What are the differential diagnoses for a 34-year-old female, 13 days post-partum, who developed obstructive jaundice in her last trimester, followed by acute kidney injury (AKI), coagulopathy, encephalopathy, and worsening jaundice, with subsequent resolution of AKI, partial correction of coagulopathy and encephalopathy, but increasing bilirubin levels and evidence of hemolysis, as indicated by high lactate dehydrogenase (LDH) levels?

Differential Diagnoses for Post-Partum Hemolytic Pattern with Persistent Hyperbilirubinemia

The most likely diagnosis is evolving or persistent HELLP syndrome with ongoing hemolysis, though acute fatty liver of pregnancy (AFLP) with hemolytic component and thrombotic microangiopathy (TTP/HUS) must be urgently excluded given the life-threatening implications. 1, 2

Primary Differential Diagnoses

1. HELLP Syndrome (Most Likely)

• HELLP syndrome can persist or worsen post-delivery, with hemolysis continuing for days after delivery despite partial improvement in other parameters 1
• The classic triad includes: hemolysis (elevated LDH, schistocytes on smear), elevated liver enzymes (AST/ALT 300-1000 U/L), and thrombocytopenia (platelets <150 × 10⁹/L) 1
• Bilirubin typically remains <5 mg/dL in HELLP, but can be higher with severe ongoing hemolysis 1
• The pattern of initial AKI with coagulopathy and encephalopathy followed by partial resolution but worsening hemolysis fits delayed or biphasic HELLP presentation 2
• Critical: Check peripheral smear for schistocytes immediately to confirm microangiopathic hemolytic anemia 2

2. Acute Fatty Liver of Pregnancy (AFLP) with Hemolytic Component

• AFLP presents with jaundice, hypoglycemia, coagulopathy, encephalopathy, and AKI—matching this patient's initial presentation 1
• Laboratory findings include AST/ALT 300-1,000 U/L, elevated PT, low fibrinogen, low antithrombin III, elevated bilirubin, and elevated LDH 1
• AFLP can have hemolysis as part of the syndrome, though less prominent than HELLP 1
• The obstructive jaundice in third trimester is atypical for AFLP, which usually presents with hepatocellular pattern 1
• Post-delivery, AFLP should improve within days to weeks; persistent worsening suggests alternative diagnosis 1

3. Thrombotic Thrombocytopenic Purpura (TTP) or Hemolytic Uremic Syndrome (HUS)

• TTP/HUS presents with microangiopathic hemolytic anemia, thrombocytopenia, AKI, and neurologic symptoms—overlapping significantly with this case 2
• Unlike HELLP, TTP/HUS can persist or worsen post-delivery and requires urgent plasma exchange 1
• Key distinguishing feature: ADAMTS13 activity <10% confirms TTP (must be checked urgently) 2
• The pattern of AKI followed by hemolysis with high LDH is classic for TTP/HUS 3

4. Intrahepatic Cholestasis of Pregnancy (ICP) Complicated by Hemolysis

• The initial presentation of obstructive jaundice in third trimester could represent severe ICP 1
• ICP should resolve within 4-6 weeks post-delivery; persistence beyond this suggests underlying chronic liver disease 4
• However, ICP does not typically cause AKI, coagulopathy, or encephalopathy 1
• The development of hemolysis post-delivery is NOT explained by ICP alone and suggests a second process 1, 4

5. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Unmasked by Hepatic Stress

• G6PD deficiency can cause massive hemolysis in the setting of hepatic dysfunction, presenting with markedly elevated bilirubin and AKI 5
• The combination of viral hepatitis or drug exposure with underlying G6PD deficiency can cause severe hemolysis 5, 6
• Check G6PD levels and review medication/oxidative stress exposures 3, 6
• This would explain the pattern change to hemolysis with high LDH 5

6. Autoimmune Hemolytic Anemia (AIHA)

• Pregnancy can trigger or unmask autoimmune hemolytic anemia 3
• Direct antiglobulin test (Coombs test) is essential to diagnose immune-mediated hemolysis 3
• AIHA presents with elevated LDH, indirect hyperbilirubinemia, low haptoglobin, and reticulocytosis 3
• Does not explain the initial obstructive jaundice or multi-organ involvement 3

Critical Immediate Workup Required

Urgent laboratory evaluation must include: 2, 3

• Peripheral blood smear (schistocytes indicate microangiopathic hemolysis—HELLP vs TTP/HUS)
• Complete hemolysis panel: LDH, haptoglobin, indirect bilirubin, reticulocyte count
• Direct antiglobulin test (Coombs) to exclude autoimmune hemolysis
• ADAMTS13 activity level (if <10%, confirms TTP requiring urgent plasma exchange)
• Coagulation studies: PT/INR, PTT, fibrinogen, D-dimer (distinguish DIC from TTP)
• G6PD level (if available, though may be falsely normal during acute hemolysis)
• Repeat platelet count, renal function, liver enzymes

Management Algorithm

Step 1: Stabilize and Monitor 1, 2

• Admit to high-dependency or intensive care unit given history of multi-organ failure
• Continuous monitoring for hepatic complications (subcapsular hematoma/rupture with severe thrombocytopenia)
• Avoid regional anesthesia if platelets <100,000/mm³ or elevated INR

Step 2: Treat Based on Most Likely Diagnosis 1, 2

• If HELLP syndrome: Supportive care, correct coagulopathy with FFP, platelet transfusion if <50,000/mm³, monitor for hepatic complications
• If TTP suspected: Urgent plasma exchange while awaiting ADAMTS13 results (do not delay treatment)
• If AFLP with persistent hepatic failure: Consider N-acetylcysteine, plasma exchange, early transplant center referral

Step 3: Address Persistent Cholestasis 4

• If obstructive jaundice persists beyond 6 weeks post-delivery, refer to hepatology for evaluation of underlying chronic liver disease (PBC, PSC, ABCB4 deficiency)
• Imaging (ultrasound/MRCP) to exclude biliary obstruction if not already done

Critical Pitfalls to Avoid

• Do not assume HELLP resolves immediately post-delivery—hemolysis can persist or worsen for days 1, 2
• Do not miss TTP/HUS—requires urgent plasma exchange and has high mortality if untreated 2
• Do not attribute all findings to a single diagnosis—this patient may have overlapping conditions (e.g., ICP + HELLP, or AFLP + hemolysis) 1
• Do not delay transplant center referral if signs of acute liver failure persist (encephalopathy, coagulopathy unresponsive to treatment) 1
• Persistence of jaundice beyond 6 weeks post-delivery is abnormal and mandates hepatology evaluation for chronic liver disease 4