Can intake of complementary and alternative medicines cause a false elevation of serum angiotensin‑converting enzyme levels in patients with cholestasis?

Can CAM Intake Cause False Elevation in Serum ACE with Cholestasis?

There is no evidence that complementary and alternative medicines (CAM) directly cause false elevations of serum angiotensin-converting enzyme (ACE) levels in cholestasis; however, CAM can cause hepatotoxicity that may lead to true elevations of serum ACE through liver injury mechanisms.

Understanding the Relationship Between Liver Disease and ACE Elevation

The key distinction here is between "false" elevation (laboratory interference) versus "true" elevation (pathophysiologic response). The evidence demonstrates that:

• Alcoholic liver disease elevates serum ACE levels in approximately 30% of patients, with mean levels of 30.8 ± 13 units/mL compared to 22.8 ± 6 units/mL in controls 1
• Various liver diseases show elevated ACE activity in progressive order: chronic persistent hepatitis < chronic aggressive hepatitis < liver cirrhosis, with acute hepatitis also showing increased activity 2
• Extrahepatic obstructive jaundice (cholestasis) actually shows subnormal ACE activity, not elevated levels 2

CAM-Induced Hepatotoxicity: The Real Concern

The more clinically relevant issue is that CAM products can cause genuine hepatotoxicity, which may then affect ACE levels:

Documented CAM Hepatotoxicity Cases:

• Carica papaya, Alstonia boonei, and Tetrapleura tetraptera extracts caused severe hepatorenal dysfunction with hepatocellular pattern injury 3
• Boldo leaf infusion caused jaundice and elevated liver enzymes, particularly in elderly patients with biliary tract disorders 4
• Red yeast rice extract and guggulsterol products caused severe hypertransaminasemia with lobular necroinflammatory changes 5

Clinical Algorithm for Evaluation

When encountering elevated ACE levels in a patient with cholestasis who uses CAM:

Step 1: Determine the Type of Cholestasis

• Extrahepatic cholestasis typically shows subnormal ACE levels 2, so elevated ACE suggests an alternative or additional process
• Intrahepatic cholestasis from hepatocellular injury may elevate ACE

Step 2: Obtain Comprehensive CAM History

As emphasized in EASL guidelines, obtain a thorough drug history including "herbal medicines, vitamins and other substances" taken within 6 weeks of presentation 6. This is imperative in the diagnostic workup.

Step 3: Assess for CAM-Induced Hepatotoxicity

• Discontinue all CAM products immediately 6
• Perform core liver aetiology screen to exclude other causes 7
• Consider RUCAM scoring to establish causality between CAM and liver injury 3

Step 4: Interpret ACE Elevation in Context

• If cholestasis is purely extrahepatic/obstructive, elevated ACE suggests concomitant hepatocellular injury (possibly CAM-induced)
• If cholestasis is hepatocellular, ACE elevation may reflect the severity of liver parenchymal disease
• ACE elevation does NOT represent laboratory interference from CAM but rather reflects true hepatic pathology

Critical Pitfalls to Avoid

Do not assume elevated ACE is "false" or artifactual. The elevation likely represents genuine hepatic injury, potentially from:

1. CAM-induced hepatotoxicity causing hepatocellular damage
2. Underlying liver disease severity (chronic hepatitis, cirrhosis)
3. Alcohol use (if present) 1

Do not overlook CAM as a cause of liver injury. Patients often do not volunteer information about herbal supplements unless specifically asked, and these products lack regulation and safety data 3, 4, 5.

Remember that extrahepatic cholestasis typically shows LOW ACE levels 2, so elevated ACE in this setting should prompt investigation for additional hepatocellular pathology.

Management Implications

• Immediately discontinue all CAM products when hepatotoxicity is suspected 6, 3, 4
• Monitor liver function tests for improvement after CAM cessation (typically shows recovery within weeks) 3, 4
• Consider supportive care including N-acetylcysteine for severe hepatotoxicity 3
• Educate patients about the hepatotoxic potential of "natural" remedies 4, 5

The bottom line: CAM does not cause false ACE elevation through laboratory interference, but it can cause real hepatotoxicity that genuinely elevates ACE levels through hepatocellular injury mechanisms.