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Revisiting HELLP syndrome
Clinica Chimica Acta 451 (2015) 117–120
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Revisiting HELLP syndrome Luci Maria Dusse a,⁎, Patrícia Nessralla Alpoim a, Juliano Teixeira Silva a, Danyelle Romana Alves Rios b, Augusto Henriques Brandão c, Antônio Carlos Vieira Cabral c a b c
Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil Centro de Medicina Fetal — Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil
a r t i c l e
i n f o
a b s t r a c t HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes and low platelets. The syndrome frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially between the 27th and 37th week of gestation. Approximately 30% of cases occur after delivery. Although the etiopathogenesis of this syndrome remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture. Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. However, this syndrome can present nonspecific symptoms and the diagnosis may be difficult to be established. Laboratory tests and imaging exams are essential for differential diagnosis with other clinical conditions. Treatment of HELLP syndrome with corticosteroids, targeting both lung maturation of the fetus is still an uncertain clinical value. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women. © 2015 Elsevier B.V. All rights reserved.
Article history: Received 4 May 2015 Received in revised form 14 October 2015 Accepted 22 October 2015 Available online 23 October 2015 Keywords: HELLP syndrome Preeclampsia Laboratorial tests Glycemia Differential diagnosis Treatment
Contents 1.
Introduction . . . . . . . . 1.1. Etiopathogenesis . . . 1.2. Frequency . . . . . . 1.3. Diagnostic criteria . . 1.4. Clinical Symptoms . . 1.5. Differential Diagnosis . 1.6. Treatment . . . . . . 2. Conclusion . . . . . . . . . Acknowledgments . . . . . . . . References . . . . . . . . . . .
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1. Introduction HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical
⁎ Corresponding author at: Faculdade Farmácia, Sala 4104, Universidade Federal Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, MG CEP:31270-901, Brazil. E-mail address: [email protected] (L.M. Dusse).
http://dx.doi.org/10.1016/j.cca.2015.10.024 0009-8981/© 2015 Elsevier B.V. All rights reserved.
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condition that leads to hemolysis, elevated liver enzymes and low platelets [1]. Weinstein was undoubtedly the researcher with the greatest importance to advance the recognition of HELLP syndrome. He studied in detail 29 cases that were published in 1982 [1] and other 57 cases, published in 1985 [2]. The etiology of HELLP syndrome is not yet fully elucidated. Such syndrome is associated with severe clinical complications which may lead to both mother and fetus death, thus it is necessary to have a faster diagnosis and appropriate clinical intervention [3,4].
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L.M. Dusse et al. / Clinica Chimica Acta 451 (2015) 117–120
1.1. Etiopathogenesis HELLP syndrome is typically seen in patients with severe preeclampsia, although it can occur in the absence of this disease. This variant sometimes does not present hypertension, proteinuria and edema. Patients may have a general malaise or viral-like symptoms, which makes the HELLP syndrome clinical diagnosis a challenge [3]. Evaluating the natural progression of the syndrome, Dr. Weinstein concluded that thrombocytopenia occurred first. After, there is an increase in liver enzymes and finally hemolysis. In 25% of cases, the syndrome was manifested in the postpartum period [1]. Pain in the right upper quadrant around a week before admission was emphasized by Weinstein. A rare life-threatening complication of HELLP syndrome is hepatic hemorrhage and rupture, which occurs in approximately 0.5% of cases [4]. Although the etiopathogenesis of this condition remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture [1,5,6]. 1.2. Frequency HELLP syndrome's frequency varies from 0.5 to 0.9% pregnancies. It manifests before the delivery in 70% of cases and occurs preferentially between the 27th and 37th week of gestation [4]. Approximately 10% of cases manifest before the 27th week and 20% after the 37th [7]. The syndrome affects primarily pregnant women with higher white ethnicity [9]. Approximately 30% of HELLP syndrome cases occur after delivery, usually up to 48 h, even though some take up to 7 days. In these cases, the prognosis is worse, the presenting risk of renal failure and pulmonary edema significantly increased compared to the syndrome occurrence prior to labor [10,11]. In general, postpartum syndrome occurs in women who had proteinuria and hypertension in pregnancy. However, in about 10 to 20% of cases they are not associated with these previous symptoms [4,12]. Although variable, the manifestation of HELLP syndrome is fast. In more than 50% of cases, excessive weight gain and the presence of generalized edema are signs of HELLP development [13].
pronounced decrease of haptoglobin plasma levels, sometimes reaching to undetectable levels, since this protein is not produced in response to its consumption [17,18]. Although haptoglobin plasma decrease is an important parameter for the diagnosis of acute hemolysis, its determination is not usually used for HELLP syndrome diagnosis [18]. The elevated liver enzymes reflect injury to the liver microcirculation and consequent impairment of its function. An increase in plasma asparate aminotransferase (AST) and alanine aminotransferase (ALT) reflects hepatic injury. The elevation of glutathione S-transferase-A1 (GST-A1) is a more sensitive and earlier indicator of acute injury [20]. However, GST-a1 assessment is not routinely performed, and it is thus not used for the diagnosis of HELLP syndrome [19]. Endothelial injury is associated with activation and aggregation of platelets and the increased peripheral consumption of these, resulting in thrombocytopenia. Other clinical conditions associated with pregnancy can also determine thrombocytopenia, such as gestational thrombocytopenia in immune thrombocytopenic purpura (ITP) and PE [21]. Platelets count less than 100 × 109/L are relatively rare in PE and gestational thrombocytopenia, but frequent in ITP and mandatory in HELLP syndrome [12,22]. Currently there are two major definitions for diagnosing the HELLP syndrome. In the Tennessee Classification System, Sibai has proposed strict criteria for true HELLP syndrome, platelet count b 100 × 109/L, AST ≥ 70 UI/L and LDH ≥ 600 UI/L, besides the data of intravascular hemolysis (observed in the peripheral blood analysis of the microscopic film abnormal), increased serum bilirubin (≥ 20.5 μmol/L or ≥1.2 mg/ 100 mL) and elevated LDH levels (N 600 U/L) [12,13]. The MississippiTriple Class is based on the nadir of platelets count any time during the course of the disease. Class 1 and class 2 are associated with hemolysis (LDH N 600 U/L) and elevated AST levels (≥ 70 U/L), while class 3 requires only LDH N 600 U/L and AST ≥ 40 U/L in addition to the specific count (platelet count in class 1: b 50 × 109/L, class 2: 50 × 109/L − 100 × 109/L and class 3: N100 × 109/L). Class 3 is considered as a clinical significant transition stage or a phase of the HELLP syndrome which has the ability of progression [23–25]. Incomplete or partial form of HELLP syndrome occurs and it is defined by only one or two elements of the triad (hemolysis, hepatic changes with increased enzymes and thrombocytopenia) [7,13,23,26]. It can progress to complete form [23,26]. A partial or full reversal of the syndrome can rarely occur [27,28]. 1.4. Clinical Symptoms
1.3. Diagnostic criteria The diagnosis of the complete form of HELLP syndrome requires the presence of symptomatic triad, hemolysis, hepatic changes with increased enzymes and thrombocytopenia, as well as severe symptoms, as general malaise, with or without vomiting, pain in the right upper quadrant of the abdomen, excessive weight gain and the presence of generalized edema [1,2,13,14]. Laboratory tests are important for HELLP syndrome diagnosis and should always be requested in cases of preeclampsia, eclampsia and in pregnant women with pain in the right upper quadrant of the abdomen. Hemolysis is a major feature of this syndrome and results from microangiopathic hemolytic anemia. The fragmentation of erythrocytes is secondary to endothelial damage and fibrin deposition in vascular walls. These fragments identification in blood film (schizocytes) suggest microangiopathic anemia [15,16]. The hemolytic process is associated with decreased hematocrit and hemoglobin values [17,18]. Hemoglobinemia or hemoglobinuria can be macroscopically identified in about 10% of pregnant women with HELLP syndrome [19]. The free plasma hemoglobin binds to haptoglobin and hemoglobin– haptoglobin complex is rapidly sequestered by the liver. It avoids hemoglobin loss or accumulation in the kidneys and iron excretion, which keeps away the iron deleterious actions. This process leads to a
Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. Pregnant women often report discomfort a few days before the presentation of abdominal pain [12,27]. Approximately 30–60% of pregnant women have headache and about 20%, visual symptoms. The intensity of symptoms is exacerbated at night. However, this syndrome can present nonspecific symptoms, which could lead to a misinterpretation of viruses [12]. The spontaneous rupture of a liver subcapsular hematoma is more frequent in the liver's right lobus [4,12,29]. This process is accompanied by symptoms such as a sudden beginning, epigastric pain, backache and pain in the right shoulder, anemia and hypotension [30,31]. A low index of suspicion is warranted in patients with such symptoms to prompt emergent imaging and to allow rapid diagnosis, since it is associated with a significant increase in maternal and perinatal morbidity and mortality. Hepatic rupture can also occur in postpartum [32]. 1.5. Differential Diagnosis HELLP syndrome symptoms can be confused with other clinical conditions and a differential diagnosis can be a challenge. The obstetrician should pay attention to the nuances of the clinical history (pyelonephritis with septicemia, cholecystolithiasis, pancreatic, cocaine intoxication) and
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the behavior of laboratory abnormalities (viral hepatitis, CIV), since in some cases the therapeutic approach may differ and an error or a delayed diagnosis may worsen the maternal and perinatal prognosis [8]. HELLP syndrome can be diagnosed as viral hepatitis, cholangitis and other acute diseases. Other clinical conditions that can mimic HELLP syndrome are acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and antiphospholipid syndrome (SAF) [16,33]. AFLP usually occurs between the 30th and 38th week of gestation, with a history of one or two weeks of malaise, anorexia, nausea, vomiting, abdominal pain, headache and jaundice. Hypertension and proteinuria are usually absent, and leukocytosis, increased levels of creatinine, uric acid, ammonia, liver enzymes (alkaline phosphatase, AST and ALT) and bilirubin are present [33–35]. The prolongation of prothrombin time, due to factors II and V decreasing, supports the AFLP diagnosis, while hypoglycemia suggests HELLP syndromes. Liver ultrasonography may reveal increased echogenicity in severe cases of AFLP [33,36]. TTP should be distinguished by the intense thrombocytopenia and very low or undetectable ADAMTS13 activity [37]. ADAMTS13 specifically cleaves unusually-large von Willebrand factor (UL-VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, including TTP. High levels of UL-VWF in maternal plasma reflect the virtual absence of ADAMTS13, which supports TTP [38]. For HUS diagnosis, the triad of renal failure, microangiopathic hemolytic anemia and thrombocytopenia should be considered [39]. Finally, for SAF diagnosis, the guidelines established should be strictly applied [40]. Imaging exams are highlighted as major allies in the search of correct diagnosis for HELLP syndrome. Ultrasound, tomography or magnetic resonance are especially helpful in patients with clinical suspicion of hepatic impairment and should always be performed in these cases [41]. The best option for HELLP syndrome diagnosis, in cases not characterized as urgent, should be undergoing magnetic resonance. However, the complexity and the cost of this exam limit its use. On the other hand, glucose determination is a routine and inexpensive laboratorial test, whose request should be encouraged in order to maintain glucose levels within the reference range, therefore avoiding the worsening of patients [1,2,14].
of any effect of corticosteroids on substantive clinical outcomes. Preeclamptic women receiving steroids showed significantly greater improvement in platelet counts, which was greater for those receiving dexamethasone than those receiving betamethasone. To date, there is insufficient evidence of benefits in terms of substantive clinical outcomes to support the routine use of corticosteroids for the management of HELLP. They should be used in clinical situations, in which increased rate of recovery in platelet count is considered clinically worthwhile [44].
1.6. Treatment
References
Treatment of HELLP syndrome is based on syndrome symptoms. The unique resolution of the condition is the delivery. Patients with hypertensive crisis should be treated with antihypertensive as nifedipine or hydralazine. When indicated, prophylaxis with magnesium sulfate should be used in schemes described in the literature. Patients with gestational age less than 34 weeks, clinically stable, may have delayed the delivery by 36 to 48 h, in which they can be benefited from the use of corticosteroids for fetal lung maturation [42]. Treatment of HELLP syndrome with corticosteroids, aimed at both pulmonary maturation of the fetus and the recovery of platelet count of the mother is common, but its clinical value remains unclear [41,43]. Woudstra et al. (2010) evaluated eleven trials (550 women) comparing corticosteroids with placebo or no treatment and no difference was found in the risk of maternal or perinatal death. The only clear effect of treatment on individual outcomes was improved platelet count and this effect was stronger in women who commenced treatment antenatal. These authors also evaluated two trials (76 women), comparing dexamethasone with betamethasone and no clear evidence of a difference between groups in respect to severe perinatal morbidity or death was found. Maternal death and severe maternal morbidity were not reported. In respect to platelet count, dexamethasone was superior to betamethasone, both when treatment was commenced antenatally and postnatally. They concluded that there was no clear evidence
2. Conclusion Some important observations were made by Dr. Weinstein in the early 1980s and are very useful nowadays for pregnant women with HELLP syndrome management. The first observation is that the disease is progressive and the patient does not appear to be sick. The second one highlights hypoglycemia as an important marker of worsening. Hypoglycemia occurs by decreased glycogen stores in the liver and increased circulating insulin. Curiously, glycemia has not been considered throughout time. A search in Pub Med revealed that 20 case reports involving HELLP syndrome were published in the last three years, but none of them included this routine laboratorial parameter. Knowing the complexity of HELLP syndrome, attention for the role of hypoglycemia in the management of this syndrome should be disclosed. The third one emphasizes that there is no correlation between platelet count and liver enzyme levels to diagnose HELLP syndrome. The fourth one shows that all record of women who died from HELLP syndrome related complaints of heartburn and pain in the right upper quadrant during the third trimester of gestation and these symptoms were mistakenly treated with drugs not indicated for this syndrome [1]. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women. Acknowledgments The authors thank FAPEMIG and CNPq/Brazil. LMD is grateful to CNPq Research Fellowship (302794/2012-3).
[1] L. Weinstein, Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy, Am. J. Obstet. Gynecol. 142 (1982) 159–167. [2] L. Weinstein, Preeclampsia/eclampsia with hemolysis, elevated liver enzymes, and thrombocytopenia, Obstet. Gynecol. 66 (1985) 657–660. [3] A.K. Ertan, S. Wagner, H.J. Hendrik, H.A. Tanriverdi, W. Schmidt, Clinical and biophysical aspects of HELLP-syndrome, J. Perinat. Med. 30 (2002) 483–489. [4] B.M. Sibai, M.K. Ramadan, I. Usta, M. Salama, B.M. Mercer, S.A. Friedman, Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), Am. J. Obstet. Gynecol. 169 (1993) 1000–1006. [5] E.R. Norwitz, C.D. Hsu, J.T. Repke, Acute complications of preeclampsia, Clin. Obstet. Gynecol. 45 (2002) 308–329. [6] J.T. Stevenson, D.J. Graham, Hepatic hemorrhage and the HELLP syndrome: a surgeon's perspective, Am. Surg. 61 (1995) 756–760. [7] J.R. Barton, B.M. Sibai, Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome, Clin. Perinatol. 31 (2004) 807–833 vii. [8] C. Benedetto, L. Marozio, A. Tancredi, et al., Biochemistry of HELLP syndrome, Adv. Clin. Chem. 53 (2011) 85–104. [9] L. Weinstein, It has been a great ride: the history of HELLP syndrome, Am. J. Obstet. Gynecol. 193 (2005) 860–863. [10] B.M. Sibai, M.K. Ramadan, Acute renal failure in pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets, Am. J. Obstet. Gynecol. 168 (1993) 1682–1687 discussion 1687-1690. [11] A.J. Drakeley, P.A. Le Roux, J. Anthony, J. Penny, Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit, Am. J. Obstet. Gynecol. 186 (2002) 253–256. [12] B.M. Sibai, Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count, Obstet. Gynecol. 103 (2004) 981–991.
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[13] B.M. Sibai, The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am. J. Obstet. Gynecol. 162 (1990) 311–316. [14] L. Weinstein, Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. 1982, Am. J. Obstet. Gynecol. 193 (2005) 859 discussion 860. [15] E.F. Magann, J.N. Martin, Twelve steps to optimal management of HELLP syndrome, Clin. Obstet. Gynecol. 42 (1999) 532–550. [16] J.K. Baxter, L. Weinstein, HELLP syndrome: the state of the art, Obstet. Gynecol. Surv. 59 (2004) 838–845. [17] A. Marchand, R.S. Galen, F. Van Lente, The predictive value of serum haptoglobin in hemolytic disease, JAMA 243 (1980) 1909–1911. [18] G. Wilke, W. Rath, E. Schutz, V.W. Armstrong, W. Kuhn, Haptoglobin as a sensitive marker of hemolysis in HELLP-syndrome, Int. J. Gynaecol. Obstet. 39 (1992) 29–34. [19] W. Rath, A. Faridi, J.W. Dudenhausen, HELLP syndrome, J. Perinat. Med. 28 (2000) 249–260. [20] M.F. Knapen, T.P. Mulder, J.G. Bisseling, R.H. Penders, W.H. Peters, E.A. Steegers, Plasma glutathione S-transferase alpha 1–1: a more sensitive marker for hepatocellular damage than serum alanine aminotransferase in hypertensive disorders of pregnancy, Am. J. Obstet. Gynecol. 178 (1998) 161–165. [21] M. Parnas, E. Sheiner, I. Shoham-Vardi, et al., Moderate to severe thrombocytopenia during pregnancy, Eur. J. Obstet. Gynecol. Reprod. Biol. 128 (2006) 163–168. [22] L.M. Dusse, D.R.A. Rios, M.B. Pinheiro, A.J. Cooper, B.A. Lwaleed, Pre-eclampsia: relationship between coagulation, fibrinolysis and inflammation, Clin. Chim. Acta 412 (2011) 17–21. [23] J.N. Martin, C.H. Rose, C.M. Briery, Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child, Am. J. Obstet. Gynecol. 195 (2006) 914–934. [24] J.N. Martin, P.G. Blake, K.G. Perry, J.F. McCaul, L.W. Hess, R.W. Martin, The natural history of HELLP syndrome: patterns of disease progression and regression, Am. J. Obstet. Gynecol. 164 (1991) 1500–1509 discussion 1509-1513. [25] J.N. Martin, B.K. Rinehart, W.L. May, E.F. Magann, D.A. Terrone, P.G. Blake, The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification, Am. J. Obstet. Gynecol. 180 (1999) 1373–1384. [26] F. Audibert, S.A. Friedman, A.Y. Frangieh, B.M. Sibai, Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, Am. J. Obstet. Gynecol. 175 (1996) 460–464. [27] J.G. Aarnoudse, H.J. Houthoff, J. Weits, E. Vellenga, H.J. Huisjes, A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study, Br. J. Obstet. Gynaecol. 93 (1986) 145–155. [28] W. Visser, H.C. Wallenburg, Temporising management of severe pre-eclampsia with and without the HELLP syndrome, Br. J. Obstet. Gynaecol. 102 (1995) 111–117.
[29] A.C. Araujo, M.D. Leao, M.H. Nobrega, et al., Characteristics and treatment of hepatic rupture caused by HELLP syndrome, Am. J. Obstet. Gynecol. 195 (2006) 129–133. [30] C. Wicke, P.L. Pereira, E. Neeser, I. Flesch, E.A. Rodegerdts, H.D. Becker, Subcapsular liver hematoma in HELLP syndrome: evaluation of diagnostic and therapeutic options–a unicenter study, Am. J. Obstet. Gynecol. 190 (2004) 106–112. [31] B.K. Rinehart, D.A. Terrone, E.F. Magann, R.W. Martin, W.L. May, J.N. Martin, Preeclampsia-associated hepatic hemorrhage and rupture: mode of management related to maternal and perinatal outcome, Obstet. Gynecol. Surv. 54 (1999) 196–202. [32] Y. Gilboa, R. Bardin, D. Feldberg, G.N. Bachar, Postpartum hepatic rupture and retroperitoneal hematoma associated with HELLP syndrome, Isr. Med. Assoc. J. 8 (2006) 219–220. [33] B.M. Sibai, Imitators of severe pre-eclampsia/eclampsia, Clin. Perinatol. 31 (2004) 835–852 vii-viii. [34] T.A. Knox, L.B. Olans, Liver disease in pregnancy, N. Engl. J. Med. 335 (1996) 569–576. [35] E. Groot, P.G. de Groot, R. Fijnheer, P.J. Lenting, The presence of active von Willebrand factor under various pathological conditions, Curr. Opin. Hematol. 14 (2007) 284–289. [36] J.A. Ibdah, M.J. Bennett, P. Rinaldo, et al., A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women, N. Engl. J. Med. 340 (1999) 1723–1731. [37] MP A, Relapse of thrombotic thrombocytopenic purpura associated with decreased VWF cleaving activity. [38] M. Uemura, Y. Fujimura, S. Ko, M. Matsumoto, Y. Nakajima, H. Fukui, Pivotal role of ADAMTS13 function in liver diseases, Int. J. Hematol. 91 (2010) 20–29. [39] H.M. Tsai, A mechanistic approach to the diagnosis and management of atypical hemolytic uremic syndrome, Transfus. Med. Rev. (2014). [40] V. Pengo, A. Tripodi, G. Reber, et al., Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Crommittee of the International Society on Thrombosis and Haemostasis, J. Thromb. Haemost. 7 (2009) 1737–1740. [41] J.N. Martin, Milestones in the quest for best management of patients with HELLP syndrome (microangiopathic hemolytic anemia, hepatic dysfunction, thrombocytopenia), Int. J. Gynaecol. Obstet. 121 (2013) 202–207. [42] J.M. Alexander, K.L. Wilson, Hypertensive emergencies of pregnancy, Obstet. Gynecol. Clin. N. Am. 40 (2013) 89–101. [43] S. Aloizos, C. Seretis, N. Liakos, et al., HELLP syndrome: understanding and management of a pregnancy-specific disease, J. Obstet. Gynaecol. 33 (2013) 331–337. [44] D.M. Woudstra, S. Chandra, G.J. Hofmeyr, T. Dowswell, Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy, Cochrane Database Syst. Rev. (2010), CD008148.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Revisiting HELLP syndrome Luci Maria Dusse a,⁎, Patrícia Nessralla Alpoim a, Juliano Teixeira Silva a, Danyelle Romana Alves Rios b, Augusto Henriques Brandão c, Antônio Carlos Vieira Cabral c a b c
Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil Centro de Medicina Fetal — Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil
a r t i c l e
i n f o
a b s t r a c t HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes and low platelets. The syndrome frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially between the 27th and 37th week of gestation. Approximately 30% of cases occur after delivery. Although the etiopathogenesis of this syndrome remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture. Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. However, this syndrome can present nonspecific symptoms and the diagnosis may be difficult to be established. Laboratory tests and imaging exams are essential for differential diagnosis with other clinical conditions. Treatment of HELLP syndrome with corticosteroids, targeting both lung maturation of the fetus is still an uncertain clinical value. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women. © 2015 Elsevier B.V. All rights reserved.
Article history: Received 4 May 2015 Received in revised form 14 October 2015 Accepted 22 October 2015 Available online 23 October 2015 Keywords: HELLP syndrome Preeclampsia Laboratorial tests Glycemia Differential diagnosis Treatment
Contents 1.
Introduction . . . . . . . . 1.1. Etiopathogenesis . . . 1.2. Frequency . . . . . . 1.3. Diagnostic criteria . . 1.4. Clinical Symptoms . . 1.5. Differential Diagnosis . 1.6. Treatment . . . . . . 2. Conclusion . . . . . . . . . Acknowledgments . . . . . . . . References . . . . . . . . . . .
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1. Introduction HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to describe the clinical
⁎ Corresponding author at: Faculdade Farmácia, Sala 4104, Universidade Federal Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, MG CEP:31270-901, Brazil. E-mail address: [email protected] (L.M. Dusse).
http://dx.doi.org/10.1016/j.cca.2015.10.024 0009-8981/© 2015 Elsevier B.V. All rights reserved.
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condition that leads to hemolysis, elevated liver enzymes and low platelets [1]. Weinstein was undoubtedly the researcher with the greatest importance to advance the recognition of HELLP syndrome. He studied in detail 29 cases that were published in 1982 [1] and other 57 cases, published in 1985 [2]. The etiology of HELLP syndrome is not yet fully elucidated. Such syndrome is associated with severe clinical complications which may lead to both mother and fetus death, thus it is necessary to have a faster diagnosis and appropriate clinical intervention [3,4].
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1.1. Etiopathogenesis HELLP syndrome is typically seen in patients with severe preeclampsia, although it can occur in the absence of this disease. This variant sometimes does not present hypertension, proteinuria and edema. Patients may have a general malaise or viral-like symptoms, which makes the HELLP syndrome clinical diagnosis a challenge [3]. Evaluating the natural progression of the syndrome, Dr. Weinstein concluded that thrombocytopenia occurred first. After, there is an increase in liver enzymes and finally hemolysis. In 25% of cases, the syndrome was manifested in the postpartum period [1]. Pain in the right upper quadrant around a week before admission was emphasized by Weinstein. A rare life-threatening complication of HELLP syndrome is hepatic hemorrhage and rupture, which occurs in approximately 0.5% of cases [4]. Although the etiopathogenesis of this condition remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture [1,5,6]. 1.2. Frequency HELLP syndrome's frequency varies from 0.5 to 0.9% pregnancies. It manifests before the delivery in 70% of cases and occurs preferentially between the 27th and 37th week of gestation [4]. Approximately 10% of cases manifest before the 27th week and 20% after the 37th [7]. The syndrome affects primarily pregnant women with higher white ethnicity [9]. Approximately 30% of HELLP syndrome cases occur after delivery, usually up to 48 h, even though some take up to 7 days. In these cases, the prognosis is worse, the presenting risk of renal failure and pulmonary edema significantly increased compared to the syndrome occurrence prior to labor [10,11]. In general, postpartum syndrome occurs in women who had proteinuria and hypertension in pregnancy. However, in about 10 to 20% of cases they are not associated with these previous symptoms [4,12]. Although variable, the manifestation of HELLP syndrome is fast. In more than 50% of cases, excessive weight gain and the presence of generalized edema are signs of HELLP development [13].
pronounced decrease of haptoglobin plasma levels, sometimes reaching to undetectable levels, since this protein is not produced in response to its consumption [17,18]. Although haptoglobin plasma decrease is an important parameter for the diagnosis of acute hemolysis, its determination is not usually used for HELLP syndrome diagnosis [18]. The elevated liver enzymes reflect injury to the liver microcirculation and consequent impairment of its function. An increase in plasma asparate aminotransferase (AST) and alanine aminotransferase (ALT) reflects hepatic injury. The elevation of glutathione S-transferase-A1 (GST-A1) is a more sensitive and earlier indicator of acute injury [20]. However, GST-a1 assessment is not routinely performed, and it is thus not used for the diagnosis of HELLP syndrome [19]. Endothelial injury is associated with activation and aggregation of platelets and the increased peripheral consumption of these, resulting in thrombocytopenia. Other clinical conditions associated with pregnancy can also determine thrombocytopenia, such as gestational thrombocytopenia in immune thrombocytopenic purpura (ITP) and PE [21]. Platelets count less than 100 × 109/L are relatively rare in PE and gestational thrombocytopenia, but frequent in ITP and mandatory in HELLP syndrome [12,22]. Currently there are two major definitions for diagnosing the HELLP syndrome. In the Tennessee Classification System, Sibai has proposed strict criteria for true HELLP syndrome, platelet count b 100 × 109/L, AST ≥ 70 UI/L and LDH ≥ 600 UI/L, besides the data of intravascular hemolysis (observed in the peripheral blood analysis of the microscopic film abnormal), increased serum bilirubin (≥ 20.5 μmol/L or ≥1.2 mg/ 100 mL) and elevated LDH levels (N 600 U/L) [12,13]. The MississippiTriple Class is based on the nadir of platelets count any time during the course of the disease. Class 1 and class 2 are associated with hemolysis (LDH N 600 U/L) and elevated AST levels (≥ 70 U/L), while class 3 requires only LDH N 600 U/L and AST ≥ 40 U/L in addition to the specific count (platelet count in class 1: b 50 × 109/L, class 2: 50 × 109/L − 100 × 109/L and class 3: N100 × 109/L). Class 3 is considered as a clinical significant transition stage or a phase of the HELLP syndrome which has the ability of progression [23–25]. Incomplete or partial form of HELLP syndrome occurs and it is defined by only one or two elements of the triad (hemolysis, hepatic changes with increased enzymes and thrombocytopenia) [7,13,23,26]. It can progress to complete form [23,26]. A partial or full reversal of the syndrome can rarely occur [27,28]. 1.4. Clinical Symptoms
1.3. Diagnostic criteria The diagnosis of the complete form of HELLP syndrome requires the presence of symptomatic triad, hemolysis, hepatic changes with increased enzymes and thrombocytopenia, as well as severe symptoms, as general malaise, with or without vomiting, pain in the right upper quadrant of the abdomen, excessive weight gain and the presence of generalized edema [1,2,13,14]. Laboratory tests are important for HELLP syndrome diagnosis and should always be requested in cases of preeclampsia, eclampsia and in pregnant women with pain in the right upper quadrant of the abdomen. Hemolysis is a major feature of this syndrome and results from microangiopathic hemolytic anemia. The fragmentation of erythrocytes is secondary to endothelial damage and fibrin deposition in vascular walls. These fragments identification in blood film (schizocytes) suggest microangiopathic anemia [15,16]. The hemolytic process is associated with decreased hematocrit and hemoglobin values [17,18]. Hemoglobinemia or hemoglobinuria can be macroscopically identified in about 10% of pregnant women with HELLP syndrome [19]. The free plasma hemoglobin binds to haptoglobin and hemoglobin– haptoglobin complex is rapidly sequestered by the liver. It avoids hemoglobin loss or accumulation in the kidneys and iron excretion, which keeps away the iron deleterious actions. This process leads to a
Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain, nausea and vomiting. Pregnant women often report discomfort a few days before the presentation of abdominal pain [12,27]. Approximately 30–60% of pregnant women have headache and about 20%, visual symptoms. The intensity of symptoms is exacerbated at night. However, this syndrome can present nonspecific symptoms, which could lead to a misinterpretation of viruses [12]. The spontaneous rupture of a liver subcapsular hematoma is more frequent in the liver's right lobus [4,12,29]. This process is accompanied by symptoms such as a sudden beginning, epigastric pain, backache and pain in the right shoulder, anemia and hypotension [30,31]. A low index of suspicion is warranted in patients with such symptoms to prompt emergent imaging and to allow rapid diagnosis, since it is associated with a significant increase in maternal and perinatal morbidity and mortality. Hepatic rupture can also occur in postpartum [32]. 1.5. Differential Diagnosis HELLP syndrome symptoms can be confused with other clinical conditions and a differential diagnosis can be a challenge. The obstetrician should pay attention to the nuances of the clinical history (pyelonephritis with septicemia, cholecystolithiasis, pancreatic, cocaine intoxication) and
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the behavior of laboratory abnormalities (viral hepatitis, CIV), since in some cases the therapeutic approach may differ and an error or a delayed diagnosis may worsen the maternal and perinatal prognosis [8]. HELLP syndrome can be diagnosed as viral hepatitis, cholangitis and other acute diseases. Other clinical conditions that can mimic HELLP syndrome are acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and antiphospholipid syndrome (SAF) [16,33]. AFLP usually occurs between the 30th and 38th week of gestation, with a history of one or two weeks of malaise, anorexia, nausea, vomiting, abdominal pain, headache and jaundice. Hypertension and proteinuria are usually absent, and leukocytosis, increased levels of creatinine, uric acid, ammonia, liver enzymes (alkaline phosphatase, AST and ALT) and bilirubin are present [33–35]. The prolongation of prothrombin time, due to factors II and V decreasing, supports the AFLP diagnosis, while hypoglycemia suggests HELLP syndromes. Liver ultrasonography may reveal increased echogenicity in severe cases of AFLP [33,36]. TTP should be distinguished by the intense thrombocytopenia and very low or undetectable ADAMTS13 activity [37]. ADAMTS13 specifically cleaves unusually-large von Willebrand factor (UL-VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, including TTP. High levels of UL-VWF in maternal plasma reflect the virtual absence of ADAMTS13, which supports TTP [38]. For HUS diagnosis, the triad of renal failure, microangiopathic hemolytic anemia and thrombocytopenia should be considered [39]. Finally, for SAF diagnosis, the guidelines established should be strictly applied [40]. Imaging exams are highlighted as major allies in the search of correct diagnosis for HELLP syndrome. Ultrasound, tomography or magnetic resonance are especially helpful in patients with clinical suspicion of hepatic impairment and should always be performed in these cases [41]. The best option for HELLP syndrome diagnosis, in cases not characterized as urgent, should be undergoing magnetic resonance. However, the complexity and the cost of this exam limit its use. On the other hand, glucose determination is a routine and inexpensive laboratorial test, whose request should be encouraged in order to maintain glucose levels within the reference range, therefore avoiding the worsening of patients [1,2,14].
of any effect of corticosteroids on substantive clinical outcomes. Preeclamptic women receiving steroids showed significantly greater improvement in platelet counts, which was greater for those receiving dexamethasone than those receiving betamethasone. To date, there is insufficient evidence of benefits in terms of substantive clinical outcomes to support the routine use of corticosteroids for the management of HELLP. They should be used in clinical situations, in which increased rate of recovery in platelet count is considered clinically worthwhile [44].
1.6. Treatment
References
Treatment of HELLP syndrome is based on syndrome symptoms. The unique resolution of the condition is the delivery. Patients with hypertensive crisis should be treated with antihypertensive as nifedipine or hydralazine. When indicated, prophylaxis with magnesium sulfate should be used in schemes described in the literature. Patients with gestational age less than 34 weeks, clinically stable, may have delayed the delivery by 36 to 48 h, in which they can be benefited from the use of corticosteroids for fetal lung maturation [42]. Treatment of HELLP syndrome with corticosteroids, aimed at both pulmonary maturation of the fetus and the recovery of platelet count of the mother is common, but its clinical value remains unclear [41,43]. Woudstra et al. (2010) evaluated eleven trials (550 women) comparing corticosteroids with placebo or no treatment and no difference was found in the risk of maternal or perinatal death. The only clear effect of treatment on individual outcomes was improved platelet count and this effect was stronger in women who commenced treatment antenatal. These authors also evaluated two trials (76 women), comparing dexamethasone with betamethasone and no clear evidence of a difference between groups in respect to severe perinatal morbidity or death was found. Maternal death and severe maternal morbidity were not reported. In respect to platelet count, dexamethasone was superior to betamethasone, both when treatment was commenced antenatally and postnatally. They concluded that there was no clear evidence
2. Conclusion Some important observations were made by Dr. Weinstein in the early 1980s and are very useful nowadays for pregnant women with HELLP syndrome management. The first observation is that the disease is progressive and the patient does not appear to be sick. The second one highlights hypoglycemia as an important marker of worsening. Hypoglycemia occurs by decreased glycogen stores in the liver and increased circulating insulin. Curiously, glycemia has not been considered throughout time. A search in Pub Med revealed that 20 case reports involving HELLP syndrome were published in the last three years, but none of them included this routine laboratorial parameter. Knowing the complexity of HELLP syndrome, attention for the role of hypoglycemia in the management of this syndrome should be disclosed. The third one emphasizes that there is no correlation between platelet count and liver enzyme levels to diagnose HELLP syndrome. The fourth one shows that all record of women who died from HELLP syndrome related complaints of heartburn and pain in the right upper quadrant during the third trimester of gestation and these symptoms were mistakenly treated with drugs not indicated for this syndrome [1]. In conclusion, three decades after the tireless efforts of Dr. Weinstein to characterize HELLP syndrome, it remains a challenge to the scientific community and several questions need to be answered for the benefit of pregnant women. Acknowledgments The authors thank FAPEMIG and CNPq/Brazil. LMD is grateful to CNPq Research Fellowship (302794/2012-3).
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