Pregnancy, pruritus and pain, oh my! A case-based approach to abnormal liver chemistries in pregnancy

Approach to Abnormal Liver Chemistries in Pregnancy

First, it is important to understand the normal physiologic changes that occur in liver chemistries during pregnancy. See the table below for a summary:

Figure 1 - Physiologic changes in laboratory tests during pregnancy

Taken from: Tran, R, Ahn J, Reau N. ACG Clinical Guideline: Liver Disease and Pregnancy. Am. J Gastroenterol. Feb 2016

• If liver chemistries are out of proportion to what is expected in pregnancy, it’s time to get to work!  (Figure 2).
• The first step in assessing a woman at any stage of pregnancy with an abnormal liver panel should be similar to the work up performed in a non-pregnant patient.
• When routine work up is negative, pregnancy related causes of liver disease should then be explored. It is important to think about diseases unique to pregnancy, diseases coincidental to pregnancy and diseases exacerbated by pregnancy.
• Using gestational age can guide your differential diagnosis, but should not be used as a ‘hard and fast’ rule (Figure 3). 

Figure 2: Proposed Diagnostic Algorithm for Abnormal Liver Enzymes Seen in Pregnancy

Taken from: Tran, R, Ahn J, Reau N. ACG Clinical Guideline: Liver Disease and Pregnancy. Am. J Gastroenterol. Feb 2016

Figure 3: Liver Diseases specific to pregnancy and corresponding trimester

Adapted from: Westbrook, R, Dusheiko G, Williamson C. Pregnancy and liver disease. J of Hepatology. April 2016 and Lee, Richard. Approach to liver disease occurring during pregnancy. UpToDate. Jan 22, 2019

Why check bile acids and why are they dangerous?

•  Maternal bile acids can cross the placenta --> accumulate in the fetus and amniotic fluid --> increase risk for intrauterine demise, pre-term delivery, meconium stained amniotic fluid and neonatal respiratory distress syndrome.
• In a prospective study conducted between 1999 and 2002, fetal complications did not arise until bile acids were ≥ 40 μmol /L.
• In the graph below, you can see the rates of complications in patients with no Intrahepatic cholestasis of pregnancy (ICP) (bile acid levels <10 μmol/L), mild ICP (maximum bile acid levels of 10‐39 μmol) and severe ICP (bile acid levels ≥40 μmol/L at any time). The rates of all complications differed between the severe ICP group and the other groups (preterm delivery, and meconium staining of amniotic fluid, placenta, and membranes, P < 0.001; asphyxial events, P < .01)

Figure 4: Fetal complication rates in pregnant women with ICP

Taken from Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rate. Hepatology. Aug 2004. 

White bars = no ICP; Gray bars = mild ICP,  Black bars = severe ICP

What is the role of ursodeoxycholic acid in ICP?

The main goals of treatment in ICP is to:

1. Decrease symptoms
2. Reduce risk of perinatal morbidity and mortality
   • In ICP, bile acid concentrations are typically >10 mmol/l. Increased bile acid concentration (>40 mmol/l) can identify higher risk, and may correlate with fetal distress as shown in the trial above

• Ursodeoxycholic Acid (UDCA) is the only treatment routinely recommend in guidelines, principally for improvement of maternal symptoms and laboratory tests
• Start at 10-15 mg/kg maternal body weight
• Generally regarded as a safe medication, with nausea and dizziness as the most common side effects
• Evidence behind UDCA
  • Decrease in pruritis and LFT’s typically within 2-4 weeks in some studies
  • However, one of the largest randomized trial performed in 2019 showed UDCA may not be as effective in reducing a composite of adverse perinatal outcomes (composite of perinatal death, preterm delivery, or neonatal unit admission for at least 4 hours) or total bile acid concentration) and therefore suggests reconsideration for routine use
• See Hersh Shroff's post on the use of UDCA in cholestatic liver disease for more info

Timing of delivery

• The American College of Obstetricians and Gynecologists recommends delivery at 36 to 37 weeks of gestation, or at diagnosis if diagnosed at term. Earlier delivery may be indicated depending on clinical circumstances.
• Fetus complications include preterm delivery, meconium stained amniotic fluid, and increased risk of neonatal respiratory distress.

Important Considerations

• Important to check liver profile and bile acids after delivery to ensure improvement. It may take labs 6-8 weeks post-delivery to normalize with a high recurrence rate on subsequent pregnancies.
• If labs do not return to normal values, work up for underlying hepatobiliary disease should be performed.
• Some studies have shown ICP may be associated with subsequent development of diseases such as hepatobiliary cancer, cardiovascular disease, Crohn’s disease, diabetes, and thyroid disease.