HELLP syndrome is a well-known variant of pre-eclampsia pregnancy complication. The syndrome was first described in 1982 as characterised by hemolysis (H), elevated liver enzymes (EL) and low platelet count (LP), to which the acronym HELLP refers.
Symptoms usually start manifesting from the second trimester up to several days after birth and may be fatal to both the mother and the fetus. Diagnosis is challenging because it can appear in the absence of pre-eclampsia and some of the symptoms may not be evident. There is yet to be a consensus on the thresholds of the symptoms, thus many cases have been misdiagnosed.
Signs and symptomsEdit
The first signs of HELLP start appearing midway through the third trimester, though the signs can appear in earlier and later stages. Symptoms vary in severity and between individuals and are commonly mistaken with normal pregnancy symptoms, especially if they are not severe.
HELLP syndrome patients suffer from general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anaemia, and hypertension. Some patients may also suffer from a headache and visual issues. These symptoms may also become more severe at night time. 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.
Elevated body mass index (BMI) and metabolic disorders, as well as, antiphospholipid-antibody syndrome (APLS) significantly increase the risk of HELLP syndrome in all female patients. Females who have had or are related to a female with previous HELLP syndrome complications tend to be at a higher risk in all their subsequent pregnancies.
The risk of suffering from HELLP syndrome is not conclusively associated with a specific genetic variation, but it is highly likely that a combination of genetic variations, such as FAS gene, VEGF gene, glucocorticoid receptor gene and the tol-like receptor gene, increase the risk.
HELLP syndrome is still not fully comprehended, therefore, its pathophysiology is still unclear and an exact cause is yet to be found. However, it shares a common pathophysiological mechanism, which is endothelial cell injury, with other conditions, such as acute renal failure and thrombotic thrombocytopenic purpura. Increasing the understanding of HELLP syndrome’s pathophysiology will enhance diagnostic accuracy, especially in the early stages. This will lead to advancements in the prevention, management, and treatment of the condition, which will increase the likelihood of both maternal and fetal survival and recovery.
Inflammatory and coagulation cascadesEdit
As a result of endothelial cell injury, a cascade of pathological reactions manifests and become increasingly severe and even fatal as signs and symptoms progress. Following endothelial injury, vasospasms and platelet activation occur alongside the decreased release of the endothelium-derived relaxing factor and increased the release of von Willebrand factor (vWF), leading to general activation of the coagulation cascade and inflammation. Placental components, such as inflammatory cytokines and syncytiotrophoblast particles interact with the maternal immune system and endothelial cells, further promoting coagulation and inflammation. These interactions also elevate leukocyte numbers and interleukin concentrations, as well as increase complement activity.
Low platelet countEdit
vWF degradation in HELLP syndrome is inhibited due to decreased levels of degrading proteins, leading to an increased exposure of platelets to vWF. As a result, thrombotic microangiopathies develop and lead to thrombocytopenia.
As a result of the high number of angiopathies, the erythrocytes fragment as they pass through the blood vessels with damaged endothelium and large fibrin networks, leading to macroangiopathic haemolytic anaemia. As a consequence of hemolysis, lactic acid dehydrogenase (LDH) and hemoglobin are released, with the latter binding to serum bilirubin or haptoglobin.
During the coagulation cascade, fibrin is deposited in the liver and leads to hepatic sinusoidal obstruction and vascular congestion, which increase intrahepatic pressure. Placenta-derived FasL (CD95L), which is toxic to human hepatocytes, leads to hepatocyte apoptosis and necrosis by inducing the expression of TNFα and results in the release of liver enzymes. Hepatic damages are worsened by the disrupted portal and total hepatic blood flow that result as a consequence of the microangiopathies. Collectively, all the hepatic changes and damages result in hepatic dysfunction in the form of hepatic necrosis, haemorrhages, and capsular rupture.
Early and accurate diagnosis, which relies on laboratory tests and imaging exams, is essential for treatment and management and significantly reduces the morbidity rate. However, diagnosis of the syndrome is challenging, especially due to the variability in the signs and symptoms and the lack of consensus amongst healthcare professionals. Similarities to other conditions, as well as normal pregnancy features, commonly lead to misdiagnosed cases or more often, delayed diagnosis.
There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia and microangiopathic haemolytic anaemia 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 haemoglobin levels.
- Increased serum bilirubin levels and visual disturbances.
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.
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.
- Class I HELLP syndrome is characterised by a platelet count below 50,000/µL.
- Class II HELLP syndrome is characterised by a platelet count of 50,000-100,000/µL.
- Class III HELLP syndrome is characterised by a platelet count of 100,000-150,000/µL. alongside the appearance of the other two main clinical criteria. Class I is the most severe, with increased risk of morbidity and mortality.
Another classification system, introduced in Memphis, categorises HELLP syndrome based on its expression.
- Partial expression of the condition is characterised by the manifestation of one or two of the main diagnostic criteria.
- The complete expression of the condition is characterised by the manifestation of all three main diagnostic criteria.
The only current recommended and most effective treatment is delivery of the baby, as the signs and symptoms diminish and gradually disappear following the delivery of the placenta. Prompt delivery is the only viable option in cases with multiorgan dysfunction or multiorgan failure, haemorrhage and considerable danger to the fetus. Certain medications are also used to target and alleviate specific symptoms.
A number of steroidal drugs, such as corticosteroids for fetal lung maturation, can increase maternal platelet count and improve neonatal health, however, the number and severity of their side effects are inconclusive and there is no consensus concerning whether their benefits are worthwhile.
With treatment, maternal mortality is about 1 percent, although complications such as placental abruption, acute renal failure, subcapsular liver hematoma, permanent liver damage, and retinal detachment occur in about 25% of women. Perinatal mortality (stillbirths plus death in infancy) is between 73 and 119 per 1000 babies of woman with HELLP, while up to 40% are small for gestational age. In general, however, factors such as gestational age are more important than the severity of HELLP in determining the outcome in the baby.
HELLP syndrome affects 10-20% of pre-eclampsia patients and is a complication in 0.5-0.9% of all pregnancies. Caucasian women over 25 years of age comprise most of the diagnosed HELLP syndrome cases. In 70% of cases before childbirth, the condition manifests in the third trimester, but 10% and 20% of the cases exhibit symptoms before and after the third trimester, respectively. Postpartum occurrences are also observed in 30% of all HELLP syndrome cases.
HELLP syndrome was identified as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982. In a 2005 article, Weinstein wrote that the unexplained postpartum death of a woman who had hemolysis, abnormal liver function, thrombocytopenia, and hypoglycemia motivated him to review the medical literature and to compile information on similar women. He noted that cases with features of HELLP had been reported as early as 1954.
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