Diabetul zaharat autoimun al adultului

ALEXANDRA BULGAR¹, A. BREHAR², A. COJOCARU¹

¹Centrul Medical Nova, Bucuresti

²Institutul National de Endocrinologie “C.I.Parhon”, Bucuresti

Rezumat:

Diabetul autoimun latent al adultului (LADA) reprezinta o forma lent progresiva autoimuna de diabet care apare la varsta adulta pe fondul unei distrugeri autoimune a celulelor β pancreatice datorita auto-anticorpilor ciculanti: anti-insulina (IAA), anti-decarboxilaza acidului glutamic 65 (GADA 65), anticorpi anti-celule insulare (ICA), anti- tirozin fosfataza (IA-2A). In literatura de specialitate se descriu doua forme: LADA tipul I caracterizat printr-un titru ridicat al GADA și asemanari fenotipice cu diabetul zaharat tip 1 și LADA tipul II cu titruri mai scazute de autoanticorpi și asemanari fenotipice cu diabetul zaharat tip 2. Stabilirea diagnosticului  corect al tipului de diabet este necesara pentru un tratamentul adecvat al pacientului.

Abstract:

Latent autoimmune diabetes in adults (LADA) describes a slowly progressive autoimmune diabetes form that occurs in adult age on the background of an autoimmune destruction of the β pancreatic cells by circulating autoantibodies. This autoantibodies are against insulin (IAA), glutamic acid decarboxylase 65 (GADA 65), islet cells antibodies (ICA), tyrosine phosphatase like protein (IA-2A). There are described two forms: LADA type I (with higher GADA levels and phenotypic similarities with T1DM) and LADA type II (with lower levels of antibodies and similarities with T2DM). It is very important to establish a proper diagnosis of the type of diabetes for an adequate therapy.

Abrevieri: BMI Body mass index, CTLA4 cytotoxic T-lymphocyte-associated antigen 4, GAD Glutamic acid decarboxylase, HbA1c Glycated haemoglobin A1c, HLA Human leukocyte antigen, IA-2 Anti-bodies against Tyrosine-phosphatase related IA-2 molecule, IAA Insulin auto-antibodies, ICA Islet cell antigen, , LADA Latent autoimmune diabetes in adults, PTPN22 Protein tyrosine phosphatase non-receptor type 22, TCF7L2 Transcription factor 7-like 2, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, ZnT8 Zinc transporter 8

Introducere

Diabetul autoimun latent al adultului (LADA) reprezinta o forma de diabet zaharat reprezentand aproximativ 2-12% din toate cazurile de diabet, caracterizat printr-o distrugere autoimuna a celulelor β pancreatice [1].
Aceasta forma lent progresiva de diabet autoimun a fost descrisa pentru prima data de Zimmet et al. fiind utilizați si alti termini pentru a descrie aceasta condiție: diabet de tip 1.5, diabet zaharat de tip 1 latent, diabet zaharat insulinodependent lent progresiv (IDDM) [2-6], aceasta forma de diabet avand caracteristicile unei boali autoimune cu prezența  autoanticorpilor similar pentru diabet zaharat tip 1 și unele trasaturi ale diabetului zaharat de tip2          [7,8,9].

Factorii de risc implicati in epidemiologia acestei forme de diabet zaharat sunt reprezentati    de distributia geografica, susceptibilitatea genetica, factorii de mediu, sexul și varsta  la diagnostic[10,11].

De obicei, pacienții sunt diagnosticati dupa varsta de 35 de ani și sunt adesea diagnosticati eronat  ca diabet zaharat tip 2, controlul glicemic obtinandu-se cu tratament  cu sulfoniluree pentru o perioada variabila, intre cateva luni sau ani, ulterior fiind necesara insulinoterapia [1].

Studiile recente arata ca prevalența reala a LADA bazata pe depistarea auto-anticorpilor in randul adultilor cu diabet zaharat este 10-30% la caucazieni si populatiile asiatice și acești pacienți au antecedente personale sau familiale de alte boli autoimune, cum ar fi boala Graves, tiroidita Hashimoto, boala celiaca [7,12,13-24].

În 2007, Carlsson S et al. în Nord-Trøndelag Health Study a demonstrat ca antecedentele familiale de diabet zaharat au reprezentat un factor de risc important pentru dezvoltarea LADA [24].

Printre factorii de risc pentru dezvoltarea LADA se mentioneaza si alele HLA de clasa II DR3, DR4 precum și DQB1 * 0302 și DQB1 * 0201, iar aceste alele HLA de clasa II sunt de asemenea implicate în susceptibilitatea diabetului zaharat tip 1 [25-31,42]. Alele HLA DQB1 * 0602 și DR2 sunt relativ frecvente la pacienții cu LADA și sunt rareori intalnite in diabetul zaharat de tip 1 avand un rol protector, explicand si varsta de debut a LADA [32-41].
Factor de risc genetic pentru diabetul zaharat de tip 1, gena CTLA-4, a fost descrisa si la pacienții cu LADA și cateva studii au raportat, de asemenea, prezenta genei PTPN22 la pacienții cu LADA [31,43-46].

Exista studii care au identificat gena TCF7L2 la pacienții cu LADA și variante ale genei sunt de asemenea descrise la pacientii cu diabet zaharat de tip 2 [39,47,48].

In cazul  pacienților diagnosticati cu LADA sunt detectati auto-anticorpi care sunt, de ase menea, identificati si în diabetul zaharat de tip 1: auto-anticorpii GAD, IAA și autoanticorpii IA-2 și recent auto-anticorpii  ZnT8 și alti auto-anticorpi nespecifici, inclusiv ATPO și anticorpi împotriva gliadinei [21,26,50-59]. Datele din literaratura arata ca pre zenta auto-anticorpilor IA-2 la pacienții cu LADA se asociaza cu o progresie mai rapida catre insulinodependenta [60,61].

Criteriile de diagnostic

Avand in vedere faptul ca pacientii cu aceasta forma de diabet sunt frecvent diagnosticati in mod eronat ca avand diabet zaharat tip 2 s-a incercat identificarea unor criterii de diagnostic care sa faciliteze stabilirea exacta a diagnosticului.

Trei criterii sunt recomandate de catre Immunology of Diabetes Society pentru a stabili diagnosticul de LADA [62](tabel 1).

Tabel 1

Diabetul zaharat tip1 se  caracterizeaza prin  distrugerea autoimuna a celulelor-β pancre atice cu prezența auto-anticorpilor: anticorpi anti-celule insulare (ICA), anticorpi impotriva  decarboxilazei 65 a acidului glutamic (GADA 65), anticorpi anti-tirozin fosfataza (IA-2A), anticorpi anti-insulina (IAA) [1]. Acesti auto-anticorpi sunt de asemenea prezenti la pacienții diagnosticati cu LADA și studii recente arata ca IAA și IA-2A sunt mai rar intalniti decat GADA [3,12]. Falorni A et al. raporteaza ca diagnosticul de LADA se bazeaza pe identificarea auto-anticorpilor anti-glutamic decarboxilazei (GADA), care sunt cel mai bun indicator pentru screening-ul LADA. Prezenta unui titru mare sau a unui numar multiplu de auto-anticorpi la pacienții LADA se coreleaza cu distrugerea rapida a celulelor beta pancreatice, iar pacienții cu un singur auto-anticorp sau un titru scazut de auto-anticorpi vor prezenta o distructie mai lenta a celulelor β pancreatice [53,63].

Clasificarea LADA

Numeraoase date din literatura de specialitate arata ca pe baza titrului de anticorpi anti GAD identificati la acesti pacienti, exista doua subtipuri de LADA: LADA tip I și LADA tip II.

LADA tip I este caracterizat print-un titru mai crescut de GADA și asemanari fenotipice cu diabetul zaharat de tip 1 (IMC scazut, predispozitie la cetoza, nivel redus al peptidului C) în timp ce pacienții cu niveluri mai scazute de GADA au fost clasificati în LADA tip II [1] (tabel 2).

Tabel 2

Screening-ul LADA

Diabetul autoimun latent la adulțului  (LADA) prezinta  unele trasaturi ale diabetului zaha rat tip 2, pe fondul unei distrugeri autoimune lent progresive a celulelor β pancreatice. Deoarece pacienții cu LADA sunt adesea diagnosticati in mod eronat ca diabet zaharat tip 2, Fourlanos et al. au stabilit cinci parametrii clinici care sunt predictivi pentru LADA [51,65](figura1).

Figura  1

Acesti cinci parametrii clinici de risc pentru LADA propusi de Fourlanos avut et.al au o sensibilitate de 90% și o specificitate de 71% in identificarea pacientilor cu  LADA în prezența a cel puțin doua carac teristici clinice, iar una sau niciuna dintre caracteristici a avut o valoare predictiva negativa de 99% [51,65].

Algoritmul de identificare a subiecților cu LADA

Manifestarile heterogene din LADA au impus stabilirea unui algoritm pentru identificarea subiecților cu LADA propus de Pozzilli P. în 2001 [7](figura 2).

Deoarece datele din literatura raporteaza o prevalența mai mare a auto-anticorpilor decarboxilazei acidului glutamic (GADA) în LADA, testarea pentru GADA poate fi utilizata pentru screening-ul LADA.
Rezultatele UKPDS au stabilit ca „prezența atat a ICA cat și GADA a fost un puternic predictor pentru necesitatea insulinoterapiei decat prezenta doar a anticorpilor GADA, la pacienții> 45 de ani„, astfel testarea, atat ICA și GADA poat fi utila pentru stabilirea diagnosticului de LADA [66]. Pentru pacientii GADA negativi cu risc ridicat (scorul clinic pentru LADA> 2) trebuie testati si alti auto-anticorpi (IAA, IA-2A).

Algoritm pentru diagnosticul LADA

Figura 2

Concluzii

Diabetul autoimun latent al adultului (LADA) este o tulburare în care distructia β celulara pancreatica autoimuna este lenta. Sunt descrise doua forme: LADA tip I (cu niveluri mai ridicate de GADA și asemanari fenotipice cu T1DM) și LADA tip II (cu niveluri mai scazute de anticorpi și asemanari cu T2DM). Folosind scorul de risc clinic in cinci puncte propus  de Fourlanos et al, precum și utilizand algoritmul propus de P. Pozzilli s-ar putea identifica un numar mare de pacienți cu LADA care initial au fost diagnosticati  eronat cu diabet zaharat de tip 2.

Este important sa se stabileasca un diagnostic corect al tipul de diabet, pentru ca un tratament adecvat sa fie adoptat, avand în vedere ca inițierea precoce a tratamentului cu insulina în LADA poate intarzia progresia distrugerii beta-celulare.

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