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

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

Case

25-year-old female with hyperthyroidism who is 30 weeks pregnant initially presented with costovertebral tenderness, pelvic pain and nausea. Pain resolved after passing a kidney stone, but  initial labs are concerning for abnormal liver chemistries with AST of 118 U/L, ALT of 162 U/L, alkaline phosphatase of 200 U/L, total bilirubin of 2.0 mg/dL and INR of 1.0.  What is the next best step?

A. Emergent delivery

B.Check for long chain 3 hydroxyacyl CoA dehydrogenase (LCHAD) deficiency

C. Obtain a liver biopsy

D. Ultrasound with dopplers, viral hepatitis and autoimmune hepatitis work up

E. CT scan of abdomen and pelvis

Answer

Incidence of abnormal liver chemistries in pregnancy is approximately 3-5%. It is essential to recognize when elevated labs represent normal physiologic changes in pregnancy and when these abnormal results require immediate attention and further workup. The first step in assessing elevated liver chemistries in pregnant patients is the same as that in non-pregnant patients including evaluating for viral hepatitis and autoimmune disease, assessing for medication toxicity, etc. While there are some diseases that do require emergent delivery or early delivery (such as acute fatty liver of pregnancy, eclampsia, HELLP), we do not yet know the cause of abnormal liver chemistries in this clinical scenario. LCHAD is one of the enzymes involved in fatty acid oxidation. In fetuses that are homozygous for LCHAD deficiency, levels of long chain metabolites accumulate in maternal blood and hepatocytes, leading to toxic effects and, in some cases, acute fatty liver of pregnancy. In some clinical scenarios, a liver biopsy may be necessary. However, most etiologies in this population can be determined by serological and clinical parameters and use of a liver biopsy is premature in this case. Finally, CT scans carry risk of teratogenesis and therefore should only be used if absolutely necessary. Ultrasound is safe and is therefore the preferred imaging modality 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

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

Back to the case

A liver ultrasound revealed patent hepatic and portal veins, no biliary abnormalities noted. Liver enzymes continued to increase to AST/ALT in the 400’s. Patient remained normotensive, pain resolved, but now with new onset of pruritus. Baby doing well, no distress.

Viral work up was negative 
No culprit medications were identified
ANA elevated 1:320, anti-smooth and anti-mitochondrial antibody pending, immunoglobulins within normal limits.
Pregnancy related work up:
– Bile Acids 74 (<10 is considered normal)
– Platelets, haptoglobin and LDH normal
– No schistocytes seen
– Urinalysis without protein

Why check bile acids and why are they dangerous?

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

Back to the case

Given onset of pruritus and elevated bile acids, we began treatment with ursodeoxycholic acid for ICP. Anti-smooth muscle and anti-mitochondrial came back negative. Pruritis resolved within one week of starting treatment, and liver chemistries resolved within four weeks, with plans to deliver at 37 weeks. 

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.

Take Home Points:

  • 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
  • Can use gestational age to help guide diagnosis, but should not be used as a definitive rule
  • Presence of pruritus with elevated bile acids in pregnancy is commonly seen in ICP
  • Higher levels of bile acids may be associated with fetal complications
  • Controversial data regarding use of ursodeoxycholic acid in ICP; generally well tolerated, if used
Written by:

Transplant Hepatologist, Piedmont Health

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Take Home Points:

  • 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
  • Can use gestational age to help guide diagnosis, but should not be used as a definitive rule
  • Presence of pruritus with elevated bile acids in pregnancy is commonly seen in ICP
  • Higher levels of bile acids may be associated with fetal complications
  • Controversial data regarding use of ursodeoxycholic acid in ICP; generally well tolerated, if used