What is the diagnostic approach for bile acid-related disease?

From the Guidelines

The diagnostic approach for bile acid-related disease involves a stepwise evaluation beginning with clinical assessment and laboratory testing, prioritizing the most recent and highest quality evidence from 2024 1. Initial workup should include liver function tests (ALT, AST, alkaline phosphatase, GGT, bilirubin), serum bile acid levels, and lipid profiles. Specific tests for primary bile acid disorders include measurement of total and individual bile acids in serum, urine, and sometimes stool samples. For conditions like Primary Biliary Cholangitis (PBC), testing for antimitochondrial antibodies (AMA) is essential, with titers ≥1:40 considered diagnostic when combined with elevated alkaline phosphatase, as supported by earlier guidelines 1. For Primary Sclerosing Cholangitis (PSC), magnetic resonance cholangiopancreatography (MRCP) is the preferred imaging modality to visualize bile duct strictures and dilations, as noted in studies from 2009 1. In cases of bile acid synthesis disorders, specialized testing includes urine bile acid analysis using mass spectrometry and genetic testing for specific enzyme deficiencies. Liver biopsy may be necessary when noninvasive testing is inconclusive, particularly for conditions like PBC, PSC, or drug-induced cholestasis. For bile acid malabsorption, the gold standard is the 75SeHCAT retention test (where available), with retention values <10% at 7 days indicating malabsorption. Alternative tests include serum 7α-hydroxy-4-cholesten-3-one (C4) and fecal bile acid measurements. Notably, the most recent guideline from 2024 1 emphasizes the importance of serum bile acid levels in diagnosing intrahepatic cholestasis of pregnancy, with levels >10 mmol/L being diagnostic in the setting of pruritus. This comprehensive approach allows for accurate diagnosis of the specific bile acid-related disorder, enabling appropriate treatment selection, and is supported by the combination of clinical assessment, laboratory testing, and imaging modalities as outlined in the guidelines and studies from 2009 1 and the recent update from 2024 1.

Some key points to consider in the diagnostic approach include:

• Clinical assessment and history taking to identify symptoms and potential causes of bile acid-related disease
• Laboratory testing, including liver function tests and serum bile acid levels
• Imaging modalities, such as MRCP, for visualization of bile duct strictures and dilations
• Specialized testing, including urine bile acid analysis and genetic testing, for bile acid synthesis disorders
• Liver biopsy for inconclusive cases or specific conditions like PBC, PSC, or drug-induced cholestasis
• The 75SeHCAT retention test or alternative tests for bile acid malabsorption
• Recent guidelines from 2024 1 highlighting the role of serum bile acid levels in diagnosing intrahepatic cholestasis of pregnancy.

By following this stepwise evaluation and considering the most recent and highest quality evidence, clinicians can accurately diagnose bile acid-related diseases and select appropriate treatments to improve patient outcomes.

From the FDA Drug Label

Patient Management Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed

The diagnostic approach for bile acid-related disease is not explicitly stated in the provided drug label. However, it can be inferred that laboratory and clinical assessments are used to monitor patients for progression of primary biliary cholangitis (PBC) and hepatic adverse reactions.

• Laboratory assessments may include monitoring of total bilirubin, direct bilirubin, and prothrombin time.
• Clinical assessments may include evaluation for signs of portal hypertension, such as ascites, gastroesophageal varices, and persistent thrombocytopenia. It is essential to closely monitor patients with compensated cirrhosis, concomitant hepatic disease, and/or severe intercurrent illness for new evidence of portal hypertension or increases in liver function tests 2.

From the Research

Diagnostic Approach for Bile Acid-Related Disease

The diagnostic approach for bile acid-related disease involves various methods, including:

• Measurement of fasting and postprandial serum conjugated bile acids (CBA) 3
• 75Selenium-homotaurocholic-acid-test (75SeHCAT) with a <10% retention threshold 4
• Evaluation of fasting serum 7-α-hydroxy-4-cholesten-3-one (C4) 4
• Assessment of total fecal bile acid (BA) excretion over 48 hours 4
• Measurement of fibroblast growth factor 19 (FGF19) 4

Diagnostic Accuracy of Different Methods

The diagnostic accuracy of different methods for bile acid malabsorption (BAM) varies, with:

• 75SeHCAT showing an average sensitivity and specificity of 87.32 and 93.2%, respectively 4
• Serum C4 having an average sensitivity and specificity of 85.2 and 71.1%, respectively 4
• Total fecal BA excretion having an average sensitivity and specificity of 66.6 and 79.3%, respectively 4
• Fasting serum FGF19 having the lowest sensitivity and specificity of 63.8 and 72.3%, respectively 4

Limitations and Future Directions

The current diagnostic methods for BAM have limitations, including substantial heterogeneity in the extracted data 4. Therefore, there is a need for novel biomarkers aimed at objective detection of BAM to improve the management of this condition 4. Additionally, the diagnostic sensitivity of serum conjugated bile acid determination is poor in mild liver disease 3.