What is the differential diagnosis (D/d) between HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count) syndrome and Acute Fatty Liver of Pregnancy (AFLP)?

Differential Diagnosis: HELLP Syndrome vs. Acute Fatty Liver of Pregnancy

While both HELLP syndrome and AFLP present with overlapping features in the third trimester, AFLP is distinguished by hepatic encephalopathy, hypoglycemia, severe coagulopathy with prolonged PT and low fibrinogen, and progression to acute liver failure, whereas HELLP syndrome is characterized by the diagnostic triad of hemolysis, elevated liver enzymes, and thrombocytopenia <100×10⁹/L with prominent preeclampsia (95% of cases). 1

Key Distinguishing Clinical Features

HELLP Syndrome

• Preeclampsia is present in 95% of cases with hypertension and proteinuria 1, 2
• Neurological symptoms predominate: severe headache, visual disturbances, peripheral edema 1, 3
• Abdominal pain (right upper quadrant or epigastric), nausea, vomiting in 65% 1
• Encephalopathy is NOT a feature of HELLP syndrome 3
• Occurs in 0.2-0.6% of pregnancies, typically third trimester or within 48 hours postpartum 1

Acute Fatty Liver of Pregnancy

• Hepatic encephalopathy is the hallmark finding that should raise high suspicion for AFLP over HELLP 1, 3
• Polydipsia/polyuria are characteristic of AFLP and absent in HELLP 1, 3
• Hypoglycemia is a defining feature of AFLP 1, 4, 3
• Preeclampsia present in only ~50% of cases 1
• Jaundice is more common and pronounced compared to HELLP 3, 2
• Occurs in 0.01% of pregnancies (much rarer than HELLP) 1
• Associated with male fetus and multifetal pregnancy 1

Laboratory Differentiation

HELLP Syndrome Diagnostic Criteria

• Hemolysis: elevated LDH, low haptoglobin, schistocytes on blood smear 1
• Elevated liver enzymes: ALT typically <500 U/L 1
• Low platelets: <100×10⁹/L (diagnostic threshold) 1
• Bilirubin typically <5 mg/dL 1
• Fibrinogen levels usually normal or mildly decreased 5
• DIC occurs in minority of cases 1

AFLP Laboratory Features

• Prolonged PT/INR and low fibrinogen are characteristic 1, 3, 5
• DIC present in >75% of cases 1
• Hypoglycemia (<72 mg/dL per Swansea criteria) 1, 3
• Leukocytosis (>11×10⁶/L) 1, 3
• Elevated ammonia (>42 IU/L) 1
• More pronounced hyperbilirubinemia compared to HELLP 3, 5
• Antithrombin levels <65% 3
• Initial lack of hemolysis and thrombocytopenia may be present early 3
• Elevated creatinine (>1.7 mg/dL) more common than in HELLP 1, 5

Most Useful Discriminating Laboratory Values

Upon admission, measure fibrinogen, creatinine, cholesterol, and total bilirubin to differentiate AFLP from HELLP syndrome 5:

• Low fibrinogen strongly suggests AFLP 5
• Higher creatinine and bilirubin favor AFLP 5, 2
• Hypoglycemia is pathognomonic for AFLP 4, 3

Imaging Findings

HELLP Syndrome

• Hepatic infarcts, hematoma, or rupture possible 1
• No ascites typically 1
• Abdominal ultrasound mandatory if symptoms suggest hepatic hematoma (abdominal, epigastric, or right shoulder pain) 1
• Higher risk of hepatic hemorrhage with platelets <20×10⁹/L 1

AFLP

• Fatty infiltration on imaging (bright liver on ultrasound) 1
• Ascites may be present 1
• Intrahepatic hemorrhage or rupture <2% 1

Diagnostic Criteria

Swansea Criteria for AFLP

Six or more of the following criteria suggest AFLP 1:

• Vomiting
• Abdominal pain
• Polydipsia/polyuria
• Encephalopathy
• Elevated transaminases (>42 IU/L)
• Elevated bilirubin (>0.8 mg/dL)
• Hypoglycemia (<72 mg/dL)
• Leukocytosis (>11×10⁶/L)
• Elevated uric acid (>5.7 mg/dL)
• Elevated ammonia (>42 IU/L)
• Ascites or bright liver on ultrasound
• Renal impairment (creatinine >1.7 mg/dL)
• Coagulopathy (PT >14 seconds)
• Microvesicular steatosis on biopsy

Important caveat: The Swansea criteria have high sensitivity but low specificity in severe AFLP with acute liver failure features 1

Clinical Course and Prognosis

HELLP Syndrome

• Fluctuating clinical course with rapid exacerbation within hours or transient remissions 3
• Maternal mortality ~1% in developed countries 3, 2
• Perinatal mortality 7-20% 3
• Higher rates of neonatal complications: small for gestational age (57.1%), respiratory distress syndrome (39.2%), neonatal sepsis (34.2%) 2

AFLP

• Rapidly progressive to acute liver failure if delivery not immediate 3
• Maternal mortality 1.8-18% (historically up to 92% pre-1970) 1, 3, 6
• Perinatal mortality 9-23% 1, 3, 6
• More maternal organ dysfunction: jaundice (85.7%), acute kidney injury (61.9%), DIC (66.7%), sepsis (47.6%) 2
• Infectious complications in 53% of AFLP cases vs 29% in HELLP 6
• Major intra-abdominal bleeding requiring laparotomy more common in AFLP 6

Critical Management Pitfalls

Liver biopsy should NOT be obtained unless it will change management, as both conditions require expeditious delivery regardless of histologic confirmation 1

Do not delay delivery waiting for a definitive diagnosis between HELLP and AFLP—focus on supportive care, correcting coagulopathy, managing hypertension and seizures, and preparing for delivery 1

For AFLP with encephalopathy, elevated lactate >2.8 mg/dL, MELD score >30, or Swansea criteria >7, immediate ICU admission is required 1, 4

Screen newborns of mothers with AFLP for long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, as there is a strong association with this fetal metabolic disorder 1

Early referral to transplant center is mandatory for AFLP with severe hepatic impairment or HELLP with hepatic rupture/acute liver failure 1, 4