Clinica Chimica Acta 451 (2015) 117–120

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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
Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil
b
Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil
c
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

Article history: HELLP syndrome was first described in 1982 by Weinstein et al. and the term HELLP refers to an acronym used to
Received 4 May 2015 describe the clinical condition that leads to hemolysis, elevated liver enzymes and low platelets. The syndrome
Received in revised form 14 October 2015 frequency varies from 0.5 to 0.9% pregnancies and manifests preferentially between the 27th and 37th week of
Accepted 22 October 2015
gestation. Approximately 30% of cases occur after delivery. Although the etiopathogenesis of this syndrome
Available online 23 October 2015
remains unclear, histopathologic findings in the liver include intravascular fibrin deposits that presumably
Keywords:
may lead to hepatic sinusoidal obstruction, intrahepatic vascular congestion, and increased intrahepatic pressure
HELLP syndrome with ensuing hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and eventually capsular rupture.
Preeclampsia Typical clinical symptoms of HELLP syndrome are pain in the right upper quadrant abdomen or epigastric pain,
Laboratorial tests nausea and vomiting. However, this syndrome can present nonspecific symptoms and the diagnosis may be
Glycemia difficult to be established. Laboratory tests and imaging exams are essential for differential diagnosis with
Differential diagnosis other clinical conditions. Treatment of HELLP syndrome with corticosteroids, targeting both lung maturation of
Treatment 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.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
1.1. Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.2. Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.3. Diagnostic criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.4. Clinical Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.5. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
2. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

1. Introduction condition that leads to hemolysis, elevated liver enzymes and low plate-
lets [1]. Weinstein was undoubtedly the researcher with the greatest
HELLP syndrome was first described in 1982 by Weinstein et al. and importance to advance the recognition of HELLP syndrome. He studied
the term HELLP refers to an acronym used to describe the clinical 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
⁎ Corresponding author at: Faculdade Farmácia, Sala 4104, Universidade Federal Minas
syndrome is associated with severe clinical complications which may
Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, MG CEP:31270-901, Brazil. lead to both mother and fetus death, thus it is necessary to have a faster
E-mail address: lucidusse@gmail.com (L.M. Dusse). diagnosis and appropriate clinical intervention [3,4].

http://dx.doi.org/10.1016/j.cca.2015.10.024
0009-8981/© 2015 Elsevier B.V. All rights reserved.
118 L.M. Dusse et al. / Clinica Chimica Acta 451 (2015) 117–120
1.1. Etiopathogenesis
HELLP syndrome is typically seen in patients with severe preeclamp-
sia, 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, his-
topathologic 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 ethnic-
ity [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].
1.3. Diagnostic criteria
The diagnosis of the complete form of HELLP syndrome requires the
presence of symptomatic triad, hemolysis, hepatic changes with in-
creased 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 microan-
giopathic 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
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 im-
portant 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 microcircula-
tion 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 preg-
nancy 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 Mississippi-
Triple 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 consid-
ered 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 de-
fined 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
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 presen-
tation 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 con-
ditions 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
 L.M. Dusse et al. / Clinica Chimica Acta 451 (2015) 117–120
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 throm-
bocytopenic 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 leukocy-
tosis, 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 decreas-
ing, 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 hemo-
lytic 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 mag-
netic 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 charac-
terized 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].
1.6. Treatment
Treatment of HELLP syndrome is based on syndrome symptoms. The
unique resolution of the condition is the delivery. Patients with hyper-
tensive 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) com-
paring 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 antena-
tal. These authors also evaluated two trials (76 women), comparing
dexamethasone with betamethasone and no clear evidence of a differ-
ence 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
119
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 out-
comes 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].
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. Hypo-
glycemia 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 in-
volving 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 hypoglyce-
mia 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 com-
plaints of heartburn and pain in the right upper quadrant during the
third trimester of gestation and these symptoms were mistakenly treat-
ed 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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