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Revisiting HELLP syndrome

Luci Maria Dusse, Patrcia Nessralla Alpoim, Juliano Teixeira Silva,


Danyelle Romana Alves Rios, Augusto Henriques Brandao, Antonio Carlos
Vieira Cabral

PII: S0009-8981(15)30026-7
DOI: doi: 10.1016/j.cca.2015.10.024
Reference: CCA 14149

To appear in: Clinica Chimica Acta

Received date: 4 May 2015


Revised date: 14 October 2015
Accepted date: 22 October 2015

Please cite this article as: Dusse Luci Maria, Alpoim Patrcia Nessralla, Silva Ju-
liano Teixeira, Rios Danyelle Romana Alves, Brandao Augusto Henriques, Cabral
Antonio Carlos Vieira, Revisiting HELLP syndrome, Clinica Chimica Acta (2015), doi:
10.1016/j.cca.2015.10.024

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Revisiting HELLP syndrome

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Luci Maria Dusse1-PhD

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Patrcia Nessralla Alpoim1- PhD

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Juliano Teixeira Silva1- Pharmacyst

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Danyelle Romana Alves Rios2 -PhD

Augusto Henriques Brando3- PhD


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Antnio Carlos Vieira Cabral3-PhD
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1
Faculdade de Farmcia/Universidade Federal de Minas Gerais/Brazil
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2
Campus Centro Oeste Dona Lindu, Universidade Federal de So Joo Del-
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Rei, Brazil.
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3
Centro de Medicina Fetal Hospital das Clnicas/ Universidade Federal de
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Minas Gerais/Brazil

Correspondent Author:

Luci Dusse

Faculdade Farmcia/Sala4104

Universidade Federal Minas Gerais/Brazil

Av.Antnio Carlos,6627

Belo Horizonte/MG CEP:31270-901

Phone:55313409-6880 FAX:55313409-6985

email:lucidusse@gmail.com
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ABSTRACT

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

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leads to hemolysis, elevated liver enzymes and low platelets. The syndrome

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frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially

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between the 27th and 37th weeks of gestation. Approximately 30% of cases

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occur after delivery. Although the etiopathogenesis of this syndrome remains

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unclear, histopathologic findings in the liver include intravascular fibrin deposits

that presumably may lead to hepatic sinusoidal obstruction, intrahepatic


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vascular congestion, and increased intrahepatic pressure with ensuing hepatic

necrosis, intraparenchymal and subcapsular hemorrhage, and eventually


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capsular rupture. Typical clinical symptoms of HELLP syndrome are pain in the
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right upper quadrant abdomen or epigastric pain, nausea and vomiting.

However, this syndrome can present nonspecific symptoms and the diagnosis
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may be difficult to be established. Laboratory tests and imaging exams are

essential for differential diagnosis with other clinical conditions. Treatment of


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HELLP syndrome with corticosteroids, targeting both lung maturation of the

fetus is still 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.

Key words: HELLP Syndrome; Preeclampsia; Laboratorial tests; Differential

diagnosis; Treatment.

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I. Introduction

HELLP syndrome was first described in 1982 by Weinstein et al. and the

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term HELLP refers to an acronym used to describe the clinical condition that

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leads to hemolysis, elevated liver enzymes and low platelets [1]. Weinstein was

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undoubtedly the researcher with the greatest importance to advance the

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recognition of HELLP syndrome. He studied in detail 29 cases that were

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published in 1982 [1] and other 57 cases, published in 1985 [2].

The etiology of HELLP syndrome is not yet fully elucidated. Such


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syndrome is associated with severe clinical complications which may lead to

both mother and fetus death, thus being necessary a faster diagnosis and
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appropriate clinical intervention [3, 4].


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II. Etiopathogenesis
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HELLP syndrome is typically seen in patients with severe preeclampsia,


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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].

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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

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0.5% of cases [4].

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Although the etiopathogenesis of this condition remains unclear,

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histopathologic findings in the liver include intravascular fibrin deposits that

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presumably may lead to hepatic sinusoidal obstruction, intrahepatic vascular

congestion, and increased intrahepatic pressure with ensuing hepatic necrosis,

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intraparenchymal and subcapsular hemorrhage, and eventually capsular
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rupture [1, 5, 6].

III. Frequency
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HELLP syndromes frequency varies from 0.5 to 0.9% pregnancies. It


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manifests before the delivery in 70% of cases and occurs preferentially between
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the 27th and 37th weeks of gestation [4]. Approximately 10% of cases manifest
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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 hours, even though some take up to 7 days. In these cases, the

prognosis is worse, 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


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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

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HELLP development [13].

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IV. Diagnostic criteria

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The diagnosis of the complete form of HELLP syndrome requires the

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presence of symptomatic triad, hemolysis, hepatic changes with increased
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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,
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13, 14].

Laboratory tests are important for HELLP syndrome diagnosis and


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should always be requested in cases of preeclampsia, eclampsia and in


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pregnant women with pain in the right upper quadrant of the abdomen.
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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) suggests 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].
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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

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iron deleterious actions. This process leads to a pronounced decrease of

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haptoglobin plasma levels, sometimes reaching to undetectable levels, since

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this protein is not produced in response to its consumption [17, 18]. Although

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haptoglobin plasma decrease is an important parameter for the diagnosis of

acute hemolysis, its determination is not usually used for HELLP syndrome

diagnosis [18].
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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


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injury. The elevation of glutathione S-transferase-A1 (GST-A1) is a more

sensitive and earlier indicator of acute injury [20]. However, GST-a1


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assessment is not routinely performed, and it is thus not used for the diagnosis
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of HELLP syndrome [19].


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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

100x109/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


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criteria for true HELLP syndrome, platelet count<100x109/L, AST70UI/L and

LDH600UI/L, besides the data of intravascular hemolysis (observed in the

peripheral blood analysis of the microscopic film abnormal), increased serum

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bilirubin (20.5mol/L or 1.2mg/100mL) and elevated LDH levels (>600U/L)

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[12, 13]. The Mississippi-Triple Class is based on the nadir of platelets count

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any time during the course of the disease. Class 1 and class 2 are associated

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with hemolysis (LDH>600U/L) and elevated AST levels (70 U/L), while class 3

requires only LDH>600U/L and AST40U/L in addition to the specific count

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(platelet count in class 1: <50x109/L, class 2: 50x109/L -100x109/L and class 3:

>100x109/L. Class 3 is considered as a clinical significant transition stage or a


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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


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only one or two elements of the triad (hemolysis, hepatic changes with

increased enzymes and thrombocytopenia) [7, 13, 23, 26]. It can progress to
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complete form [23, 26]. A partial or full reversal of the syndrome can rarely
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occur [27, 28].


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VI. Clinical Symptoms

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.

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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

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frequent in the livers right lobus [4, 12, 29]. This process is accompanied by

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symptoms such as a sudden beginning, epigastric pain, backache and pain in

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the right shoulder, anemia and hypotension [30, 31]. A low index of suspicion is

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warranted in patients with such symptoms to prompt emergent imaging and to

allow rapid diagnosis, since it is associated with a significant increase in

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maternal and perinatal morbidity and mortality. Hepatic rupture can also occur
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in postpartum [32].

VII. Differential Diagnosis


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HELLP syndrome symptoms can be confused with other clinical


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conditions and a differential diagnosis can be a challenge. The obstetrician


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should pay attention to the nuances of the clinical history (pyelonephritis with
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septicemia, cholecystolithiasis, pancreatic, cocaine intoxication) and 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 weeks of gestation,
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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,

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ammonia, liver enzymes (alkaline phosphatase, AST and ALT) and bilirubin are

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present [33-35]. The prolongation of prothrombin time, due to factors II and V

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decreasing, supports the AFLP diagnosis, while hypoglycemia suggests HELLP

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syndromes. Liver ultrasonography may reveal increased echogenicity in severe

cases of AFLP [33, 36]. TTP should be distinguished by the intense

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thrombocytopenia and very low or undetectable ADAMTS13 activity [37].
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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-


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threatening systemic disease, including TTP. High levels of UL-VWF in

maternal plasma reflect the virtual absence of ADAMTS13, which supports TTP
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[38].
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For HUS diagnosis, the triad of renal failure, microangiopathic hemolytic


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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,
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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].

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VIII. Treatment

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Treatment of HELLP syndrome is based on syndrome symptoms. The

unique resolution of the condition is the delivery. Patients with hypertensive

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crisis should be treated with antihypertensive as nifedipine or hydralazine.
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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 hours, in


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which they can be benefited from the use of corticosteroids for fetal lung

maturation [42]. Treatment of HELLP syndrome with corticosteroids, aimed at


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both pulmonary maturation of the fetus and the recovery of platelet count of the
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mother is common, but its clinical value remains unclear [41, 43].
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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


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betamethasone, both when treatment was commenced antenatally and

postnatally. They concluded that there was no clear evidence of any effect of

corticosteroids on substantive clinical outcomes. Preeclamptic women receiving

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steroids showed significantly greater improvement in platelet counts, which was

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greater for those receiving dexamethasone than those receiving

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betamethasone. To date, there is insufficient evidence of benefits in terms of

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substantive clinical outcomes to support the routine use of corticosteroids for

the management of HELLP. They should be used in clinical situations, in which

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increased rate of recovery in platelet count is considered clinically worthwhile
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[44].

IX. Conclusion
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Some important observations were made by Dr. Weinstein in the early


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1980s and are very useful nowadays for pregnant women with HELLP
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syndrome management. The first observation is that the disease is progressive


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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. 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].


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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

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pregnant women.

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Acknowledgement

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The authors thank FAPEMIG and CNPq/Brazil. LMD is grateful to CNPq Research

Fellowship (302794/2012-3).

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Revisiting HELLP syndrome

Highlights

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HELLP syndrome is a severe and progressive clinical condition

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Laboratory tests and imaging exams are essential for diagnosis
Etiopathogenesis of this syndrome remains unclear

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There is insufficient evidence to support the routine use of corticosteroids

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for treatment

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