'Minor' liver function test abnormalities: Discussion
As a product of the degradation primarily of haem, and excreted in bile, circulating bilirubin concentrations are determined by the balance of production and excretion.
Production is increased principally in disorders of red blood cell metabolism and excretion by disorders of hepatic conjugation (producing unconjugated or indirect bilirubin) or removal (producing conjugated or direct bilirubin). Laboratory discrimination of direct from indirect bilirubin is becomes less reliable at lower total bilirubin concentrations (typically under approximately 40-50 micromoles/L).
Using the same principles as for alkaline phosphatase and a typical range of 5- 21 micromol/L 2.5 % of a population would be expected to have a total bilirubin over 21 and 0.1% over 25 micromol/L. Users should again check their local ranges.
The clinical assessment should logically seek to exclude drugs which interfere in the bilirubin reaction (propranolol, oxytetracycline, methotrexate, and levodopa)
[Aranda-Michel and Sherman, 1998] and take this into account in the decision to investigate further for stable raised bilirubin.
As described above, a raised bilirubin in conjunction with other LFT abnormalities will prompt further investigation directed by predominant pattern of hepatocellular (transaminases) or cannalicular (GGT, alkaline phosphatase) changes.
Identification of raised bilirubin in conjunction with raised cannalicular enzyme (alkaline phosphatase and/or GGT) should prompt consideration of potential intra or extra-hepatic cholestasis and is not described further in this answer.
Saturation of the conjugation process by excess production of bilirubin will lead to a predominance of unconjugated bilirubin. One review describes raised bilirubin > 50% conjugated and raised bilirubin > 70% unconjugated as representing direct and indirect hyperbilirubinaemia respectively
[Aranda-Michel and Sherman, 1998]. If the rise is isolated, and predominantly unconjugated, exclusion of increased haem turnover leaves a highly probable diagnosis of Gilbert's disease. No further investigation is recommended if bilirubin concentrations fall or do not continue to rise on interval retesting. The British Columbian guideline recommended interval retesting of 1-3 months for rises in any liver test < 1.5 ULN. This is consistent in the case of a small bilirubin rise in an asymptomatic patient, particularly in light of the bimodal serum decrease time, which has a long terminal phase (due to delta bilirubin formation
[Van Hootegem et al, 1985]). Commonsense would suggest that within this period, retesting be performed in the earlier part for larger rises and later for smaller rises. It would be unlikely to see large rises in bilirubin eg > 3 ULN in the absence of other changes and a laboratory opinion would appear reasonable in this instance (author interpretation).
Haemolysis is conventionally diagnosed by the laboratory appearances on a blood film, combined with reduced haptoglobin, reticulocytosis and raised LDH. There is no clear evidence as to whether one or all of these tests are required.
If evidence of haemolysis is found, further investigation will be determined by the clinical context, usually in conjunction with secondary care advice or referral.
Resorption of large haematomas can produce a similar pattern of hyperbilirubinaemia; this should be clinically apparent provided test requesters are aware of this as a possible cause.