When normal is not: The dilemma of interpreting laboratory averages of bioactive molecules subject to heterogeneous regulatory feedback and epigenetic mosaicism

SummaryComplex regulatory systems control the levels of many bioactive molecules in the serum. These systems involve the integration of feedback responses from numerous tissues. End-organs and tissues can manifest epigenetic mosaicism, particularly with aging or disease states. We propose that an isolated lab value may reflect a blended average of inhomogeneous feedback responses from target tissues in various states of dysfunction. Reliance on such data may underestimate the state of systemic dysfunction. Yet in clinical practice, normal serum levels of a given molecule and its associated regulatory machinery are often assumed to reflect normal body homeostasis and tissue function. Organism-wide integration of abnormally high and low levels of bioactivity of a molecule in different tissues may yield apparently normal serum values of the bioactive molecule and known components of its regulatory system. We specifically discuss thyroid hormone regulation and function as a case example. Epigenetic reprogramming of either regulatory loops or tissue responses represents another way in which normal serum levels of the molecule may obscure target-organ dysfunction. The proposed idea has broad implications for disease pathogenesis, diagnosis, and therapies. A model where individual tissues employ illegitimate signaling to subvert the concerns of the organism as a whole is also proposed.