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.

Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.

Sulfur assimilation is an essential metabolic pathway that regulates sulfation, amino acid metabolism, nucleotide hydrolysis, and organismal homeostasis. We recently reported that mice lacking bisphosphate 3'-nucleotidase (BPNT1), a key regulator of sulfur assimilation, develop iron-deficiency anemia (IDA) and anasarca. Here we demonstrate two approaches that successfully reduce metabolic toxicity caused by loss of BPNT1: 1) dietary methionine restriction and 2) overproduction of a key transcriptional regulator hypoxia inducible factor 2α (Hif-2a). Reduction of methionine in the diet reverses IDA in mice lacking BPNT1, through a mechanism of downregulation of sulfur assimilation metabolic toxicity. Gaining Hif-2a acts through a different mechanism by restoring iron homeostatic gene expression in BPNT1 deficient mouse intestinal organoids. Finally, as loss of BPNT1 impairs expression of known genetic modifiers of iron-overload, we demonstrate that intestinal-epithelium specific loss of BPNT1 attenuates hepatic iron accumulation in mice with homozygous C282Y mutations in homeostatic iron regulator (HFEC282Y), the most common cause of hemochromatosis in humans. Overall, our study uncovers genetic and dietary strategies to overcome anemia caused by defects in sulfur assimilation and identifies BPNT1 as a potential target for the treatment of hemochromatosis.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings.

Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70-90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited.Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment.Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model.Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000-3000 and 4000-5000 mg/dl, respectively.Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation.

BACKGROUND: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). OBJECTIVE: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. METHODS: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks. RESULTS: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded. CONCLUSION: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.

Gestational Alloimmune Liver Disease: A Devastating Condition Preventable With Maternal Intravenous Immunoglobulin.

BACKGROUND: Gestational alloimmune liver disease, a form of profound liver failure in the newborn, is the main underlying cause of the entity formerly known as neonatal hemochromatosis. Antepartum maternal intravenous immunoglobulin (IVIG) has been shown to prevent gestational alloimmune liver disease, which otherwise has a recurrence risk above 90% in subsequent pregnancies. CASE: A 30-year-old woman, gravida 3 para 0120, presented early in gestation. Her previous pregnancy had been complicated by fetal growth restriction, oligohydramnios, and ultimately fatal fulminant neonatal liver failure. With gestational alloimmune liver disease recognized as the primary diagnosis for the liver failure, we began maternal weekly IVIG therapy. She delivered a healthy newborn at term without evidence of hepatic dysfunction. CONCLUSION: Recognition of gestational alloimmune liver disease enables antepartum treatment that dramatically alters the course of disease.

Antenatal immunoglobulin for prevention of neonatal hemochromatosis.

Neonatal hemochromatosis (NH) is a rare disease with a poor prognosis, particularly prior to 2008. Antenatal maternal high-dose immunoglobulin (Ig) is effective in preventing NH recurrence, but the adverse effects of this treatment have not been documented as yet. Here, we report on a patient who underwent high-dose Ig treatment to prevent NH recurrence. The patient was a 31-year-old pregnant Japanese woman. Her first child died of NH after receiving living donor liver transplantation. The patient received high-dose Ig treatment to prevent recurrence of NH from gestational weeks 16 to 35. During the treatment, platelet count gradually decreased, and cesarean section was required at 35 gestational weeks. The child did not develop liver failure. High-dose Ig prevented the recurrence of NH. Caution should be exercised due to possible adverse effects of this treatment.

Neonatal hemochromatosis: management, outcome, and prevention.

Neonatal hemochromatosis (NH) is a rare disorder but the most common cause of acute liver failure in neonates. NH is characterized by severe hepatic injury and iron overload and is associated with high perinatal mortality and morbidity rates. NH is often preceded by oligohydramnios and intrauterine growth restriction, suggesting an important impact of NH during fetal life. Stillbirth and prematurity are not uncommon. During the last decade, major discoveries on the etiology of NH have radically changed the management and outcome of this disease. NH is now regarded as an alloimmune disease and is, as such, often referred to as gestational alloimmune liver disease. Antenatal treatment with intravenous immunoglobulins starting at 14 weeks' gestation has been shown to prevent the development of NH in subsequent pregnancies. Postnatal treatment, previously based on the use of anti-oxidants and chelation therapy, has now successfully been replaced by exchange transfusions and intravenous immunoglobulins substitution. This review summarizes the latest discoveries on the etiology of NH and the new recommendations concerning its management and prevention.

Plasmapheresis as an alternative to high-dose intravenous immunoglobulin in the prevention of gestational alloimmune liver disease.

Gestational alloimmune liver disease occurs due to trans-placental passage of maternal antibodies to a fetal hepatocyte antigen that produces complement-mediated hepatocyte injury. High-dose intravenous immunoglobulin therapy during gestation is highly effective at decreasing the risk to the neonate but treatment is expensive. This case presents for the first time the use of plasmapheresis as a potential cheaper alternative when treatment with immunoglobulins is unavailable.

A retinoic acid receptor agonist tamibarotene suppresses iron accumulation in the liver.

OBJECTIVE: Hepatic iron overload (HIO) and iron-induced oxidative stress have recently emerged as an important factor for the development and progression of insulin resistance. The aim of this study was to evaluate the effect of tamibarotene, a selective retinoic acid receptor α/ß agonist, on hepatic iron metabolism, based on our previous findings that retinoids suppress hepatic iron accumulation by increasing hepatic iron efflux through the regulation of hemojuvelin and ferroportin expression. DESIGN AND METHODS: We quantitated the non-heme iron content and iron metabolism-related gene expression in the liver, and serum lipid and blood glucose levels in KK-A(y) mice after dietary administration of tamibarotene. RESULTS: It was demonstrated that tamibarotene significantly reduced blood glucose and hepatic iron, but not serum lipids, and that hemojuvelin expression significantly decreased while ferroportin increased, as observed previously. CONCLUSIONS: These results suggest that tamibarotene is a promising alternative for the treatment of insulin resistance associated with HIO.

Why do people choose not to have screening for hemochromatosis?

AIM: Hemochromatosis is a common disorder of iron overload most commonly due to homozogosity for the HFE C282Y substitution. A workplace-screening program was conducted in which over 11,000 individuals were screened for this mutation. A substudy of this project was to ascertain why people chose not to attend information and screening sessions offered in their workplace. METHOD: Staff were recruited by email, questionnaires in common areas, and direct approach. A purpose-designed questionnaire sought the reasons for not attending information and screening sessions. RESULTS: The nonattender questionnaire was distributed at 24 workplaces and completed by 872 individuals. The most common reason for not attending sessions, accounting for 70.1%, was practical (e.g., unaware of session, too busy, or unavailable). Other relatively common reasons were that the individual had low iron levels or were a blood donor (14.9%), or that hemochromatosis was considered unimportant (12.2%). Insurance concerns were very rarely cited as the reason for nonattendance (1.0%). CONCLUSION: The nonattender data presented here indicate that concerns about insurance, anxiety, and use of genetic information are not major factors for why people did not attend workplace information and screening sessions for hereditary hemochromatosis. Practical barriers were the major reasons identified. This highlights that when implementing screening programs, as many practical barriers as possible need to be overcome, so that a maximum number of people who would like to be informed about screening are given the opportunity to do so.

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis.

The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation.

Haemochromatosis in a Brazilian tapir (Tapirus terrestris) in an Australian zoo.

A 23-year-old Brazilian, or lowland, tapir with a 6-month history of loss of body condition developed clinical signs and laboratory findings consistent with liver failure. The animal was euthanased and a diagnosis of hepatic haemochromatosis was made based on histopathology. Two other healthy tapirs in the same collection had chronically elevated serum and tissue iron concentrations. The excessive accumulation of iron in tissues with resultant tissue damage (i.e. haemochromatosis) has been reported in a range of captive species. This and other reported cases of haemochromatosis in the Brazilian tapir would suggest that this condition is an important consideration in the management of this species in zoos. Further research into the endogenous regulation of iron metabolism, especially the role of hepcidin, in tapirs and other species at risk of iron storage disorders may be helpful in the prevention of this condition.

[Prophylactic prenatal therapy with intravenous immunoglobulins for patients at risk for neonatal haemochromatosis]. / Prophylaktische pränatale Therapie mit intravenösen Immunglobulinen bei Risiko für eine Neonatale Hämochromatose.

Neonatal haemochromatosis (NH) is a connatal hepatopathy that is lethal in 32% and necessitates liver transplantation in 63% of the survivors. The classical diagnostic criteria of extrahepatic siderosis do not apply in all patients who are suspected to have NH. The hypothesis of NH as an alloimmune disease is supported by the quantitative immunohistochemical proof of C5b-9 complement complexes on the hepatocytes of liver biopsy material. This has opened a new perspective in the therapy and prophylaxis for this severe disease. Prophylactic therapy with intravenous immunoglobulins (IVIG) for mothers at risk can prevent a relevant NH in most cases.

BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice.

BACKGROUND & AIMS: Abnormal hepcidin regulation is central to the pathogenesis of HFE hemochromatosis. Hepatic bone morphogenetic protein 6 (BMP6)-SMAD signaling is a main regulatory mechanism controlling hepcidin expression, and this pathway was recently shown to be impaired in Hfe knockout (Hfe(-/-)) mice. To more definitively determine whether HFE regulates hepcidin expression through an interaction with the BMP6-SMAD signaling pathway, we investigated whether hepatic Hfe overexpression activates the BMP6-SMAD pathway to induce hepcidin expression. We then investigated whether excess exogenous BMP6 administration overcomes the BMP6-SMAD signaling impairment and ameliorates hemochromatosis in Hfe(-/-) mice. METHODS: The BMP6-SMAD pathway and the effects of neutralizing BMP6 antibody were examined in Hfe transgenic mice (Hfe Tg) compared with wild-type (WT) mice. Hfe(-/-) and WT mice were treated with exogenous BMP6 and analyzed for hepcidin expression and iron parameters. RESULTS: Hfe Tg mice exhibited hepcidin excess and iron deficiency anemia. Hfe Tg mice also exhibited increased hepatic BMP6-SMAD target gene expression compared with WT mice, whereas anti-BMP6 antibody administration to Hfe Tg mice improved the hepcidin excess and iron deficiency. In Hfe(-/-) mice, supraphysiologic doses of exogenous BMP6 improved hepcidin deficiency, reduced serum iron, and redistributed tissue iron to appropriate storage sites. CONCLUSIONS: HFE interacts with the BMP6-SMAD signaling pathway to regulate hepcidin expression, but HFE is not necessary for hepcidin induction by BMP6. Exogenous BMP6 treatment in mice compensates for the molecular defect underlying Hfe hemochromatosis, and BMP6-like agonists may have a role as an alternative therapeutic strategy for this disease.

Hereditary haemochromatosis - diagnosis and management.

BACKGROUND: Hereditary haemochromatosis is a common inherited disorder in which excessive iron is absorbed and which, over time, may cause organ damage. Genetic predisposition leads to disease in some but not all cases. OBJECTIVE: This article discusses the presentation, testing, treatment and management of hereditary haemochromatosis. DISCUSSION: Hereditary haemochromatosis is autosomal recessive and is more common in people of Celtic or northern European descent. Although more than 90% of cases of hereditary haemochromatosis are due to C282Y homozygosity (carrying two copies of the C282Y gene) not all C282Y homozygous individuals will progress through all stages of disease development. Clinical disease is less common in females due to physiological blood loss from menstruation and pregnancy. Most importantly, early diagnosis and treatment of hereditary haemochromatosis prevents complications and results in a normal life expectancy. Venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload, which include severe fatigue, arthritis, impotence, raised alanine aminotransferase/aspartate aminotransferase, fibrosis or cirrhosis, diabetes, and cardiomyopathy.

Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin.

OBJECTIVES: Neonatal hemochromatosis is the result of severe fetal liver injury that seems to result from maternal-fetal alloimmunity. Women who have had an infant affected with neonatal hemochromatosis are at high risk in subsequent pregnancies for having another affected infant. This study was designed to determine whether therapy directed at limiting the severity of gestational alloimmunity can reduce the occurrence of severe neonatal hemochromatosis in infants of women at risk. A secondary objective was to use a prospectively collected data set to examine questions of vital interest about neonatal hemochromatosis. METHODS: Women with a history of pregnancy ending in documented neonatal hemochromatosis were treated with intravenous immunoglobulin at 1 g/kg of body weight weekly from week 18 until the end of gestation. Extensive data were prospectively collected regarding the gestational histories of the subjects. The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls. RESULTS: Forty-eight women were enrolled to be treated during 53 pregnancies. The gestational histories of these women demonstrated the high risk of occurrence of neonatal hemochromatosis: 92% of pregnancies at risk resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant. In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. When compared on a per-woman or per-infant basis, the outcome of gestation at risk for neonatal hemochromatosis was improved by gestational therapy. CONCLUSIONS: Neonatal hemochromatosis seems to be the result of a gestational alloimmune disease, and occurrence of severe neonatal hemochromatosis in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous immunoglobulin during gestation.

Diagnosis and current treatments for primary iron overload.

Primary iron overload encompasses a variety of genetic iron overload syndromes, dominated in frequency by HFE-related, or Type 1 hemochromatosis, for which French diagnostic and therapeutic guidelines have been recently proposed. Differential diagnosis of Type 1 hemochromatosis can be made from both clinical data and genetic studies. Venesection therapy and family screening remain the basis for the curative and preventive management of most genetic iron overload diseases.