Lines of Evidence	Influence on conclusion
Line of Evidence 1 – Triggers of copper release from the liver in WD patients are variable and unpredictable, both in nature and timing	?
Line of Evidence 2 – Copper can be sequestered in the liver of some WD patients for many years with no overt extrahepatic (or hepatic) toxicity, at hepatic levels significantly higher than the hepatic levels expected from estimated daily exposure in non‐WD individuals	↓↓↓
Line of Evidence 3 – In other WD patients, copper toxicity is observed in extrahepatic organs, notably the brain. However, neither the measured amount of hepatic copper nor the timeframe (latency) after which copper toxicity is manifested following hepatic retention are clearly established.	↑↑↑
Line of Evidence 4 – In human studies, no adverse effects were detected at levels of copper supplementation of 8 mg/day for 12 months used as a treatment for Alzheimer disease (at this exposure level copper retention has been reported for up to 5 months)	↓↓↓
Line of Evidence 5 – Evidence of sudden severe copper toxicity in WD patients and in farm animals associated with conditions of stress or altered physiology, or unknown	↑↑↑
Conclusion – based on a process of weighing the influence of the different lines of evidence, their consistency of and semi‐formal expert judgement, the overall evidence supports the premise that extrahepatic toxicity is dependent on hepatic copper retention, under permissive conditions, but such conditions cannot be predicted (LoE 1).	Extremely likely (95–99% probability) under permissive conditions