Intrahepatic Cholestasis Of Pregnancy

Question 1

Intrahepatic cholestasis of pregnancy is a liver disease unique to pregnancy that is characterised by … and elevated bile acids.

Answer 1

Intrahepatic cholestasis of pregnancy is a liver disease unique to pregnancy that is characterised by pruritus and elevated bile acids.

Question 2

What is the most common pregnancy-associated liver disease?

Answer 2

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-associated liver disease. It is characterised by pruritus (i.e. itching), elevated bile acids, and variable elevations in liver function tests (e.g. ALT/AST). It is due to cholestasis (i.e. decreased bile flow) and classically occurs in the late second or third trimester.

Question 3

Why is intrahepatic cholestasis of pregnancy important to recognise?

Answer 3

ICP is important to recognise because it is associated with an increased risk of fetal demise and stillbirth, particularly when the bile acid concentration is ≥ 100 micromol/L.

Question 4

Pregnancy-associated liver diseases include:

Answer 4

Intrahepatic cholestasis of pregnancy (ICP)
HELLP syndrome (haemolytic anaemia, elevated liver function tests, low platelets)
Acute fatty liver of pregnancy (AFLP)
Liver dysfunction in pre-eclampsia
Liver dysfunction in hyperemesis gravidarum

Question 5

Aetiology & pathophysiology of ICP

Answer 5

ICP is a pregnancy-related liver disorder meaning it occurs during pregnancy, most commonly in the late second or third trimester. The exact cause is unknown by is likely due to a combination of genetic susceptibility, hormonal and environmental factors.

Question 6

What is the cardinal feature of ICP ?

Answer 6

The cardinal feature of ICP is pruritus, which may precedes abnormalities in bile acids and liver function tests.

Question 7

Symptoms of ICP

Answer 7

Usually, symptoms begin in the late second or third trimester.

Pruritus: usually starts and predominates in soles and palms. It is worse at night. Ranges from mild to severe.
Right upper quadrant pain
Nausea
Anorexia
Steatorrhoea: excess fat in faeces (pale, oily, difficult to flush)

Question 8

Signs of ICP

Answer 8

Scratch marks
Excoriation
Jaundice (up to 25%): 1-4 weeks after pruritus onset
Primary skin lesions or stigmata of chronic liver disease warrant consideration of an alternative diagnosis

Question 9

How is the diagnosis of ICP usually made?

Answer 9

The diagnosis of ICP is usually made on the presence of pruritus and elevated bile acids in pregnancy.

Question 10

Bile acids measured in ICP

Answer 10

Serum bile acids should be measures in all suspected ICP cases. Seen in > 90% of affected pregnancies. If initially normal, important to check weekly unless empirical treatment was started.

The primary bile acids measured are cholic and chenodeoxycholic acid. Severe cholestasis is generally defined as bile acids > 40 micromol/L but the exact cut-off is variable and depends on the local laboratory normal values.

Question 11

Patients with ICP may have deranged liver function tests, such as…

Answer 11

AST/ALT: elevated ~60%. Levels should be unaffected by pregnancy. Values usually minimally elevated (i.e. < x2 ULN).
ALP: may be elevated but it is raised in pregnancy anyway due to the expression of a placental isoenzyme (an enzyme with identical structure/function).
Bilirubin: elevated in up to 25%. Rarely > 100 umol/L.

Extremely high levels of AST/ALT or bilirubin should warrant investigation for an alternative diagnosis.

Question 12

Imaging in ICP

Answer 12

A liver ultrasound is commonly completed in patients with deranged liver function tests to exclude an alternative diagnosis. There are no structural defects (e.g. biliary dilatation, mass lesion) associated with ICP.

Question 13

The most significant risk of ICP to the fetus is ….

Answer 13

The most significant risk of ICP to the fetus is stillbirth.

Question 14

Fetal effects of ICP:

Answer 14

Stillbirth: unclear mechanism
Spontaneous preterm labour
Iatrogenic preterm labour
Meconium-stained amniotic fluid
Neonatal respiratory distress syndrome
Need for neonatal ICU admission

Question 15

The risk of serious fetal effects correlates with a higher degree of …

Answer 15

The risk of serious fetal effects correlates with a higher degree of maternal bile acids. Levels ≥ 100 micromol/L is associated with a significantly increased risk of stillbirth at any point during pregnancy. Rates of stillbirth increase with gestational age.

Question 16

The principal treatment of ICP is …

Answer 16

The principal treatment of ICP is ursodeoxycholic acid (UDCA) although this does not seem to improve fetal outcomes.

Question 17

Maternal management of ICP

Answer 17

All patients with ICP should be offered UDCA to reduce symptoms and to improve liver function tests and bile acids. UDCA can be started empirically for pruritus or initiated once bile acids/LFTs become abnormal. An improvement is usually seen in 1-2 weeks of therapy.

Once initiated, weekly blood can be assessed to determine the level of bile acids. However, UDCA does not seem to affect fetal/neonatal outcomes. Several additional agents can be used for refractory cases including glutathione precursor S-adenosyl-methionine, cholestyramine, or rifampicin.

Question 18

Pregnancy management of ICP

Answer 18

Patients usually have frequent blood tests and monitoring during the antepartum period once ICP is diagnosed, but the value of fetal monitoring is unclear especially as fetal demise is suspected to be a sudden event.

The key to pregnancy management is the timing of delivery. This needs to balance the risk of stillbirth with increasing gestational age versus the increased perinatal risk with earlier delivery. In general, delivery before 37+0/40 should be avoided if bile acids are not elevated.

Question 19

If bile acids are elevated in ICP, what should happen in terms of delivery?

Answer 19

Bile acids ≥ 100 micromol/L: consider delivery at 36 weeks gestations. Certain situations may warrant even earlier delivery (e.g. excruciating/unremitting maternal pruritus)
Bile acids < 100 micromol/L: consider delivery at 36-39+0 weeks gestation. Consider delivery at diagnosis if diagnosed >39+0 weeks.
No special requirements are needed during labor, but continuous fetal monitoring should be used (e.g. cardiotocograph - CTG).

Question 20

When should pruritus associated with ICP resolve?

Answer 20

Following delivery, pruritus and liver function abnormalities should improve rapidly. Patients can still breastfeed and UDCA is usually stopped on the day of delivery (low levels may be detected in breastmilk but not expected to have adverse effects). If LFTs do not improve, patients should be referred to hepatology to investigate for underlying liver disease.

Importantly, ICP will recur in 60-70% of pregnancies, but the clinical course is highly variable.