“Neonatal hemochromatosis”: A re-vision
Authors: A. S. Knisely, Diego Vergani
Journal: Hepatology (2010)

Analogy is useful when we are trying to understand things new to us; but it also may delude, as when the first elephant that we blindly explore becomes a pillar, a fan, a snake, a wall, a rope. In 1957, when Hans Cottier1 described a novel oddity—sibling newborns with advanced liver disease and iron deposits in various extrahepatic epithelia (the pancreas and thyroid) and in the myocardium, but with sparing of the spleen and lymph nodes ("a disease picture like hemochromatosis," as he put it)—he had already published 16 articles or reports. The fourth compared tissue siderosis between transfusional and idiopathic hemochromatosis.2 Cottier knew patterns of siderosis. He had, one might conclude, the prepared mind that chance is said to favor. IVIG, intravenous immunoglobulin; NH, neonatal hemochromatosis. For decades, Cottier's simile framed thought on severe liver disease manifest at or shortly after birth, which came, as a syndrome, to be called "neonatal hemochromatosis" (NH). In NH, hepatocellular loss is profound. Sometimes, perhaps when the insult to the liver is recent, the stroma of the lobule is empty; or fibrosis may accompany parenchymal distortion with proliferated neocholangioles and nodules of disordered hepatocytes, approximating postnecrotic cirrhosis. Clinically, the conceptus exhibits both edema and oligohydramnios with growth lag, and at birth, abrupt withdrawal of placental/maternal support precipitates a sepsis-like collapse, including hypoglycemia, oliguria, and a hemorrhagic diathesis.3 Oligohydramnios and growth lag aside, all these features also typify liver failure of postnatal onset, whether acute disease or acutely decompensated chronic disease. They are not the features of iron storage disease in older children or adults, with micronodular cirrhosis and slowly evolving injury. However, if lesions in iron-handling genes could be implicated in iron storage disorders manifest in later life, why could they not be implicated in an iron storage disorder manifest in utero? For years, increased iron loading across the placenta or abnormal fetal susceptibility to normal iron loading was hypothesized to underlie NH, and clinical and histopathological disparities were shrugged away. 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 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 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 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. Is full complement activation characteristic of acute liver failure tout court? The question arises of what triggers complement activation in the first place. Pan et al.8 suggest that an antibody directed against a liver alloantigen present in the affected babies but not in their mothers is the initial stimulus. If so, the complement system will be activated through the classical pathway, by which a complement-fixing antibody sets in motion the activation cascade, rather than through the spontaneously activating alternative pathway. Whether the classical pathway is activated can be directly tested through the detection and measurement of fragments such as C4d that are uniquely generated thereby.9, 10 These can be assayed in biological fluids and in tissue, as certainly will soon be done in NH. In parallel, measuring a species formed only by activation of the alternative pathway, such as Ba,9, 10 also is in order, even if results only exclude participation of this pathway in liver injury. Is the antibody postulated to be capable of causing NH an alloantibody or an autoantibody? Without knowing the antigen targeted, one cannot favor either possibility. Keep in mind the heart block of neonatal lupus: A mother with systemic lupus erythematosus who synthesizes the anti-Ro52 autoantibody can transplacentally pass it to the fetus. Autoantibody recognition of the fetal cardiac autoantigen causes heart block of variable degree, yet the same autoantibody does not clinically affect the mother's cardiac conduction system.11 The target of the putative antibody of NH can, therefore, be a father-encoded alloantigen but is more plausibly an autoantigen, as half-siblings with NH show who share a mother but not a father. An autoimmune disease in the mother characterized by autoantibodies of the immunoglobulin G isotype would be accompanied by placental transfer of such autoantibodies. As in neonatal lupus, tissue damage—liver damage in NH—could manifest itself in the fetus or infant without maternal illness. Curiosity undoubtedly prompts investigation of the nature of the antigen or antigens targeted in NH. Whether this is immediately relevant to patient management is, however, moot. Administration of intravenous immunoglobulin (IVIG) to the mother of an affected infant is beneficial during a subsequent pregnancy,12 regardless of whether the immune response is alloimmune or autoimmune and regardless of the antigen targeted by the antibody. IVIG likely acts through one of the mechanisms postulated by Pan et al.,8 namely inhibition of complement activation. This effect is what matters to the practicing physician. However, elucidation of any single targeted antigen's identity will permit distinction of cases of NH, at a minimum, between children of seropositive and seronegative mothers. Should seronegativity exclude mothers from IVIG treatment? What might lead to NH in infants of seronegative mothers? Development of a serum assay will focus further investigation and refine clinical treatment. Some aspects of NH must still be elucidated. How exactly does the pattern of siderosis arise that more than 50 years ago caught Cottier's eye? Analogy, used carefully, may help. In Wilson disease, acute injury to a copper-loaded liver releases copper into plasma, in which high concentrations of non–ceruloplasmin-bound copper cause hemolysis and renal injury. This constitutes a redistribution of copper within the organism from the liver to extrahepatic sites. The third-trimester conceptus is iron-replete, with transferrin saturations physiologically >70%, and the normal third-trimester fetal liver contains abundant stainable iron.13 Severe liver injury in this setting, with hepatocellular mass lost and apotransferrin synthesis diminished, redistributes iron within the organism from the liver to extrahepatic sites and effectively pours a quart of iron into a pint pot: Spillover causes hypersaturation of transferrin and extrahepatic siderosis. However, what carriers take non–transferrin-bound iron through the blood, and what routes bring it into only those cells affected by hemochromatotic siderosis? Although the answers are not necessarily of clinical relevance, these questions should still intrigue us. The history of NH finally throws an interesting light on Pasteur's apophthegm of "Le hasard ne favorise que les esprits préparés."14 Among Cottier's first 16 publications, none addresses liver disease. If someone familiar with the histopathology of postnatal liver failure had autopsied the infants whom Cottier described, might "hemochromatosis in the newborn" ever have led us the dance that it has? Pasteur15 also more importantly said, "Ayez le culte de l'esprit critique … Sans lui tout est caduc. Il a toujours le dernier mot" ("Venerate the critical frame of mind … Without it, nothing holds good. It always has the last word"). Perhaps the work of Whitington's group, showing how fruitful Pasteur's esprit critique can be, will spur new looks at other disorders whose pathogeneses and mechanisms, viewed through the wrong analogy, now are stubbornly obscure.