HELLP syndrome means 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.
HELLP syndrome is a group of symptoms that occur in pregnant women who have:
- H: hemolysis (the breakdown of red blood cells)
- EL: elevated liver enzymes
- LP: low platelet count
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 straightforward 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.
A classification system, which was developed in Mississippi, measures the severity of the syndrome using the lowest observed platelet count in the patients alongside the appearance of the other two main clinical criteria. Class I is the most severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.[rx]
- Class I HELLP syndrome is characterized by a platelet count below 50,000/µL.
- Class II HELLP syndrome is characterized by a platelet count of 50,000-100,000/µL.
- Class III HELLP syndrome is characterized by a platelet count of 100,000-150,000/µL.
Another classification system, introduced in Memphis, categorizes HELLP syndrome based on its expression.
- Partial expression of the condition is characterized by the manifestation of one or two of the main diagnostic criteria.
- The complete expression of the condition is characterized by the manifestation of all three main diagnostic criteria.[rx]
Causes of HELLP Syndrome
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-hydroxy acyl-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.
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.[rx]
The coagulation cascade is activated by the 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 break down 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.
Symptoms of HELLP Syndrome
The physical symptoms of HELLP Syndrome may seem at first like preeclampsia. Pregnant women developing HELLP syndrome have reported experiencing one or more of these symptoms:
- Nausea/vomiting/indigestion with pain after eating
- Abdominal or chest tenderness and upper right upper side pain (from liver distention)
- Shoulder pain or pain when breathing deeply
- Fatigue or feeling unwell
- Fluid retention and excess weight gain
- Changes in vision
- Pain in the upper right or mid part of the abdomen
- Blurry vision
- Nosebleed or another bleeding that will not stop easily (rare)
- Seizures or convulsions (rare)
HELLP syndrome patients suffer from general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anemia, and hypertension. Some patients may also suffer from a headache and visual issues. These symptoms may also become more severe at night.[rx][rx]As the condition progresses and worsens, a spontaneous hematoma occurs following the rupture of the liver capsule, which occurs more frequently in the right lobe. The presence of any combinations of these symptoms, subcapsular liver hematoma in particular, warrants an immediate check-up due to the high morbidity and mortality rates of this condition.[rx][rx][rx]
Signs to look for include:
- High blood pressure
- Protein in the urine
The most common reasons for mothers to become critically ill or die are liver rupture or stroke (cerebral edema or cerebral hemorrhage). These can usually be prevented when caught in time. If you or someone you know has any of these symptoms, please see a healthcare provider immediately.
Signs and symptoms of HELLP syndrome are the same as for other health conditions. So sometimes HELLP is misdiagnosed as:
- Flu or other illness caused by a virus
- Gallbladder disease – The gallbladder is an organ under your liver that stores bile, a fluid your liver makes to help the body break down fat.
- Hepatitis. This is inflammation (swelling) of the liver.
- Idiopathic thrombocytopenic purpura (also called ITP) – This is a bleeding disorder. If you have ITP, you may bruise easily or have a lot of bruising (also called purpura). You also may bleed easily or heavily. For example, you may have bleeding from the gums or nose or bleeding into the skin that looks like a rash of pinpoint red spots.
- Lupus flare – A lupus flare is a period of time when you have many or intense lupus symptoms. Lupus is an autoimmune disorder that can cause health problems during pregnancy. Autoimmune disorders are health conditions that happen when antibodies (cells in the body that fight off infections) attack healthy tissue by mistake. Lupus and other autoimmune disorders can cause swelling, pain, and sometimes organ damage. Lupus also can affect joints, skin, kidneys, lungs, and blood vessels.
- Thrombotic thrombocytopenic purpura – This is a rare condition that causes blood clots to form in small blood vessels throughout the body. These clots can cause serious health problems if they block the flow of blood to organs, like the brain, kidneys, and heart.
What health problems can HELLP cause?
HELLP syndrome can cause:
- Bleeding and blood clotting problems. Some women with HELLP develop disseminated intravascular coagulation (also called DIC). This is a blood clotting disorder that can lead to heavy bleeding (also called hemorrhage).
- Fluid buildup in the lungs (also called pulmonary edema). This can cause breathing problems.
- Kidney failure
- Liver hemorrhage or failure
- Placental abruption. This is a serious condition in which the placenta separates from the wall of the uterus before birth.
Diagnosis 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.[rx]
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.[rx][rx]
Lab Test and Imaging
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)
There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia in patients suspected to have preeclampsia.
- A blood smear will often exhibit abnormalities, such as schistocytes, bur cells, and helmet cells, which indicate erythrocyte damage.
- Thrombocytopenia, which is the earliest coagulopathy present in all HELLP syndrome patients, is indicated by low platelet count (below 100 x 109 L-1) or by testing the levels of fibrin metabolites and antithrombin III.
- Elevated serum levels of certain proteins, in particular, LDH, alanine transaminase (ALT), and aspartate transaminase (AST), are indicative of hepatic dysfunction. Extremely high serum levels of these proteins, specifically LDH levels > 1,400 IU/L, AST levels > 150 IU/L, and ALT levels > 100 IU/L, significantly elevate the risk of maternal mortality.
A number of other, but less conclusive, clinical diagnostic criteria are also used in diagnosis alongside the main clinical diagnostic criteria for HELLP syndrome.
- De novo manifestation of hypertension with systolic pressure and diastolic pressure above 160mmHg and 110 mmHg, respectively.
- Proteinuria, leucocytosis, and elevated uric acid concentrations > 7.8 mg.
- Decreased serum haptoglobin and hemoglobin levels.
- Increased serum bilirubin levels and visual disturbances.[rx][rx]
Imaging tests, such as ultrasound, tomography, or magnetic resonance imaging (MRI), are instrumental in the correct diagnosis of HELLP syndrome in patients with suspected liver dysfunction. Unurgent cases must undergo MRI, but laboratory tests, such as glucose determination, are more encouraged in mild cases of HELLP syndrome.[rx][rx]
Treatment of HELLP Syndrome
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 little significance in the improvement of perinatal outcomes between expectant management versus delivery before 34 weeks.[rx] 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 the 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 the 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.[rx]
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.[rx]
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%.[rx] 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.[rx]
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.[rx]
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
Acute renal failure
Fetal complications include
Intrauterine growth restriction (IUGR)
Respiratory distress syndrome[rx]
Complications may include:
- Poor blood flow to your organs
- Blood clotting problems
- Placenta problems
- Liver problems
- Fluid buildup in your lungs
- Early delivery
If HELLP syndrome is severe, you and your baby may be in danger. You may need to deliver the baby early to prevent more problems. It may take several days after delivery to recover from HELLP syndrome.
Tips to help you get the most from a visit to your healthcare provider:
- Know the reason for your visit and what you want to happen.
- Before your visit, write down questions you want to be answered.
- Bring someone with you to help you ask questions and remember what your provider tells you.
- At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
- Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
- Ask if your condition can be treated in other ways.
- Know why a test or procedure is recommended and what the results could mean.
- Know what to expect if you do not take the medicine or have the test or procedure.
- If you have a follow-up appointment, write down the date, time, and purpose for that visit.
- Know how you can contact your provider if you have questions.