What is the meaning and pathophysiology of HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome?

HELLP Syndrome: Definition and Pathophysiology

HELLP syndrome is a life-threatening obstetric emergency representing the severe end of the pre-eclampsia spectrum, characterized by microangiopathic hemolytic anemia, hepatocellular injury, and consumptive thrombocytopenia, with maternal mortality reaching 3.4%. 1, 2

Definition and Diagnostic Criteria

HELLP is an acronym standing for:

• Hemolysis
• Elevated Liver enzymes
• Low Platelet count

The syndrome occurs in 0.2-0.9% of all pregnancies and complicates 10-20% of cases with severe pre-eclampsia. 3, 4, 5

Diagnostic Laboratory Thresholds

According to the Tennessee Classification System, HELLP requires all three components 3:

• Hemolysis: LDH >600 U/L with evidence of microangiopathic hemolytic anemia on peripheral blood smear 1
• Elevated liver enzymes: AST ≥70 U/L and/or ALT elevation 3
• Low platelets: <100,000/mm³ 6, 3

The Mississippi Triple-class System further stratifies severity by nadir platelet counts, with counts below 50,000/mm³ indicating the most severe disease and highest risk of complications 1, 3.

Pathophysiology

Primary Placental Dysfunction

HELLP syndrome originates from aberrant placental development with incomplete trophoblast invasion of spiral arteries, leading to placental ischemia and oxidative stress. 5, 7 This represents a more acute and predominant inflammatory process compared to standard pre-eclampsia, with the liver as the primary target organ 5.

Cascade of Systemic Injury

The pathophysiological sequence involves 5, 7:

1. Endothelial Activation and Damage

• Systemic endothelial dysfunction occurs from placenta-derived inflammatory cytokines 7
• More severe endothelial injury than typical pre-eclampsia 5

2. Microangiopathic Hemolysis

• Red blood cells fragment as they pass through damaged small vessels 1
• Peripheral blood smear shows schistocytes and burr cells 1
• Elevated LDH reflects both hemolysis and hepatocellular injury 3

3. Hepatocellular Injury

• Direct hepatocyte damage from ischemia and inflammatory mediators 5
• Periportal and focal parenchymal necrosis 1
• The degree of liver enzyme elevation correlates with disease severity and maternal risk 6
• Can progress to subcapsular hematoma and hepatic rupture in severe cases 1

4. Consumptive Thrombocytopenia

• Platelet activation and consumption at sites of endothelial damage 5
• Platelet count directly correlates with severity of liver dysfunction and predicts adverse maternal outcomes 6
• Fibrin degradation products are elevated (>10 µg/L) despite normal PT/PTT 1

5. Coagulation System Activation

• Greater activation than in pre-eclampsia alone 5
• Microthrombi formation in hepatic sinusoids 5
• DIC can develop in severe cases 1

Clinical Presentation Timeline

Approximately 70% of cases develop antepartum between 27-37 weeks gestation, while 30% occur within 48 hours postpartum. 3 The syndrome can rarely present in the second trimester or as late as 72 hours after delivery 4.

Key Clinical Features

Patients typically present with 1, 2:

• Epigastric or right upper quadrant pain (from hepatic capsular distension)
• Nausea and vomiting
• Upper abdominal tenderness
• Hypertension (>160/90 mmHg defines severe disease) 1, 2
• Proteinuria (>5g/24h in severe cases) 2
• Peripheral edema

Progressive Complications

Without prompt intervention, the syndrome progresses to 1:

• Oliguria (<400 mL/24h) and acute tubular necrosis
• Cortical necrosis and renal failure
• Cerebral symptoms and eclampsia
• Pulmonary edema and ARDS
• Hepatic rupture (rare but catastrophic)
• Panhypopituitarism

Diagnostic Pitfalls

HELLP syndrome is frequently misdiagnosed initially because symptoms mimic non-obstetric conditions 1, 2, 4:

• Acute cholecystitis
• Viral hepatitis
• Idiopathic thrombocytopenic purpura
• Hemolytic uremic syndrome
• Acute fatty liver of pregnancy
• Appendicitis

The key distinguishing feature is the triad of laboratory findings in the context of pregnancy, particularly in the third trimester with hypertension and proteinuria. 2

Genetic and Immunologic Factors

The syndrome likely involves genetic predisposition combined with a disordered immunologic maternal response to placental antigens. 5 This explains why some women with pre-eclampsia progress to HELLP while others do not, despite similar initial presentations.