[Hepatitis B: new guidelines of disease management]. / Hépatite B : nouvelles recommandations de prise en charge.

Hepatitis B virus (HBV) infection is a major public health concern associated with major clinical complications, notably chronic liver disease that can progress with time to cirrhosis or even to hepatocellular carcinoma. The management of HBV-infected patients is complex and requires the close collaboration between the general practitioner and the specialist. This review presents an overview of recently published guidelines, from the European Association for the Study of the Liver, and suggests strategies for initial management and referral of HBV-infected patients for the general practitioner.

L'infection par le virus de l'hépatite B est un problème de santé publique majeur associé à des complications cliniques importantes, en particulier une hépatopathie chronique, pouvant évoluer rapidement jusqu'au stade de cirrhose et au développement d'un carcinome hépatocellulaire (CHC). La prise en charge des patients infectés est complexe et nécessite une collaboration rapprochée entre le praticien généraliste et le spécialiste. Cet article résume les recommandations européennes publiées cette année et vise à donner au médecin généraliste des outils pour la prise en charge initiale des individus infectés avant qu'ils ne soient adressés à une consultation spécialisée.

A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice.

Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice.

Regulation of iron transport and the role of transferrin.

BACKGROUND: Iron is utilized by several proteins as cofactor for major biological processes. However, iron may also harm cells by catalyzing the generation of free radicals and promoting oxidative stress. Acquisition, transport, utilization and storage of iron are tightly controlled to meet physiological needs and prevent excessive accumulation of the metal within cells. Plasma transferrin has been known for years as a central player in iron metabolism, assigned to circulate iron in a soluble, non-toxic form and deliver it to the erythron and other tissues. Recent data uncovered an additional role of transferrin as an upstream regulator of hepcidin, a liver-derived peptide hormone that controls systemic iron traffic. SCOPE OF REVIEW: Here, we review basic features of iron metabolism, highlighting the function of transferrin in iron transport and cellular iron uptake. We further discuss the role of hepcidin as an orchestrator of systemic iron homeostasis, and the mechanisms underlying hepcidin regulation in response to various physiological cues. Emphasis is given on the role of transferrin on iron-dependent hepcidin regulation. MAJOR CONCLUSIONS: Transferrin exerts a crucial function in the maintenance of systemic iron homeostasis as component of a plasma iron sensing system that modulates hepcidin expression. GENERAL SIGNIFICANCE: Proper expression of transferrin and hepcidin are essential for health, and disruption of their regulatory circuits is associated with iron-related disorders. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

Conditional disruption of mouse HFE2 gene: maintenance of systemic iron homeostasis requires hepatic but not skeletal muscle hemojuvelin.

UNLABELLED: Mutations of the HFE2 gene are linked to juvenile hemochromatosis, a severe hereditary iron overload disease caused by chronic hyperabsorption of dietary iron. HFE2 encodes hemojuvelin (Hjv), a membrane-associated bone morphogenetic protein (BMP) coreceptor that enhances expression of the liver-derived iron regulatory hormone hepcidin. Hjv is primarily expressed in skeletal muscles and at lower levels in the heart and the liver. Moreover, a soluble Hjv form circulates in plasma and is thought to act as a decoy receptor, attenuating BMP signaling to hepcidin. To better understand the regulatory function of Hjv, we generated mice with tissue-specific disruption of this protein in hepatocytes or in muscle cells. The hepatic ablation of Hjv resulted in iron overload, quantitatively comparable to that observed in ubiquitous Hjv-/- mice. Serum iron and ferritin levels, transferrin saturation, and liver iron content were significantly (P < 0.001) elevated in liver-specific Hjv-/- mice. Hepatic Hjv mRNA was undetectable, whereas hepcidin expression was markedly suppressed (12.6-fold; P < 0.001) and hepatic BMP6 mRNA up-regulated (2.4-fold; P < 0.01), as in ubiquitous Hjv-/- counterparts. By contrast, the muscle-specific disruption of Hjv was not associated with iron overload or altered hepcidin expression, suggesting that muscle Hjv mRNA is dispensable for iron metabolism. Our data do not support any significant iron-regulatory function of putative muscle-derived soluble Hjv in mice, at least under physiological conditions. CONCLUSION: The hemochromatotic phenotype of liver-specific Hjv-/- mice suggests that hepatic Hjv is necessary and sufficient to regulate hepcidin expression and control systemic iron homeostasis.

Hemojuvelin deficiency promotes liver mitochondrial dysfunction and predisposes mice to hepatocellular carcinoma.

Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). We utilized Hjv-/- mice to dissect mechanisms for hepatocarcinogenesis. We show that suboptimal treatment with diethylnitrosamine (DEN) triggers HCC only in Hjv-/- but not wt mice. Liver proteomics data were obtained by mass spectrometry. Hierarchical clustering analysis revealed that Hjv deficiency and DEN elicit similar liver proteomic responses, including induction of mitochondrial proteins. Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv-/- animals, which is only partially corrected by iron depletion. Consistent with these data, primary Hjv-/- hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv-/- mice develop spontaneous HCC. Moreover, low expression of HJV or hepcidin (HAMP) mRNAs predicts poor prognosis in HCC patients. We conclude that Hjv has a hepatoprotective function and its deficiency in mice promotes mitochondrial dysfunction and hepatocarcinogenesis.

Non-invasive assessment of liver fibrosis: it is time for laboratory medicine.

Chronic liver diseases (CLDs) represent a major cause of morbidity and mortality worldwide. In all etiologies of CLDs, staging of liver fibrosis is essential for both prognosis and management. Until a few years ago, liver biopsy was the only tool for the diagnosis of liver fibrosis in patients with CLDs. However, liver biopsy is an invasive and costly procedure. More recently, various serum biomarkers and laboratory tests have been proposed as surrogates of liver histology. Due to inadequate diagnostic accuracy or to lack of sufficient validation, guidelines still do not recommend them as a substitute for liver biopsy that is still considered the gold standard for the diagnosis of liver fibrosis. Notably, non-invasive serum biomarkers, when combined, may reduce by 50%-80% the number of liver biopsies needed for correctly classifying hepatic fibrosis. However, liver biopsy cannot be avoided completely, but should be used in those cases in which non-invasive methods show poor accuracy. In this view, serum biomarkers and liver biopsy represent a union between laboratory medicine and hepatology.

Tissue-Specific Regulation of Ferroportin in Wild-Type and Hjv-/- Mice Following Dietary Iron Manipulations.

Hepcidin is a liver-derived peptide hormone that limits iron egress from tissues to the bloodstream. It operates by binding to the iron exporter ferroportin, which blocks iron transport and tags ferroportin for degradation. Genetic hepcidin inactivation leads to hereditary hemochromatosis, a disease of iron overload. We used wild-type and Hjv-/- mice, a model of hemochromatosis, to examine the expression of ferroportin and other proteins of iron metabolism in hepcidin target tissues. The animals were previously subjected to dietary iron manipulations. In Hjv-/- mice, hepcidin messenger RNA correlated significantly with hepatic iron load (r = 0.8211, P < 0.001), but was substantially lower compared with wild-type controls. Duodenal ferroportin and divalent metal transporter 1 (DMT1), as well as splenic and hepatic ferroportin, were overexpressed in these animals. A high-iron diet (2% carbonyl iron) suppressed duodenal DMT1 levels in both wild-type and Hjv-/- mice; however, it did not affect duodenal ferroportin expression in Hjv-/- mice, and only reduced it in wild-type mice. In contrast, the high-iron diet decreased splenic ferroportin exclusively in Hjv-/- mice, whereas it induced hepatic ferroportin exclusively in wild-type mice. Conclusion: Our data show that dietary iron differentially affects ferroportin expression in mouse tissues and are consistent with hepcidin-dependent and hepcidin-independent mechanisms for ferroportin regulation. In the Hjv-/- mouse model of hemochromatosis, duodenal ferroportin remains unresponsive to iron but DMT1 is appropriately iron-regulated.

NAFLD and MAFLD as emerging causes of HCC: A populational study.

BACKGROUND & AIMS: There are conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic-associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterised HCC population between 1990 and 2014. METHODS: We identified all patients with HCC resident in the canton of Geneva, Switzerland, diagnosed between 1990 and 2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardised incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome, or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. RESULTS: A total of 76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990 and 2014. Between the time periods 1990-1994 and 2010-2014, there was a significant increase in HCC incidence in women (standardised incidence ratio [SIR] 1.83, 95% CI 1.08-3.13, p = 0.026) but not in men (SIR 1.10, 95% CI 0.85-1.43, p = 0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0-29%, p = 0.037) than in men (2-12%, p = 0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and from 7% to 67% in women (p <0.001). From 2000-2004 to 2010-2014, the SIR of NAFLD-HCC increased to 1.92 (95% CI 0.77-5.08) for men and 12.7 (95% CI 1.63-545) in women, whereas it decreased or remained stable for other major aetiologies of HCC. CONCLUSIONS: In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women. LAY SUMMARY: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, increasingly arising in patients with liver disease caused by metabolic syndrome, termed non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). We assessed all patients with HCC between 1990 and 2014 in the canton of Geneva (western Switzerland) and found an increase in all HCC cases in this timeframe, particularly in women. In addition, we found that HCC caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall HCC cases.

Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin.

UNLABELLED: Functional inactivation of HFE or hemojuvelin (HJV) is causatively linked to adult or juvenile hereditary hemochromatosis, respectively. Systemic iron overload results from inadequate expression of hepcidin, the iron regulatory hormone. While HJV regulates hepcidin by amplifying bone morphogenetic protein (BMP) signaling, the role of HFE in the hepcidin pathway remains incompletely understood. We investigated the pathophysiological implications of combined Hfe and Hjv ablation in mice. Isogenic Hfe (-)/(-) and Hjv (-)/(-) mice were crossed to generate double Hfe (-)/(-) Hjv (-)/(-) progeny. Wild-type control and mutant mice of all genotypes were analyzed for serum, hepatic, and splenic iron content, expression of iron metabolism proteins, and expression of hepcidin and Smad signaling in the liver, in response to a standard or an iron-enriched diet. As expected, Hfe (-)/(-) and Hjv (-)/(-) mice developed relatively mild or severe iron overload, respectively, which corresponded to the degree of hepcidin inhibition. The double Hfe (-)/(-) Hjv (-)/(-) mice exhibited an indistinguishable phenotype to single Hjv (-)/(-) counterparts with regard to suppression of hepcidin, serum and hepatic iron overload, splenic iron deficiency, tissue iron metabolism, and Smad signaling, under both dietary regimens. We conclude that the hemochromatotic phenotype caused by disruption of Hjv is not further aggravated by combined Hfe/Hjv deficiency. Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism. KEY MESSAGES: Combined disruption of Hfe and Hjv phenocopies single Hjv deficiency. Single Hjv(-)/(-) and double Hfe(-)/(-)Hjv(-)/(-) mice exhibit comparable iron overload. Hfe and Hjv regulate hepcidin via the same pathway.

Chronic hepatitis C and liver fibrosis.

Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy.

Iron-dependent regulation of hepcidin in Hjv-/- mice: evidence that hemojuvelin is dispensable for sensing body iron levels.

Hemojuvelin (Hjv) is a bone morphogenetic protein (BMP) co-receptor involved in the control of systemic iron homeostasis. Functional inactivation of Hjv leads to severe iron overload in humans and mice due to marked suppression of the iron-regulatory hormone hepcidin. To investigate the role of Hjv in body iron sensing, Hjv-/- mice and isogenic wild type controls were placed on a moderately low, a standard or a high iron diet for four weeks. Hjv-/- mice developed systemic iron overload under all regimens. Transferrin (Tf) was highly saturated regardless of the dietary iron content, while liver iron deposition was proportional to it. Hepcidin mRNA expression responded to fluctuations in dietary iron intake, despite the absence of Hjv. Nevertheless, iron-dependent upregulation of hepcidin was more than an order of magnitude lower compared to that seen in wild type controls. Likewise, iron signaling via the BMP/Smad pathway was preserved but substantially attenuated. These findings suggest that Hjv is not required for sensing of body iron levels and merely functions as an enhancer for iron signaling to hepcidin.

Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing.

The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.