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Adresa de coresponden:Dr. Gabriela Oproiu, IOMC Alfred Rusescu, Str. Lacul Tei Nr. 120, Sector 2, Bucureti

BOALA ADDISON LA COPIL

Dr. Gabriela Oproiu1, Dr. Camelia Procopiuc2, Dr. Sigrid Covaci1

1Institutul pentru Ocrotirea Mamei i Copilului Alfred Rusescu, Bucureti2Institutul Naional de Endocrinologie C.I. Parhon, Bucureti

REZUMAT

Boala Addison reprezint insuficiena adrenocortical datorat distruciei sau disfunciei cortexului adrenal.Afecteaz att funcia glucocorticoid, ct i pe cea mineralocorticoid. De obicei, debutul bolii se nregistreazatunci cnd 90% sau mai mult din ambele cortexuri adrenale sunt distruse sau nefunc ionale. Prezentmcazul unui pacient cu simptome i semne clasice de insuficien adrenal acut, care a fost diagnosticat ncele din urm cu insuficien adrenal autoimun.

Cuvinte cheie: Boala Addison, copil

PREZENTRI DE CAZ

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PREZENTARE DE CAZ

Pacient, B.E., n vrst de 12 ani, se prezint nclinic pentru fatigabilitate important, ameeli,dureri abdominale, inapeten, grea uneori aso-ciat cu vrsturi i pierdere progresiv n greutate,aprute n urm cu 6 luni naintea prezentrii. naceste 6 luni pacientul a solicitat ngrijire medicalla mai muli medici. Investigaiile efectuate fiind nlimite normale, a primit tratament simptomatic nspecial pentru simptomatologia digestiv (drota-verinum i trimebutin).

Examenul clinic: stare general modificat, greutate 36 kg,

talie = 168 cm ameeli paloare tegumentar, hiperpigmentare tegu-

mentar la nivelul genunchilori extremit-ilor (pliuri palmare i plantare), transpiraii

profuze i extremiti reci.A.V. = 70 bpm, regulat; TA = 90/60 mmHg nclinostatism i 80/50 mmHg n ortostatism; paci-entul neputnd menine ortostatismul din cauzaameelii posturale severe.

Restul aparatelori sistemelor au fost n limitenormale

Ex. F.O. a avut aspect normal.Datele de laborator au aratat: leucocitoz cu mo-

nocitoz, absena sindromului inflamator biologic,niveluri normale ale bilirubinei totale i conjugate,

TGO, TGP, proteine totale, LDH, CK, creatininiacid uric. Valori notabile au fost: glucoz 54mg/dl(valori normale 70-110), uree 58,3 mg/dl (valorinormale 20-50), sodiu seric 108 mmoli/L (valorinormale 136-145), potasiu seric 6,1 mmol/L(valorinormale 3,5-5,1), clor seric 77 mmoli/L (valori nor-male 97-111). Testele suplimentare au artat o va-loare a sodiului urinar crescuti o valoare a pota-

siului urinar sczut.Valoarea ACTH plasmatic a fost mult crescut:2.000 pg/ml (valori normale 3-66) i valoarea cor-tisolului plasmatic a fost mai puin de 1g/dl.Testrile endocrinologice au artat o valoare cres-cut a TSH: 27.2 IU/ml (valori normale 0,5-4,5) io valoare a prolactinei de 51,72 ng/ml (valori nor-male 2,64-13,13). Valorile DHE-A, FSH i LH aufost n limite normale. ECG, EEG i ecografia ab-dominal au fost normale.

Pacientul a fost diagnosticat cu insuficien a-

drenal acut (criz adrenal). A fost iniiat terapiacu corticosteroizi n doz suprafiziologic (HHC100 mg iv n bolus i apoi la fiecare 8 ore), reechi-librare hidric cu soluie salini astfel s-a obinutcontrolul endocrinologic. n plus, pacientul a primitun mineralocorticoid (fludrocortizon), glucoz pa-renterali tratament antibiotic, conform protocoluluide tratament. n decurs de cteva zile valoarea so-diului seric s-a corectat, ajungnd la valori normale,iar starea general a pacientului s-a mbuntit.Pacientul a fost externat cu recomandarea de

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continuare a tratamentului la domiciliu cu prednisoni fludrocortizon oral, sub urmrire endocrinologi-c. Pacientul i rudele acestuia au fost instruite cuprivire la atenia deosebit ce trebuie acordat pen-tru meninerea strii de sntate, i despre aportulcrescut de lichide i dublarea dozelor de meninere

a terapiei de substituie atunci cnd se mboln-vete.

DISCUII I CONCLUZII

Insuficiena adrenalprimar, sau boala Addison,este o boal rar, care trecut cu vederea poate fiamenintoare pentru via. ntrzierile semnifica-tive n punerea diagnosticului sunt frecvente, avndn vedere c simptomele principale (fatigabilitatea,anorexia i pierderea n greutate) sunt nespecifice.

Dup stabilirea diagnosticului, terapia de substituieglucocorticoid i mineralocorticoid poate ame-liora simptomatologia i poate fi salvatoare de via.Recunoaterea bolii de ctre medic este de impor-tan vital, n vederea asigurrii unui diagnostic itratament prompt.

Unele studii sugereaz faptul c insuficienaadrenal primar n populaia pediatric este celmai frecvent atribuit hiperplaziei adrenale conge-nitale, care se ntlnete cu o frecven de apro-

ximativ 1 la 15.000 de nateri (1). Atunci cnd afost descris pentru prima dat, de ctre Addison,tuberculoza era de departe cauza cea mai comun ainsuficienei adrenale primare. n prezent, tubercu-loza rmne o cauz major de insuficien supra-renal n rile n curs de dezvoltare, implicarea su-prarenalei aprnd n 5% dintre pacienii cutuberculoz activ. Cu toate acestea, n rile indus-trializate, distrucia autoimuna glandei suprarenalese ntlnete n 80-90% dintre cazurile de insufi-cien adrenal primar (2,3). Boala Addison auto-

imun este frecvent asociat altor boli autoimune,cel mai frecvent bolilor tiroidiene autoimune, ane-mia pernicioasi diabetul zaharat (4). De fapt, naproximativ 60% dintre cazuri boala Addison apareca parte a unor sindroame poliendocrine, cu o pre-ponderen la femei (5). Sindromul poliendocrin detip II este cel mai frecvent sindrom poliendocrin icuprinde: insuficiena adrenal autoimun (100%)i boala tiroidian autoimun (69%). Diabetul zaha-rat tip 1 (52%), insuficiena gonadal primar (4%),

vitiligo (5%) i gastrita autoimun potfi

, de aseme-nea, ntlnite n sindromul poliendocrin de tip II(4,5). Alte cauze de insuficien adrenal primarsunt rare n rile dezvoltate i includ diverse in-fecii, boli genetice, hemoragie adrenal bilateral,

boli infiltrative sau metastaze, sau boal indusmedicamentos.

n cazul nostru, dac ntr-o prim etap ne-am fiputut gndi, avnd n vedere valorile crescute aleTSH i prolactin, la o insuficien adrenal primarn cadrul unui sindrom poliendocrin, normalizarea

valorilor imediat dup nceperea tratamentului desubstituie cu glucocorticoid i mineralocorticoidau exclus diagnosticul.

Exceptnd cazul n care un pacient se afl n cri-z adrenal, diagnosticul de insuficien adrenaleste n general ntrziat. Cea mai frecventproblemn ratarea diagnosticului este lipsa de suspiciuneclinic, datorat n principal semnelor i simpto-melor nespecifice (6). n unele studii, mai mult de50% din pacieni au semne i simptome ale boliiAddison, cu debutul la mai mult de un an naintea

diagnosticrii (7). Mai mult, aproximativ 60% dinpacienii cu boala Addison au solicitat ngrijiremedical de la doi sau mai muli medici nainte cadiagnosticul corect sfie stabilit (8).

n ceea ce privete caracteristicile clinice alebolii Addison, cel mai evident semn este reprezen-tat de pigmentarea pielii. Hiperpigmentarea este ob-servat pe zonele expuse la soare, cicatrice recente,axile, cute palmare, puncte de presiune i mucoase(bucal, vaginal, vulvar, anal). Simptomele pre-zente n boala Addison sunt reprezentate de: sl-biciune, oboseal (100%), simptome gastro-intes-tinale (92%): grea, vrsturi, constipaie, dureriabdominale, diaree, poft de sare (16%), ameealpostural (12%), dureri articulare sau musculare (6-13%). Semnele clinice observate n boala Addisonsunt reprezentate de: scderea n greutate (100%),hiperpigmentare (94%), hipotensiune (88-94%),vitiligo (10-20%) i calcificri auriculare (5%). Lapacienii cu insuficien adrenal primar suntcomune modificri ale datelor de laborator. Hipo-

natremia (88%), hiperpotasemia (64%), hipercalce-mia (6%), azotemia (55%), anemia (40%) i eozino-filia (17%) sunt tipice.

Diagnosticul de insuficien adrenal primareste susinut prin msurarea, dimineaa devreme(ntre 8 i 9 a.m.), a nivelurilor de cortisol seric(sczut) i ACTH (crescut).

Boala Addison poate mima frecvent o afec-iune gastrointestinal (cu crampe abdominale,grea persistent i vrsturi, sau diaree) sau oboal psihiatric. Pacienii sunt uneori diagnosticai

greit ca avnd depresie sau anorexie nervoas.Complicaiile bolii Addison includ criza adrenal

(cu hipotensiune care poate merge pn la oc ichiar moarte) i efectele adverse ale medicaieiglucocorticoide i mineralocorticoide.

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n ceea ce privete managementul pe termenlung al bolii Addison, educaia pacientului despreprevenirea i managementul crizei adrenale esteimperativ. Pacienii cu insuficien adrenal artrebui s dein un card cu informaii despre terapiacurent i recomandrile pentru tratamentul n

situaii de urgen. Purtarea unei brri sau colierde avertizare este, de asemenea, necesar. Pacieniitrebuie s i dubleze/tripleze doza de prednison n

caz de febr, infecii sau diaree. n caz de vrsturi,hipotensiune arterial, intervenii chirurgicale, seva administra HHC 100 mg iv bolus, apoi 100 mgla 8 ore, serfiziologic si glucoz 5%.

n concluzie, boala Addison este o boal uor dediagnosticat i de tratat dac ne gndim la ea, ns

nerecunoscuti netratat poate fi amenintoare devia.

Addison disease in children

Gabriela Oproiu, MD1; Camelia Procopiuc, MD2; Sigrid Covaci, MD1

1The Institute for Mother and Child Protection Alfred Rusescu, Bucharest2The National Institute of Endocrinology C.I. Parhon, Bucharest

ABSTRACT

Addison disease is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal

cortex. It affects both glucocorticoid and mineralocorticoid function. The onset of disease usually occurs

when 90% or more of both adrenal cortices are dysfunctional or destroyed. We present a patient that had

classic symptoms and signs of acute adrenal insufficiency, who was ultimately diagnosed with autoimmune

adrenal insufficiency.

Key words:Addison disease, children

CASE REPORT

Patient B.E., 12 years old, presented in the clinicwith important fatigability, dizziness, abdominalpain, poor appetite, nausea with occasional vomit-

ing and progressive weight loss over six monthprior to presentation. In this six month the patient hadsought medical attention from more physicians. In-vestigations were within normal limits and the pa-tient receivedsymptomatic treatment,especially fordigestive symptoms (drotaverinum and trimebuti-num).

Physical examination: modified general condition, weight 36 kg

and stature 168 cm; dizziness;

pale skin, hyperpigmentation of the kneesand extremities (palmar and plantar creases),profuse sweating and cold extremities;

pulse 70 bpm, regular and blood pressure90/60 mmHg supine and 80/50 mmHg sitting;

he could not stand on account of severe pos-tural dizziness;

all other systems were essentially normal; fundoscopy revealed a normal fundus.Laboratory testing revealed: leukocytosis with

monocytosis, absence of infl

ammatory syndrome,normal levels of total and conjugated bilirubin,TGP, TGO, total proteins, LDH, CK, creatinine anduric acid. Of note are glucose 54 mg/dl (normalrange 70-110), ureea 58.3 mg/dl (normal range 20-50), sodium 108 mmol/L (normal range 136-145),potassium 6,1 mmol/L (normal range 3.5-5.1),chloride 77 mmol/L (normal range 97-111). Furthertesting showed increased urine sodium and de-creased urine potassium. The plasma adrenocorti-cotropic hormone (ACTH) was elevated at 2.000

pg/ml (normal range 3-66) and plasma cortisol lev-el was less than 1g/dl. Further endocrine testingshowed an elevated thyroid-stimulating hormonelevel of 27.2 IU/mL (normal 0.5-4.5), and a pro-lactin level of 51.72 ng/ml (normal 2.64-13.13).

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Dehydroepiandrosterone (DHE-A), follicle-stimu-lating hormone (FSH) and luteinizing hormone(LH) levels were all within normal limits. Electro-cardiogram, encephalogram and abdominal ultra-sound were normal.

The patient was diagnosed with primary acute

adrenal insufficiency (adrenal crisis). Stress-dosesteroids (hydrocortisone 100 mg intravenously inbolus and the every 8 hours) and volume resuscita-tion with saline solution was initiated and endocri-nological control was obteined. In addition to corti-costeroid andfluid replacement, a mineralocorticoid(fludrocortisone), parenteral glucose and antibioticwere prescribed, according to treatment protocol.Over several days, the sodium level corrected tonormal and the patient and the patients status wasmuch improved. The patient was subsequently dis-

charged home on oral prednisone and fludrocorti-sone with endocrinology follow-up. Patient andrelatives were instructed regarding the importanceof careful atention to health and fluid intake and todouble meintenance doses when ill until medicalattention is obtained.

DISCUSSION AND CONCLUSIONS

Primary adrenal insufficiency, or Addisons dis-ease, is an uncommon disease that can be life threat-ening if overlooked. Significant delays in diagnosisare common because the main presenting symp-toms (such as fatigue, anorexia, and weight loss)are nonspecific. Once adrenal insufficiency is sus-pected, the diagnostic work-up is well established.After the diagnosis is made, glucocorticoid andmineralocorticoid replacement therapy can relievesymptoms and be life-saving. Physician awarenessof this disease is vital to ensure prompt diagnosisand treatment.

Some studies suggest that primary adrenal in-sufficiency in the pediatric population is most com-monly attributed to congenital adrenal hyperplasia,which occurs in about 1 in 15,000 births (1). Whenfirst described by Addison, tuberculosis was by farthe most common etiology of adrenal insufficiency.Today, tuberculosis remains a major cause of adre-nal insufficiency in the developing world with ad-renal involvement occurring in 5% of patients withactive tuberculosis. In industrialized countries,however, autoimmune destruction of the adrenal

gland accounts for 80% to 90% of cases of primaryadrenal insufficiency (2,3).Autoimmune Addisonsdisease is often associated with other autoimmunediseases, most frequently with autoimmune thyroiddisease, pernicious anemia, and diabetes mellitus

(4).In fact, in approximately 60% of these cases,autoimmune Addisons disease occurs as part of anautoimmune polyendocrine syndrome (APS), witha female preponderance (5).Autoimmune polyen-docrine syndrome type II is the most common poly-endocrine syndrome and comprises autoimmune

adrenal insufficiency (100%) and autoimmune thy-roid disease (69%). Type 1 diabetes mellitus (52%),primary gonadal failure (4%), vitiligo (5%), andautoimmune gastritis can also be seen as part ofAPS type II (4,5). Other causes of primary adrenalinsufficiency are rare in developed countries, butinclude various infections, genetic disorders, bilat-eral adrenal hemorrhage, infiltrating diseases ormetastasis, or drug-induced.

Inour case, if in a firststep,wecouldthink, be-cause of the elevatedTSHandprolactin, at adrenal

insufficiency as a part of an autoimmune polyendo-crine syndrome, normalization immediately afterstartingglucocorticoidandmineralocorticoidreplace-ment hadexcludedthe diagnosis.

Unless a patient presents with acute adrenal cri-sis, the diagnosis of adrenal insufficiency is oftendelayed. The most common problem in missed di-agnosis is lack of clinical suspicion mainly becausethe signs and symptoms are nonspecific (6). Insome reports, up to 50% of patients have signs andsymptoms of Addisons disease for more than oneyear before the diagnosis is established (7). Fur-thermore, a survey of patients with the disease re-vealed that 60% had sought medical attention fromtwo or more physicians before the correct diagnosiswas even considered (8).

The most obvious feature seen in primary adre-nal insufficiency is skin pigmentation. The pigmen-tation is seen in sun-exposed areas, recent ratherthan old scars, axillae, nipples, palmar creases,pressure points, and in mucous membranes (bucal,

vaginal, vulval, anal). The symptoms of Addisondisease are: weakness, tiredness, fatigue (100%),anorexia (100%), gastrointestinal symptoms (92%):nausea, vomiting, constipation, abdominal pain, di-arrhea, salt craving (16%), postural dizziness(12%), muscle or joint pains (6-13%). The signsseen in Addison disease are weight loss (100%),hyperpigmentation (94%), hypotension (88-94%),vitiligo (10-20%) and auricular calcification (5%).In patients with chronic adrenal insufficiency, manylaboratory abnormalities are common. Hyponatre-

mia (88%), hyperkalemia (64%), hypercalcemia(6%), azotemia (55%), anemia (40%) and eosino-philia (17%) are typical (9).

The diagnosis of primary adrenal insufficiencyis verified by combined measurement of early

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morning (between 8 and 9 a.m.) serum cortisol(low) and plasma ACTH (high) levels.

Addisons disease can often mimic a gastroin-testinal disorder (with abdominal cramps, persis-tent nausea and vomiting, or diarrhea) or a psychi-atric disease. Patients are sometimes misdiagnosed

as having depression or anorexia nervosa.The complications of Addisons disease includeadrenal crisis (with hypotension leading to shockand even death), side effects of glucocorticoid and

mineralocorticoid terapy.

In regards to the long-term management of Ad-disons disease, patient education about the preven-

tion and management of adrenal crisis is impera-tive. All patients with adrenal insufficiency shouldcarry a card with information about current therapyand recommendations for treatment in emergencysituations. A warning bracelet or necklace is alsorecommended. Incase offever, infection, diarrhea

will double / triple dose ofprednisone. In case ofvomiting, hypotension (BP < 100 mmHg), surgerywill be given100 mgivbolusHHCthen 100mg ev-ery 8 hours, salineand glucose5%.

In conclusionAddisons diseaseis a diseaseeasytodiagnoseandtreatif we think aboutit, but unrec-ognizedand untreatedcanbelifethreatening.

1. Rebecca Perry, Oufae Kecha, Jean Paquette, Celine Huot, Guy VanVilet and Cheri Deal Primary Adrenal Insufficiency in Children: TwentyYears Experience at the Sainte-Justine Hospital, Montreal-http://jcem.

endojournals.org/content/90/6/3243.full

2. Arlt W., Allolio B. Adrenal insufficiency. Lancet. 2003 May 31;361(9372):1881-1893

3. Lvs K., Husebye E.S. Addisons disease. Lancet. 2005 Jun 1117;365(9476):2058-2061

4. Martn Martorell P., Roep B.O., Smit J.W. Autoimmunity in Addisonsdisease. Neth J Med. 2002 Aug; 60(7):269-75. Review. Erratum in: Neth

J Med. 2002 Oct;60(9):378. Martorell PM [corrected to Martn Martorell P].

5. Eisenbarth G.S., Gottlieb P.A. Autoimmune polyendocrine syndromes.N Engl J Med. 2004, May 13; 350(20):2068-2079. Review

6. Dorin R.I., Qualls C.R., Crapo L.M. Diagnosis of adrenal insufficiency.Ann Intern Med. 2003 Aug 5;139(3):194-204. Review. Erratum in:Ann

Intern Med. 2004 Feb 17;140(4):315

7. Zelissen P.M. Addison patients in the Netherlands: medical report ofthe survey. The Hague: Dutch Addison Society, 1994

8. Ten S., New M., Maclaren N. Clinical review 130: Addisons disease2001. J Clin Endocrinol Metab. 2001 Jul; 86(7):2909-2022. Review

9. Williams textbook of Endocrinolgy, 11th edition, Ed. Saunders, 2007;471:485

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