HELLP Syndrome

J Gastrointestin Liver Dis

December 2007 Vol.16 No 4, 419-424
Address for correspondence:
HELLP Syndrome a Multisystemic Disorder
Dan Mihu
1
, Nicolae Costin
1
, Carmen Mihaela Mihu
2
, Andrada Seicean
3
, Rzvan Ciortea
1
1) Clinic of Obstetrics-Gynecology. 2) Department of Histology. 3) 3
rd
Medical Clinic,
University of Medicine and Pharmacy, Cluj-Napoca
Abstract
HELLP syndrome is a multisystemic disorder with an
incidence of 0.17-0.85% of all pregnancies. Its etiopatho-
genesis is not completely understood. The most widely
accepted hypotheses are: a change in the immune feto-mater-
nal balance, platelet aggregation, endothelial dysfunction,
arterial hypertension and an inborn error of the fatty acid
oxidative metabolism. Hepatic involvement occurs by
intravascular fibrin deposition and hypovolemia. Materno-
fetal complications cause a 6.7-70% perinatal mortality rate
and a 1-24% maternal mortality rate. The recognition of
HELLP syndrome and the rapid initiation of therapy are
required for the improvement of materno-fetal prognosis.
Key words
HELLP syndrome - preeclampsia- pregnancy - liver
hematoma - diagnosis- therapy
Introduction
HELLP syndrome is a multisystemic disorder that
complicates pregnancy and has a poor prognosis. It was
first described by Weinstein in 1982. The acronym is for
hemolysis (H), elevated liver enzymes (EL),
thrombocytopenia (low platelet count LP) (1). The name
of the syndrome (hell + help) suggests the severity of
maternal and fetal prognosis. It occurs in 0.17-0.85% of all
pregnancies, and is more frequent in older multiparous
Caucasian women. In 70% of the cases, the disorder is
diagnosed antepartum: 10% before 27 weeks of gestation
(WG), 70% between 27-37 WG, 20% after 37 WG (2). In 30%
of cases it is diagnosed postpartum.
HELLP syndrome is frequently associated with severe
preeclampsia or eclampsia, but can also be diagnosed in
the absence of these disorders. The risk of recurrence in a
subsequent pregnancy is estimated at 19-27% (3).
Pathogenesis
The pathogenesis of HELLP syndrome is not completely
understood.
Morphopathological lesions in preeclampsia involve a
deficient remodeling of maternal vascularization through
the placental trophoblast, occurring early during the course
of pregnancy. Because trophoblast invasion invariably
brings the fetus in contact with the immunocompetent
maternal cells, feto-maternal interactions during the course
of pregnancy are crucial for the prognosis (4). In the third
trimester of pregnancy, there is a remarkable activation of
maternal leukocytes in peripheral blood. Fetally derived
soluble HLA antigen (sHLA-DR) levels are linked to the
activated immunocompetent cells, and are due to an intense
immune maternal response to the fetus. Since sHLA-DR
molecules are able to induce cell apoptosis, even low sHLA-
DR levels can be important for the regulation of the maternal
immune system or for the maintenance of the feto-maternal
immune balance during pregnancy (5). In HELLP syndrome,
high plasma sHLA-DR levels are found. The syndrome can
be considered an acute rejection of the fetal allograft.
Moreover, the assessment of sHLA-DR levels can be used
for the identification of the patients with preeclampsia at
risk of the HELLP syndrome during pregnancy (5).
In preeclampsia, there is an abnormal expression of cell
adhesion molecules, as well as of the endothelial cell growth
factor and its receptor in the trophoblast, causing a
uteroplacental vascular insufficiency that will result in an
abnormal release and metabolization of nitric oxide,
prostaglandins and endothelin in the placental tissue. These
changes induce platelet aggregation, endothelial
dysfunction and arterial hypertension (6). Transmembrane
Fas proteins, which belong to the tumor necrosis factor
receptor family (TNFRSF), expressed by T lymphocytes that
regulate the invasion of the trophoblast in the myometrium,
also play a role. The substitution of a single nucleotide at
position 670 of the maternal (not fetal) TNFRSF6 gene
Assoc. Prof. Dan Mihu
Clinic of Obstetrics-Gynecology
21 Decembrie Str, no 55-57
Cluj-Napoca, Romania
E-mail: carmenmihu2004@yahoo.com
Mihu et al 420
results in an increased capacity of maternal lymphocytes to
recognize and destroy the trophoblast during invasion of
the uterine wall and spiral arteries, leading to an increased
risk for HELLP syndrome (7).
Circulating platelets adhere to the damaged or activated
endothelium, causing an increase in platelet clearance (8).
The significantly increased levels of tissue plasminogen
activator and plasminogen activator inhibitor-1 (PAI-1) in
the context of HELLP syndrome compared to normal
pregnancy suggest that platelet activation and the alteration
of plasminogen activation are involved in the pathogenesis
of this syndrome (9).
The vascular endothelium can be damaged by segmental
vasospasm, followed by the formation of a fibrin matrix at
the site of the lesion. The break of the platelet membrane
and the release of arachydonic acid and other vasoactive
mediators produce vasoconstriction, vasospasm and
accelerated platelet aggregation (6, 9).
Endothelial cell activation, with the release of von
Willebrand factor multimers, cause consumption thrombo-
cytopenia and thrombotic microangiopathy in the HELLP
syndrome. The enzyme responsible for the cleavage of von
Willebrand factor multimers ADAMTS13 has also a low level
in women with HELLP syndrome compared to healthy
pregnant women (10).
A reduction in T and B lymphocyte function, as well as
in the monocyte function, has been found, preceding the
laboratory diagnosis of HELLP syndrome by 1-2 weeks (11).
An inborn error of fatty acid oxidative metabolism may
occur in fetuses born in the context of HELLP syndrome. A
mutation allows a long chain fatty acid, i.e. a 3-hydroxyacyl
metabolite that is produced by the fetus or the placenta, to
accumulate at maternal level due to a long chain 3-hydroxy-
acyl coenzyme A dehydrogenase deficiency (LCHAD),
which results in an insufficient mitochondrial oxidation of
fatty acids required for ketogenesis, once the liver glycogen
source has been exhausted (12).
Hepatic involvement in pregnant women is more frequent
when fetuses have a severe enzymatic deficiency (LCHAD).
Given the recessive autosomal transmission, molecular
diagnosis is recommended for all pregnant women with
HELLP syndrome, for those with acute fatty liver of preg-
nancy (AFLP), as well as their partners and children (13, 14).
The pathogenesis of liver involvement in HELLP
syndrome is unknown. A complex chain of events is initiated
in the liver by intravascular fibrin deposition with sinusoidal
obstruction, associated with hypovolemia, which is
demonstrated by a decrease in the liver blood flow on
Doppler examination in patients with preeclampsia, who have
subsequently developed HELLP syndrome (15). Hepatic
ischemia causes hepatic infarction, subcapsular hematomas
and intraparenchymatous hemorrhage, which may result in
hepatic rupture, with vital risk (6, 16).
HELLP syndrome should not be considered as a variant
of disseminated intravascular coagulation (DIC), even if
microangiopathic hemolytic anemia is characteristic for both
disorders. There are significant differences between these
two entities. The prothrombin time, the partial thrombo-
plastin time and serum fibrinogen levels are normal in HELLP
syndrome, but are usually altered in DIC. Evaluation of more
sensitive markers of DIC, such as antithrombin III, alpha-2
antiplasmin, plasminogens, fibrin monomer, D-dimers,
fibronectin, fibrinopeptide A, prekallicrein, might better
differentiate DIC from HELLP syndrome (1, 2).
The liver pathology is similar to that of the liver in
preeclampsia, presenting focal hepatocyte necrosis,
periportal hemorrhage and fibrin deposits in the hepatic
sinusoids. Macrovesicular fatty loading of the liver is
different from that of AFLP. Hematomas are most frequently
present in the right hepatic lobe (75%) (17). Liver capsule
rupture, a rare but severe complication, is associated with
hemoperitoneum.
Diagnosis
Clinical picture
Onset occurs in the last trimester of pregnancy in 70%
of patients, and immediately after delivery in the rest of
patients (18). In a study performed on 61 patients with HELLP
syndrome, eclampsia was present in 52%, correlated with
headache, nausea and vomiting, visual disorders and
epigastric pain, with a reserved maternal prognosis (19).
Some patients present a pseudoinfluenza syndrome,
complaining of headache and visual disorders. Most (90%)
present a prodrome several days before seeing a doctor. In
certain cases, hemorrhage or gastrointestinal bleeding may
occur. Physical examination reveals pain in the right upper
abdominal quadrant, a significant weight gain and genera-
lized edemas. Importantly, severe arterial hypertension is
not constant and even absent in HELLP syndrome.
Because early diagnosis is crucial, pregnant women with
these symptoms should undergo paraclinical investigations
for HELLP syndrome (4).
An association with diabetes insipidus (20) or with
antiphospholipid syndrome might be evident (21). In women
with an early onset of preeclampsia, less than 34 WG,
antiphospholipid antibodies should be searched for (22). In
the presence of this association, maternal and fetal mortality
increase up to 50% (23).
The main disorders that should be considered in the
differential diagnosis are gastrointestinal and liver diseases,
renal and hematologic disorders. A difficult differential
diagnosis is with AFLP, which also occurs in multiparous
women after 30 WG. It has similar manifestations as HELLP
syndrome (cytolysis and thrombocytopenia), but
hypoglycemia and prolongation of the prothrombin time are
present and the evolution is towards acute liver failure.
Morphopathological aspect is of microvesicular steatosis,
but liver puncture biopsy is rarely performed because of
defective coagulation (24).
Biological investigation
The early diagnosis of HELLP syndrome is based on the
detection of hemolysis, altered liver tests, and renal
dysfunction (1, 2, 25, 26).
HELLP Syndrome 421
Hemolysis is evidenced by an increase in lactate dehy-
drogenase (LDH) levels >600 UI/L and a decrease in serum
haptoglobin values. These early sensitive markers of HELLP
syndrome can be detected before the increase of serum un-
conjugated bilirubin level and decrease of hemoglobin va-
lues. Glutathione S transferase and glutathione S transfe-
rase are early markers of the hemolysis and liver damage.
The prothrombin time and the activated partial
thromboplastin time (APTT) are normal in early stages, but
the levels of fibrin degradation products, D-dimers, and
thrombin-antithrombin complexes are increased, being
markers of secondary fibrinolysis and platelet aggregation.
Antithrombin III < 79%, D-dimers > 4 g/ml and thrombin-
antithrombin complexes >26 mg/ml have been proposed as
criteria for the induction of delivery in HELLP syndrome
(17).
Thrombocytopenia is the major and early cause of
alteration of coagulation in the HELLP syndrome. Multiple
factors are involved in the pathogenesis of thrombo-
cytopenia: vascular endothelial damage, alteration of
prostacyclin production and increased fibrin deposits in
the vascular wall. Acceleration of platelet destruction,
platelet activation, increased platelet volumeand mega-
karyocyte production have also been found. An increase in
the response of platelet calcium to arginin-vasopressin,
which precedes thrombocytopenia and occurs in the first
trimester of pregnancy, has been reported and proposed as
a possible predictor of preeclampsia.
When platelet count decreases to less than 50,000/mm
3
,
an association with DIC can be considered, with a worse
prognosis (19).
Maternal platelet count decreases immediately after
delivery, then rises starting with day 3 postpartum, reaching
>100,000/mm
3
after day 6 postpartum. The lack of an increase
in platelet levels after 96 hours from delivery indicates a
severe disorder, with the possible development of multiple
organ failure (27).
Acute liver failure is rare due to the double vasculari-
zation of the liver and to its capacity to function under low
oxygen uptake conditions. However, microangiopathy with
sinusoidal obstruction causes hepatocyte necrosis
responsible for the increase of aspartate aminotransferase
(AST) (mean 250 UI/L) and alanine aminotransferase (ALT)
levels (26). In 30% of cases, a moderate increase in gamma
GT, alkaline phosphatase and serum bilirubin is found (26).
As hepatic necrosis and intraparenchymal hemorrhage are
focal lesions, the hepatic syntheses are maintained. The
prothrombin time is normal, except for severe cases
complicated by DIC.
A few patients present significant renal involvement,
independent of blood pressure values and of hemolysis
degree. Uric acid >7.8 mg/dl is an independent risk factor for
materno-fetal morbidity and mortality (27).
Hyaluronic acid levels increase in preeclampsia to > 100
g/L, being a reliable marker for HELLP syndrome. The
increased serum fibronectin levels indicates vascular
involvement in preeclampsia. Higher -fetoprotein or human
chorionic gonadotropin (HCG) values in the second
trimester of pregnancy increase the risk of HELLP syndrome
up to 47 times. Markers of HELLP syndrome with a predictive
value are searched for, by proteome analysis. Serum amyloid
A is so far selected, at values > 3.5 mg/L (28).
Imaging of the liver
Liver imaging is important for the evaluation of
subcapsular or intraparenchymal hemorrhage and hepatic
rupture. In pregnant women, ultrasound (US) and MRI are
preferred due to the absence of ionizing radiation. CT is the
method of election in the postpartum period (29,30).
Transabdominal US evidences intrahepatic hematomas as
hypoechogenic structures. CT or MRI can detect
hemoperitoneum, intrahepatic hematoma, and an irregular
interface between the normal hepatic parenchyma and
intrahepatic hematoma corresponding to the capsule rupture
site (30). Hepatic arteriography, an invasive procedure, can
establish the site of hemorrhage and is only performed before
arterial embolization (30).
Liver biopsy
Liver biopsy has a risk of hemorrhage and hepatic
rupture. Periportal hemorrhage, focal parenchymatous
necrosis and macrovesicular steatosis can be observed in
1/3 of patients. Fibrin deposits and hyaline deposits are
shown by immunofluorescence at the level of liver sinusoids.
Liver specimens show a positive reaction with IL-1 , IL-
8,TNF and neutrophil elastase antibodies. These are
negative in patients with AFLP (31).
Classification
Two classifications for the HELLP syndrome are
commonly used (1,2). The Tennessee System classification
is based on the assessment of the following parameters:
AST>70 UI/L, LDH >600 UI/L, thrombocytes <100,000/ mm
3
.
Accordingly, there are two forms: complete (all elements
present) and partial HELLP syndrome (one or two elements
present). The Mississippi classification relies on the
thrombocyte counts: class I (<50,000/mm
3
), class II (50,000-
100,000/mm
3
) and class III (100,000-150,000/mm
3
).
Complications and prognosis
Cerebral hemorrhage is the most severe complication,
being fatal in 50-65% of cases. The sudden increase in
diastolic blood pressure over 120 mmHg raises the risk of
lethal complications such as hypertensive encephalopathy,
ventricular arrhythmias, DIC. Cerebral complications are rare,
but particularly severe. Transcranial Doppler US evidences
cerebral vascular changes similar to vasospasms. The
velocity of the cerebral blood flow is increased (32).
Renal complications occur at the microvascularization
level (vascular thrombosis, occlusion of renal arteriole
lumens, hypoperfusion). HELLP syndrome might cause both
tubular necrosis potentially reversible and cortical necrosis
(in most cases with sequelae). Cortical ischemia can generate
Mihu et al 422
arterial hypertension, and microangiopathic thrombosis
causes renal dysfunction. Renal failure in HELLP syndrome
can be due to coagulation disorders, hemorrhage and shock.
Its incidence is about 8% (27).
Nephrogenic diabetes insipidus is a rare complication.
It is characterized by resistance to arginin-vasopressin
mediated by high vasopressinase levels. The increased
vasopressinase levels may occur as a result of deficient
hepatic metabolization (33, 34).
Hepatic complications include infarction, hemorrhage
and hematomas. Hepatic rupture occurs in 1/40,000 to 1/
250,000 cases. Because of the presence of hepatic
hemorrhage and subcapsular hematoma, minor trauma
(vomiting, patient transportation, liver palpation, labor,
seizures) may induce hepatic rupture. Most frequently, the
rupture of Glisson capsule occurs at the lower liver margin,
causing sudden epigastric pain, anemia and hypotension.
Imaging or paracentesis are diagnostic for intraperitoneal
hemorrhage. The maternal mortality rate varies from 18 to
86%, and the perinatal mortality can reach 80% (7).
The prognosis of pregnancies complicated by HELLP
syndrome depends on early diagnosis and early therapeutic
approach (2). Perinatal infantile mortality varies between 6.7
and 70%. It is caused by the premature detachment of the
normally inserted placenta, intrauterine asphyxia, and pre-
maturity. About 60% of fetuses die intrauterinely, 30% show
intrauterine growth retardation, and 25% thrombocytopenia.
Maternal mortality varies between 1 and 24% and can be
due to coagulation disorders, hemorrhagic complications,
cardiopulmonary, central nervous system, hepatic and
gastrointestinal disorders (35-37).
The critical state of the patient is improved after the
induction of delivery. Patient counselling regarding the risk
of recurrence of HELLP syndrome for subsequent
pregnancies is mandatory, although the higher risk is for
developing preeclampsia (43%) or other complications in a
new pregnancy (27).
Patients with atypical forms of preeclampsia or HELLP
syndrome should be investigated for antiphospholipid
antibodies (38).
The early recognition of HELLP syndrome and the
initiation of early therapy are required in order to ensure the
favorable evolution of the mother and fetus.
the delay of delivery. The improvement of thrombocytopenia
has been more frequently observed for the low doses
compared to the high doses (40-42). In an analysis performed
on 170 patients with HELLP syndrome, comparing the
dexamethasone group to a control group, maternal mortality
and morbidity due to the premature detachment of the
normally inserted placenta, acute pulmonary edema and
hepatic rupture occurred at the same rate, and perinatal
infantile mortality and morbidity were similar. The maternal
advantage of corticotherapy was an extension of the time
period between hospital admission and the induction of
delivery, and the fetal advantage was an increase in weight
at birth. The conclusion was that steroid therapy should
only be administered to very well selected cases, since it
does not improve prognosis (43, 44).
Plasmapheresis with fresh frozen plasma has been
proposed as a therapeutic method in patients who show a
progressive increase in bilirubinemia, serum creatinin, and
have severe thrombocytopenia. This is also recommended
for patients in whom HELLP syndrome persists for more
than 72 hours postpartum, but has no favorable results in
patients with fulminant hemolysis (45, 46).
Hypertension in preeclampsia can be treated with i.v.
Mg sulfate, hydralazine, calcium channel antagonists,
nitroglycerine or sodium nitroprussiate (in hypertensive
crisis). Diuretics are not used as a routine because they
increase maternal hypovolemia and worsen uteroplacental
hypoperfusion (2, 4, 47).
Obstetric approach
The induction of delivery is the only specific therapy in
HELLP syndrome. In pregnant women with a gestational
age of more than 34 WG, immediate induction of delivery is
recommended. Severe maternal complications are more
frequent when the induction of pregnancy is delayed for
more than 12 hours (48). At a gestational age between 24-34
WG, a consensus of the NIH recommends the use of cortico-
steroids to accelerate fetal pulmonary maturity, to reduce
the risk of necrotic hemorrhagic rectocolitis and
intraventricular hemorrhage of the fetus.
If no obstetric complications are present, vaginal delivery
is preferred. Delivery by cesarean section is required in 60%
of cases. In the case of cesarean section, subfascial drainage
may be necessary in order to reduce the risk of hematomas.
If during the cesarean section, a small liver hematoma with
an intact Glisson capsule is detected, its evacuation is not
required. When the hematoma is extensive, even if the
Glisson capsule is intact, it is recommended to open the
capsule and evacuate the hematoma in order to avoid its
extension and secondary hepatic rupture (49).
Epidural anesthesia can be recommended when the
thrombocyte count is higher than 100,000/ mm
3
, when there
are no coagulation disorders and the bleeding time is normal
(50,51).
Surgical approach
The rupture of a subcapsular liver hematoma followed
by shock represents a surgical emergency (52,53). Massive
blood transfusions and the correction of coagulopathy with
Therapy
The management of patients with preeclampsia and
HELLP syndrome is controversial. Most therapeutic
modalities are similar to those applied for severe
preeclampsia. Treatment should be performed in Intensive
Care Units (ICU) with dialysis and ventilatory support in
severe cases, and consists of plasma expanders,
antithrombotic agents, heparin, antithrombin, aspirin in low
doses, prostacyclin, immunosuppressive agents, steroids,
fresh frozen plasma, dialysis.
The administration of corticoids is followed by a rapid
improvement of clinical and laboratory parameters, allowing
HELLP Syndrome 423
fresh frozen plasma and thrombocyte mass are mandatory
(7). Immediate laparotomy is recommended. The options are:
the surgical ligature of the hemorrhagic hepatic segment,
suture and drainage, suture of the omentum, surgical mesh
at the level of the liver in order to improve its integrity
(7,17,50). Emergency surgical intervention should be
performed if the patient shows hemodynamic instability,
massive blood loss, increasing pain or hematoma infection
(54).
Recent data also support the conservative approach in
patients who are hemodynamically stable, under careful
clinical, biological and imaging monitoring. Favorable results
have been obtained by arterial embolization during hepatic
arteriography (30).
The use of argon coagulation for hemostasis after the
rupture of liver hematoma has been reported. If necrotic
areas are detected intraoperatively, their resection is not
required in the same operative time, and can be subsequently
performed (55). Administration of recombinant F VIIa might
suppress the hemorrhage and save the patients life in cases
that do not respond to surgical treatment (56, 57). Liver
transplantation is necessary when hemorrhage cannot be
arrested during laparotomy or in the context of fulminant
liver failure (58).
Conclusion
HELLP syndrome is due to a generalized microangiopathy
usually occurring in older multiparous women in the third
trimester of pregnancy, which develops with focal liver
involvement, hemolysis and thrombocytopenia. Hepatic
(rupture), cerebral (hemorrhage) and DIC complications are
severe and are associated with a high maternal death rate
and important perinatal mortality. Severe thrombocytopenia
worsens prognosis. The induction of delivery, materno-fetal
treatment and monitoring under ICU conditions are required.
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