As mechanisms of iron handling were better defined and were examined in individual families affected

by NH, primary defects in these mechanisms appeared less likely. Awareness grew at the same time that recurrence rates of NH within sibships were too high for Mendelian single-gene recessive disease. Reports appeared of mothers by whom two men successively fathered infants with NH,4, 5 and mothers with autoimmune disease who bore infants with NH were described.5, 6 If NH were a unitary disorder, then single-gene models of defective iron handling did not accommodate important characteristics of NH.5 The analogic map of NH drawn by Cottier as “ein der Hämochromatose vergleichbares Krankheitsbild” no longer fit, clinically Tanespimycin in vivo or histopathologically,

the increasingly better explored territories of iron storage disorders of NH itself. In recent years, Whitington and coworkers7 have offered a new map, that of maternal immunity against a fetal antigen, not necessarily one involved in iron handling. This new paradigm defines Lorlatinib research buy NH as an alloimmune disorder, analogous to some instances of neonatal thrombocytopenia, in which transplacental transmission of a maternal antibody against an isoantigen results in cellular injury. It accounts for non-Mendelian occurrence and classes NH as an instance of liver failure with clinical and histopathological particularities explained by placentomaternal

dependence and fetal physiology. The new map also has permitted predictions about the mechanisms of the disease and about effective treatment of mothers at risk of bearing infants with NH. The report by Pan et al.8 in the current issue of HEPATOLOGY, filling in a blank space on that map, describes an immunohistochemical search for signs of complement activation in the livers of children with NH who died or underwent transplantation. Complement comprises over 40 sequentially interacting proteins whose activation is key in the pathogenesis of immune-mediated tissue damage.9 Once determined by insensitive measurements of intact C3 and C4 factors, complement activation is currently assessed directly by detection MCE of activation fragments, neoantigens, or complexes formed only when complement is activated.10 That hepatocyte surfaces bear C5b-C9 as an activated final assemblage unit proves that the complement system has been fully activated and can punch holes into the plasma membrane of hepatocytes that will inexorably undergo osmotic lysis. Is the pathogenesis of NH solved? Not yet. We learn from this article that complement is fully activated in the acute liver failure of NH, but in the absence of sufficient numbers of acute liver failure controls without NH, we can not say if this finding is NH-specific.