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 pronounced decrease of haptoglobin plasma levels, sometimes reaching

to undetectable levels, since this protein is not produced in response to
HELLP syndrome is typically seen in patients with severe preeclamp- its consumption [17,18]. Although haptoglobin plasma decrease is an im-
sia, although it can occur in the absence of this disease. This variant portant parameter for the diagnosis of acute hemolysis, its determination
sometimes does not present hypertension, proteinuria and edema. is not usually used for HELLP syndrome diagnosis [18].
Patients may have a general malaise or viral-like symptoms, which The elevated liver enzymes reflect injury to the liver microcircula-
makes the HELLP syndrome clinical diagnosis a challenge [3]. tion and consequent impairment of its function. An increase in plasma
Evaluating the natural progression of the syndrome, Dr. Weinstein asparate aminotransferase (AST) and alanine aminotransferase (ALT)
concluded that thrombocytopenia occurred first. After, there is an reflects hepatic injury. The elevation of glutathione S-transferase-A1
increase in liver enzymes and finally hemolysis. In 25% of cases, the (GST-A1) is a more sensitive and earlier indicator of acute injury [20].
syndrome was manifested in the postpartum period [1]. However, GST-a1 assessment is not routinely performed, and it is thus
Pain in the right upper quadrant around a week before admission not used for the diagnosis of HELLP syndrome [19].
was emphasized by Weinstein. A rare life-threatening complication of Endothelial injury is associated with activation and aggregation of
HELLP syndrome is hepatic hemorrhage and rupture, which occurs in platelets and the increased peripheral consumption of these, resulting
approximately 0.5% of cases [4]. in thrombocytopenia. Other clinical conditions associated with preg-
Although the etiopathogenesis of this condition remains unclear, his- nancy can also determine thrombocytopenia, such as gestational
topathologic findings in the liver include intravascular fibrin deposits thrombocytopenia in immune thrombocytopenic purpura (ITP) and
that presumably may lead to hepatic sinusoidal obstruction, intrahepatic PE [21]. Platelets count less than 100 × 109/L are relatively rare in PE
vascular congestion, and increased intrahepatic pressure with ensuing and gestational thrombocytopenia, but frequent in ITP and mandatory
hepatic necrosis, intraparenchymal and subcapsular hemorrhage, and in HELLP syndrome [12,22].
eventually capsular rupture [1,5,6]. Currently there are two major definitions for diagnosing the HELLP
syndrome. In the Tennessee Classification System, Sibai has proposed
1.2. Frequency 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
HELLP syndrome's frequency varies from 0.5 to 0.9% pregnancies. It hemolysis (observed in the peripheral blood analysis of the microscopic
manifests before the delivery in 70% of cases and occurs preferentially film abnormal), increased serum bilirubin (≥ 20.5 μmol/L or ≥1.2 mg/
between the 27th and 37th week of gestation [4]. Approximately 10% 100 mL) and elevated LDH levels (N 600 U/L) [12,13]. The Mississippi-
of cases manifest before the 27th week and 20% after the 37th [7]. The Triple Class is based on the nadir of platelets count any time during
syndrome affects primarily pregnant women with higher white ethnic- the course of the disease. Class 1 and class 2 are associated with
ity [9]. hemolysis (LDH N 600 U/L) and elevated AST levels (≥ 70 U/L), while
Approximately 30% of HELLP syndrome cases occur after delivery, class 3 requires only LDH N 600 U/L and AST ≥ 40 U/L in addition to
usually up to 48 h, even though some take up to 7 days. In these cases, the specific count (platelet count in class 1: b 50 × 109/L, class 2:
the prognosis is worse, the presenting risk of renal failure and pulmonary 50 × 109/L − 100 × 109/L and class 3: N100 × 109/L). Class 3 is consid-
edema significantly increased compared to the syndrome occurrence ered as a clinical significant transition stage or a phase of the HELLP
prior to labor [10,11]. syndrome which has the ability of progression [23–25].
In general, postpartum syndrome occurs in women who had Incomplete or partial form of HELLP syndrome occurs and it is de-
proteinuria and hypertension in pregnancy. However, in about 10 fined by only one or two elements of the triad (hemolysis, hepatic
to 20% of cases they are not associated with these previous symptoms changes with increased enzymes and thrombocytopenia) [7,13,23,26].
[4,12]. Although variable, the manifestation of HELLP syndrome is fast. It can progress to complete form [23,26]. A partial or full reversal of
In more than 50% of cases, excessive weight gain and the presence of the syndrome can rarely occur [27,28].
generalized edema are signs of HELLP development [13].
1.4. Clinical Symptoms
1.3. Diagnostic criteria
Typical clinical symptoms of HELLP syndrome are pain in the right
The diagnosis of the complete form of HELLP syndrome requires the upper quadrant abdomen or epigastric pain, nausea and vomiting.
presence of symptomatic triad, hemolysis, hepatic changes with in- Pregnant women often report discomfort a few days before the presen-
creased enzymes and thrombocytopenia, as well as severe symptoms, tation of abdominal pain [12,27]. Approximately 30–60% of pregnant
as general malaise, with or without vomiting, pain in the right upper women have headache and about 20%, visual symptoms. The intensity
quadrant of the abdomen, excessive weight gain and the presence of of symptoms is exacerbated at night. However, this syndrome can
generalized edema [1,2,13,14]. present nonspecific symptoms, which could lead to a misinterpretation
Laboratory tests are important for HELLP syndrome diagnosis and of viruses [12].
should always be requested in cases of preeclampsia, eclampsia and in The spontaneous rupture of a liver subcapsular hematoma is more
pregnant women with pain in the right upper quadrant of the abdomen. frequent in the liver's right lobus [4,12,29]. This process is accompanied
Hemolysis is a major feature of this syndrome and results from microan- by symptoms such as a sudden beginning, epigastric pain, backache and
giopathic hemolytic anemia. The fragmentation of erythrocytes is pain in the right shoulder, anemia and hypotension [30,31]. A low index
secondary to endothelial damage and fibrin deposition in vascular of suspicion is warranted in patients with such symptoms to prompt
walls. These fragments identification in blood film (schizocytes) suggest emergent imaging and to allow rapid diagnosis, since it is associated
microangiopathic anemia [15,16]. with a significant increase in maternal and perinatal morbidity and
The hemolytic process is associated with decreased hematocrit and mortality. Hepatic rupture can also occur in postpartum [32].
hemoglobin values [17,18]. Hemoglobinemia or hemoglobinuria can
be macroscopically identified in about 10% of pregnant women with 1.5. Differential Diagnosis
HELLP syndrome [19].
The free plasma hemoglobin binds to haptoglobin and hemoglobin– HELLP syndrome symptoms can be confused with other clinical con-
haptoglobin complex is rapidly sequestered by the liver. It avoids ditions and a differential diagnosis can be a challenge. The obstetrician
hemoglobin loss or accumulation in the kidneys and iron excretion, should pay attention to the nuances of the clinical history (pyelonephritis
which keeps away the iron deleterious actions. This process leads to a with septicemia, cholecystolithiasis, pancreatic, cocaine intoxication) and
 L.M. Dusse et al. / Clinica Chimica Acta 451 (2015) 117–120 119

the behavior of laboratory abnormalities (viral hepatitis, CIV), since in of any effect of corticosteroids on substantive clinical outcomes.
some cases the therapeutic approach may differ and an error or a delayed Preeclamptic women receiving steroids showed significantly greater
diagnosis may worsen the maternal and perinatal prognosis [8]. improvement in platelet counts, which was greater for those receiving
HELLP syndrome can be diagnosed as viral hepatitis, cholangitis and dexamethasone than those receiving betamethasone. To date, there is
other acute diseases. Other clinical conditions that can mimic HELLP insufficient evidence of benefits in terms of substantive clinical out-
syndrome are acute fatty liver of pregnancy (AFLP), thrombotic throm- comes to support the routine use of corticosteroids for the management
bocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and of HELLP. They should be used in clinical situations, in which increased
antiphospholipid syndrome (SAF) [16,33]. AFLP usually occurs between rate of recovery in platelet count is considered clinically worthwhile
the 30th and 38th week of gestation, with a history of one or two weeks [44].
of malaise, anorexia, nausea, vomiting, abdominal pain, headache and
jaundice. Hypertension and proteinuria are usually absent, and leukocy-
2. Conclusion
tosis, increased levels of creatinine, uric acid, ammonia, liver enzymes
(alkaline phosphatase, AST and ALT) and bilirubin are present [33–35].
Some important observations were made by Dr. Weinstein in the
The prolongation of prothrombin time, due to factors II and V decreas-
early 1980s and are very useful nowadays for pregnant women with
ing, supports the AFLP diagnosis, while hypoglycemia suggests HELLP
HELLP syndrome management. The first observation is that the disease
syndromes. Liver ultrasonography may reveal increased echogenicity
is progressive and the patient does not appear to be sick. The second one
in severe cases of AFLP [33,36]. TTP should be distinguished by the
highlights hypoglycemia as an important marker of worsening. Hypo-
intense thrombocytopenia and very low or undetectable ADAMTS13
glycemia occurs by decreased glycogen stores in the liver and increased
activity [37]. ADAMTS13 specifically cleaves unusually-large von
circulating insulin. Curiously, glycemia has not been considered
Willebrand factor (UL-VWF) multimers under high shear stress, and
throughout time. A search in Pub Med revealed that 20 case reports in-
down-regulates VWF function to form platelet thrombi. Deficiency of
volving HELLP syndrome were published in the last three years, but
plasma ADAMTS13 activity induces a life-threatening systemic disease,
none of them included this routine laboratorial parameter. Knowing
including TTP. High levels of UL-VWF in maternal plasma reflect the
the complexity of HELLP syndrome, attention for the role of hypoglyce-
virtual absence of ADAMTS13, which supports TTP [38].
mia in the management of this syndrome should be disclosed. The third
For HUS diagnosis, the triad of renal failure, microangiopathic hemo-
one emphasizes that there is no correlation between platelet count and
lytic anemia and thrombocytopenia should be considered [39]. Finally,
liver enzyme levels to diagnose HELLP syndrome. The fourth one shows
for SAF diagnosis, the guidelines established should be strictly applied
that all record of women who died from HELLP syndrome related com-
[40].
plaints of heartburn and pain in the right upper quadrant during the
Imaging exams are highlighted as major allies in the search of
third trimester of gestation and these symptoms were mistakenly treat-
correct diagnosis for HELLP syndrome. Ultrasound, tomography or mag-
ed with drugs not indicated for this syndrome [1].
netic resonance are especially helpful in patients with clinical suspicion
In conclusion, three decades after the tireless efforts of Dr. Weinstein
of hepatic impairment and should always be performed in these cases
to characterize HELLP syndrome, it remains a challenge to the scientific
[41].
community and several questions need to be answered for the benefit of
The best option for HELLP syndrome diagnosis, in cases not charac-
pregnant women.
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, Acknowledgments
whose request should be encouraged in order to maintain glucose levels
within the reference range, therefore avoiding the worsening of patients The authors thank FAPEMIG and CNPq/Brazil. LMD is grateful to
[1,2,14]. CNPq Research Fellowship (302794/2012-3).

1.6. Treatment References

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