The Computational Acid–Base Chemistry of Hepatic Ketoacidosis

Opposing evidence exists for the source of the hydrogen ions (H(+)) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H(+) exchange (~H(+)e). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~H(+)e for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~H(+)e coefficients, where negative revealed ~H(+) release and positive revealed ~H(+) uptake. Results revealed that for the liver (pH = 7.0), the net ~H(+)e for the reactions of ketogenesis ending in each of acetoacetate (AcAc), β-hydroxybutyrate (β-HB), and acetone were −0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H(+) release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H(+) dissociation. Nevertheless, there is a net ~H(+) release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H(+) coefficients for β-HB and AcAc oxidation were −0.9649 and 0.0363 (muscle), and −0.9719 and 0.0291 (brain), respectively. The larger ~H(+) release values for β-HB oxidation result from covalent ~H(+) release during the oxidation–reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H(+) coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for β-HB:AcAc:acetone, the net ~H(+)e coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to −0.1983, −0.0003, −0.2872, and −0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H(+) coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H(+) release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, β-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H(+) release. The extent of this release is dependent on the final proportionality between acetoacetate, β-hydroxybutyrate, and acetone.