What is the differential diagnosis and management of elevated transaminases (liver enzymes) in pregnancy?

Differential Diagnosis of Elevated Transaminases in Pregnancy

The differential diagnosis of elevated transaminases in pregnancy must be organized by trimester, with first/second trimester elevations most commonly due to hyperemesis gravidarum, viral hepatitis, or drug-induced liver injury, while third trimester elevations require urgent evaluation for preeclampsia/HELLP syndrome, acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy. 1

Initial Diagnostic Workup

When transaminases are elevated at any gestational age, immediately obtain the following laboratory tests:

• Total serum bile acids (non-fasting) - essential for identifying intrahepatic cholestasis of pregnancy and risk stratification 1, 2
• Complete liver panel including AST, ALT, bilirubin, GGT, alkaline phosphatase, and platelets 3
• Viral hepatitis serologies (HBsAg, anti-HCV, HAV IgM, HEV if travel history to endemic areas) 1, 4
• Autoimmune markers (AMA, ANA, SMA) to exclude autoimmune hepatitis or primary biliary cholangitis 2, 3
• Coagulation studies (PT, fibrinogen) if third trimester presentation to assess for AFLP or HELLP 1

Trimester-Specific Differential Diagnosis

First and Second Trimester (Weeks 1-27)

Hyperemesis gravidarum is the most common cause in early pregnancy:

• Transaminases typically elevated 2-4 times upper limit of normal 5
• Liver tests elevated in 40-50% of severe cases 3
• AST and ALT levels average 52.9 and 83.3 IU/L respectively 5
• Management: Anti-emetics (cyclizine, doxylamine/pyridoxine, prochlorperazine, or promethazine as first-line) 3
• Transaminases normalize with symptom resolution 5

Viral hepatitis presents with non-specific symptoms:

• Look for asthenia, anorexia, polyalgia, abdominal pain, diarrhea, fever, and pruritus 4
• Transaminases typically elevated 25-fold 4
• Critical action: Serovaccination of newborn at birth for hepatitis B 4
• Consider hepatitis E if recent travel to North Africa, Middle East, Southeast Asia, or Mexico 4

Drug-induced liver injury requires detailed medication history:

• Review all prescribed, over-the-counter, and herbal products 3
• Ondansetron has been reported to cause transaminase elevation (AST 267 U/L, ALT 605 U/L) 6
• Management: Discontinue all non-essential medications and monitor for improvement 4

Early-onset intrahepatic cholestasis of pregnancy:

• Bile acids >10 μmol/L with pruritus before third trimester suggests underlying genetic disorder 1, 2
• Requires genetic evaluation and multidisciplinary management 2
• Do not start ursodeoxycholic acid before obtaining baseline bile acids, as this prevents definitive diagnosis 7

Pre-existing chronic liver disease (PBC, PSC, autoimmune hepatitis):

• Up to one-third of PBC diagnoses are made during pregnancy, often misdiagnosed as ICP 1
• 50% of women with pre-existing cholestatic disease develop worsening or de novo pruritus 3
• Continue ursodeoxycholic acid throughout pregnancy - it is safe and associated with stable liver tests 1, 3

Third Trimester (Weeks 28-40)

Preeclampsia with severe features and HELLP syndrome are obstetric emergencies:

• Look for hypertension, epigastric or right upper quadrant pain, headache 1, 4
• Critical pitfall: Hypertension may be absent; epigastric or left shoulder pain may be only signs 4
• Platelets <100,000/μL, hemolysis on peripheral smear 8
• Management: Control severe hypertension with labetalol, nifedipine, or methyldopa; administer magnesium sulfate to prevent eclamptic seizures; deliver promptly once coagulopathy and hypertension corrected 3

Acute fatty liver of pregnancy (AFLP) has high mortality if unrecognized:

• Presents with nausea, vomiting, right upper quadrant pain, jaundice, hypoglycemia 1
• Swansea criteria: Six or more findings including elevated transaminases (>42 IU/L), bilirubin (>0.8 mg/dL), hypoglycemia (<72 mg/dL), elevated uric acid (>5.7 mg/dL), coagulopathy (PT >14 seconds), renal impairment (creatinine >1.7 mg/dL) 1
• PT prolonged, fibrinogen reduced, lactate dehydrogenase elevated - these differentiate from preeclampsia 1
• If hepatic encephalopathy present, AFLP is highly likely 1
• Management: Intensive care admission for encephalopathy, elevated lactate, or high Swansea score; expedite delivery once coagulopathy and metabolic derangements treated 3
• Screen newborn for LCHAD deficiency 1

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver-specific disorder:

• Pruritus typically in third trimester with bile acids >10 μmol/L 1
• Transaminases elevated up to 10-20 times upper limit of normal, bilirubin <6 mg/dL 1
• Bile acid levels correlate with stillbirth risk - highest risk when >100 μmol/L 1
• Management algorithm:
  • Bile acids >40 μmol/L: Start ursodeoxycholic acid 10-15 mg/kg/day in divided doses 1, 3
  • Bile acids >100 μmol/L: Deliver at 36 weeks or at diagnosis if after 36 weeks 1
  • Bile acids <100 μmol/L: Deliver at 36-39 weeks depending on timing of diagnosis 1
  • Bile acids <40 μmol/L: Consider delivery at term 1

Rare thrombotic microangiopathies (TTP, complement-mediated HUS, catastrophic APS):

• Present similarly to preeclampsia with severe features 8
• Require multidisciplinary approach with hematology and nephrology 8
• Early recognition critical to avoid serious maternal morbidity and mortality 8

Key Management Principles

For elevated transaminases in first/second trimester without clear etiology:

• Transaminases up to 3-4 times upper limit of normal can be safely observed with careful history and viral hepatitis testing 5
• 69 patients in one series normalized during follow-up without intervention 5
• Repeat testing every 1-2 weeks if symptoms persist 7

For third trimester elevations:

• Abnormal results associated with shorter duration of pregnancy and require urgent evaluation 5
• Never delay delivery for laboratory confirmation in unstable patients 3

Imaging and procedures when needed:

• Ultrasound and liver elastography safe at any gestation 3
• MRCP safe at any gestation for evaluating PSC with worsening cholestasis 1, 3
• ERCP can be performed in second/third trimester when clinically necessary (fetal radiation <0.1-0.5 mGy, well below 50 mGy threshold) 3

Critical Pitfalls to Avoid

• Do not assume normal alkaline phosphatase rules out liver disease - alkaline phosphatase increases to 133-418 IU/L in normal third trimester 3
• Do not diagnose ICP based on pruritus alone - this leads to unnecessary preterm deliveries 7
• Do not stop immunosuppressive medications in women with pre-existing liver disease - clinical deterioration poses greater risk than medication continuation 3
• Do not use obeticholic acid in pregnancy - lacks safety data 1, 3
• Do not start ursodeoxycholic acid before obtaining baseline bile acids - prevents subsequent diagnosis 7

Postpartum Follow-Up

• Verify complete resolution of transaminases and bile acids within 3 months of delivery 2, 3
• If abnormalities persist, refer to hepatology for evaluation of underlying chronic liver disease 2, 7
• Counsel about recurrence risk: ICP recurs in up to 90% of subsequent pregnancies 2
• Women with history of ICP have increased risk of later developing chronic hepatitis, liver fibrosis, hepatitis C, and cholangitis 2
• Up to 70% of women with pre-existing cholestatic disease have postnatal deterioration requiring close postpartum monitoring 3