What are the other differential diagnoses to consider in a postpartum patient with slightly elevated bilirubin level?

Differential Diagnoses for Postpartum Hyperbilirubinemia

In a postpartum patient with slightly elevated bilirubin, you must immediately exclude maternal sepsis (total bilirubin >2 mg/dL indicates end-organ injury), followed by HELLP syndrome and acute fatty liver of pregnancy, as these carry significant maternal mortality risk and require urgent intervention. 1

Life-Threatening Conditions to Exclude First

Maternal Sepsis

• Total bilirubin >2 mg/dL meets criteria for hepatic end-organ injury in sepsis diagnosis (applies from 20 weeks gestation through 3 days postpartum). 1
• Look for concurrent signs: persistent hypotension (SBP <85 mmHg or MAP <65 mmHg), platelets <100×10⁹/L, creatinine >1.2 mg/dL, lactate >2 mmol/L, or altered mental status. 1
• Critical pitfall: Chorioamnionitis/endometritis patients have high false alarm rates on sepsis screening tools, but elevated bilirubin still warrants full sepsis evaluation. 1

HELLP Syndrome/Preeclampsia

• Characterized by hemolysis, elevated liver enzymes (AST/ALT typically elevated), and low platelets (<100×10⁹/L). 2
• Occurs in 0.2-0.6% of pregnancies, typically third trimester or postpartum period. 2
• Requires immediate delivery and carries maternal mortality risk—never assume intrahepatic cholestasis of pregnancy (ICP) without excluding HELLP first. 2

Acute Fatty Liver of Pregnancy (AFLP)

• Rare (0.005-0.01% of pregnancies) but life-threatening condition presenting in third trimester or postpartum. 2
• Presents with elevated liver enzymes and bilirubin, often with coagulopathy and hypoglycemia. 2

Pregnancy-Specific Cholestatic Conditions

Intrahepatic Cholestasis of Pregnancy (ICP)

• Bilirubin typically <5 mg/dL with mild jaundice in only 10-15% of cases; if bilirubin is prominently elevated, consider alternative diagnoses. 2
• Characterized by elevated serum bile acids (>10-11 μmol/L) with ALT typically <500 U/L. 2
• Key distinguishing feature: Normal LDH levels (elevated LDH suggests HELLP syndrome instead). 2
• Symptoms typically resolve within days to weeks postpartum; persistence beyond 6 weeks postpartum mandates hepatology referral for underlying liver disease. 1, 2

Primary Biliary Cholangitis (PBC) or Primary Sclerosing Cholangitis (PSC)

• Up to one-third of new PBC diagnoses are made during pregnancy, often misdiagnosed as ICP. 1
• PBC: Look for anti-mitochondrial antibodies (AMA), elevated IgM; 60-70% show increased liver disease activity postpartum. 1
• PSC: Associated with inflammatory bowel disease (60-80% of cases); one-third show deterioration in liver tests postpartum. 1
• Ultrasound is initial imaging test of choice to evaluate bile duct abnormalities. 1

Autoimmune and Viral Hepatitis

Autoimmune Hepatitis (AIH) Flare

• The postpartum period is a high-risk time for AIH flares or new AIH diagnosis due to immune reconstitution following delivery. 1
• Look for: Elevated AST/ALT, hypergammaglobulinemia, increased IgG, positive ANA/anti-SMA (type 1) or anti-LKM antibodies (type 2). 1
• AIH should be strongly considered in any postpartum patient with liver dysfunction and hypergammaglobulinemia with selective IgG elevation. 1
• History of non-adherence to immunosuppressive therapy or recent de-escalation increases risk. 1

Viral Hepatitis

• No longer a common cause of jaundice in pregnant/postpartum women in the United States due to vaccination programs. 3
• Hepatitis E: AST/ALT >400 IU/ml, bilirubin >3 mg/dL, positive anti-HEV-IgM and HEV RNA. 1
• Hepatitis B reactivation: Elevated HBV DNA, HBsAg positive, 10-25% positive anti-HBc IgM. 1
• Hepatitis A or C superinfection: AST/ALT >400 IU/ml, bilirubin >3 mg/dL with positive serology/PCR. 1

Drug-Induced and Metabolic Causes

Drug-Induced Liver Injury (DILI)

• Obtain detailed medication history including over-the-counter medicines and herbals (check LiverTox® database). 1
• Criteria: ALT >5× ULN or ALT >3× ULN with bilirubin >2× ULN. 1
• Can mimic AIH in 9-12% of cases; differentiation requires follow-up after steroid trial—DILI resolves without relapse upon steroid discontinuation, while genuine AIH universally relapses. 1

Gilbert Syndrome

• Benign disorder affecting 7-10% of population with mildly elevated unconjugated bilirubin and normal liver function tests. 4, 5
• Diagnosis of exclusion: Mild unconjugated hyperbilirubinemia with normal transaminases, biliary markers, and red blood cell counts. 5

Biliary Obstruction

Cholelithiasis/Choledocholithiasis

• Currently the most common cause of jaundice in pregnant/postpartum women (25% of cases), surpassing viral hepatitis. 3
• Obtain hepatobiliary ultrasound to exclude gallstones and biliary obstruction. 2
• Look for elevated alkaline phosphatase and gamma-GT in addition to bilirubin. 1

Hemolytic Causes

Wilson Disease (Acute Presentation)

• High bilirubin (>10 mg/dL, mainly indirect), Coombs-negative hemolysis, mild-moderate transaminase elevation (<500 IU/ml). 1
• AST:ALT ratio >2.2, low alkaline phosphatase, ALP:total bilirubin ratio <4. 1
• Low ceruloplasmin (<20 mg/dL) and high 24-hour urinary copper (>100 μg, usually >500 μg/24h). 1

Diagnostic Algorithm

1. Immediately assess for sepsis criteria: Check vital signs, lactate, complete blood count with platelets, coagulation studies, creatinine. 1
2. Exclude HELLP/AFLP: Obtain LDH, peripheral smear for hemolysis, glucose, coagulation studies. 2
3. Measure bile acids and liver transaminases: Distinguish ICP (bile acids >10 μmol/L, normal LDH) from other causes. 2
4. Obtain hepatobiliary ultrasound: Exclude biliary obstruction and gallstones. 1, 2
5. Check autoimmune and viral serologies: ANA, anti-SMA, IgG levels, viral hepatitis panel (especially HEV in endemic areas). 1
6. Review medication history: Consider DILI if recent drug exposure. 1
7. If diagnosis unclear or labs persist >6 weeks postpartum: Refer to hepatology for evaluation of underlying chronic liver disease. 1, 2