IgG subclass levels in referred hemochromatosis probands with HFE p.C282Y/p.C282Y.

BACKGROUND: IgG subclass levels in hemochromatosis are incompletely characterized. METHODS: We characterized IgG subclass levels of referred hemochromatosis probands with HFE p.C282Y/p.C282Y (rs1800562) and human leukocyte antigen (HLA)-A and -B typing/haplotyping and compared them with IgG subclass levels of eight published cohorts of adults unselected for hemochromatosis. RESULTS: There were 157 probands (82 men, 75 women; mean age 49±13 y). Median serum ferritin, mean body mass index (BMI), median IgG4, and median phlebotomy units to achieve iron depletion were significantly higher in men. Diabetes, cirrhosis, and HLA-A*03,-B*44, -A*03,B*07, and -A*01,B*08 prevalences and median absolute lymphocyte counts in men and women did not differ significantly. Mean IgG subclass levels [95% confidence interval] were: IgG1 5.31 g/L [3.04, 9.89]; IgG2 3.56 g/L [1.29, 5.75]; IgG3 0.61 g/L [0.17, 1.40]; and IgG4 0.26 g/L [<0.01, 1.25]. Relative IgG subclasses were 54.5%, 36.6%, 6.3%, and 2.7%, respectively. Median IgG4 was higher in men than women (0.34 g/L [0.01, 1.33] vs. 0.19 g/L [<0.01, 0.75], respectively; p = 0.0006). A correlation matrix with Bonferroni correction revealed the following positive correlations: IgG1 vs. IgG3 (p<0.01); IgG2 vs. IgG3 (p<0.05); and IgG2 vs. IgG4 (p<0.05). There was also a positive correlation of IgG4 vs. male sex (p<0.01). Mean IgG1 was lower and mean IgG2 was higher in probands than seven of eight published adult cohorts unselected for hemochromatosis diagnoses. CONCLUSIONS: Mean IgG subclass levels of hemochromatosis probands were 5.31, 3.56, 0.61, and 0.26 g/L, respectively. Median IgG4 was higher in men than women. There were positive associations of IgG subclass levels. Mean IgG1 may be lower and mean IgG2 may be higher in hemochromatosis probands than adults unselected for hemochromatosis.

Hepatitis B virus seroprevalence among HIV-infected patients receiving combination antiretroviral therapy three decades after universal neonatal hepatitis B immunization program in Taiwan.

BACKGROUND/PURPOSE: This multicenter study aimed to evaluate the seroprevalence of hepatitis B virus (HBV) and the use of combination antiretroviral therapy (cART) among patients receiving HIV care in Taiwan. METHODS: We retrospectively reviewed the medical records of HIV-infected adult patients who initiated cART at 11 designated hospitals in Taiwan between 2012 and 2016. The clinical information collected included serological profiles on HBV, hepatitis C virus (HCV), and syphilis, plasma HIV RNA load, nadir CD4 cell count, and antiretrovirals with activity against both HBV and HIV (tenofovir disoproxil fumarate [TDF], lamivudine [LAM], and emtricitabine [FTC]). RESULTS: We analyzed 1800 HIV-infected patients; 1742 (96.8%) were male and 794 (44.1%) were born after July, 1986, when nationwide universal neonatal HBV vaccination was implemented. HBsAg positive results were 11.6% (209/1800), which decreased significantly from 18.1% (182/1006) in those born before July 1986 to 3.4% (27/794) in those born after. In multivariable analysis, HBsAg positivity was significantly associated with age (adjusted odds ratio [aOR] 1.06, 95% confidence interval [CI] 1.05-1.08), CD4≧200 cells/µL (aOR 0.73, 95% CI 0.53-0.99), and HCV seropositivity (aOR 1.62, 95% CI 1.06-2.50). Of 209 HBV/HIV-coinfected patients, 31.1% started cART containing only LAM with anti-HBV activity, while 68.9% started cART containing TDF plus LAM or coformulated TDF/FTC. CONCLUSIONS: The overall prevalence of HBV/HIV coinfection remained high among HIV-infected patients in Taiwan. Despite recommendations of the HIV treatment guidelines for the management of HBV infection, a substantial proportion of HIV/HBV-coinfected patients received cART containing only LAM for HBV infection.

Atypical juvenile hereditary hemochromatosis onset with positive pancreatic islet autoantibodies diabetes caused by novel mutations in HAMP and overall clinical management.

BACKGROUND: Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death. METHODS: The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464). RESULTS: Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases. CONCLUSION: It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.

Leukocyte telomere length is associated with iron overload in male adults with hereditary hemochromatosis.

BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality. AIM: To evaluate the relationship between ATL and IO in patients with HH. METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR. RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05). DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.

Gut leakage enhances sepsis susceptibility in iron-overloaded ß-thalassemia mice through macrophage hyperinflammatory responses.

Iron overload induces intestinal-permeability defect (gut leakage), and gut translocation of organismal molecules might enhance systemic inflammation and sepsis severity in patients with thalassemia (Thal). Hence, iron administration in Hbbth3/+ mice, heterozygous ß-globin-deficient Thal mice, was explored. Oral iron administration induced more severe secondary hemochromatosis and gut leakage in Thal mice compared with wild-type (WT) mice. Gut leakage was determined by 1) FITC-dextran assay, 2) spontaneous serum elevation of endotoxin (LPS) and (1→3)-ß-d-glucan (BG), molecular structures of gut-organisms, and 3) reduction of tight-junction molecules with increased enterocyte apoptosis (activated caspase-3) by immunofluorescent staining. Iron overload also enhanced serum cytokines and increased Bacteroides spp. (gram-negative bacteria) in feces as analyzed by microbiome analysis. LPS injection in iron-overloaded Thal mice produced higher mortality and prominent cytokine responses. Additionally, stimulation with LPS plus iron in macrophage from Thal mice induced higher cytokines production with lower ß-globin gene expression compared with WT. Furthermore, possible gut leakage as determined by elevated LPS or BG (>60 pg/mL) in serum without systemic infection was demonstrated in 18 out of 41 patients with ß-thalassemia major. Finally, enhanced LPS-induced cytokine responses of mononuclear cells from these patients compared with cells from healthy volunteers were demonstrated. In conclusion, oral iron administration in Thal mice induced more severe gut leakage and increased fecal gram-negative bacteria, resulting in higher levels of endotoxemia and serum inflammatory cytokines compared with WT. Preexisting hyperinflammatory cytokines in iron-overloaded Thal enhanced susceptibility toward infection.NEW & NOTEWORTHY Although the impact of iron accumulation in several organs of patients with thalassemia is well known, the adverse effect of iron accumulation in gut is not frequently mentioned. Here, we demonstrated iron-induced gut-permeability defect, impact of organismal molecules from gut translocation of, and macrophage functional defect upon the increased sepsis susceptibility in thalassemia mice.

B-cell depletion induces prolonged remission in patients with giant cell hepatitis and autoimmune hemolytic anemia.

BACKGROUND: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare and severe immune-mediated disorder. Despite aggressive immunosuppressive treatments, the mortality is high. Prednisone has been effectively employed to achieve remission, but with a risk of relapse, if discontinued, and with severe side effects. A possible causative role of humoral immune response has paved the way to anti CD-20 monoclonal antibody (rituximab; RTX). Nevertheless, data about timing of remission and long-term side effects are sparse. METHODS AND MATHERIALS: We have retrospectively evaluated 3 refractory GCH-AHA patients in whom a prolonged remission has been achieved with RTX. In all patients, response to first and second line therapy was incomplete or transitory and severe steroid side effects occurred. RESULTS: A stable and sustained remission was achieved after multiple doses of RTX allowing withdrawing all the other treatments. No life-threatening infections have been recorded, however two patients developed persistent, paucisymptomatic hypogammaglobulinaemia. The only patient who did not develop hypogammaglobulinemia received IgG replacement during RTX. CONCLUSION: RTX induced complete and long-lasting remission allowing discontinuing all the other immunosuppressive drugs. A persistent, paucisymptomatic hypogammaglobulinaemia has been the unique side effect. Although further studies need to replicate our data, RTX can be considered as an effective and safe therapy for sustained remission in patients with severe refractory GCH-AHA.

Impaired Transmigration of Myeloid-Derived Suppressor Cells across Human Sinusoidal Endothelium Is Associated with Decreased Expression of CD13.

Human monocytic myeloid-derived suppressor cells (MO-MDSCs) within the hepatic compartment suppress inflammation and impair immune surveillance in liver cancer. It is currently not known whether recruitment of MO-MDSCs from blood via hepatic sinusoidal endothelium (HSEC) contributes to their enrichment within the hepatic compartment. We compared the transmigratory potential of MO-MDSCs and monocytes after adhesion to hepatic endothelial monolayers in flow-based assays that mimic in vivo shear stress in the sinusoids. Despite comparable binding to HSEC monolayers, proportionally fewer MO-MDSCs underwent transendothelial migration, indicating that the final steps of extravasation, where actin polymerization plays an important role, are impaired in MO-MDSCs. In this article, we found reduced levels of CD13 on MO-MDSCs, which has recently been reported to control cell motility in monocytes, alongside reduced VLA-4 expression, an integrin predominantly involved in adherence to the apical side of the endothelium. CD13 and VLA-4 blocking and activating Abs were used in flow-based adhesion assays, live-cell imaging of motility, and actin polymerization studies to confirm a role for CD13 in impaired MO-MDSC transmigration. These findings indicate that CD13 significantly contributes to tissue infiltration by MO-MDSCs and monocytes, thereby contributing to the pathogenesis of hepatic inflammation.

Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron.

The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus Hepcidin analogs may be useful for treatment of siderophilic infections.

The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system.

INTRODUCTION: Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis, and its involvement in the genetic disease termed hereditary hemochromatosis (HH). While HH patients are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and increased incidence of autoimmune diseases that have thereby implicated HFE in the immune response. Growing evidence has supported an immunological role for HFE with recent studies describing HFE specifically as it relates to MHC I antigen presentation. METHODS/RESULTS: Here, we present a comprehensive overview of the relationship between iron metabolism, HFE, and the immune system to better understand the origin and cause of immune defects in HH patients. We further describe the role of HFE in MHC I antigen presentation and its potential to impair autoimmune responses in homeostatic conditions, a mechanism which may be exploited by tumors to evade immune surveillance. CONCLUSION: Overall, this increased understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron-related diseases, as well as of the immune defects related to this condition.

Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis.

BACKGROUND: Neonatal hemochromatosis caused by a gestational alloimmune mechanism or gestational alloimmune liver disease (GALD) is a rare perinatal disorder characterized by intra- and extrahepatic iron overload. It is believed to result from complement-mediated liver injury, in which the classical complement pathway is activated by maternal antibody/fetal antigen complexes, leading to hepatocyte lysis by the membrane attack complex C5b9. According to some authors, C5b9 expression in more than 75% of liver parenchyma is specific for GALD. METHODS: We conducted a retrospective multicentric immunohistochemical study with anti-C5b9 in GALD cases (n = 25) and non-GALD cases with iron overload (n = 36) and without iron overload (n = 18). RESULTS: C5b9 was expressed in 100% of GALD cases but involved more than 75% of the liver parenchyma in only 26% of the cases. C5b9 was detected in 26.75% of the non-GALD cases with more than 75% of positive parenchyma in maternal erythrocytic alloimmunization, herpes and enterovirus hepatitis, bile acid synthetic defect, DGUOK mutation, Gaucher disease, cystic fibrosis, and giant-cell hepatitis with autoimmune hemolytic anemia. CONCLUSION: Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease.

HLA Class I Chromosomal Region, Genes, and Products: Facts and Questions.

Among the various areas of recent investigation in the field of human MHC class I antigens, the following have been selected for discussion in this review: (1) classical HLA class I genes: are they ubiquitously expressed?, what are the special features of their polymorphism?, are HLA-C molecules functional?, (2) non-classical HLA class I gene products: how restricted is their tissue distribution?, do they exhibit a little polymorphism?, what is their function, if any? (3) non-HLA genes recently detected in the HLA class I chromosomal region: are some of them involved in immunological function and development?, (4) other novel coding sequences present, or possibly present, in the region: the hemochromatosis gene, grc region and associated tumor suppressor genes, housekeeping genes, human equivalent of the murine H-2M region and Ped gene; (5) transcriptional regulation: are there cis-regulatory elements, including locus control region(s). located elsewhere than in the promoters? are CpG methylation, gene imprinting, chromatin structure, DNA rearrangement also implicated? what are the transcription factors involved and how do they interact with each other? is there HLA class I locus-, allele-, or isoform-specific regulation? is class I gene expression dysregulated in human tumors? The answers to these questions are crucial for the development of the future directions for research.

Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives.

We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A (∗) 01, B (∗) 08; A (∗) 02, B (∗) 44; A (∗) 03, B (∗) 07; A (∗) 03, B (∗) 14; and A (∗) 29, B (∗) 44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.

Hepatitis aloinmune fetal / Fetal alloimmune hepatitis

La hepatitis aloinmune fetal, conocida anteriormente como hemocromatosis neonatal, ha demostrado en los últimos años ser una enfermedad completamente distinta a la hemocromatosis del adulto, tanto en su etiología como en su la fisiopatología. Este conocimiento abre nuevas perspectivas tanto en la prevención de la enfermedad en futuros embarazos, así como en el tratamiento con inmunoglobulina endovenosa en la madre durante el embarazo y eventualmente el tratamiento postnatal, en el que el trasplante de hígado juega un rol primordial.

Fetal alloimmune hepatitis, until few years ago was known as neonatal hemochromatosis, has shown to be a completely different disease from hemochromatosis in the adult, in its etiology and pathophysiology. This knowledge opens up opportunities of counselling in future pregnancies as well as in the treatment with intravenous immunoglobulin to the mother during pregnancy, and eventually the postnatal treatment, in which liver transplantation plays a primary role.

Review of fetal and neonatal immune cytopenias.

The fetoplacental interface plays a unique role in pathologies of the fetus and neonate, and is increasingly being recognized for effects on fetal and neonatal development that resonate into adulthood. In this review, we will use several exemplary disorders involving each of the 3 types of blood cells to explore the effect of perinatal insults on subsequent development of the affected cell line. We will present new data regarding outcomes of infants treated prenatally for fetal and neonatal alloimmune thrombocytopenia (FNAIT) and contrast these with outcomes of infants affected by hemolytic disease of the fetus and newborn. We also will explore the differences between FNAIT and passively transferred antibodies, as seen in maternal idiopathic thrombocytopenic purpura. Neonatal hemochromatosis is an example of a disease that previously was largely fatal, but whose newly discovered etiology as an immune-mediated perinatal disorder has resulted in development of highly effective treatment. Finally, we will examine the interplay between lymphopoiesis and the placenta in an effort to further explore the phenomenon of neutropenia in preeclampsia, whose etiology remains unknown.

Invariant Natural Killer T Cells are Reduced in Hereditary Hemochromatosis Patients.

PURPOSE: Invariant natural killer T (iNKT) cells are CD1d restricted-T cells that react to lipid antigens. iNKT cells were shown to be important in infection, autoimmunity and tumor surveillance. Alterations in the number and function of these cells were described in several pathological conditions including autoimmune and/or liver diseases. CD1d is critical for antigen presentation to iNKT cells, and its expression is increased in liver diseases. The liver is the major organ affected in Hereditary Hemochromatosis (HH), an autosomal recessive disorder caused by excessive iron absorption. Herein, we describe the study of iNKT cells of HH patients. METHODS: Twenty-eight HH patients and 24 control subjects from Santo António Hospital, Porto, were included in this study. Patient's iron biochemical parameters (serum transferrin saturation and ferritin levels) and the liver function marker alanine transaminase (ALT) were determined at the time of study. Peripheral blood iNKT cells were analyzed by flow cytometry using an anti-CD3 antibody and the CD1d tetramer loaded with PBS57. RESULTS: We found a decrease in the percentage and number of circulating iNKT cells from HH patients when compared with control population independently of age. iNKT cell defects were more pronounced in untreated patients, relating with serum ferritin and transferrin saturation levels. No correlation was found with ALT, a marker of active liver dysfunction. CONCLUSIONS: Altogether, our results demonstrate that HH patients have reduced numbers of iNKT cells and that these are influenced by iron overload.

Transient neonatal liver disease after maternal antenatal intravenous Ig infusions in gestational alloimmune liver disease associated with neonatal haemochromatosis.

OBJECTIVES: Neonatal haemochromatosis is a rare gestational disease that results in severe foetal liver disease with extrahepatic iron overload, sparing the reticuloendothelial system. Recurrence can be prevented with intravenous immunoglobulin (IVIG) infusions during pregnancy, supporting an alloimmune aetiology. The aim of the study was to assess the effect of antenatal treatment with IVIG infusion on the outcome of pregnancies in women with a history of documented neonatal haemochromatosis likely owing to gestational alloimmune disease and to analyse IVIG tolerance. METHODS: From 2004 to 2012, 8 pregnant women were treated with IVIG at 1 g/kg body weight weekly from 18 weeks' gestation until birth in a prospective multicentre study. RESULTS: All 8 neonates born to the treated women survived. Five developed mild neonatal liver disease with hepatomegaly (n = 1), hyperechogenic liver (n = 2), abnormal liver function tests (n = 1), raised serum ferritin (n = 3) and α-fetoprotein (n = 5) levels, or mild iron overload on liver magnetic resonance imaging (n = 1). Ferritin and α-fetoprotein levels normalised before 14 days and 2 months, respectively. A per-mother-basis analysis comparing outcomes of treated (n = 8) and untreated (n = 9) gestations showed a significant improvement in the survival of neonates with gestational IVIG therapy (survival 8/8 vs 0/9, P < 0.001). Adverse effects of IVIG infusion occurred in 5 mothers leading to discontinuation of treatment in 1 case. Preterm neonates born before 37 weeks' gestation had a decreased risk of neonatal liver disease (P = 0.04). CONCLUSIONS: Antenatal treatment with IVIG infusion in women at risk for gestational alloimmune disease recurrence improves the outcome of pregnancies despite mild signs of transient neonatal liver disease.

Primary biliary cirrhosis-specific antimitochondrial antibodies in neonatal haemochromatosis.

BACKGROUND AND AIM: Neonatal hemochromatosis (NH) is characterised by severe liver injury and extrahepatic siderosis sparing the reticuloendothelial system. Its aetiology is obscure, although it has been proposed as an alloimmune disease, resulting from immunological reaction to self-antigens (alloantigens) which the body recognizes as foreign. We studied an infant with NH and his mother whose sera contained antimitochondrial antibody (AMA), the hallmark of primary biliary cirrhosis (PBC). MATERIAL AND METHODS: To investigate the origin of AMA in the infant, we studied isotype distributions in serum from the mother and infant. Serum samples were obtained at diagnosis of NH, after liver transplantation (LT; age 1 month), and over the ensuing 17 months. RESULTS: At NH diagnosis, infant and maternal serum contained AMA of the IgG isotype, predominantly of the G3 and G1 subclasses. AMA strongly reacted against the pyruvate dehydrogenase complex E2 subunit (PDC-E2), the major PBC-specific AMA autoantigen. Anti-PDC-E2 responses in both infant and mother declined over time, being present 2 months after LT (mother and child) and absent 10 months later (mother) and 17 months later (child). CONCLUSION: The association of maternally transferred IgG1 and IgG3 subclass AMA with the appearance of liver damage in an infant with NH may suggest a causal link between antibody and liver damage.

Transforming growth factor-ß and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis.

AIM: To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis. METHODS: A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied, with all subjects having liver biopsy data and DNA available for testing. This study assessed the association of eight single nucleotide polymorphisms (SNPs) in a total of six genes including toll-like receptor 4 (TLR4), transforming growth factor-beta (TGF-ß), oxoguanine DNA glycosylase, monocyte chemoattractant protein 1, chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity. Genotyping was performed using high resolution melt analysis and sequencing. The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration. RESULTS: There were significant associations between the cofactors of male gender (P = 0.0001), increasing age (P = 0.006), alcohol consumption (P = 0.0001), steatosis (P = 0.03), hepatic iron concentration (P < 0.0001) and the presence of hepatic fibrosis. Of the candidate gene polymorphisms studied, none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors. We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied. Importantly, in this large, well characterised cohort of patients there was no association between SNPs for TGF-ß or TLR4 and the presence of fibrosis, cirrhosis or increasing fibrosis stage in multivariate analysis. CONCLUSION: In our large, well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.

French retrospective multicentric study of neonatal hemochromatosis: importance of autopsy and autoimmune maternal manifestations.

Neonatal hemochromatosis is a rare disease that causes fetal loss and neonatal death in the 1st weeks of life and is one of the most common causes of liver failure in the neonate. The diagnosis is mostly made retrospectively, based on histopathologic features of severe liver fibrosis associated with hepatic and extrahepatic siderosis. Several etiologies may underlie this phenotype, including a recently hypothesized gestational alloimmune disease. Fifty-one cases of liver failure with intrahepatic siderosis in fetuses and neonates were analyzed retrospectively. Maternal and infant data were collected from hospitalization and autopsy reports. All available slides were reviewed independently by 3 pathologists. Immunologic studies were performed on maternal sera collected immediately after delivery. The diagnosis of neonatal haemochromatosis was retained in 33 cases, including 1 case with Down syndrome and 1 case with myofibromas. Liver siderosis was inversely proportional to fibrosis progression. In fetuses, iron storage was more frequent in the thyroid than in the pancreas. Perls staining in labial salivary glands was positive in 1 of 5 cases. Abnormal low signal intensity by magnetic resonance imaging was detected in the pancreas in 2 of 7 cases. Renal tubular dysgenesis was observed in 7 of 23 autopsy cases. Chronic villitis was seen in 7 of 15 placentas. Half of the mothers presented with an autoimmune background and/or autoantibodies in their sera. Our work highlights the importance of autopsy in cases of neonatal hemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochromatosis could reflect maternal immune system dysregulation.

[The new paradigm of neonatal hemochromatosis: fetal alloimmune hepatitis]. / El nuevo paradigma de la hemocromatosis neonatal: hepatitis fetal aloinmunitaria.

The classical model of neonatal hemochromatosis was based on the analogy with hereditary hemochromatosis. Medical treatment consisted on the antioxidant-chelator cocktail. The new hypothesis of an alloimmune origin of the process by which the pregnant woman mounts an IgG-based destructive response against fetal hepatocytes offers a pathogenic explanation, allowing treatment to be focused on the immunological aspects, with excellent results, and opens the possibility of preventive treatment in future pregnancies. This new paradigm produces a deep impact in diagnosis, prognosis and treatment of the disease, that should be called "fetal alloimmune hepatitis".