - ass. syndrome

                   / chondrodysplasia punctata, X-linked ichthyosis, ocular albinism

3) mutation of gonadotropins

    ; point mutation of β-subunit of LH or FSH

4) melatonin-related hypogonadism

    ; marked elevated plasma conc. of melatonin

5) other disorder

  X-linked form of congenital adrenal hypoplasia

  polyglandular autoimmune syndrome

  Bardet-Biedl,Prader-Willi,multiple lentigines, several syndrome of ataxia

Diagnosis

1) gonadotropin & gonadal steroid level ; prepuberal range

2) noctural pulsatile secretion of LH ; not ocurr

3) gonadotropin response standard GnRH stimulation test

    ; marked blunted  

4) GH,ACTH deficiency 동반되면 pituitary deficiency의심

5) anosmia 있으면 permanant gonadotropin deficiecy

Treatment

; Indication

    - *15세까지 puberty 일어나지 않고 testosterone<50mg/dl testosterone투여

; testosterone enanthate 100-200mg/mo IM for 4month

  - initiate puberty

    - testes remain small

    - puberty 없으면 second course

; testosterone with hCG

    - 500-1000 IU sc or im 3 times weekly

           --> growth of testes & spermatogenesis

    - 6-12개월동안 치료하여도 반응이 일어나지 않으면

           --> human menopause gonadotropin

                   / 37.5 - 150 IU 3times weekly

                   / 2 정도 치료

; GnRH

    - more physiologic but cumbersome

    - episodic administration(sc or iv)

Chapter 536. Pseudoprecocity Resulting From Tumors Of The Testes

1. Leydig cell tumor

   unilat,benign

   5-9 발생

   plasma testosterone : marked elevate

      LH FSH level 감소

2. Testicular adrenal test

   bilat.

   congenital adrenal hyperplasia에서 많이 발생

3. Fragile X - syndrome

   testes bilat.enlarge,not nodular

   no precocious puberty

   hormonal study & testicular histology : 정상

4. Sex card tumors with annular tubules

   bilat. multifocal

   Peuts - Jeghers syndrome 관련

5. Unilat. cryptorchidism

   contralat.testis 정상보다 25% 정도 크다

Chapter 537. Gynecomastia

Def inition

; occurance of mammary tissue in male

Etiology

Nonpathologic

# newborn infant - maternal hormone때문에 발생

# Physiologic Pubertal Gynecomastia

    ; midpuberty boy 2/3 에서 발생

  ; only one breast

  ; *tenderness(+) but transitory

  ; *spontaneous regression within a few mo

    ; LH, FSH, prolactin, testosterone, estrone, estradiol

           - same as in boys without gynecomastia

    ; Treatment

           - reassurance

# Familial Gynecomastia

  - X- linked or AD sex- limited trait

  - normal gonadotropin, testosterone, prolactin, streoid- bindimg globulin

    - increased peripheral conversion of C19-steroids to estrogens(increased aromatiztion)

# exogeneous estrogen

    - increased pigmentation of nipple and areola 특징적

Pathologic

    ; 11β-hydroxylase deficiency of CAH

    ; Leydig cell tumors of testis

    ; feminizing tumors of adrenal

    ; Peutz-Jeghers syndrome with sex- cord tumor with annular tubules of testes

    ; Klinefelter synd

    ; certain type of male pseudohermaphroditism

           - Reifenstein synd, testicular feminization syndrome, 17 -KS reductase defect

    ; prolactinoma

# Adult

    ; liver cirrhosis

  ; congetive heart failure digitalis therapy

  ; bronchogenic ca.

    ; marijuana smoking

    ; ketoconazole

  ; fibrolamellar carcinorma of liver

Chapter 538. Hypofunction of the ovaries

538.1 Hypergonadotropic Hypogonadism In The Female

; 사춘기 전에는 진단힘듬

Turner Syndrome

; consists of sexual infantilism, webbed neck, cubitum valgum

Pathogenesis

; *affected patients 50%에서 증상을 나타낸다.

; chromosomal patterns

    - 45,X (75%), 45,X/46,XX(15%)

    - others 45,X/46x,i(Xq), 45,X/46,X,r(X), 45,X/46fra

; not increase with maternal age

; *X-linked gene inactivation escape하기 때문에 sex differentiation 가능하다.

; 45,X karyotype 99% spontaneus abortion

    - 자연 유산의 5-10% 차지

    - mosaicisms 유산은 없다.

; *난소 성숙 과정 촉진되어 모든 난자들이 2세경에 없어짐

    - ovary streak해지고, connective tissue로만 구성

Clinical Manifestation

# At Birth

    ; edema of the dorsum of hand & feet

    ; loose skinfold at nape of neck

    ; low-birth & decreased length

# Childhood

    ; webbing of neck

 a low post hairline

 small mandible

 prominent ears

 epicanthic folds

 high arched palate

 broad chest, widely spaced nipples

 cubitum valgam, hyperconvex finger nails

 short stature ; cardinal finding

 sexual maturation fail

# associated defect

cardiac ; nonstenotic bicuspid aortic valves (1/3)

           그외  aortic stenosis, COA

           anomalous pulmonary veneous drainage

renal defect ; US

      pelvic  kidney, horseshoe kidney

      double collecting system, complete abscence or one kidney,

      ureteropelvic junction obstruction

small & streak ovary, sexual maturation fail

recurrent bilat otitis media(75%)

   -> sensorineural hearing defect

language ; dysfunction

   intelligence ; normal

adult에서 perceptual spatial skill 장애

goiter ; lymphocytic thyroditis

inflammatiry bowel disease ; abd pain, tenesmus

                              bloody diarrhea

gastrointestinal telangiectasia ; recurrent GI bleeding

Lab Data

   1) chromosomal analysis, DNA probe analysis

   2) U-S ; heart, kidney, ovaries

   3) X-ray ; skeletal abnormality

     shortening of 4 th metatasal & metacarpal bone

     epiphyseal dysgenesis in the joint, knee & elbow

     madelung deformity

     scoliosis

     inadequate mineralization

   4) gonadotropin

     infancy ; 증가 특히 FSH

     2-3 or 6-8 까지 감소

     10-11 성인 level 증가

Treatment

     growth hormone단독 혹은 anabolic steroid height velocity증가

        시킴   

     12- 13세에 estrogen 보충

XX Gonadal Dysgenesis

1. phenotypical & genetical normal female gonadal lesion갖고 있고

    45 X 지만 Turner syndrome dml somatic feature없다.

2. pure gonadal dysgenesis or pure ovarian dysgenesis라고

3. external genitalia 성장은 정상

4. sexual maturation fail

5. sensorial defness 동반

45,X/ 46,XY Gonadal Dysgenesis

1. mixed gonadal dysgensis major finding  short stature

2. three major clinical phenotype

   1) no masculization

      female phenotype, somatic sign of tunner syndrome

      follopian tube & uterus 존재

      steak ovary

   2) mild virilization

      prepubetal clitorimegaly

      normal mullerian structure

      pubertal virilization

      intraabdominal testis, contra streak gonad

         bilat fallopian tube

   3) frank ambiguity of genitalia

      most freqent phenotype

      testes & vas deferance labioscrotal fold한쪽에 보임

         streak gonad contralateral side

      infantile or rudimetary uterus존재

3. 25%에서 gonad tumor ( gonadoblastoma)발생

XXX, XXXX and XXXXX Females

1. XXX female

     1/1000 live born female

     원인 ; maternal meiotic nondisjunction

     normal female phenotype

     sexual development ; normal

     coordination, behavior, academic performance 다양

2. XXXX AND XXXXX FEMALES

     mental retarded

     asso. defect ; epicanthal fold, hypertelorism

                      clinodactyly, simian crease,

                      radioular synostosis, cong.heart disease

Noonan Syndrome 

1. normal 46 XX chromosome

2. turner syndrome phenotype차이

     mental retadation

     cardiac defect

     gonadal defect(+)

        normal sexual maturation

Other Ovarian Defect

    1. cytotoxic drug & radiation

    2. autoimmune ovarian failure in type I autoimmune polyendocrinopathy

    3. premature menopause

    4. *galactosemia

           ; ovarian damage by accumulation of galactose-1-phosphate

    5. ataxia telangiectasia ; ovarian hypoplasia

538.2  Hypogonadotropic Hypogonadism In The Female (Secondary Hypogonadism)

Etiology

   1) hypopitutarism

   2) isolated deficiency of gonadotrpins

      pitiutary 정상 hypothalamus on defect

Diagnosis

   repeated measure of FSH  & LH ; 특히 sleep동안

Polycystic Ovaries (=Stein- Leventhal Syndrome)

 1) classic polycystic ovaries syndrome(PCOS)

      obesity

      hirsuitism

      secondary amenorrhea

      bilat enlarged polycystic ovaries

      가임기의  anovulatory infertility TMC cause

 2) Lab

      testosterone or androstenedion증가

         하지만  dexamethasone으로 억제 되지 않음

      increased ratio of LH to FSH level

         LH GnRH 대해  exaggerated response

      premenorcheal girl에서 야간보다 아침에 증가

 3) associ coith

      insulin-resistant hyperinsulinemia

      acanthosis nigricans

 4) DDx

      adrenal disorder

      women treated with valproate for epilepsy.

 5) Treatment

      contraceptive pill

      tesolactone.

Chapter 539. Pseudoprecocity Due To Leision Of The Ovary

Estrogenic Lesions Of The Ovary

 1. Juvenile Glanulosa - cell tumor

      childhood estrogenic manifestation 지니는 TMC ovary

         neoplasm granulos-cell tumor이다.

      luteinization 흔함

      solid, cystic

   1) clinical manifestation

      반수가 10세전에 발생

      unilat

      breast ; enlarge, rounded form

      mensturation(+), ovulation(-)

      mass ; low abd에서 쉽게 촉진

      Lab

          plasma estradiol; marked elevate

          gonadotopin ; 억제 LHRH 반응(-)

 

          α-FP ; 증가

 2. Follicular cyst

      prepubertal children ; small cyst (0.7cm)

      puberty, true isosexual precocious puberty female  

            ; large cyst (1-6cm)

      gonadotropin ; 감소 

             estradiol ; marked elevation

      GnRH stimualtion test ; response(-)

      Tx ; cystic aspiration or cystectomy

Androgenic Lesion Of The Ovary

 1. arrhenoblastoma

 2. gonadoblastoma

      phenotype female

      accelerated growth, acne, clitorial enlargement

         growth of sexual hair

      palpable abd mass

      testosterone, androstenedione level 증가

Chapter 540. Hermaphrodism (Intersexuality)

# hermaphroditism

    ; discrepancy between the morphology of gonad and external genitalia

Table 540-1

Embryonic Sexual Differentiation

 1) female ; 46, XX

    (1) X-chromosome long & short arm

    (2) Turner syndrome ; X- chromosome short arm deletion

 2) male

    (1) Y-chromosome  short arm 성결정에 결정적

    (2) testicular-determining factor(TDF) short arm 위치

    (3) Y chromosome

       major portion ; Y specific sequence 구성

                         X chromosome pairing하지 않음

       minor portion ; X chromsome sequence 공유

                         X chromosome pairing

           minor portion gene sequence sex chromatin사이에 재결합하게 되어

          autosomal gene처럼 행동 ---> "peudoautosomal"

       TDF (testis determining factor)  Y chromosome  pairng

          & exchange (psedoautosomal) region 근처에 위치

          ---> "SRY" (sex-determing region of Y)

          TDF indifferent genital ridge testis 발달시킨다.

       fetal testis(6-7wk) Sertoli cell에서 MIS(mullerian-inhibiting                                                             substance) 분비

          ---> mullerian duct regression

       8 fetal wks ; Leydig cell of testis testosterone 생산

            testosterone분비는 hCG 의해 stimulation된다

                                            (peak : 8-12 wks)

       teststerone  wolffian duct virilization시켜서

          ---> epididymis, vas deferance, seminal vesicle 형성

       DHT (dihydrotestosterone ; testosterone active metabolite)

          ; external genitalia형성

          ; genital fold fusion하여 penis & scrotum 형성

540 1. Female Pseudohermaphroiditism

       genotype ; XY (46)

       gonad ; ovary

       external genitalia ; virilized

 

   ;  MIS 없기 때문에 uterus, tubes, ovary 발달

   ;  대개 intrauterine life동안 과다한 androgen female fetus 노출되어         생김

   ;  virilization of external genitalia

      ( clitoral hypertrophy & labioscrotal fusion )

Congenital Adrenal Hyperplasia

    ; most common

  1) +- 21- hydroxylase defect -+

     |                          most highly virilized

     +- 11- hydroxylase defect -+

     +- type II 3β- hydroxy steroid dehydrogenase defect

            --minimal virilized

  2) salt-loser non-salt-loser환아보다 virilization 심함

  3) complete penile urethra형성으로 male cryptochism 유사

Aromatase Deficiency  

  1) aromatase androgen estrogen으로 conversion되는데  중요한 역활

  2) in genotype female, aromatase deficiency

  3) fetal life ; female pseudohermaphrotism

  4) puberty ; hypergonadotropic hypogonadism

  5) ovarian failure to synthesize estrogen 때문

  6) maternal serum & urine & cord blood estrogen(low) &

        androgen(high)

Masculiniziog Maternal Tumor

# maternal androgen producing tumor

      benign adrenal adenoma

      androblastoma

       leuteoma

      klukenberg tumor

 # maternal virilization Sx

      enlargement of clitoris

      acne

      voice deepening

      decreased lactation

      hirsuitism

      androgen level 상승

 # unexplained female pseudohermaphroitism환아의 mother

      plasma testosterone

      DHEAS( dehydroepiandrosterone sulfate)

      androstenedione측정이 필요

Administration Of Androgenic Drug To Women During Pregnancy

      유발 물질 testosterone & 17-methyltestosterone

               progestin

      congenital defect 관련되기도 한다.

     (특히 urinary & gastrointestinal tract)

      Y - specific DNA sequence(including SRY) 없다

540.2 Male Pseudohermatism

; genotype - XY

; gonad - invariable testis (rudimentary - normal)

; external gentalia

    - incomplete virilized, ambigous또는 complete female

Defect In Testicular Diffentiaton

   1) Y chromosome short arm deletion,  male determing gene deletion

      있는 경우는 미분화된 gonad testis 분화시키지 못한다

       phenotype female이다

       gonad ; undiffentiated streak

   2) Y chromosome long arm deletion(Y q-)

       normal developed male

       azospemic & short stature

DENYS-DRASH Syndrome

   1) 특징 ; nneuropathy c ambiguous genitalia or Wilms tumor

   2) phenotype ; 대개 46, XY

      normal external genitalia

      Mullerian duct (+) ; fetal testicular function global deficiency

   3) renal involve

       infant시기의 proteinuria onset 3세까지 nephrotic syndrome              end stage renal failure 이행

         : 조직병리학적 소견 ;  focal or diffuse mesangial sclerosis

        Wilms tumor ; focal or diffuse mesangial sclerosis

       gonadoblastoma

         : wilms tumor gene constitutional point mutation발견 ( WT1 )

           ---> chromosome 11p13 위치

WAGR Syndrome

   1) 특징

       wilms tumor

       anhydria

       genitourinary malfomation

       tetardation

   2) 46, XY male만이 genital abnormality 나타난다

      ; cryptorchism - severe deficiency of virilization

   3) dysgenetic gonad에서 gonadoblastoma 발생

   4) wilms tumor; 2세경

   5) deletion of one copy of chromosome 11p13

      ; deletion region testicular development critical aniridia              gene (PAX6) Wilms tumor suppressor gene(WT1) 포함

Camtomelic Syndrome

   1) short - limbed dysplasia

   2) sex reversal with complete female phenotype ; 46 XY환아의 60%

   3) gonad ; ovary 형태지만 조직학적으로 ovary testes element 가짐

   4) 특징 ; anterior bowing of femor & tibia & by malformation of other               origin

   5) SOX 3 (SRY-related HMG-box genes)

      : testes-determining factor SRY 구조적 연관성

XY Pure Gonadal Dysgenesis (Swyer Syndrome)

; *normal structure & female phenotype

    - vagina, uterus, fallopian tube

; 사춘기에 breast development & menache 없다

; *no defects ass. with 45,X patients

; testis-determining factor gene(SRY) mutation ; 15%

; gonad

  - total undifferentiated streak 형태

    - neoplastic change

           / gonadoblastoma, dysgerminoma : 나이에 무관하게 제거

XY Gonadal Agenesis Syndrome (=embryonic testicular regression syndrome)

; external genitalia는약간 모호하나 여성생식와 같은 모양

 ---> 대개 female 간주

; hypoplasia of labia, labioscrotal fusion, small clitoris-like phallus, perineal urethral opening

; *no uterus, gonadal tissue, vagina

; *hCG stimlation test testosterone 증가

  - *somewhere Leydig cell function

; pathogenesis

    - *fetal life동안 active long enough for MIS

    - *not long enough for testosterone production to virilization

Testicular degeneration

    - 8-12wks

    - testicular regeneration

  8 이전에 나타나면 : Swyer syndrome

  14-20 : rudimentary testis syndrome

  20주이후 : anorchia

Defects In Testicular Hormone

   : XY fetus inadequate masculinization으로 male pseudohemaphroditism       나타낸다

   : testosterone level 사춘기 이전에는 normally low

Leydig Cell Aplasia 

   1) mild virilized female

   2) testis, epidydimis, vas 있다.

      uterus, fallopian tube 없다.

   3) 혈중 testosterone 감소.

20,22-Desmolase Deficiency 

   1) 20,22-desmolase : 모든 steroid hormone 생합성에서 cholesterol side         chain cleave 필요한 효소

   2) enzyme absence adrenal에서 steroid 합성을 없다.

   --> adrenal lipid 축적 (lipoid adrenal hyperplasia)

   3) affected male : female phenotype 나타내나 male genital duct

       가진다.

   4) salt-losing manifestation & early adrenal crisis

3β-Hydroxysteroid Dehydrogenase Deficiency  

   1) male /c congenital adrenal hyperplasia

      : hypospadia /c /s bifid scrotum & cryptorchism

   2) affected infant : 출생후 salt-losing manifestation 발생

   3) adrenal & gonad에서 impaired steroidogenesis 결과로 type 3β            -hydroxysteroid enzyme 대한 gene point mutation     

Deficiency Of 17-Hydroxylase/17,20Lyase 

   1) genetic male with phenotypic female

   2) various virilization

   3) deoxycorticosterone & corticoisterone 증가

       ---> hypertension & hypokalemia

   4) cortisol 감소하나 corticotropin (ACTH) & corticosterone 증가되어          eucorticoid state유지

   5) 사춘기에 virilization 일어나지 않으며 testosterone치의 감소와

       gonadotropin 상승이 있다

   6) MIS fetal production 정상이므로 Mullerian duct remnant 존재         하지 않는다

   7) phenotypic XY female

      Tx of gonadectomy

            replacement therapy with hydrocortisone & sex steroid

   8) gene : chromosome 10

Drficiency Of 17-Ketosteroid Reductase

   1) conversion of androstenedione to testosterone

   2) complete or near complete female phenotype in 46,XY male

   3) Mullerian duct 없고 shallow vagina

   4) Dx : ratio of testosterone to androstenedione

           대부분의 환아는 사춘기때 menstruation & virilization failure                문에 진단됨

   5) 사춘기때 testosterone level 정상일 있다.

     : peripheral conversion of androstenedione into testosterone

   6) late onset form of 17-ketosteroid reductase def.

     : gynecomastia in young adult males

Persistent Mullerian Duct Syndrome      

   1) complete virilazed male mullerian duct derivatives 지속됨.

   2) gene : chromosome 19

   3) cryptorchism : 80% of affected male

   4) fallopian tube & uterus (+)

   5) testicular function : normal

   6) mutation of gene coding for MIS & nondetectable MIS

   7) Tx : 가능한한 mullerian structure remove

Defect In Androgen Action

    : testosterone fetal synthesis 정상이나 androgen action inherited          abnormality 인한 defective virilization

5α-Reductase Deficiency    

; muation of gene coding for 5α-reductase 2

; affected male fetus에서 *severe ambiguity of external genitalia

1) at birth

    ; *small phallus, bifid scrotum, urogenital sinus /c perineal hypospadia, blind vaginal pouch

  ; *no mullerian structure

  ; *present vas deferens, epidydimis, seminal vesicles

    ; identified as female

2) at puberty

  ; *normal masculinization, enlarge phallus, descent testis & normal growth

    ; *spermatogenesis

    ; no gynecomastia, scanty beard growth , absent acne

    ; retared growth of prostate, facial hair

; 혈중 testosterone 정상이나 DHT 감소 --> elevated testosterone:DHT ratio

; FSH, LH 정상

Testicular Ferminization Syndrome

    : failure of virilization genetic male, X-linked recessive

1) at birth

        external genitalia : female

    blind vaginal pouch, uterus : absent

    testes : intraabdominal or inguinal canal

2) at puberty

  normal breast development

  menstruation : absent

  sexual hair : absent

  testes : normal testosterone & DHT

  LH 증가, FSH 정상, estradiol 정상 성인 여자 농도.

3) 대개의 환아는 absent androgen binding

4) Tx

    testes 발견 즉시 remove

         1/3 환아에서 50세경에 malignant tumor (seminoma) develop 가능

    at puberty : replacement therapy /c estrogen

Incomplete Testicular Feminization  

      : some degree of masculinization

      : lesser degree of insensitivity to androgen

   1) at birth

      : enlarged phallus, labioscrotal fusion, blind vaginal pouch,

       uterus : absent,       testes : in inguinal canal or labioscrotal fold

   2) at puberty

      : breast develop, axillary & pubic hair

Reinfenstein Syndrome  

      : X-linked recessive

      : androgen 대한 end-organ responsiveness 감소.

      : partial androgen insensitivity

   1) at birth

      : small phallus, hypospadia, cryptorchism

   2) after puberty

      : inadequate masculinization, female escutcheon, azoospermia,       

             infertility

   3) adult

      : testosterone & DHT --- n'l elevated

        LH, FSH --- elevated

      neonate : testosterone & LH --- elevated

Undeterminated Causes        

  * Smith-Lemli-Opitz syndrome

   1) Sx: prenatal & postnatal growth retardation

             microcephaly

             ptosis

             anteverted nares

             broad alveolar ridges

             syndactyly of 2nd & 3rd toe

             severe mental retardation

   2) genotypic male : genital ambiguity

                          complete sex reversal /c female external genitalia

   3) Mullerian duct derivatives : absent

   4) affected 46,XX : normal genitalia

   5) Dx : low serum cholesterol percursor 7-dehydrocholesterol 상승.

540.3  True Hermaphroditism

  (1) both ovarian & testicular tissue : present

   (2) ambiguous genitalia

   (3) chromosomal study

        +- 70% : 46,XX

       +- 10% : 46,XY

       +- 20% : 46,XX/46,XY mosaicism

   (4) gonad : ovotestes - m/c

             bilateral

   (5) reared as female

   (6) male true hermaphroditism : 대개 infertile

 

   (7) 5% patient develop

       gonadoblatoma

       dysgerminoma

       seminoma

Diagnosis & Management 

    : 신생아에서 ambiguous genitalia 출생후 되도록 빨리 성을 결정해

      주는 것이 좋다.

    : chromosomal analysis 결과를 기다리는 동안 ultrasound examination        시행하여 uterus ovary 유무를 확인한다.

 1) presence of uterus & absence of gonad 경우

    : virilized XX female

    : female pseudohermaphrodites

      highly virilized 되더라도 reared as female

 2) absence of uterus with or without gonad 경우

    : male pseudohermaphroditism

    : XX karyotype

    : male pseudohermaphroditism : reared as female

      But, 5α-reductase deficiency : reared as male

            ( 사춘기때 정상적으로 virilize 되기 때문)

           androgen receptor defect : reared as female

           45,X/46,XY : phenotype male 일지라도 reared as female

                (이유) a. short in stature

                          b. have uterus

                          c. require gonadectomy

  3) small phallus(micropenis) XY male 환아에서 receptor disorder

      의심시

         : 3 monthly IM injection of testosterone ennanthate (25-50mg)

Section 6. Dibetes Mellitus

; syndrome of disturbed energy homeostasis caused by a deficiency of insulin or its action

    --> abnormal metabolism of carbohydrate, protein, and fat

; endocrine-metabolic disorder of childhood and adolescence

; Morbidity and mortality

    metabolic derangement

  long term complications

           - retinophathy, nephropathy, neurophathy, ischemic heary disease, and arterial obstruction with gangrene of the extremities

Classification

Table XXVI-1

Type I Diabetes (IDDM) ( Juvenile-Onset Diabetes)

; characterized by severe insulinopenia & dependence on exogenous insulin

; onset in childhood but maybe at any age

; Distinct features

    - asso. with HLA

  - *presence of circulating antibody to cytoplasmic & cell surface component of islet cell

    - *antibodies to insulin in absence of prior exposure to exogenous injection of insulin

    - *antibodies to GAD (glutamic acid decarboxylase) in pancreatic islet abundantly

    - lymphocytic infiltration of islet early

    - other autoimmune disease

Type II Diabetes (NIDDM)

; fasting plasma glucose > 140 mg/dl & 2hr value > 200 mg/dl

    - 유발 요인없이 oral GTT 1회이상

# Characteristics

    ; after 40, but may at any age

    ; abnormal glucose tolerance

    ; in obese individual

    ; insulin resistance

    ; strong family H

    ; no asso. with HLAs & autoimmunity, islet antibody

# Genetic Basis

   ; *defects in glucokinase, GLUT-2 glucose transport, glycogen synthase, insulin receptors, Rad(Ras associated with diabetes), apolipotrotein C-III

Secondary Diabetes

  1) cystic fibrosis

  2) endocrine ds other than pancreatic ds

      ; Cushing syndrome

  3) drug & poison ingestion : rodendicide vacor

  4) certain genetic syndrome : insulin receptor 이상

Type I Diabetes Melitus

Epidemiology    

; *highly correlated with increasing age

; 백인 > 흑인

; *남여비는 비슷

; *사회 경제적 상태와는 무관

# 2 Peak Age Group

    ; 5-7

           - 취학함으로써 감염에 노출 기회가 많아짐

    ; 사춘기

       - gonadal steroid 성장호르몬분비 증가에 의해 growth sput

             --> 인슐린 작용에 길항

       - emotional stress

; *seasonal variation : 가을, 겨울에 많다.

; *viral infection : mump, congenital rubella

Etiology & Pathogenesis

# Basic Cause Of Initial Clinaical Finding

  ; sharply diminished secretion of insulin

    - insulin secreting reservior 정상의 20%이하일때 symptomatic DM 발현

# Autoimmune Mechanism

    ; autoimmune destruction of β-cells

  ; associated autoimmune disease

           - addison diease, Hashimoto thyroiditis, pernicious anemia

  ; *associated increased frequency with certain HLAs, located chromosome 6

           - *HLA-B8, -DR3, -BW15 and -DR4

# HLA antigens

  HLA-D3 or D4 ; 2-3 빈도높음

    D3 and D4 both ; 발생빈도가 7-10 증가

# viral infection -- triggering factor

   ; mumps, rubella, coxsackie virus infection

# IDDM발생에 autoimmune basis 관계한다는 증거 

    (1) islet cell antibody

       islet cell surface & cytoplasmic determinent ICA 발견

       새로 진단받은 환아의 80 - 90 %

    (2) initial diagnosis시에 antibody 존재

         ; antibodies to GAD (환자의 80%)

           spontaneous anti-insulin antibodies (30-40% 환자)

    (3) abnormal T cell function

         ; suppressor / killer T cell ratio 변화가 IDDM 발병시 존재

    (4) autoaggression

         ; autoantibody + complement, T-cell, other factor --> islet cell 파괴

Pathophysiology

# Function Of Insulin

    ; major anabolic hormone

    ; normal metabolism

           - regular swing between postprandial, high-insulin anabolic state and fasted, low-insulin catabolic state

    ; affect three major tissues                            

       - *liver (more sensitive), muscle, and adipose tissue 

Table XXVI-2

# Progressive Failure Of Insulin Secretion

    ; initial manifestation

           - postprandial hyperglycemia

    - cf) fasting hyperglycemia

                   / *late manifestation

                   / indicate excessive endogenous glucose production

                   / *reflect severe insulin deficiency

    ; secondary change

           - increase of the stress hormones (epinephrine, cortisol, growth hormone, glucacon)

                   --> accelerate and exaggerate rate and magnitude of metabolic decompensations

        - counter-regulatory hormone (stress H) 역할

            insulin 분비 방해 ; epinephrine

            insulin 작용 길항 ; Epi, cortisol, GH

            glycogenolysis, gluconeogenesis, lipolysis, ketogenosis 촉진

          ; Epi, cortisol, GH, glucagon

            glucose utilization clearance 저하

          ; Epi, cortisol, GH

    ; excessive glucose production & impairment of its utilization

        --> hyperglycermia with glucosuria

# Glucosuria

       progressive insulin deficiency, glucose 생산 과다, utilization impairment 발생

       renal threshold ( 180 mg/dl ) 초과시 발생하며,    

          osmotic diuresis 결과 ;  (i) polyuria

                                  (ii) urinary electrolyte loss

                                  (iii) dehydration

                                  (iv) compensatory polydipsia   

# metabolic decompensation 악화 (ketoacidosis유발)시키는 요인

      dehydration

      trauma

      infection

# hyperosmolality

      hyperglycemia 결과로 초래되며,

         symptomatology 기여함 (특히, cerebral obtundation in diabetic ketoacidosis)

      Serum osmolality (in mOsm/Kg) can be estimated

         [serum Na+(meq/L) + K+(mEq/L)] x 2 + glucose (mg/dl) / 18  +  BUN (mg/dl) / 3

      serum osmolality diabetic ketoacidosis 치료시에 중요한 implication

  6) insulin deficiency counter-regulatory hormone 증가로 인하여

      --> accelerated lipolysis & impaired lipid synthesis

      --> total lipid, cholesterol, triglyceride, free fatty acid 혈중 농도가 증가

  7) insulin deficiency glucagon 과다로 인하여

      --> free fatty acid로부터 ketone body (특히, β-hydroxybutyrate, acetoacetate) 형성

      --> peripheral utilization renal excretion 능력을 초과시 ketoacid 축적

      --> ketoacidosis (metabolic acidosis) 발생,

      --> exess CO2 배출 위해 compensatory deep rapid respiration (Kussmaul 호흡)

  acetone

      - acetoacetate nonenzymatic concersion에의해 형성

      - 호흡에서 fruity odor

      - urine으로 배설되면서 cations further increase losses of water and

          electrolyte 일으킴     

Clinical Manifestations

# 전형적인 임상양상

    ; *polyuria, polydipsia, polyphasia, weight loss

    ; variable, often less than 1mo

           - enuresis : clue to polyuria

# incidious onset with lethargy, weakness, wt loss

    ; loss of weight in spite of an increased dietary intake

# pyogenic skin infections & monilal vaginitis in teenage girls

# Ketoacidosis

    ; 25% initial presentation of diabetes

    ; 초기 경할때 ; vomiting, polyuria, dehydration

        진행시 ; kussmaul 호흡, 호흡에서 acetone냄새

                    abdominal pain or rigidity (appendicitis, pancreatitis 감별)

                    cerebral obtundation(뇌기능 저하), coma

        lab finding

            (i) hyperglycemia, ketoremia, glucosuria, ketonuria, metabolic acidosis,

            (ii) leukocytosis

            (iii) nonspecific increase of S-amylase, s-lipase 대개 증가하지 않음

Diagnosis

# 3 general categories

    ; history suggestive of DM

           - polyuria with polydipsia, failure to gain weight or loss of weight in spite of voracious appetite

    ; transient or persistent glucosuria

    ; clinical manifestations of metabolic acidisis with or without stupor or coma

# diagnosis depends on demonstration of hyperglycemia with glucouria with or without ketonuria

    ; *polyuria, polydysia 전형적인 증상이 동반되면 당부하 검사는 따로 필요치 않다.

Renal Glucosuria

  isolated congenital disoder

  Fanconi syndrome

  renal tubular disoder due to

      (i) severe heavy metal intoxication (lead)

      (ii) drug ingestion (outdated tetracycline)

      (iii) inborn error of metabolism (cystinosis)

   - 이때 vomiting, diarrea, 혹은 음식의 불충분 섭취로 유발된 starvation ketosis

      diabetic ketoacidosis 감별이 필요하며, hyperglycemia 없는 점으로 DM 구별됨

       - 또한 urinary sugar 전부 glucose 아니며, galactosemia, pentosuria,

          fructosuria 보임

  Trauma, infection, emotional upheaval(감정격화) 연관되어, glucosuria( /c /s mild               hyperglycemia) 나타날 있지만, 대개 recovery동안에 glucosuria remission된다.            insuline분비의 limited capacity 뜻하며, stress hormone 혈중농도  상승에 의해

            unmasked

        DM 임상양상 혹은 고혈당의 가능성을 나중에 recheck 보아야 한다.

           acute illness 회복후 수주후 glucose tolerance test시행

  3) postprandial determination of blood glucose or oral glucose telerance tests 등과 같은            screening procedures 소아에서는 추천되지 않는데 이유는

        ; low detection rate

  4) Diabetic ketoacidosis

     (1) differentiated from acidosis and/or coma due to other causes

         hypoglycemia

         uremia

         gastroenteritis with metabolic acidosis

         lactic acidosis

         salicilate intoxication

         encephalitis , and other intracranial lesions

     (2) exist when 

         hyperglycemia (glucose>300mg/dl)

         ketonemia (ketone strong positive > 1:2 dilution serum)

         acidosis (PH < 7.3,  HCO3 < 15mEq/L)

         glucosuria

         ketonuria

         clinical features

     (3) Precipitating factor

           ; stress such as truma, infection, vomiting, and psychologic distubances

     (4) 소아 당뇨병때 당뇨혼수가 오는 이유

         매일 운동량이 다르다

         식사를 일정하게 유지하기 힘들다

         감염의 빈도가 높다

 

  5) non-ketotic hyperosmolar coma

     (1)  mild diabetes 가진 middle-aged or elderly환자에서 호발하며,

          mortality rate 40-70%       

          소아에서는 드물며 발생되면 pre-existing neurologia damage incedence 높다.

     (2) 특징

        severe hyperglycemia > 600mg/dl

        ketosis ; mild or absent

        nonketotic acidosis(lactic)

        severe dehydration

        depressed sensorium or frank coma

        various neurologic signs

             ; grandmal seizure, hyperthermia, hemiparesis, positive Babinski sign

     (3) Respiration ; usually shallow, lactic acidosis동반시 kussmaul 호흡양상

     (4) S-osmorality > 350 mosm/kg

         low production of ketone hyperosmolality 일으키며

                   epinephrine lipolytic effect      -+

                   insuline antilipoytic effect       | ==> lipolysis 방해

                   theraeutic use of β-bloker 관계  -- 

        conciousess depression DKA 아니라 hyperosmolarity정도에 비례

        hemoconcentration으로 cerebral a. & v.  thrombosis

        전해질 장애 ; hyponatremia, hypokalemia, acidosis

        탈수 증상

 

 

     (5) Treatment

        direct replacement of vascular volume deficit

        correction of hyperosmolar state ( see later under management of ketoacidosis)

            (i) 0.45% NaCl solution.

               ; volume deficit 1/2 12시간에 투여하고 나머지는 이후 24시간에 투여

            (ii) 혈당이 300mg/dl 되면

               ; 5% D/W in 0.2% NaCl 바꾸고

                 KCl 20mEq/l보충 ( hypokalemia예방위해 )

        혈청 potassium, 혈당농도를 monitoring

               ; 12시간에는 2시간 간격으로, 다음 24시간에는 4시간