Serum Bile Acids

Bile acids are made from cholesterol in hepatocytes (cholic and chenodeoxycholic acids), conjugated with glycine or taurine, secreted into bile, and reabsorbed in the terminal ileum, with over 95% returning through the portal vein for extraction by hepatocytes.

This enterohepatic cycling gives fasting serum concentrations of under 10 micromol/L, and a postprandial rise after gallbladder emptying.

Impaired hepatocyte uptake, biliary secretion or cholestasis raises serum bile acids sharply, and they are the most sensitive marker of cholestasis and of liver dysfunction in several settings.

The main clinical use is intrahepatic cholestasis of pregnancy, which affects 0.5 to 1% of pregnancies in Europe (higher in Scandinavia, South Asia and Chile at 5 to 15%). A fasting total bile acid of 19 micromol/L or more confirms the diagnosis, and levels of 100 micromol/L or more carry a markedly raised risk of stillbirth. Serum bile acids also help in unexplained pruritus, drug induced cholestasis, inherited cholestatic disorders and for assessing portosystemic shunting.

Indications. Pruritus in pregnancy, especially of the palms and soles, in the second or third trimester. Unexplained generalised itching with normal liver enzymes. Suspected cholestatic liver disease. Monitoring of intrahepatic cholestasis of pregnancy and response to ursodeoxycholic acid. Neonatal and infant cholestasis (with specialist interpretation). Suspected bile acid synthesis defects. Suspected portosystemic shunting in dogs and humans (rarely). Monitoring after biliary diversion or transplantation.

Specimen. Serum 1 to 2 mL, taken fasting (overnight 8 hours) for the fasting value, with a postprandial sample 2 hours after a meal if required. Stable at 2 to 8 °C for several days. Haemolysis and lipaemia should be avoided. Enzymatic spectrophotometric assays measure total bile acids, and liquid chromatography with tandem mass spectrometry measures individual conjugated species.

Reference values.

• Fasting total bile acids: under 10 micromol/L (some laboratories under 6 or 14 micromol/L).
• Postprandial (2 hours): under 19 micromol/L in non-pregnant people, with a normal rise of 2 to 3 times.
• Pregnancy: non-fasting values under 19 micromol/L are accepted as normal.

Intrahepatic cholestasis of pregnancy.

• Diagnosis: pruritus with total bile acids 19 micromol/L or more, with other causes of liver disease excluded. Alanine aminotransferase is raised in 60% and bilirubin in 10 to 20%.
• Severity bands: mild 19 to 39 micromol/L, moderate 40 to 99 micromol/L, severe 100 micromol/L or more.
• Foetal risk rises with bile acid concentration: stillbirth risk stays close to background (about 0.13%) when bile acids are under 100 micromol/L, but reaches 3% at 100 micromol/L or more, with preterm birth, meconium stained liquor and neonatal respiratory distress. Spontaneous preterm labour rises at 40 micromol/L or more.
• Ursodeoxycholic acid relieves itching in some women and improves liver tests, but does not reliably reduce stillbirth risk.
• Timing of delivery is brought forward to 35 to 36 weeks at 100 micromol/L or more, and 36 to 38 weeks at 40 to 99 micromol/L in many units.
• Bile acids and liver enzymes return to normal 2 to 8 weeks after delivery. Persistence beyond 8 weeks suggests chronic liver disease or inherited cholestasis (ABCB4, ABCB11, ATP8B1 variants).

Other conditions.

• Cholestatic liver disease (primary biliary cholangitis, primary sclerosing cholangitis, biliary obstruction): bile acids rise in parallel with alkaline phosphatase and gamma glutamyltransferase.
• Hepatocellular disease (hepatitis, cirrhosis): fasting levels may be normal, with raised postprandial levels (sensitive for impaired uptake).
• Inherited disorders: progressive familial intrahepatic cholestasis types 1 to 3 (low gamma glutamyltransferase in types 1 and 2, high in type 3), benign recurrent intrahepatic cholestasis, and bile acid synthesis defects (low or absent serum bile acids with cholestasis).
• Bile acid malabsorption: serum bile acid precursor C4 (7-alpha-hydroxy-4-cholesten-3-one) is raised, with faecal bile acids and SeHCAT retention as alternatives.
• Portosystemic shunts: raised postprandial values.
• Drug induced cholestasis, parenteral nutrition associated liver disease and sepsis: raised.

Critical values and findings needing immediate action.

• Total bile acids 100 micromol/L or more in pregnancy: urgent obstetric review, foetal surveillance and planned early delivery, and weekly bile acid and liver function monitoring.
• Bile acids 40 micromol/L or more with symptoms in pregnancy: increased surveillance and review of delivery timing.
• Severe pruritus with jaundice and prolonged prothrombin time: vitamin K, and exclusion of acute liver failure.
• Neonatal conjugated hyperbilirubinaemia: urgent paediatric liver assessment for biliary atresia.
• Sudden reduction in foetal movements in a woman with cholestasis: same day assessment.

Interferences and pitfalls.

• Non-fasting samples in non-pregnant patients give higher values, and the fasting state should be recorded.
• Normal bile acids do not exclude cholestasis early, and bile acids can lag behind symptoms by days. Repeat testing at 1 to 2 weeks is done when itching continues.
• Alanine aminotransferase may be normal in a proportion of women with intrahepatic cholestasis of pregnancy, and diagnosis rests on bile acids.
• Results take days in some laboratories, so treatment decisions in strongly suggestive cases (itching of palms and soles, onset in the third trimester) are not delayed.
• Assays differ between laboratories, with some reporting total bile acids by enzymatic method only.
• Ursodeoxycholic acid therapy raises measured total bile acids by enzymatic assays, which complicates monitoring, and specialised assays discriminate it.
• Bile acids rise after meals, with ileal disease, after cholecystectomy and with bile acid sequestrants (reduced).
• Other causes of itching in pregnancy (pemphigoid gestationis, polymorphic eruption, atopic eruption, viral hepatitis, pre-eclampsia, acute fatty liver of pregnancy, HELLP syndrome) are excluded.

Special groups.

• Pregnancy: recurrence in later pregnancies is 40 to 90%, women are at higher risk of gallstones, hepatitis C, hepatobiliary disease and gestational diabetes, and oestrogen containing contraception can cause recurrence.
• Neonates and infants: bile acids are interpreted with direct bilirubin and gamma glutamyltransferase, and specialist laboratories measure primary bile acid synthesis defects.
• Older adults: raised levels point to primary biliary cholangitis or biliary obstruction.
• Regions: high prevalence in Chile, Scandinavia and South Asia.

Follow up tests. Full liver function tests with gamma glutamyltransferase, bilirubin (total and direct), prothrombin time, hepatitis A, B, C and E serology, autoimmune liver screen (antimitochondrial antibody), liver ultrasound, foetal growth and monitoring, repeat bile acids weekly during pregnancy, repeat liver tests 6 to 8 weeks after delivery, genetic testing (ABCB4, ABCB11) in persistent or recurrent disease, and C4 or SeHCAT for bile acid malabsorption.