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Reumatologia/Rheumatology
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6/2014
vol. 52
 
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Review paper

HELLP syndrome: a complication or a new autoimmune syndrome?

Paola Triggianese
,
Carlo Perricone
,
Roberto Perricone
,
Caterina De Carolis

Reumatologia 2014; 52, 6: 377–383
Online publish date: 2014/11/30
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Introduction

Pregnancy-associated diseases with placental origin are multifactorial conditions to which both maternal and feto-placental factors contribute, and the combination of these factors leads to differences in disease features. These diseases have a familial component suggesting a genetic background. Hypertensive disorders of pregnancy (HDP) include gestational hypertension, generally defined as new-onset hypertension (≥ 140 mmHg systolic or ≥ 90 mmHg diastolic blood pressure) arising after 20 gestational weeks (GW), and pre-eclampsia (PE), defined as gestational hypertension accompanied by proteinuria (excretion of ≥ 300 mg protein every 24 hours) [1, 2]. Poor early placentation is especially associated with an early disease onset. Hypertensive disorders of pregnancy are among of the major causes of maternal and perinatal morbidity and mortality, and increase the future risk of cardiovascular disease for both mother and offspring. Moreover, predisposing cardiovascular or metabolic risks for endothelial dysfunction, as part of an enhanced systemic inflammatory response, might dominate in the origin of late onset PE. Meta-analyses of epidemiological studies investigating the association between exposure to ambient air pollution and pregnancy-induced hypertensive disorders including gestational hypertension and PE report that exposure to air pollution (in particular nitrogen oxides and particulate matter) increases the risk of HDP [3]. The HELLP syndrome is a pregnancy-specific disease characterized by hemolysis (due to microangiopathic hemolytic anemia), elevated lactate dehydrogenase (LDH), elevated liver enzymes caused by acute liver damage, and a platelet count decreased by the enhanced consumption [4]. It is considered a severe variant of hypertensive disorders in pregnancy together with the PE and the eclampsia that affect maternal and perinatal mortality and morbidity. HELLP occurs in 0.01–0.2% of the general population, accounting for 10% to 12% of complicated gestations with PE or eclampsia. The Tennessee Classification diagnostic criteria for HELLP include hemolysis, increased LDH and liver enzymes, and a low platelet count. The Mississippi Triple-class Classification criteria further classify the disease by the nadir of the platelet count [5]. It is well known that alterations in the placenta and in the trophoblast invasion of spiral arteries have a central role, but the utero-placental lesions seem to be not specific to hypertensive disorder alone. Thus, there is an increasing interest in the role of the inflammatory and the immunologic mechanisms involved in the pathogenesis of the HELLP syndrome.

Inflammation and antioxidant mechanisms

Hypertensive disorders of pregnancy are characterized by metabolic disturbances similar to those found in cardiovascular diseases including endothelial dysfunction, inflammation, and oxidative stress [1]. Prospective longitudinal studies of cytokine expression in the circulation during normal pregnancy show that as pregnancy progresses, there is an overall decrease in pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), accompanied by an increase in the anti-inflammatory cytokines such as interleukin 10 (IL-10) [6]. The balance between pro- and anti-inflammatory cytokines is essential for implantation, placental development and pregnancy outcome. Changes in the T helper (h)1/Th2 balance in the feto-maternal interface in favor of Th1 can lead to adverse pregnancy outcomes, including recurrent spontaneous miscarriages [7, 8]. Increased Th1 cytokines, including TNF-α, have been found in women suffering from recurrent spontaneous abortion (RSA) [7, 8]. Evidence suggests that inflammatory cytokines deriving from placenta such as TNF-α, interleukin IL-6 and IL-10 are increased during pregnancy-induced hypertension [8]. However, it is well known that immune cells communicate by cytokines and chemokines and that these interactions influence the immune differentiation and activation. Inflammatory cytokines and T lymphocytes have recently been reported to be involved in animal models of HELLP syndrome: HELLP rats show increased plasma levels of TNF-α, IL-6 and IL-17, and CD8+T lymphocytes [9]. Disorders in the cytokine and chemokine expression and alterations in the cell signaling may be involved in the alteration of the placenta function in terms of angiogenesis, cell recruitment, and lymphoid trafficking (Fig. 1). In the context of cellular signaling pathways, evidence suggests a role of the mitogen-activated protein kinases (MAPKs), a family of serine/threonine kinases, in the organogenesis of the placenta [10]. In human placenta, p38a MAPK is activated by a variety of extracellular stimuli such as inflammatory cytokines (IL-1, TNF-α) and growth factors, UV irradiation, high osmotic stress, and chemical agents. Adams et al. show that the loss of p38a MAPK causes placental defects and embryonic death [11]. The authors documented that placental p38a MAPK is significantly lower in the HELLP syndrome compared with the controls suggesting a correlation between the p38a MAPK gene and the development of placental insufficiency as occurs in HELLP syndrome [10]. Heat shock proteins (Hsps) are ubiquitous molecules that are usually considered to be intracellular proteins with molecular chaperone and cytoprotective functions. However, Hsp70 (HSPA1A) is present in the peripheral circulation of healthy non-pregnant and pregnant individuals [12]. In normal pregnancy, circulating Hsp70 levels are decreased and show a positive correlation with gestational age and an inverse correlation with maternal age [13]. The capacity of extracellular Hsp70 to elicit innate and adaptive pro-inflammatory immune responses involving the conversion of dendritic cells (DCs) from tolerogenic to immunogenic and the stimulation of the cytolytic activity of natural killer (NK) cells and γ/δ T cells might be harmful in pregnancy, and may lead to maternal immune rejection of the fetus [12, 14]. A decreased circulating Hsp70 level, consequently, may promote the maintenance of immunological tolerance to the fetus. Indeed, elevated circulating Hsp70 concentrations are associated with an increased risk of several pregnancy complications. Molvarec et al. report that serum Hsp70 levels are significantly higher in patients with HELLP syndrome than in severely pre-eclamptic patients without HELLP syndrome [13]. Furthermore, serum Hsp70 levels show a very strong correlation with the markers of hemolysis (plasma free hemoglobin level, serum LDH activity and total bilirubin level) and of hepatocellular injury (serum aminotransferase activities, such as aspartate aminotransferase, AST, and alanine aminotransferase, ALT) in the HELLP syndrome. Moreover, circulating Hsp70 concentration may also reflect the severity of the disease [15]. Extracellular Hsp70 can stimulate pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) production of antigen-presenting cells and can also activate the classical complement pathway [16, 17]. Increasing attention in the physiopathology of inflammatory and immune-mediated diseases has been focused on the role of reactive oxygen species (ROS) since they are produced during inflammation. Glutathione (GSH) is the most abundant non-protein intracellular thiol which acts to scavenge ROS as well as to regenerate other antioxidants from their oxidized forms. Glutathione exerts diverse effects on the immune system, either stimulating or inhibiting the immunological response in order to control inflammation [18]. It is well reported that GSH acts in association with ROS and the complement system (CS) in modulating the inflammatory response mediated by NFκB: GSH inhibits complement-ROS mediated JNK (c-jun-N-terminal kinase/stress-activated protein) in a dose-dependent fashion, resulting in interference with apoptosis [18]. Glutathione acts in association with the CS in modulating the inflammatory response [19]. It is well reported that GSH levels are decreased in the HELLP syndrome [20]. These findings are relevant for the design of interventions aimed at the modulation of GSH metabolism to inhibit CS-mediated damage in autoimmune diseases [19, 20].

The complement system and the innate immune cells

The CS is involved in the pathogenesis of several autoimmune diseases. Complement activation contributes to inflammation-driven tissue injury, which occurs during the ischemia/reperfusion processes, vasculitides, nephritis, arthritis, and many others diseases [21]. It is known that during normal pregnancy, the CS is activated at the maternal-fetal interface through the relative hypoxia as well as the presence of externalized phosphatidylserine on the outer leaflets of trophoblast. CS dysregulation has an essential and causative role in damage to the fetal-placental unit [22]. Evidence confirmed the role of both the classic and the alternative pathway of CS in the initiation of the cascade and the contribution to fetal damage in experimental models and provided evidence linking the CS to angiogenic factor imbalance associated with placental dysfunction [22]. Therefore, biomarkers of CS dysregulation may prove useful for prediction or treatment of complicated pregnancies such as PE/HELLP syndrome [23]. Decreased GSH levels can modulate the immune response influencing the proliferation of NK cells [24]. NK cells are the predominant leukocyte population in the endometrium at the time of implantation and in early pregnancy [25, 26]. The role of NK cells has been reported to be immunosurveillance; these cells may also mediate the angiogenesis necessary for continuation of the pregnancy or for the remodeling of the spiral arteries to uteroplacental arteries [24]. In this context, evidence supports a key role of the innate rather than adaptive immunity in the pathogenesis of PE, in particular the increase of circulating neutrophils and monocytes, and NK cells [27]. Inhibitory and activating receptors such as immunoglobulin-like (KIR), C-type lectin and natural cytotoxicity receptors, could play a role in the course of the systemic inflammatory response observed in PE [28, 29]. Indeed, patients with early-onset severe PE without HELLP syndrome have increased NK cell function related to cytokine production, cytotoxicity and expression of lectin-like receptors such as NKG2 [30]. Abnormalities in number and activation of NK cells have also been related to RSA suggesting a possible pathogenic role of these cells in this condition [30]. According to evidence in the literature comparing the percentage of peripheral blood NK cells in infertile and RSA women versus fertile controls, we previously reported that women with reproductive failure show significantly higher NK cell levels than controls [31–34]. Furthermore, evidence in the literature documented that the state of activation of decidual DC represents one of the central players influencing the immunological mechanisms in the pathogenesis of HELLP syndrome [35].

Gene variants and autoimmunity

HELLP has a hereditary familial component [36]. The genetic contribution is likely complex, involving genetic variants and fetal-maternal gene-gene interactions. Several gene variants are probably associated with increased risk of HELLP syndrome: the vascular endothelial growth factor (VEGF) gene, the coagulation factor V Leiden mutation, the glucocorticoid receptor gene, and the Toll-like receptor gene [5]. These variants contribute to altered immune regulation and apoptosis, defects in angiogenesis and vasculogenesis, uncontrolled inflammation, and thrombophilia [5]. Several maternal risk factors are probably associated with a higher risk of HELLP syndrome such as the metabolic syndrome, infertility treatment, as well as the presence of autoimmune diseases. Metabolic disorders and cardiovascular risk factors might dominate in the origin of late onset PE, since it seems to be related to endothelial cell dysfunction as well as systemic vascular resistance [37]. An imbalance between anti-angiogenic factors (e.g. soluble VEGF receptor-1, s-Flt1, and soluble endoglin, s-Eng) and pro-angiogenic factors (e.g. placental growth factor – PlGF) has been associated with PE [38]. Many biomarkers are reported in maternal blood predicting early onset HELLP syndrome such as an abnormal concentration of the placental protein 13 (PP13) and angiogenic factors (VEGF, s-Flt1, s-Eng) [39, 40]. Moreover, meta-analyses on non-classical cardiovascular biomarkers after HDP suggest persistent endothelial inflammation [41]. Women with rheumatologic diseases are more likely to have PE and miscarriage than healthy women [42]. Appenzeller et al. reported the relationship between HELLP syndrome, antiphospholipid syndrome (APS) and antiphospholipid (aPL) antibodies [43]. The APS is an autoimmune disease characterized by one or more aPL which react towards negatively charged plasmatic proteins and many components of coagulation (platelets, endothelial cells, humoral factors). Targets of aPL are phosphatidylserine, protein C and S, antithrombin III, prothrombin, annexin V, and 2 glycoprotein I [44]. The relationship between HELLP syndrome and APS is well described, and HELLP syndrome can be considered in the group of thrombotic microangiopathy as a microangiopathic APS [43].

Diagnosis and therapeutic options

Main diagnostic criteria of the HELLP syndrome include the Tennessee Classification and the Mississippi Triple-class System. According to the Tennessee Classification, the following criteria should be satisfied: micro-angiopathic hemolytic anemia with abnormal blood smear, low serum haptoglobin and elevated LDH levels, a platelet count below 100 × 109/l, an elevation of AST above 70 IU/l and LDH above 600 IU/l or bilirubin more than 1.2 mg/dl [45]. In the Mississippi Triple-class System, there are three classes of HELLP syndromes according to the nadir of the platelet count: class 1 includes a platelet count below 50 × 109/l; class 2 includes a platelet count below 100 × 109/l; class 3 includes a platelet count below 150 × 109/l [46]. There are several conditions in differential diagnosis with HELLP: pregnancy-related diseases (benign thrombocytopenia and acute fatty liver of pregnancy); infectious, inflammatory diseases not specifically related to pregnancy (virus hepatitis, cholangitis, cholecystitis); diseases characterized by thrombocytopenia (immunologic thrombocytopenia, folate deficiency, systemic lupus erythematosus, APS); and diseases that may mimic HELLP (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome). The efficacy of corticosteroids (which can reduce inflammation and improve maternal platelet count) in the HELLP syndrome confirms the role of the inflammatory and angiogenic imbalance as well as of immune-abnormalities in the pathophysiology of the HELLP syndrome [47, 48]. Moreover, the strategy of treatment in APS and HELLP patients is similar and still a matter of debate: aspirin, low molecular weight heparin, plasma exchange, fresh frozen plasma administration, and intravenous immunoglobulins have been considered in the management of HELLP treatment. The use of antithrombin has also been suggested as a possible therapeutic option. Therapeutic options targeting the underlying immunologic mechanisms during PE/HELLP syndrome that are under investigation are summarized in Table I.
To conclude, HELLP syndrome has been for too long described just as a clinical complication of pregnancy. The unveiling of the (auto)immune pathogenic mechanisms underlying its onset is crucial for correct management and the development of effective therapies.

The authors declare no conflict of interest.

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