Frequency and clinical expression of HFE gene mutations in a Spanish population of subjects with abnormal iron metabolism

Three HFE gene mutations (HFE 845 GA, 187 CG and 193 AT) are the most common mutations related to hereditary haemochromatosis (HH). The genotype for these mutations was analysed in 359 Spanish individuals with altered iron metabolism and iron overload. Various biochemical parameters were measured in serum samples from 96 of these individuals, and the effect of the genotype on these parameters was studied. Allele frequencies were 12.95% for the HFE C282Y variant, 28.97% for the HFE H63D variant and 0.69% for the HFE S65C variant, calculated in a total of 718 chromosomes. Multiple comparisons analysis showed very significant differences (p=0.001) in transferrin saturation index (TSI) between the HFE C282Y variant homozygous and control (ten healthy volunteers) groups. Highly significant (p=0.0001) and significant (p=0.005) differences in serum ferritin values were found between the HFE C282Y variant homozygous and control groups and between compound (HFE C282Y/H63D variant) heterozygous and control groups, respectively. Very significant differences (p=0.001) in serum iron values were observed between the HFE C282Y variant homozygous and control groups. TSI and serum ferritin values detected most HFE C282Y variant homozygotes and are recommended to facilitate the clinical diagnosis of HH.     

Optimizing the diagnosis and the treatment of iron overload diseases

A number of human disorders are related to chronic iron overload, either of genetic or acquired origin. The multi-organ damage produced by iron excess leads, in adults and in children, to severe clinical consequences, affecting both quality of life and life expectancy. The diagnosis is increasingly based on a non-invasive strategy, resorting to clinical, biological and imaging data. The treatment rests on either venesection or chelation therapy, depending on the etiology. Major advances in the fields of molecular biology, pharmacology, and biotechnology pave the road for key improvements in the diagnostic and therapeutic management of the patients.     

Insights on Regulation and Function of the Iron Regulatory Protein 1 (IRP1)

Iron regulatory protein 1 (IRP1) controls the translation or stability of several mRNAs by binding to iron responsive elements (IREs) within their untranslated regions. Its activity is regulated by an unusual iron-sulfur cluster (ICS) switch. Thus, in iron-replete cells, IRP1 assembles a cubane [4Fe-4S] cluster that prevents RNA-binding activity and renders the protein to cytosolic aconitase. We show that wild type or mutant forms of IRP1 that fail to assemble a [4Fe-4S] cluster are sensitized for iron-dependent degradation by the ubiquitin-proteasome pathway. The regulation of IRP1 abundance poses an alternative mechanism to prevent accumulation of inappropriately high IRE-binding activity when the ICS assembly pathway is impaired. To study functional aspects of IRP1, we overexpressed wild type or mutant forms of the protein in human H1299 lung cancer cells in a tetracycline-inducible fashion, and analyzed how this affects cell growth. While the induction of IRP1 did not affect cell proliferation in culture, it dramatically reduced the capacity of the cells to form solid tumor xenografts in nude mice. These data provide a first link between IRP1 and cancer.     

Outcome of gastric antral vascular ectasia and related anemia after orthotopic liver transplantation

BACKGROUNDGastric antral vascular ectasia (GAVE) is a significant complication of cirrhosis. Numerous medical, surgical, and endoscopic treatment modalities have been proposed with varied satisfactory results. In a few small studies, GAVE and associated anemia have resolved after orthotopic liver transplantation (OLT). AIMTo assess the impact of OLT on the resolution of GAVE and related anemia.METHODSWe retrospectively reviewed clinical records of adult patients with GAVE who underwent OLT between September 2012 and September 2019. Demographics and other relevant clinical findings were collected, including hemoglobin levels and upper endoscopy findings before and after OLT. The primary outcome was the resolution of GAVE and its related anemia after OLT.RESULTSSixteen patients were identified. Mean pre-OLT Hgb was 7.7 g/dL and mean 12 mo post-OLT Hgb was 11.9 g/dL, (P = 0.001). Anemia improved (defined as Hgb increased by 2g) in 87.5% of patients within 6 to 12 mo after OLT and resolved completely in half of the patients. Post-OLT esophagogastroduodenoscopy was performed in 10 patients, and GAVE was found to have resolved entirely in 6 of those patients (60%). CONCLUSIONAlthough GAVE and associated anemia completely resolved in the majority of our patients after OLT, GAVE persisted in a few patients after transplant. Further studies in a large group of patients are necessary to understand the causality of disease and to better understand the factors associated with the persistence of GAVE post-transplant.     

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (> or =300 microg/L in men and >= or =200 microg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P=0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P=0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P=0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF.     

New insights into the coagulopathy of liver disease and liver transplantation

INTRODUCTION The liver plays several key roles in blood coagulation being involved in both primary and secondary hemostasis[1]. It is the site of synthesis of all coagulation factors and their inhibitors except for von Willebrand factor (vWf)[2]. Liver da…     

Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality

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Effects of Alcohol, Carbon Tetrachloride, and Choline Deficiency on Iron Metabolism in the Rat

The effects of alcohol on hepatic iron uptake and intestinal iron transport were studied in rats fed a nutritionally replete liquid diet containing varying quantities of ethanol. Results were compared with those from animals exposed to carbon tetrachloride (CCI₄) to produce hepatocellular necrosis or a choline-deficient diet to produce steatosis and cirrhosis. A high ethanol intake for 4 or 10 weeks produced hepatic steatosis. CCU produced hepatocellular necrosis. Choline deficiency was associated with steatosis ± cirrhosis. Intestinal iron transport was unaffected by ethanol, CCU, or choline deficiency. Hepatic iron uptake was significantly depressed in rats consuming 11.7 g/kg/day ethanol (p < 0.01) for 4 weeks. Choline-deficient animals studied at 14 weeks also had significantly decreased hepatic iron uptake (p < 0.01); results were similar in the cirrhotic and noncirrhotic animals. Conversely, CCI₄ exposure produced a significant 5-fold increase in hepatic iron uptake (p < 0.001). Results suggest that ethanol consumption, fatty liver, and cirrhosis are not responsible for any increase in iron absorption or of hepatic iron uptake in the rat model. Acute hepatocellular injury is followed by increased hepatic iron uptake.     

肝癌患者血清铁含量及手术前后T淋巴细胞亚群变化

目的探讨肝癌患者血清铁(Fe)含量及手术前后T淋巴细胞亚群变化,揭示Fe含量与肝癌的关系及手术对患者免疫功能的影响。方法选取100例原发性肝癌患者(肝癌组)及50名门诊体检正常者(对照组),测定血清Fe、铁蛋白(Ferr)、转铁蛋白(TRF)含量,术前第2天及术后第3天、术后第7天、术后第14天T淋巴细胞亚群CD3+、CD4+、CD8+、CD4+/CD8+水平。结果肝癌组患者血清Fe、Ferr含量明显高于对照组,TRF含量低于对照组,两组相比,差异有统计学意义(P0.05);肝癌组术前CD3+、CD4+、CD4+/CD8+水平低于对照组,CD8+水平高于对照组,两组相比,差异有统计学意义(P0.05);肝癌组术后3 d、7 d CD3+、CD4+、CD8+、CD4+/CD8+水平明显低于术前,差异有统计学意义(P0.05);术后14 d与术前相比,水平接近,差异无统计学意义(P0.05)。结论肝癌患者Fe、Ferr含量较正常人群明显增高,TRF、细胞免疫较正常人群明显下降,在术后细胞免疫被抑制状态更为严重,后随着时间延长有所恢复,因而对肝癌患者应进行血清Fe、Ferr、TRF含量监测及术后免疫干预治疗。     

原发性胆汁性胆管炎肝移植术后预后研究现状与挑战

原发性胆汁性胆管炎(PBC)是一种病因尚不明确的慢性胆汁淤积性肝病。熊去氧胆酸、奥贝胆酸等药物治疗不佳的患者最终发展为肝硬化,甚至肝衰竭。目前,肝移植是治疗PBC的唯一有效手段。主要阐述了PBC患者进行肝移植的概况、肝移植术后生存期、并发症、PBC复发以及肝移植治疗前景及挑战,为PBC移植术后的临床转归及治疗提供参考。     

Women on the liver transplantation waitlist are at increased risk of hospitalization compared to men

BACKGROUND Hospital admissions are common among patients with cirrhosis,but patient factors associated with hospitalization have not been well characterized.Given recent data suggesting increased liver transplant waitlist dropout among women,we hypothesized that women on the liver transplant waitlist would have increased rates of hospitalization compared with men.AIM To evaluate the role of gender on risk of hospitalization for patients on the liver transplant waitlist,in order to help explain gender disparities in waitlist outcomes.METHODS Patients listed for liver transplant at a single center in the United States were prospectively enrolled in the Functional Assessment in Liver Transplantation Study.Patients included in this retrospective analysis included those enrolled between March 2012 and December 2014 with at least 12 mo of follow up and without hepatocellular carcinoma.The primary and secondary outcomes were hospitalization and total inpatient days within 12 mo,respectively.Logistic and negative binomial regression associated baseline factors with outcomes.RESULTS Of the 392 patients,41%were female,with median(interquartile range)age 58 years(52-63)and model for end-stage liver disease 18(15-22).Within 12 mo,186(47%)patients were hospitalized≥1 time;48%were readmitted,with a median of 8(4-15)inpatient days.More women than men were hospitalized(54%vs 43%;P=0.03).In univariable analysis,female sex was associated with an increased risk of hospitalization[odds ratios(OR)1.6,95%confidence interval(CI)1.0-2.4;P=0.03],which remained significant on adjusted multivariable analysis(OR 1.6,95%CI:1.1-2.6;P=0.03).Female gender was also associated with an increased number of inpatient days within 12 mo in both univariable and multivariable regression.CONCLUSION Women with cirrhosis on the liver transplant waitlist have more hospitalizations and inpatient days in one year compared with men,suggesting that the experience of cirrhosis differs between men and women,despite similar baseline illness severity.Future studies should explore gender-specific vulnerabilities to help explain waitlist disparities.     

Morbidity and mortality of recurrent hepatitis C infection after orthotopic liver transplantation

Summary. Through molecular virological testing it is now clear that HCV reinfection of the allograft is virtually universal in liver transplant recipients. Although histopathological recurrence of hepatitis C occurs in the majority of patients, it is absent in a substantial minority. To date, no prognostic factors, other than genotype lb, have been identified that accurately predict these dissimilar outcomes. The natural history of recurrent hepatitis C varies. Historically, it has been regarded as generally benign. However, with increasing numbers of patients transplanted for hepatitis C it is now clear that a subgroup of patients develops severe progressive cholestatic hepatitis associated with allograft failure and death without retransplantation. Within 5 years following OLT, approximately 15–20% of patients progress to chronic active hepatitis and another 15–20% become cirrhotic. A minority of patients develop glomerulopathy or vasculitis, which are often associated with cryoglobulinaemia. The impact of immunosuppressive medications and rejection episodes on histopathological recurrence of progressive hepatitis C remains controversial and requires further studies. Although actuarial survival rates of patients transplanted for hepatitis C differ among transplantation centres, it appears that histopathological recurrence of hepatitis C does have an adverse impact on actuarial survival compared to the survival of patients transplanted for autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and metabolic liver diseases. When allograft failure develops in patients with recurrent hepatitis C, retransplantation is indicated, even though recent reports indicate that mortality may be increased, especially with concurrent renal insufficiency.     

Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), defined by excessive liver fat deposition related to the metabolic syndrome, is a leading cause of progressive liver disease, for which accurate non-invasive staging systems and effective treatments are still lacking. Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes. Recently, Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients.     

肺切除术后近期死亡原因分析及对策

目的 分析肺切除近期死亡原因。方法 回顾性分析４６例各种肺切除术后近期（一个月内）死亡病例。结果 男３７例,女９例,年龄３８￣７４岁。年龄≥６０岁和〈６０岁组近期死亡率分别为１．２３％和０．４５％（Ｐ〈０．０１）。全肺切除组和肺部分切除的近期死亡率分别为０．５１％和０．３２％（Ｐ〈０．０１）。死亡原因包括：循环并发症１７例,急性呼吸衰竭１０例,消化道并发症６例,支气管胸膜瘘脓胸２例,肾功能衰竭１０     

Selective intestinal decontamination for the prevention of early bacterial infections after liver transplantation

Bacterial infection in the first month after liver transplantation is a frequent complication that poses a serious risk for liver transplant recipients as contributes substantially to increased length of hospitalization and hospital costs being a leading cause of death in this period. Most of these infections are caused by gramnegative bacilli, although gram-positive infections, especially Enterococcus sp. constitute an emerging infectious problem. This high rate of early postoperative infections after liver transplant has generated interest in exploring various prophylactic approaches to surmount this problem. One of these approaches is selective intestinal decontamination(SID). SID is a prophylactic strategy that consists of the administration of antimicrobials with limited anaerobicidal activity in order to reduce the burden of aerobic gram-negative bacteria and/or yeast in the intestinal tract and so prevent infections caused by these organisms. The majority of studies carried out to date have found SID to be effective in the reduction of gram-negative infection, but the effect on overall infection is limited due to a higher number of infection episodes by pathogenic enterococci and coagulase-negative staphylococci. However, difficulties in general extrapolation of the favorable results obtained in specific studies together with the potential risk of selection of multirresistant microorganisms has conditioned controversy about the routinely application of these strategies in liver transplant recipients.     

Shunting of the microcirculation after mesenteric ischemia and reperfusion is a function of ischemia time and increases mortality

OBJECTIVE: Shunting of the microcirculation contributes to the pathology of sepsis and septic shock. The authors address the hypothesis that shunting of the microcirculation occurs after superior mesenteric artery occlusion (SMAO) and reperfusion, and explore functional consequences. METHODS: Spontaneously breathing animals (rats) (n = 30) underwent SMAO for 0 (controls), 30 (SMAO_30) or 60 min (SMAO_60) followed by reperfusion (4 h) with normal saline. Leukocyte-endothelial interactions in mesenteric venules were quantified in an exteriorized ileal loop using intravital microscopy. Abdominal blood flow was recorded continuously, and arterial blood gases were analyzed at intervals. The above groups were matched by comparable groups with continuous superior mesenteric artery blood flow measurements and without exteriorizing an ileal loop (controls*, SMAO_30*, SMAO_60*). RESULTS: Adherent leukocytes increased shortly after reperfusion in ischemia groups, and plateaued in these groups. Centerline velocity in the recorded venules was significantly reduced after reperfusion down to low-flow/no-flow in SMAO_60 as compared to SMAO_30 and controls, whereas perfusion of the SMA and ileal vessels persisted. The microcirculatory changes in SMAO_60 were accompanied by progressive metabolic acidosis, substantially larger volumes of intravenous fluids needed to support arterial blood pressure and significantly reduced survival (30%). SMA blood flow increased in relation to abdominal blood flow after reperfusion in SMAO_60*, and remained constant in SMAO_30* and controls*. Survival was 80% in SMAO_60*. CONCLUSION: Shunting of the microcirculation can be observed after SMAO for 60 min and reperfusion, and contributes significantly to the pathology of mesenteric ischemia and poor outcome.