Intrahepatic Cholestasis of Pregnancy

Aka: Intrahepatic Cholestasis of Pregnancy, Pregnancy Related Cholestasis, Obstetric Cholestasis

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II. Definitions

  1. Intrahepatic Cholestasis of Pregnancy
    1. Reversible pregnancy-specific cholestasis associated with Pruritus, increased serum bile acids and liver enzymes

III. Epidemiology

  1. Most common liver disease in pregnancy
  2. Incidence: 1-1.5% of pregnancies in U.S.
    1. Highest Incidence in south america: 9.2 to 15.6%
    2. Lowest Incidence in Europe: 0.1 to 0.2%

IV. Pathophysiology

  1. Related to increased serum Estrogen levels
  2. Genetic Predisposition may affect bile salt transport and excretion
    1. Mutations have been identified in gene on p23 region of Chromosome 2

V. Risk Factors

  1. Third Trimester pregnancy
  2. Multiple Gestation pregnancy (RR 5)
  3. Advanced maternal age >35 years
  4. History of Intrahepatic Cholestasis of Pregnancy in prior pregnancies (recurs in 40 to 60% of patients)
  5. History of prior Oral Contraceptive use

VI. Symptoms

  1. Severe Pruritus in third trimester of pregnancy (typically starting around 30 weeks gestation)
  2. Pruritus localized to trunk and extremities, especially palms and soles, and especially at night
  3. Jaundice occurs in 14 to 25% of patients (follows Pruritus onset by 1 to 4 weeks)
  4. Epigastric Pain may occur, but more Generalized Abdominal Pain is uncommon
  5. Other associated symptoms
    1. Malaise and Fatigue
    2. Anorexia and weight loss
    3. Insomnia
    4. Steatorrhea (fat malabsorption)
    5. Dark Urine

VII. Signs

  1. No rash
  2. No Jaundice in mild form (Prurigo gravidarum)
    1. Jaundice develops in 10% of patients, starting 2 to 4 weeks after Pruritus onset

VIII. Differential Diagnosis: Pregnancy Related Conditions

  1. See Pruritus in Pregnancy
  2. Hyperemesis Gravidarum
    1. Liver transaminases (AST, ALT) may be over 200 IU/L
    2. Alkaline Phosphatase may be increased up to twice normal
    3. Serum Bilirubin may be increased enough to cause visible Jaundice
  3. HELLP Syndrome
    1. Often associated with Preeclampsia with Severe Hypertension and Proteinuria
    2. Most commonly occurs in third trimester and immediately postpartum
  4. Acute Fatty Liver of Pregnancy
    1. Associated with more severe liver failure and Renal Insufficiency
    2. May be difficult to distinguish with HELLP Syndrome

IX. Differential Diagnosis: Non-Pregnancy Related Conditions

  1. See Acute Hepatitis
  2. Viral Hepatitis
  3. Autoimmune Liver Disease
    1. Primary Biliary Cirrhosis
    2. Primary Sclerosing Cholangitis
  4. Choledocholithiasis
  5. Hepatobilliary tract neoplasm

X. Labs

  1. Serum transaminase (AST, ALT)
    1. Serum transaminases are mIldly increased in 60% of patients (typically less than two fold over normal range)
    2. In rare cases, levels may be >1000 IU/L
  2. Serum Bilirubin
    1. May be increased in up to 25% of patients
    2. Serum Bilirubin may rise >4 mg/dl (but rarely rise >6 mg/dl)
    3. Serum Bilirubin >16 mg/dl confers adverse fetal outcome
  3. Total Bile Acid Levels
    1. May be increased up to 10 to 25 fold
    2. Serum bile acid levels >40 umol/L are associated with higher fetal mortality
    3. Findings most consistent with Intrahepatic Cholestasis of Pregnancy
      1. Total bile acid level >11uMol/L
      2. Cholic Acid to Chenodeoxycholic Acid >42%
      3. Glycine to Taurine Bile Acid Ratio <1
  4. Other lab findings
    1. GGT may also be increased in one third of patients
    2. Alkaline Phosphatase may increase up to 4 fold over normal range
  5. Liver Biopsy
    1. Indications (not indicated in typical Intrahepatic Cholestasis of Pregnancy)
      1. Jaundice without Pruritus
      2. Onset of symptoms before 20 weeks gestation
      3. Persistent lab abnormalities >8 weeks after delivery
    2. Findings consistent with Intrahepatic Cholestasis of Pregnancy
      1. Bile canaliculi widened with non-inflammatory centrilobular cholestasis
      2. Normal hepatic parenchyma
      3. Bile plugs in the hepatocytes

XI. Management

  1. Exclude other causes of liver disease (see differential diagnosis as above)
  2. General measures
    1. Low Fat Diet
    2. Consider ParenteralVitamin K Replacement
    3. Ursodeoxycholic Acid (Ursodiol, UDCA)
      1. Dosing: 500 mg orally twice daily (or 15 mg/kg/day)
      2. Reduces symptoms, reduces Serum Bilirubin levels, and prolongs gestation
      3. Brouwers (2015) Am J Obstet Gynecol 212(1): 100.e1 [PubMed]
    4. Other Pruritus symptomatic management (adjunctive to Ursodeoxycholic Acid)
      1. Topical aqueous cream with 1% Menthol
      2. Oral Antihistamines for Pruritus
        1. Hydroxyzine (Atarax) 25 to 50 mg per day in divided doses
      3. Cholestyramine (Questran)
        1. Dosing: 8 to 16 mg orally per day (divided doses)
        2. Increases bile salt excretion
        3. Poorly tolerated (not palatable) and associated with Constipation
        4. Risks further fat soluble Vitamin Deficiency (especially Vitamin K)
          1. Supplement Vitamin K 10 mg orally daily while using Cholestyramine
      4. S-Adenosyl-L-Methionine
        1. Dosing: 1000 mg orally daily
        2. Variable effects on Pruritus
  3. Lab monitoring (weekly after 30 weeks gestation)
    1. Liver Function Tests
    2. Serum bile acid levels
    3. Blood Clotting tests
  4. Consult maternal fetal medicine
    1. Increased antepartum observation for fetal well being
      1. Weekly Non-Stress Test, amniotic fluid volume and umbilical artery doppler
      2. Periodic Fetal Growth evaluation by Ultrasound starting at 30 weeks gestation
    2. Plan delivery by 35-37 weeks gestation based on Fetal Lung Maturity

XII. Course

  1. Resolves with delivery (often within 48 hours, typically by 6 weeks postpartum)
  2. After resolution in Postpartum Period, patients may safely restart Oral Contraceptives

XIII. Complications

  1. Bilirubin is toxic to fetal cardiac cells, and causes Vasoconstriction of chorionic veins
  2. Fetal Adverse effects (primarily affecting morbidity and mortality of the fetus)
    1. Preterm delivery (44% of cases)
    2. Meconium-stained amniotic fluid (25 to 45% of cases)
    3. Fetal Distress (22% of cases)
    4. Intrauterine Fetal Demise (2% of cases)
    5. Fetal malformations and birthweight do not appear to increase with Intrahepatic Cholestasis of Pregnancy
    6. Fetal adverse effects increase with degree of bile acid accumulation
  3. Maternal Antepartum Adverse Effects
    1. Fat malabsorption
    2. Fat soluble Vitamin Deficiency
      1. Vitamin K Deficiency risks Coagulopathy and intrapartum and Postpartum Hemorrhage
  4. Maternal Postpartum Associated Conditions (increased longterm risk related to cholestasis predisposition)
    1. Gallstones
    2. Pancreatitis
    3. Cirrhosis

XIV. References

  1. Swencki (2015) Crit Dec Emerg Med 29(11):2-10
  2. Erlandson (2023) Am Fam Physician 107(2): 152-8 [PubMed]
  3. Ozkan (2015) World J Gastroenterol 21(23): 7134-41 [PubMed]

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