Novel compound heterozygous mutations in the hemojuvelin gene in a juvenile hemochromatosis patient:A case report

BACKGROUND Juvenile hemochromatosis(JH)is an early-onset,rare autosomal recessive disorder of iron overload observed worldwide that leads to damage in multiple organs.Pathogenic mutations in the hemojuvelin(HJV)gene are the major cause of JH.CASE SUMMARY A 34-year-old male Chinese patient presented with liver fibrosis,diabetes,hypogonadotropic hypogonadism,hypophysis hypothyroidism,and skin hyperpigmentation.Biochemical test revealed a markedly elevated serum ferritin level of 4329μg/L and a transferrin saturation rate of 95.4%.Targeted exome sequencing and Sanger sequencing revealed that the proband had a novel mutation c.863G>A(p.R288Q)in the HJV gene which was transmitted from his father,and two known mutations,c.18G>C(p.Q6H)and c.962_963delGCinsAA(p.C321*)in cis,which were inherited from his mother.The p.R288W mutation was previously reported to be pathogenic for hemochromatosis,which strongly supported the pathogenicity of p.R288Q reported for the first time in this case.After 72 wk of intensive phlebotomy therapy,the patient achieved a reduction in serum ferritin to 160.5μg/L.The patient's clinical symptoms demonstrated a notable improvement.CONCLUSION This study highlights the importance of screening for hemochromatosis in patients with diabetes and hypogonadotropic hypogonadism.It also suggests that long-term active phlebotomy could efficiently improve the prognosis in severe JH.

Genetic diagnosis history and osteoarticular phenotype of a nontransfusion secondary hemochromatosis

BACKGROUND It is not easy to identify the cause of various iron overload diseases because the phenotypes overlap.Therefore,it is important to perform genetic testing to determine the genetic background of patients.AIM To investigate the genetic background of a patient with hemochromatosis complicated by psoriasis on both lower extremities.METHODS Ten years ago,a 61-year-old male presented with iron overload,jaundice,hemolytic anemia and microcytic hypochromic anemia.Computed tomography of the left knee joint showed enlargement of the tibial medullary cavity and thinned bone cortices.Magnetic resonance imaging showed hepatic hemochromatosis,extensive abnormal signals from bone marrow cavities and nodular lesions in the lateral medullary cavity of the upper left lateral tibia.Single photon emission computed tomography showed radial dots of abnormal concentration in the upper end of the left tibia and radial symmetry of abnormal concentrations in joints of the extremities.The patient showed several hot spot mutations of the HFE and G6PD genes detected by next-generation sequencing,but no responsible gene mutation was found.The thalassemia gene was detected by gap-PCR.RESULTS The patient was found to carry the-α4.2 and--SEA deletion mutations of the globin gene.These two mutations are common causes of Southeast Asianα-thalassemia,but rarely cause severe widespread non-transfusion secondary hemochromatosis osteoarthropathy.The simultaneous presence of an auxiliary superposition effect of a rare missense mutation of the PIEZO1 gene(NM_001142864,c.C4748T,p.A1583V)was considered.Moreover,several rare mutations of the IFIH1,KRT8,POFUT1,FLG,KRT2,and TGM5 genes may be involved in the pathogenesis of psoriasis.CONCLUSION The selection of genetic detection methods for hemochromatosis still needs to be based on an in-depth study of the clinical manifestations of the disease.

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis

AIM： To investigate whether the patatin-/ike phosph- olipase domain containing-3 gene （PNPLA3） I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis （HH）. METHODS： We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH （C282Y＋/＋ HH） patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake （〈 30/20 g/d in males or females） or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology （n = 100） or ul- trasound （n = 23）. The PNPLA3 rs738409 single nucle- otide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay （assay on demand, Applied Biosystems）. The association of the PNPLA3 I148M protein variant （p.I148M） with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS： PNPLA3 genotype was not associated with metabolic parameters, including body mass index （BMI）, the presence of diabetes, and lipid levels, but the pres- ence of the p.148M variant at risk was independently associated with steatosis [odds ratio （OR） 1.84 per p.148M allele, 95% confidence interval （CI）： 1.05-3.31; P = 0.037], independently of BMI and alanine amino- transaminase （ALT） levels. The p.148M variant was also associated with higher aspartate aminotransferase （P = 0.0014） and ALT levels （P = 0.017） at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity （stage） of fibrosis （estimated coefficient 0.56 ± 0.27, P = 0.041）. In the overall series of patients, the p.148M variant was associated with cirrhosis in lean （P = 0.049）, but not in overweight patients （P = not significant）. At logistic regression analysis, cirrhosis was associated with BMI 〉~ 25 （OR 1.82, 95% CI： 1.02-3.55）, ferritin 〉 1000 ng/mL at diagnosis （OR 19.3, 95% CI： 5.3-125）, and with the G allele in patients with BMI 〈 25 （OR 3.26, 95% CI： 1.3-10.3）. CONCLUSION： The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y＋/＋ HH.

Non-invasive methods for liver fi brosis prediction in hemochromatosis:One step beyond

Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload he-reditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive sero-logic markers for fibrosis prediction (ser um ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liv er biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver f ibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not po-ssible, or for those rare cases displaying discrepancies between radiological and biochemical markers.

Management of human factors engineering-associated hemochromatosis: A 2015 update

This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering(HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaise, lethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.

Juvenile hemochromatosis:HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage,hypogonadotropic hypogonadism,cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation(g.47G>A),treated with phlebotomies and deferasirox. She presented symptoms such as weakness,skin hyperpigmentation,joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin(SF): 5696 ng/mL,transferrin saturation(TS): 85%]. After sessions of phlebotomies(450 mL every 15 d),the patient presented partial symptomatic improvements and biochemical parameters(SF: 1000 ng/mL,Hb: 11 g/dL). One year later,deferasirox(15 mg/kg per day) was introduced to the treatment,and the patient showed total symptomatic improvement,with significant clearing of the skin,SF: 169 ng/mL,and TS: 50%. Furthermore,after the combined deferasirox-phlebotomy therapy,magnetic resonance imaging measurements revealed normalized level for liver iron(30 μmol/g; reference value < 36 μmol/g). In conclusion,combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload

BACKGROUND Patients with hepatitis C virus(HCV) and hepatocellular carcinoma(HCC) may or not develop iron overload(IO),which is associated with worst prognosis,because can cause serious damage to organs.HFE gene controls the iron uptake from gut,particularly in patients with hereditary hemochromatosis(HH).AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.METHODS We sequenced exons 2 to 5 and boundary introns of HFE gene,evaluating all polymorphic sites in patients presenting hereditary(hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls,using Sanger sequencing.We also determined the ensemble of extended haplotype in healthy control individuals,including several major histocompatibility complex loci,using sequence specific probes.Haplotype reconstruction was performed using the Arlequin and Phase softwares,and linkage disequilibrium(LD) between histocompatibility loci and HFE gene was performed using the Haploview software.RESULTS The HFE*003 allele was overrepresented(f = 71%) and HFE*001 allele was underrepresented(f = 14%) in HH patients compared to all groups.A strong linkage disequilibrium was observed among the H63 D-G,IVS2(+4)-C and C282 YG gene variants,particularly in HH;however,the mutation IVS2(+4)T>C was not directly associated with HH susceptibility.The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO(P = 0.02,OR =14.14).Although HFE is telomeric to other histocompatibility genes,the H63 DG/IVS2(+4)-C(P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls.No LD was observed between HFE alleles and other major histocompatibility loci.CONCLUSION A differential HFE association was observed for HH and for diseases associated with acquired IO(HCV,HCC).Since HFE is very distant from other histocompatibility loci,only weak associations were observed with these alleles.

Hereditary hemochromatosis:Temporal trends,sociodemographic characteristics,and independent risk factor of hepatocellular cancer–nationwide population-based study

BACKGROUND Hereditary hemochromatosis(HH)has an increased risk of hepatocellular cancer(HCC)both due to genetic risks and iron overload as iron overload can be carcinogenic;HH impacts the increasing risk of HCC,not only through the development of cirrhosis but concerning hepatic iron deposition,which has been studied further recently.AIM To evaluate HH yearly trends,patient demographics,symptoms,comorbidities,and hospital outcomes.The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients,independent of liver cirrhosis complications.The study investigated HH(without cirrhosis)as an independent risk factor for HCC.METHODS We analyzed data from National Inpatient Sample(NIS)Database,the largest national inpatient data collection in the United States,and selected HH and HCC cohorts.HH was first defined in 2011 International Classification of Disease-9th edition(ICD-9)as a separate diagnosis;the HH cohort is extracted from January 2011 to December 2019 using 275.01(ICD-9)and E83.110(ICD-10)diagnosis codes of HH.Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis(alcoholic,non-alcoholic,and biliary),viralhepatitis,alcoholic liver disease,non-alcoholic fatty liver disease(NAFLD),and non-alcoholic steatohepatitis(NASH).We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors.The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC.We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor(greedy)propensity score method using the patients'age,gender,and race.We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort.We further analyzed HH without cirrhosis(removing HH patients with a diagnosis of cirrhosis)as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model.RESULTS During the 2011-2019 period,a total of 18031 hospitalizations with a primary or secondary diagnosis of HH(excluding liver diseases)were recorded in the NIS database.We analyzed different patients’characteristics,and we found increments in inpatient population trend with a Ptrend<0.001 and total hospital cost of care trend from$42957 in 2011 to$66152 in 2019 with a Ptrend<0.001 despite no change in Length of Stay over the last decade.The multivariate analyses showed that HH without cirrhosis(aOR,28.8;95%CI,10.4–80.1;P<0.0001),biliary cirrhosis(aOR,19.3;95%CI,13.4–27.6;P<0.0001),non-alcoholic cirrhosis(aOR,17.4;95%CI,16.5–18.4;P<0.0001),alcoholic cirrhosis(aOR,16.9;95%CI,15.9–17.9;P<0.0001),hepatitis B(aOR,12.1;95%CI,10.85–13.60;P<0.0001),hepatitis C(aOR,8.58;95%CI,8.20–8.98;P<0.0001),Wilson disease(aOR,4.27;95%CI,1.18–15.41;P<0.0001),NAFLD or NASH(aOR,2.96;95%CI,2.73–3.20;P<0.0001),alpha1-antitrypsin deficiency(aOR,2.10;95%CI,1.21–3.64;P<0.0001),diabetes mellitus without chronic complications(aOR,1.17;95%CI,1.13–1.21;P<0.0001),and blood transfusion(aOR,1.80;95%CI,1.69–1.92;P<0.0001)are independent risk factor for liver cancer.CONCLUSION Our study showed an increasing trend of in-hospital admissions of HH patients in the last decade.These trends were likely related to advances in diagnostic approach,which can lead to increased hospital utilization and cost increments.Still,the length of stay remained the same,likely due to a big part of management being done in outpatient settings.Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors.More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC.

Efficacy of deferasirox for the treatment of iron overload in a child affected by Juvenile Hemochromatosis

We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.

Occult celiac disease prevents penetrance of hemochromatosis

AIM:To report a patient with C282Y homozygocity,depleted body iron and intestinal atrophy caused by celiac disease (CD) who experienced resolution of the enteropathy with subsequent normalization of iron metabolism upon gluten free diet. METHODS:To obtain information on the tissue distribution and quantitative expression of proteins involved in duodenal iron trafficking,we determined the expression of divalent-metal transporter 1 (DMT1),ferroportin 1 (FP1) and transferrin receptor (TfR1) by means of immunohist-ochemistry and real-time PCR in duodenal biopsies of this patient. RESULTS:Whereas in hereditary hemochromatosis patients without CD, DMT1 expression was up-regulated leading to excessive uptake of iron, we identified a significant reduction in protein ana mRNA expression of DMT1 as a compensatory mechanism in this patient with HH and CD. CONCLUSION:Occult CD may compensate for increased DMT1 expression in a specific subset of individuals with homozygous C282Y mutations in the hemochromatosis (HFE) gene,thus contributing to the low penetrance of HH.

An unhappy triad:Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-A case report

Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma （HCC）. Hemosiderosis has also been described to trigger carcinogenesis. A significant iron overload, as found in hereditary hemochromatosis （HHC）, is a risk factor for HCC and may also promote the symptoms of porphyria cutanea tarda （PCT）. A 68-year old male patient presented to our clinic with a suspected HCC, elevated alpha-fetoprotein but normal liver function tests. He reported a 25 year-old history of vitiligo upon exposure to sunlight. The patient underwent an extended left hemihepatectomy, and the recovery was uneventful, with the exception of a persistent hyperbilirubinemia. Perfusion problems and extrahepatic cholestasis were ruled out by CT-scan with angiography and MR-cholangiopancreatography. However, MR1 showed an iron overload. Histology confirmed the HCC （pT3, pN0, G3, R0） and revealed a portal fibrosis and hemosiderosis. Based on the skin lesions we suspected a PCT that was confirmed by laboratory tests showing elevated porphyrin, uroporphyrin, coproporphyrin and porphobilinogen. Concurrently, molecular diagnostics revealed homozygosity for the C282Y mutation within the hemochromatosis HFE gene. After phlebotomy and normalization of liver function tests the patient was discharged. This is the first case ever showing the unusual combination of HCC in a fibrotic liver with HHC and PCT. This diagnosis not only warrants oncological follow-up but also symptomatic therapy to normalize iron metabolism and thereby improve liver function and alleviate the symptoms of HHC and PCT. Thus progression of fibrosis may be prevented and liver regeneration supported.

Auditory neuropathy in a patient with hemochromatosis

Objective:To evaluate the auditory function of an individual with genetically confirmed hemochromatosis. Methods: A 57 year old male with mildly impaired sound detection thresholds underwent a range of behavioural, electroacoustic and elec-trophysiologic assessments. These included the recording of otoacoustic emissions and auditory brainstem responses, measurement of monaural temporal resolution and evaluation of binaural speech processing. Findings for this patient were subsequently compared with those of 80 healthy controls with similar audiometric thresholds. Results: The patient showed the three cardinal features of auditory neuropathy, presenting with evidence of normal cochlear outer hair cell function, disrupted neural activity in the auditory nerve/brainstem and impaired temporal processing. His functional hearing ability (speech perception) was significantly affected and suggested a reduced capacity to use localization cues to segregate signals in the presence of back-ground noise. Conclusion:We present the first case of an individual with hemochromatosis and auditory neuropathy. The findings for this patient highlight the need for careful evaluation of auditory function in individuals with the disorder.

The Hemochromatosis Distribution in Matera Province： A New SNP to Explain the Low Genotype-Phenotype Correlation

The present study aims to investigate the genotype-phenotype correlation of the hereditary hemochromatosis （HH）, a genetic disorder of iron metabolism, in Matera province （Basilicata, Italy）. Integrating both epidemiological and molecular approaches, the authors studied： （a） the frequency of the HH main mutations; （b） the association between mutations and HH cases. The majority of patients with HH are homozygous for the C282Y mutation of the HFE gene. A second mutation （H63D） is more widely distributed and its connection with HH isn＇t clear, but a low penetrance is attributed to this variant. The population-based study consists of three steps： （1） determination of iron biochemical parameters, （2） genetic test, and （3） sequencing of HFE gene and bioinformatics studies. A case report is presented in a 41-year-old male （genotype： H63D/wt） with biochemical and clinical evidences of HH, in absence of secondary iron overload factors. In the cohort of studied patients （150M：62F）, there are 18 homozygous patients; H63D/H63D genotype is found in 11 cases. In the heterozygous group, H63D/wt is the predominant genotype （61/68 subjects）. All the H63D/wt residents in the same village （Mont.） show altered biochemical parameter levels. In our case study, a substitution localized into the HFE promoter （nt225A 〉 C） is found. Results show that the H63D genotype is responsible for most cases of HH. The peculiar clinical manifestation found in Mont. suggests a founder effect. In our case, the iron overload is related to a presence of an undetected mutation, critical for the transcriptional regulation of the HFE gene.

Intestinal heme absorption in hemochromatosis gene knock-out mice

AIM To investigat the influence of hemochromatosis gene(Hfe) mutation on ^(59)Fe labelled duodenal heme absorption in mice.METHODS Heme absorption was measured in Hfe wild type and Hfe^((-/-)) mice by the duodenal tied loop and by oral gavage methods. The m RNA expression of heme oxygenase(HO-1), Abcg2 and Flvcr1 genes and levels were determined by quantitative polymerase chain reaction.RESULTS Heme absorption was significantly increased in homozygous Hfe^((-/-)) mice despite significant hepatic and splenic iron overload. While duodenal HO-1 mRNA was highly expressed in the wild type and Hfe^((-/-)) heme-treated group following 24 h heme administration, Flvcr1 a mRNA decreased. However, Abcg2 mRNA expression levels in duodenum remained unchanged. CONCLUSION Heme absorption was enhanced in Hfe^((-/-)) mice from both duodenal tied-loop segments and by oral gavage methods. HO-1 m RNA levels were enhanced in mice duodenum after 24 h of heme feeding and may account for enhanced heme absorption in Hfe^((-/-)) mice. Implications for dietary recommendations on heme intake by Hfe subjects to modulate iron loading are important clinical considerations.

Primary Non-HFE Hemochromatosis:A Review

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced.Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator(known as human factors engineering,HFE)protein,a regulator of hepcidin,and makes up approximately 90%of all hemochromatosis cases.However,four types of hemochromatosis do not involve the HFE gene.They are non-HFE hemochromatosis type 2A(HFE2,encoding HJV),type 2B(HAMP,encoding hepcidin),type 3(TFR2,encoding transferring receptor-2),and types 4A and B(SLC40A1,encoding ferroportin.NonHFE hemochromatosis is extremely rare.Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A,20/100,000 for type 2B,30/100,000 for type 3,and 90/100,000 for type 4 hemochromatosis.Current guidelines recommend that the diagnosis be made by ruling out HFE mutations,history,physical examination,laboratory values(ferritin and transferrin saturation),magnetic resonance or other imaging,and liver biopsy if needed.While less common,non-HFE hemochromatosis can cause iron overload as severe as the HFE type.In most cases,treatment involves phlebotomy and is successful if started before irreversible damage occurs.Early diagnosis and treatment are important because it prevents chronic liver disease.This review updates the mutations and their pathogenetic consequences,the clinical picture,diagnostic guidelines,and treatment of hemochromatosis.

The Evolution of Iron-Related Comorbidities and Hospitalization in Patients with Hemochromatosis:An Analysis of the Nationwide Inpatient Sample

Hemochromatosis,either hereditary hemochromatosis(HH)or secondary hemochromatosis,consists of the accumulation of iron in the liver,heart,and other organs.It leads to end-organ damage in a proportion of affected subjects.Although liver-related morbidity(cirrhosis and hepatocellular carcinoma[HCC])and mortality are well established,the frequency of these complications remains controversial.The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010.We queried the Nationwide Inpatient Sample(NIS)database from the year 2002 to 2010.We included adults(age≥18 years)and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis.Data analysis for this study was generated using SAS software version 9.4.A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis.The majority were males(57%)with a median age of 54 years(37–68),with a predominance of white patients(63.3%)followed by black(26.8%).The rate of hospitalization among patients with hemochromatosis increased by 79%between the years 2002 and 2010(34.5/100,000 in 2002 vs 61.4/100,000 in 2010).The main associated diagnoses were diabetes mellitus(20.2%),cardiac disease,including arrhythmias(14%)and cardiomyopathy(dilated 3.8%;peri-,endo-,myocarditis 1.3%),liver cirrhosis(8.6%),HCC(1.6%),and acute liver failure(0.81%).Of note,HCC was associated with cirrhosis in 1188 patients(43%of HCC patients)and male sex(87%).Diagnostic biopsies were performed in 6023(3.6%)of those patients and liver transplant was performed in 881(0.5%).In-hospital mortality occurred in 3638(2.16%)patients.In this large database study,we found a rising trend in hospitalization for hemochromatosis,possibly due to the increased recognition of this entity and billing for the condition.The incidence of cirrhosis in hemochromatosis was found to be similar to other studies(8.6%vs 9%).However,the rate of HCC was lower than previous reports(1.6%vs 2.2%–14.9%),and only 43%of HCC was associated with cirrhosis.This raises important pathophysiologic questions regarding the impact of iron overload in HCC.There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis.This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes,cardiomyopathy,cirrhosis,and HCC.Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload.

Portal Hypertension Refractory Ascites Caused by Secondary Hemochromatosis

We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis.To our knowledge,this is the first well-documented case of this association.A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites.The serum-ascites albumin gradient was 29.9 g/L.Abdominal computed tomography(CT)showed a large amount of ascites,hepatomegaly,and splenomegaly.Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue.A peripheral blood smear showed tear drop red blood cells and metarubricytes.Serum ferritin was 8,855.0 ng/mL.Therefore,we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis.We simultaneously performed the transjungular intrahepatic portal-systemic shunt(TIPS)and obtained a transjungular liver biopsy.The portal pressure gradient before TIPS was 28 mmHg,and iron staining was strongly positive on liver biopsy,which confirmed our diagnosis.After TIPS,both abdominal distention and ascites gradually resolved,and no recurrence as observed after the 12-month postoperative follow-up was observed.This case indicated that regular monitoring of iron load is important for patients with osteopetrosis.TIPS is safe and effective for portal hypertension complications due to osteopetrosis.

Unique presentation of neonatal liver failure:A case report

BACKGROUND Acute fulminant liver failure rarely occurs in the neonatal period.The etiologies include viral infection(15%),metabolic/genetic disease(10%),hematologic disorders(15%),and ischemic injury(5%).Gestational alloimmune liver disease usually manifests as severe neonatal liver failure,with extensive hepatic and extrahepatic iron overload,sparing the reticuloendothelial system.Empty liver failure is a rare cause of liver failure where a patient presents with liver failure in the neonatal period with no hepatocytes in liver biopsy.CASE SUMMARY A 5-week-old male presented with jaundice.Physical examination revealed an alert but deeply icteric infant.Laboratory data demonstrated direct hyperbilirubinemia,a severely deranged coagulation profile,normal transaminase,and normal ammonia.Magnetic resonance imaging of the abdomen was suggestive of perinatal hemochromatosis.Liver biopsy showed histiocytic infiltration with an absence of hepatocytes.No hemosiderin deposition was identified in a buccal mucosa biopsy.CONCLUSION Neonatal liver failure in the absence of hepatocellular regeneration potentially reflects an acquired or inborn defect in the regulation of hepatic regeneration.

Secondary hemochromatosis as a result of acute transfusion-induced iron overload in a burn patient

Background:Red blood cell transfusions are critical in burn management.The subsequent iron overload that can occur from this treatment can lead to secondary hemochromatosis with multi-organ damage.Case Presentation:While well recognized in patients receiving chronic transfusions,we present a case outlining the acute development of hemochromatosis secondary to multiple transfusions in a burn patient.Conclusions:Simple screening laboratory measures and treatment options exist which may significantly reduce morbidity;thus,we believe awareness of secondary hemochromatosis in those treating burn patients is critical.

Association between hereditary hemochromatosis and hepatocellular carcinoma: a comprehensive review

Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.