Continuing Education Activity
The syndrome of hemolysis, elevated liver enzymes and low platelets, otherwise referred to as HELLP syndrome, has historically been classified as a complication or progression of severe preeclampsia. This progression, however, has been challenged with recent publications that suggest these pathologies have their own etiologies. This activity reviews the evaluation and treatment of HELLP syndrome and highlights the role of the interprofessional team in the care of patients with this condition.
- Identify the etiology of HELLP syndrome.
- Describe the typical presentation of a patient with HELLP syndrome and review the laboratory findings.
- Outline the treatment options for HELLP syndrome.
- Explain the importance of collaboration amongst the interprofessional team to improve maternal and neonatal outcomes in HELLP syndrome.
The syndrome of hemolysis, elevated liver enzymes, and low platelets, otherwise referred to as HELLP syndrome, has historically been classified as a complication or progression of severe preeclampsia. This progression, however, has been challenged with recent publications that suggest these pathologies have their own etiologies. Although there is still an overlap between pre-eclamptic pregnant women who develop HELLP syndrome, their association is not as straight forward as once thought to be. Genetic analysis of the inheritability of predisposition for preeclampsia and/or HELLP syndrome in pregnancy has also been explored. Results show both genetic and immunological factors that play a role in pathogenesis.
Although the precise etiology of HELLP syndrome has not been established, current hypotheses include genetic mutations (both maternal and fetal) as well as an inflammatory origin. A review published in 2013 expressed that poor placentation in the early stages of pregnancy could account for the subsequent development of preeclampsia. Similarly, HELLP syndrome entails poor placentation during early pregnancy in conjunction with hepatic and coagulation cascade involvement. Studies done on women diagnosed with early HELLP syndrome showed clinical and laboratory value improvement when taking complement C5 protein inhibitors.
The maternal immunologic response can impair placentation as early as the first trimester by affecting trophoblast cell invasion. One case series found that fetal deficiency in long-chain 3-hydroxyacyl coenzyme A dehydrogenase, not just maternal enzyme deficiency alone, was linked to maternal development of HELLP syndrome as well as fatty liver, providing strong evidence that the fetal-maternal interaction can cause hepatic disease in mothers carrying enzyme-deficient fetuses. Evidence from these studies supports genetic testing in affected mothers, partners, and children. Prospective diagnosis can provide the proper counseling of the risks involved to mothers as well as potential harms that come with this type of deficiency in the affected child.
HELLP syndrome has a prevalence of 0.5% to 0.9%. About 70% of cases occur in the third trimester of pregnancy, and the remainder occurs within 48 hours of delivery. The mortality rate of women with HELLP syndrome is 0 to 24%, with a perinatal death rate of up to 37%.
An ischemic-reperfusion injury starts the liver damage in HELLP syndrome. The spiral arteries which fail to remodel because of inadequate trophoblast invasion or defective endothelial apoptosis result in ischemia of the placenta. This causes activation of endothelium, which is accompanied by an increased release of antiangiogenic factors to cause hypertension and proteinuria. It may lead to multiorgan microvascular injury, which is the reason for liver damage in HELLP syndrome. In addition, abnormal oxidation of fatty acids by the fetus and release of metabolic intermediates into the mother's circulation causes liver and vascular dysfunction. This occurs when the fetus has an inherited defect in mitochondrial fatty acid oxidation. The inflammatory component includes an increase in leukocytes and pro-inflammatory cytokines with a reduction in anti-inflammatory cytokines.
The coagulation cascade is activated by adhesion of platelets on the activated and damaged endothelium. Platelets release thromboxane A and serotonin, causing vasospasm, platelet aggregation, and further endothelial damage. The cascade only terminates with the delivery of the fetus. This causes the usage of platelets and hence, thrombocytopenia. The red blood cells breakdown while passing through these platelet-fibrin rich capillaries, causing microangiopathic hemolytic anemia. Multiorgan microvascular injury and hepatic necrosis lead to the development of HELLP syndrome.
One of the features of HELLP syndrome is microangiopathic hemolytic anemia. Schistocytes or helmet cells, present on a peripheral blood smear is diagnostic of microangiopathic hemolytic anemia, making peripheral smears useful in the workup for HELLP syndrome. In the liver, intravascular fibrin deposits give rise to sinusoidal obstruction, intrahepatic vascular congestion, increased hepatic pressures leading to hepatic necrosis. This may eventually result in intraparenchymal or subcapsular hemorrhage and capsular rupture.
History and Physical
The average gestational age of presentation of HELLP syndrome is 34 weeks. The majority of women with HELLP syndrome have hypertension and proteinuria prior to diagnosis. Patients are usually multiparous and over the age of 35 years old. Patients are often overweight and have edema in 50% of the cases. Many present with right upper quadrant or epigastric colicky pain with nausea and vomiting. This is usually preceded by malaise 1 to 2 days earlier. 30% to 60% also have a headache, and 20% have a visual disturbance. The condition exacerbates during the night. The symptoms continuously progress.
Apart from the clinical signs and symptoms, laboratory investigations are required to diagnose HELLP syndrome. Two classifications are used to diagnose HELLP syndrome: Tennessee and Mississippi.
Main diagnostic criteria of the HELLP syndrome
The Tennessee classification system diagnostic criteria for HELLP are:
- Increased LDH (> or =600 IU/L)
- Increased AST (>or =70 IU/L)
- Low platelets (< 100 x 10(9)/L)
The HELLP syndrome may be complete or incomplete.
Mississippi classification measures the severity of the syndrome using the lowest observed platelet count along with the other two main clinical criteria (LDH and AST). Class I is the more severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.
- Class I HELLP syndrome is characterized by a platelet count below 50,000/microL. (LDH> or=600 IU/L, AST> or= 70 IU/L)
- Class II HELLP syndrome is characterized by a platelet count of 50,000 to 100,000/microL. (LDH> or=600 IU/L, AST> or=70 IU/L)
- Class III HELLP syndrome is characterized by a platelet count of 100,000 to 150,000/microL. (LDH>OR=600 IU/L, AST> or= 40 IU/L)
Treatment / Management
Given the lack of clinical trials for the management of HELLP syndrome based on the gestational age of presentation, many treatments are experimental in nature, and there has been a little significance in the improvement of perinatal outcomes between expectant management versus delivery before 34 weeks. That being said, the course of true HELLP syndrome has the potential to quickly turn life-threatening for both mother and fetus. Therefore the recommendation is always to hospitalize patients for strict monitoring of laboratory values. During hospitalization, patients should be treated as severely pre-eclamptic and should receive magnesium sulfate for seizure prophylaxis along with blood pressure control with hydralazine, labetalol, or nifedipine in usual recommended fashion.
Maternal-fetal monitoring should be performed throughout each step of management since typically, immediate delivery is recommended for true HELLP patients except those with stable maternal-fetal conditions between 24 to 34 weeks gestation. For this group of patients, a recommendation is to give corticosteroids (betamethasone 12mg intramuscular every 12 hours for 2 doses or dexamethasone 12mg intravenously every 12 hours for 4 doses) then deliver 24 hours after the last dose. Steroid administration is not only beneficial to the fetus for lung maturity but also for improvement of laboratory values in patients, particularly in elevating platelet counts. Some patients may benefit from transfusions of red cells, platelets, and plasma. A study performed to assess the rate of epidural anesthesia in patients with HELLP saw an increase in rates of neuro-axial anesthesia in those who achieved a latency period after the administration of steroids.
HELLP syndrome should be differentiated from other disorders of pregnancy with similar features:
- Pre-eclampsia: It has normal liver enzymes and platelet count. Schistocytes are also absent.
- Acute fatty liver of pregnancy (AFL): Hypoglycemia is present in AFL but absent in HELLP syndrome.
- Thrombotic thrombocytopenic purpura (TTP): It usually manifests in 2nd or 3rd trimester, and liver abnormalities are not as elevated as in HELLP syndrome. Patients are typically normotensive and have undetectable ADAMTS 13 activity.
- Hemolytic-uremic syndrome (HUS): It has the same findings as TTP except that its incidence is higher in the post-partum period, and patients have signs of renal failure.
- Lupus flare: Liver pathology is absent in lupus.
- Antiphospholipid syndrome (APS): Dominant features of APS are arterial/venous thrombosis and repeated pregnancy loss. Lupus anticoagulant, cardiolipin antibodies, beta-glycoprotein antibodies, prothrombin time (PT), and an activated partial thromboplastin time (aPTT) should be checked to confirm the diagnosis.
- Other: Viral hepatitis, cholecystitis, cholangitis, gastritis, gastric ulcer, acute pancreatitis, upper UTI.
HELLP syndrome is a life-threatening condition. The mortality rate of women with HELLP syndrome is 0%-24%, with a perinatal death rate of up to 37%. Maternal death occurs due to disseminated intravascular coagulation (DIC), placental abruption, postpartum hemorrhage, or acute renal failure. DIC occurs in 15% to 62.5% of the cases. Placental abruption occurs in 11% to 25% of women with HELLP syndrome. Postpartum hemorrhage occurs in 12.5% to 40% and acute renal failure in 36% to 50% of the cases. Poor perinatal prognosis is because of placental abruption, intrauterine hypoxia and asphyxia, prematurity, and low birth weight.
Patients with HELLP syndrome have a 19%-27% risk of developing HELLP syndrome in subsequent pregnancies. Class 1 HELLP syndrome has the highest recurrence rate. Recurrent cases occur in the latter part of the gestation period and are less severe after two episodes.
Early diagnosis and treatment, along with maternal and neonatal intensive care, can help to reduce the mortality in HELLP syndrome.
HELLP syndrome is a life-threatening condition with high maternal and infant mortality rates. Maternal complications include:
- Placental abruption
- Cesarean section
- Recurrent thrombosis
- Liver rupture
- Cerebral infarction
- Cerebral hemorrhage
- Pulmonary/cerebral edema
- Cardiovascular instability
- Acute renal failure
- Maternal death
Fetal complications include:
- Perinatal death
- Intrauterine growth restriction (IUGR)
- Preterm delivery
- Neonatal thrombocytopenia
- Respiratory distress syndrome
- Intensive care
- Maternal-fetal medicine
Deterrence and Patient Education
Patients with HELLP syndrome should be given information about the course of the disease. The risk of maternal and perinatal complications and mortality should be explained to the patient and their family. The risk of developing HELLP can only be decreased by maintaining a healthy lifestyle to prevent diseases such as hypertension and diabetes. Regular exercise should be followed. The patient should also be counseled about the risk of HELLP syndrome in subsequent pregnancies. Regular prenatal care and laboratory testing have to be done in the subsequent pregnancies.
Enhancing Healthcare Team Outcomes
The management of HELLP syndrome and its complications requires an interprofessional team approach. Pre-eclampsia, mainly managed by an obstetrician, may benefit from help from other specialties when HELLP syndrome develops. The patient's blood pressure and diabetes can be managed with the help of an internal medicine or family medicine clinician. Complications such as cesarean section and pulmonary edema require help from anesthesiology and a hospitalist, respectively. Continuous nursing and intensive care are required by the patient if they are admitted to an ICU. A neonatologist is needed to care for the neonate and its complications.