In addition, there is marked siderosis of extrahepatic tissues, including the heart and pancreas Driscoll et al. Whitington postulated that some cases of neonatal hemochromatosis result from maternal alloimmunity directed at the fetal liver, and therefore do not represent an inherited mendelian disorder. Other causes may result from metabolic disease or perinatal infection. In particular, he commented that the disorder is not related to the family of inherited liver diseases that fall under the classification of hereditary hemochromatosis see, e.

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Feldman: gro. Amy G. This article has been cited by other articles in PMC. Abstract Neonatal hemochromatosis is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis. Gestational alloimmune liver disease GALD has been established as the cause of fetal liver injury resulting in nearly all cases of NH. These antibodies bind to fetal liver antigen and activate the terminal complement cascade resulting in hepatocyte injury and death.

GALD can cause congenital cirrhosis or acute liver failure with and without iron overload and siderosis. Practitioners should consider GALD in cases of fetal demise, stillbirth, and neonatal acute liver failure. Identification of infants with GALD is important as treatment is available and effective for subsequent pregnancies. Keywords: acute liver failure, complement, gestational alloimmune liver disease, immunoglobulin Abbreviations: GALD, gestational alloimmune liver disease; FcRn, fragment receptor; IgG, immunoglobulin G; IVIG, intravenous immunoglobulin; NH, neonatal hemochromatosis; NTBI, non-transferrin bound iron Neonatal hemochromatosis NH is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis in the distribution seen with hereditary hemochromatosis.

Because it was observed to occur in siblings NH was originally classified as part of the family of hereditary hemochromatosis disorders OMIM However, clinical evidence accrued over several decades suggested that NH is not a disease per se, but is the consequence of fetal liver injury.

Thus, search for an inherited cause of fetal liver disease capable of producing the NH phenotype ensued. In it was discovered that the liver in cases of NH showed evidence of complement-mediated hepatocyte injury, which under the circumstances must be initiated by IgG antibody binding to fetal hepatocytes.

This finding led to the deduction that gestational alloimmune liver disease GALD is the cause of fetal liver injury leading to nearly all cases of NH 1 and to the conclusion that while NH is both congenital and familial, it is not hereditable. Moreover, GALD can cause liver disease that is not accompanied by iron overload, including acute liver failure in the fetus and neonate. The discovery of the alloimmune etiology of NH has impacted approaches to its diagnosis, treatment, and prevention.

Etiology of neonatal hemochromatosis Early on, NH was described as a hereditary disorder of iron metabolism. However, until recently the cause of such injury remained a mystery. Because it was observed to affect siblings, a genetic defect was suspected, but intense investigation uncovered no gene locus. Thus, NH appeared to be congenital and familial, but not hereditary.

This exposure results in sensitization and production of IgG antibodies against the fetal-derived antigen. Unlike most gestational alloimmune disease such as hydrops fetalis, ABO incompatibility hemolysis, and alloimmune thrombocytopenia in which IgG antibodies are directed against blood elements inherited from the father, in GALD maternal IgG antibodies are directed against fetal hepatocytes.

If the antigen is uniquely expressed during fetal development, the mother may have lost tolerance to this self-antigen over time in the absence of central immune tolerance. Alternatively, if the antigen is sequestered in the mature liver, the same could occur in the absence of central tolerance. In either scenario, maternal exposure to this antigen induces an immune response that targets fetal hepatocytes. Non-hepatocyte liver cells and extrahepatic tissue do not appear to be attacked by this primary immune process.

It remains unclear how antigen exposure to the maternal circulation occurs. Once sensitization to the fetal antigen has occurred, specific reactive IgG is passed to the fetus where it binds to a hepatocyte antigen and initiates an innate immune response. The terminal complement cascade is activated by the classical pathway resulting in formation of the membrane attack complex.

Liver pathology Study of autopsy specimens has provided extensive description of the liver pathology in NH. Unlike the hazy iron staining of normal newborn liver, the hepatocyte siderosis seen in NH is coarsely granular.

Severe pan-lobular parenchymal fibrosis is a dominant feature, and regenerative nodules are commonly observed. Portal tracts are relatively spared from injury, and inflammation is minimal. Inflammation in the parenchyma consists of macrophages and neutrophils, innate immune cells that may be recruited by C3a and C5a during activation of the terminal complement cascade. Complement-mediated hepatocyte injury can be demonstrated using immunohistochemical staining for C5b-9 to identify accumulations of the membrane attack complex in hepatocytes and giant cells.

GALD can also cause acute liver injury to the fetal liver resulting in stillbirth or neonatal demise. There may not be any siderosis in the liver or other tissues. It remains unclear why certain infants develop this hyperacute liver failure while others present with congenital cirrhosis. Extrahepatic manifestations of gestational alloimmune liver disease Extrahepatic siderosis in NH is most frequently seen in the acinar epithelium of the exocrine pancreas, myocardium, epithelia of thyroid follicles, and the mucosal or minor salivary glands of the oronasopharynx and respiratory tree.

The reticuloendothelial system is relatively spared, so spleen, lymph nodes, and bone marrow contain trivial quantities of stainable iron. The mechanisms of iron overload and the specific distribution of siderosis in NH have been carefully examined. The fetal liver controls placental iron flux in a manner similar to how the postnatal liver regulates intestinal iron, by sensing iron sufficiency and producing hepcidin as a regulatory feedback molecule.

Hepcidin binds ferroportin resulting in internalization and proteosomal degradation. This decrease in ferroportin results in decreased iron influx. In fetuses with GALD, liver injury results in significantly decreased production of hepcidin. In addition, transferrin gene expression is decreased, resulting in reduced iron binding capacity. The result is fetal iron overload and an excess of circulating non-transferrin bound iron NTBI.

The tissue distribution of extrahepatic siderosis in the NH phenotype seems to be a function of the ability of various tissues to manage excess circulating NTBI. Tissues that are unaffected by siderosis express ferroportin, which permits iron export. Thus, extrahepatic tissues that are ZIP14 positive and ferroportin negative are uniquely susceptible to siderosis. Reticuloendothelial cells are spared siderosis because they express ferroportin, which in the state of hepcidin paucity is fully active.

Hepatocytes express transporters for transferrin bound iron and NTBI, and ferroportin. Accrual of hemosiderin in hepatocytes is likely to be a function of injury and perhaps relatively reduced ferroportin expression or function. Renal hypoplasia with dysgenesis of proximal tubules and paucity of peripheral glomeruli has been described in infants with NH. Expansion of the proximal tubule and associated glomeruli from the 24th week of gestation onward is dependent upon angiotensinogen, which is synthesized exclusively by the liver.

In a study of livers and kidneys from infants with GALD-NH, hepatocyte mass and angiotensinogen gene expression were markedly reduced relative to normal.

Liver expression of angiotensinogen inversely correlated with proximal tubule density. Therefore, it appears that alloimmune liver injury leads to reduced hepatocyte mass, which results in reduced angiotensinogen production, which in turn leads to defective renal development. For the other diseases, fetal liver injury resulting in impaired regulation of placental iron flux is hypothesized to cause NH.

Clinical findings GALD can present anytime from 18 weeks gestation to 3 months post-delivery. The majority of infants present with liver failure within hours of birth. NH is one of the most common causes of liver failure in the neonatal period. They may have renal involvement and be oliguric. There is frequently a history of intrauterine growth restriction, oligohydramnios, and prematurity. In rarer cases, liver disease may take days to weeks to present.

Affected twins may have different clinical presentations; with one twin severely affected and the other minimally so. Other processes that can cause neonatal liver failure include mitochondrial diseases, bile acid synthetic defects, tyrosinemia, hemophagocytic lymphohistiocytosis, ABCB11 gene mutations, hereditary galactosemia, hereditary fructose intolerance, and infection.

Clinically, NH infants are unique in that they have evidence of fetal insult and neonatal liver failure. They are extremely coagulopathic, but have low serum aminotransferases in contrast to infants with virally induced acute liver failure who have extremely high serum aminotransferases.

Infants with GALD-NH may be misdiagnosed as having tyrosinemia due to elevated tyrosine levels, but they do not have succinylacetone in the urine. Infants with NH may also be misdiagnosed as having a bile acid defect; however, they will not have the classic pattern of bile metabolites found in serum and urine by mass spectroscopy. Finally, infants with GALD-NH should not have markedly elevated lactate levels as seen in infants with mitochondrial abnormalities.

Diagnosis GALD should be suspected in infants who manifest liver disease antenatally or in the immediate post birth period. It should also be considered in cases of unexplained stillbirth, neonatal demise, or early infant death. GALD is likely underdiagnosed. In cases of stillbirth or fetal loss, practitioners may not think to look for GALD before the index living case with NH occurs.

Likewise, in live infants, symptoms of liver failure may be confused with those of global sepsis and practitioners may have difficulty making a diagnosis of NH with currently available tools. Global knowledge of this disorder and its wide spectrum of presentations may help to increase the number of cases that are accurately diagnosed.

Diagnosis of NH rests upon diagnosing extrahepatic siderosis: the complex of severe liver disease and extrahepatic siderosis defines the condition. Siderosis in the liver alone is not diagnostic as the normal newborn liver can contain quantities of iron that are stainable though quantitatively different to an experienced pathologist.

In addition, pathologic hepatic siderosis can be seen in several neonatal liver diseases. There is no known value of iron content in the liver which can accurately discriminate between NH and other causes of neonatal iron overload. Likewise, absence of liver siderosis does not rule out NH, as some GALD infants may have acute injury without iron overload and other GALD cases are associated with complete hepatocyte destruction, which precludes hepatic siderosis. Glandular tissue containing iron can most easily be obtained from a biopsy of the oral mucosa.

Bleeding, which may potentially be made worse by coagulopathy, is controlled by local measures and has not been a serious problem in any case. No fresh frozen plasma or recombinant factor VII is necessary beforehand. One must be sure to obtain a specimen that contains submucosal glands. T2 weighted MRI can also be used to document siderosis as iron-laden tissue has a different magnetic susceptibility than normal tissue, particularly in the liver and pancreas.

On autopsy, NH can be demonstrated by staining typically affected tissues for iron.


Neonatal Hemochromatosis

Normal liver vs. In cirrhosis right , scar tissue replaces normal liver tissue. Hereditary hemochromatosis is caused by a mutation in a gene that controls the amount of iron your body absorbs from the food you eat. These mutations are passed from parents to children. This type of hemochromatosis is by far the most common type. Gene mutations that cause hemochromatosis A gene called HFE is most often the cause of hereditary hemochromatosis.


Hemocromatosis hereditaria

There are 2 main treatments. And even if you do inherit 2 copies, you will not necessarily get haemochromatosis. Only a small number of people with 2 copies of this faulty gene will ever develop the condition. Read more about the causes of haemochromatosis Complications of haemochromatosis If the condition is diagnosed and treated early on, haemochromatosis does not affect life expectancy and is unlikely to result in serious problems.





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