HELLP syndrome and hemolytic uremic syndrome during pregnancy: two disease entities, same causation. Case report and literature review

Abstract

Abstract

Thrombotic microangiopathies (TMA) are a group of diseases that can complicate pregnancy and threaten the lives of both the mother and the fetus. Several conditions can lead to TMA, including thrombotic thrombocytopenic purpura (TTP), HELLP syndrome and hemolytic uremic syndrome (HUS). We describe the case of a 39-year-old woman who presented a HELLP syndrome in the immediate postpartum period. The patient had acute kidney injury (AKI), increased LDH, unmeasurable haptoglobin levels and hypocomplementemia. Her ADAMTS13 value was normal, thus ruling out TTP. Shiga toxin tests were negative, so HUS associated with E. coli was also ruled out. HELLP syndrome and atypical hemolytic-uremic syndrome (aHUS) remained the most probable diagnosis. In the days following childbirth, the patient’s transaminase and bilirubin levels normalized while the anemia persisted, as did the AKI, resulting in the institution of dialysis treatment. A diagnosis of aHUS was made and therapy with eculizumab was started. The patient’s blood counts progressively improved, urine output was restored, her indices of renal function also concomitantly improved and dialysis was interrupted. A rash appeared after the third administration of eculizumab and the treatment was suspended. The patient is currently being followed up and has not relapsed. At thirteen months after delivery her renal function is normal as are her platelet counts, LDH, haptoglobin levels and proteinuria. Tests for mutations in the genes that regulate complement activity were negative. We believe that childbirth triggered the HELLP syndrome, which in turn brought about and sustained the HUS. In fact, the patient’s liver function improved right after delivery, while her kidney injury and hemolysis persisted, and she also had an excellent response to eculizumab. To our knowledge, no other cases of HELLP syndrome associated with haemolytic uremic syndrome during pregnancy have been reported in literature, nor have cases in which treatment with eculizumab was limited to only three administrations.

Keywords: HELLP syndrome, hemolytic uremic syndrome, pregnancy, eculizumab, thrombotic microangiopathy

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Introduzione

Le microangiopatie trombotiche (MAT) rappresentano un eterogeneo gruppo di affezioni che possono complicare la gravidanza mettendo a rischio la vita della madre e del feto. Tra di esse troviamo la porpora trombotica trombocitopenica (PTT), la sindrome HELLP e la sindrome emolitica uremica (SEU), tutte caratterizzate da un danno a carico delle cellule endoteliali e trombosi dei piccoli vasi che si manifestano clinicamente con anemia emolitica, trombocitopenia, e danno d’organo [13]. I confini tra queste patologie non sono ben definiti tanto che può essere difficile o addirittura impossibile una diagnosi differenziale, considerando poi che dette condizioni possono coesistere [48]. A complicare ulteriormente l’iter diagnostico, durante la gravidanza i parametri ematologici [9], della proteinuria [10] e della concentrazione del complemento hanno range di riferimento differenti rispetto al soggetto non in gravidanza [11-12]. 

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Complement factor B mutation in atypical hemolytic uremic syndrome. Rare cause of rare disease

Abstract

Hemolytic uremic syndrome (HUS) is a rare disease characterized by microangiopathic hemolysis, platelet consumption and multiple organ failure with predominant renal involvement. In the most of cases (85-90%), it is associated with enteric infection due to Shiga-toxin or verocytotoxin (STEC-VTEC)-producer Escherichia coli. Rarely, in about 10-15% of cases, HUS develops in the presence of a disorder of alternative complement pathway regulation and it is defined atypical (aHUS).

We describe the case of a 65-year-old man who came to our attention with a clinical presentation of aHUS and a clinical course characterized by rapidly progressive acute renal failure (ARF), which required renal replacement treatments, and by a stable clinical picture of hematological impairment as a marker of a non-severe and self-limiting form. The clinical and laboratory course allowed us not to perform specific therapies such as plasma exchange and/or block of the complement with eculizumab. Less than two weeks after hospital admission, there was a gradual recovery of renal function with spontaneous diuresis and hematological remission.

Genetic screening has revealed a heterozygous mutation in the complement factor B (CFB) that is not described in the literature and therefore not yet characterized in the genotype/phenotype correlation, also for the extreme rarity of the forms associated with CFB alteration. In conclusion, the presence of a new mutation in the CFB, such as the one described in our case, is probably associated with the development of aHUS but has not led to a poor prognosis, as generally reported in the literature for known variants of the CFB.

Key words: Acute kidney injury., Atypical hemolytic uremic syndrome, Complement factor B mutations, Thrombotic microangiopathy

Sorry, this entry is only available in Italian. For the sake of viewer convenience, the content is shown below in the alternative language. You may click the link to switch the active language.

Introduzione

La Sindrome Emolitico-Uremica (SEU) è una patologia rara caratterizzata sul piano clinico da emolisi microangiopatica, consumo piastrinico e danno multiorgano con prevalente interessamento renale e sul piano istologico da una microangiopatia trombotica sistemica (1).

Nella maggior parte dei casi (85-90%), la SEU è associata a un’infezione enterica da ceppi di Escherichia coli produttori di Shiga-like o verocitotossine (STEC-VTEC); tale forma interessa prevalentemente l’età pediatrica e viene definita come forma “tipica” (2).

Più raramente, in circa il 10-15% dei casi, la SEU non è causata da batteri produttori di verocitotossine ed è definita atipica (SEUa); essa riconosce, più spesso, come meccanismo patogenetico un disordine della regolazione della via alternativa del complemento. Questa forma può manifestarsi a qualsiasi età della vita e si presenta maggiormente in forma sporadica e solo nel 20% in forma familiare. In più della metà dei casi, la SEUa è associata a mutazioni in eterozigosi a carico dei geni che codificano per le proteine regolatrici del complemento come Fattore H (CFH), Fattore I (CFI), Cofattore proteico di membrana (MCP), Fattore B (CFB) e C3 (3 – 5). In aggiunta a tali mutazioni genetiche, la SEUa può essere causata da anticorpi anti-FH (AbAnti-FH) che interferiscono con la regione C-terminale del CFH determinando una deficienza funzionale acquisita del CFH; lo sviluppo di tali anticorpi è associato a una delezione in omozigosi del gene CFHR1, responsabile della sintesi di una molecola altamente omologa al CFH (6, 7). Inoltre, nelle SEUa sono state identificate mutazioni anche a livello del sistema di attivazione della coagulazione con particolare riguardo alla trombomodulina (8) e al plasminogeno (9) e, recentemente, a carico della diacil-glicerolo-chinasi epsilon (DGKe), una chinasi espressa a livello endoteliale con funzione regolatrice nell’attivazione piastrinica e nella coagulazione, caratterizzate da una precoce manifestazione, generalmente entro il primo anno di vita (10).
 

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