A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in a coma: causes and consequences of lactate-protected hypoglycaemia.

Lactate can substitute for glucose as a metabolic substrate. We report a patient with acute liver failure who was awake despite a glucose level of 0.7 mmol/l with very high lactate level of 25 mmol/l. The hypoglycaemia+hyperlactataemia combination may be considered paradoxical since glucose is the main precursor of lactate and lactate is reconverted into glucose by the Cori cycle. Literature relevant to the underlying mechanism of combined deep hypoglycaemia and severe hyperlactataemia was assessed. We also assessed the literature for evidence of protection against deep hypoglycaemia by hyperlactataemia. Four syndromes demonstrating hypoglycaemia+hyperlactataemia were found: 1) paracetamol-induced acute liver failure, 2) severe malaria, 3) lymphoma and 4) glucose-6-phosphatase deficiency. An impaired Cori cycle is a key component in all of these metabolic states. Apparently the liver, after exhausting its glycogen stores, loses the gluconeogenic pathway to generate glucose and thereby its ability to remove lactate as well. Several patients with lactic acidosis and glucose levels below 1.7 mmol/l who were not in a coma have been reported. These observations and other data coherently indicate that lactate-protected hypoglycaemia is, at least transiently, a viable state under experimental and clinical conditions. Severe hypoglycaemia+hyperlactataemia reflects failure of the gluconeogenic pathway of lactate metabolism. The existence of lactate-protected hypoglycaemia implies that patients who present with this metabolic state should not automatically be considered to have sustained irreversible brain damage. Moreover, therapies that aim to achieve hypoglycaemia might be feasible with concomitant hyperlactataemia.

IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression.

IL-12 is a potent inducer of IFN-gamma production and drives the development of Th1 cells. Human polarized Th2 cells do not express the signaling beta2-subunit of the IL-12R and, therefore, do not signal in response to IL-12. The question was raised as to what extent the loss of the IL-12Rbeta2 chain in Th2 cells has bearing on the stability of the human Th2 phenotype. In the present report, we show that restimulation of human fully polarized Th2 cells in the presence of IL-12 primes for a shift towards Th0/Th1 phenotypes, accompanied by suppression of GATA-3 expression and induction of T-bet expression. These reversed cells are further characterized by a marked IL-12Rbeta2 chain expression and fully restored IL-12-inducible STAT4 activation. The IL-12-induced phenotypic shift proved to be stable as a subsequent restimulation in the presence of IL-4 and in the absence of IL-12 could not undo the accomplished changes. Identical results were obtained with cells from atopic patients, both with polyclonal Th2 cell lines and allergen-specific Th2 cell clones. These findings suggest the possibility of restoring IL-12 responsiveness in established Th2 cells of atopic patients by stimulation in the presence of IL-12, and that IL-12-promoting immunotherapy can be beneficial for Th2-mediated immune disorders, targeting both naive and memory effector T cells.