HELLP syndrome

HELLP syndrome is a life-threatening obstetric complication usually considered to be a variant or complication of pre-eclampsia.^[1] Both conditions usually occur during the later stages of pregnancy, or sometimes after childbirth. "HELLP" is an abbreviation of the three main features of the syndrome:^[2]

• Hemolysis
• Elevated Liver enzymes
• Low Platelet count

Signs and symptoms

HELLP usually begins during the third trimester; rare cases have been reported as early as 21 weeks gestation. Often, a woman who develops HELLP syndrome has already been followed up for pregnancy-induced hypertension (gestational hypertension), or is suspected to develop pre-eclampsia (high blood pressure and proteinuria). Up to 8% of all cases occur after delivery.

Women with HELLP syndrome often "do not look very sick."^[3] Early symptoms can include:

• In 90% of cases, either epigastric pain described as "heartburn" or right upper quadrant pain develops.^[3][4]
• In 90% of cases, malaise occurs.^[4]
• In 50% of cases, nausea or vomiting happen.^[4]

Gradual but marked onset of headaches (30%), blurred vision, and paresthesia (tingling in the extremities) can occur. Edema may occur, but its absence does not exclude HELLP syndrome. Arterial hypertension is a diagnostic requirement, but may be mild. Rupture of the liver capsule and a resultant hematoma may occur. If a woman has a seizure or coma, the condition has progressed into full-blown eclampsia.

Disseminated intravascular coagulation is also seen in about 20% of all women with HELLP syndrome,^[5] and in 84% when HELLP is complicated by acute renal failure.^[6] Pulmonary edema is found in 6% of all women with HELLP syndrome,^[5] and in 44% when HELLP is complicated by acute renal failure.^[6]

A woman with symptoms of HELLP can be misdiagnosed in the early stages, increasing the risk of liver failure and morbidity.^[7] Rarely, after a caesarean section surgery a woman may have signs and symptoms of a shock condition mimicking either pulmonary embolism or reactionary haemorrhage.

Pathophysiology

The exact cause of HELLP is unknown, but general activation of the coagulation cascade is considered the main underlying problem. Fibrin forms crosslinked networks in the small blood vessels. This leads to a microangiopathic hemolytic anemia: the mesh causes destruction of red blood cells as if they were being forced through a strainer. Additionally, platelets are consumed. As the liver appears to be the main site of this process, downstream liver cells suffer ischemia, leading to periportal necrosis. Other organs can be similarly affected. HELLP syndrome leads to a variant form of disseminated intravascular coagulation, leading to paradoxical bleeding, which can make emergency surgery a challenge.

An association has been demonstrated between long chain long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD) of the child and maternal HELLP and acute fatty liver of pregnancy (AFLP). This inherited, autosomal recessive abnormality of fatty-acid oxidation can result in significant morbidity and mortality in infants, if untreated. Treatment with dietary manipulation is possible.^[8] About 80% of infants with LCHAD deficiency have been born after pregnancies complicated by AFLP or HELLP. However, how many pregnancies complicated by AFLP or HELLP result in infants with LCHAD deficiency is not known.^[9]

Diagnosis and classification

HELLP syndrome can be difficult to diagnose due to the variability of symptoms among pregnant women (frequently a woman will have no symptoms other than general abdominal pain), and early diagnosis is key in reducing morbidity. If not treated in a timely manner, a woman can become critically ill or die due to liver rupture/hemorrhage or cerebral edema.

In a woman with possible HELLP syndrome, a batch of blood tests is performed: a full blood count, a coagulation panel, liver enzymes, electrolytes, and renal function studies. Often, fibrin degradation product levels are determined, which can be elevated. Lactate dehydrogenase is a marker of hemolysis and is elevated (>600 U/l). Proteinuria is present but can be mild.

In one 1995 study, a positive D-dimer test in the presence of pre-eclampsia was reported to be predictive of woman who will develop HELLP syndrome.^[7][10]

The diagnostic criteria for and subtypes of HELLP vary across studies, which "makes comparison of published data difficult."^[1] The classifications include:

• Criteria developed at the University of Tennessee:^[4][11]
  • HELLP is characterized by hemolysis on peripheral blood smear with serum lactate dehydrogenase >600 IU/l; serum aspartate aminotransferase >70 IU/l; and platelet count <100,000/μl.
  • Partial HELLP syndrome is characterized by one or two features of HELLP.
• Criteria developed at the University of Mississippi, as of 1999:^[12]
  • "The diagnosis of HELLP syndrome required the presence of thrombocytopenia (perinatal platelet nadir ≤150,000 cells/μl), evidence of hepatic dysfunction (increased aspartate aminotransferase level of ≥40 IU/l, increased alanine aminotransferase level of ≥40 IU/l, or both, with increased lactate dehydrogenase (LDH) level of ≥600 IU/l), and evidence of hemolysis (increased LDH level, progressive anemia)...."
  • "Class 1 HELLP syndrome featured severe thrombocytopenia with a platelet nadir of ≤50,000 cells/μl, class 2 HELLP syndrome featured moderate thrombocytopenia with a platelet nadir between >50,000 and ≤100,000 cells/μl, and class 3 HELLP syndrome featured mild thrombocytopenia with a platelet nadir between >100,000 and ≤150,000 cells/μl."
• Criteria developed at the University of Mississippi, as of 2006: "For a patient to merit a diagnosis of HELLP syndrome, class 1 requires severe thrombocytopenia (platelets ≤50,000/μl), evidence of hepatic dysfunction (AST [aspartate aminotransferase] and/or ALT [alanine aminotransferase] ≥70 IU/l), and evidence suggestive of hemolysis (total serum LDH ≥600 IU/l); class 2 requires similar criteria except thrombocytopenia is moderate (>50,000 to ≤100,000/μl); and class 3 includes patients with mild thrombocytopenia (platelets >100,000 but ≤150,000/μl), mild hepatic dysfunction (AST and/or ALT ≥40 IU/l), and hemolysis (total serum LDH ≥600 IU/L)."^[13]

Treatment

The only effective treatment is prompt delivery of the baby. Several medications have been investigated for the treatment of HELLP syndrome, but evidence is conflicting as to whether magnesium sulfate decreases the risk of seizures and progress to eclampsia. The disseminated intravascular coagulation is treated with fresh frozen plasma to replenish the coagulation proteins, and the anemia may require blood transfusion. In mild cases, corticosteroids and antihypertensives (labetalol, hydralazine, nifedipine) may be sufficient. Intravenous fluids are generally required. Hepatic hemorrhage can be treated with embolization, as well, if life-threatening bleeding ensues.

The University of Mississippi standard protocol for HELLP includes corticosteroids.^[14] However, a 2009 review found "no conclusive evidence" supporting corticosteroid therapy,^[1] and a 2010 systematic review by the Cochrane Collaboration also found "no clear evidence of any effect of corticosteroids on substantive clinical outcomes" either for the mothers or for the newborns,^[15]

Prognosis

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.^[5] 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.^[16] In general, however, factors such as gestational age are more important than the severity of HELLP in determining the outcome in the baby.^[17]

Epidemiology

Its incidence is reported as 0.5-0.9% of all pregnancies, and 10-20% of women with severe pre-eclampsia.^[1] HELLP usually occurs in Caucasian women over the age of 25.^[7]

History

HELLP syndrome was identified as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982.^[2] 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.^[3] He noted that cases with features of HELLP had been reported as early as 1954.^[3][18]

See also

• Acute fatty liver of pregnancy
• Hypertrophic decidual vasculopathy

References