Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States.

There have been conflicting data regarding liver transplantation (LT) outcomes for hereditary hemochromatosis (HH), with no recent data on LT outcomes in patients with HH in the past decade. Using the United Network for Organ Sharing registry, we evaluated waitlist and post-LT survival in all adult patients listed for HH without concomitant liver disease from 2003 to 2019. Post-LT survival for HH was compared with a propensity-matched (recipient and donor factors) cohort of recipients with chronic liver disease (CLD). From 2003 to 2019, 862 patients with HH were listed for LT, of which 55.6% ( n = 479) patients underwent LT. The 1- and 5-year post-LT survival rates in patients with HH were 88.7% (95% confidence interval [CI], 85.4%-91.4%) and 77.5% (95% CI, 72.8%-81.4%), respectively, and were comparable with those in the propensity-matched CLD cohort ( p value = 0.96). Post-LT survival for HH was lower than for Wilson's disease, another hereditary metabolic liver disease with similar LT volume ( n = 365). Predictors for long-term (5-year) post-LT mortality included presence of portal vein thrombosis (hazard ratio [HR], 1.96; 95% CI, 1.07-3.58), obesity measurements greater than Class II (HR, 1.98; 95% CI, 1.16-3.39), and Karnofsky performance status (HR, 0.98; 95% CI, 0.97-0.99) at the time of LT. The leading cause of post-LT death ( n = 145) was malignancy (25.5%), whereas cardiac disease was the cause in less than 10% of recipients. In conclusion, short- and long-term survival rates for HH are excellent and comparable with those of other LT recipients. Improving extrahepatic metabolic factors and functional status in patients with HH prior to LT may improve outcomes.

Haemochromatosis in a kidney transplant recipient: a case report.

BACKGROUND: Iron overload is inevitably related to chronic kidney disease (CKD) treatment. Haemochromatosis leads to multiorgan damage and is associated with increased mortality. Primary haemochromatosis is the most common autosomal recessive disease in white populations. In most cases, the classic form of hereditary haemochromatosis is caused by mutations, mainly C282Y and H63D, in the haemochromatosis gene (HFE). Secondary haemochromatosis can be triggered by iron administration and blood transfusions. Haemochromatosis is rarely reported in kidney transplant recipients. Atypical factors may evoke haemochromatosis in patients without HFE mutations or other standard risk factors. CASE PRESENTATION: In the current study, we present a patient who started to have haemochromatosis symptoms after kidney transplantation. A 37-year-old man after kidney transplantation from a deceased donor was admitted to the hospital due to high serum ferritin levels and impaired graft function. The patient's past medical history included arterial hypertension, embolization of both renal arteries and necrosis of the left femoral head. Glomerulonephritis was suspected as a cause of CKD; however, severe kidney failure was diagnosed, kidney biopsy was not performed, and the patient started intermittent haemodialysis. While on dialysis to treat anaemia, the patient had received erythropoietin and iron intravenously, and the maximal serum ferritin level was 2115 ng/ml. After kidney transplantation, ferritin levels started to increase rapidly, with a maximum level of 9468 ng/ml one and a half years after surgery. His genetic study showed HFE C282Y heterozygosity. Symptoms of haemochromatosis, such as skin hyperpigmentation, elevated activity of aminotransferases, impaired glucose tolerance and heart failure, were observed. Therapeutic phlebotomy was started, and 36 procedures were performed. After treatment, graft function significantly improved, most haemochromatosis symptoms resolved, and the serum ferritin level significantly decreased. CONCLUSIONS: Haemochromatosis can occur in heterozygotic HFE patients after kidney transplantation. Iron administration, infections, type of immunosuppression and liver dysfunction should be considered potential triggers of haemochromatosis in this group of patients.

Left ventricular deformation mechanics over time in patients with thalassemia major with and without iron overload.

BACKGROUND: Myocardial iron overload in patients with thalassemia major (TM) is one of the most important complications. The purpose of the study was to identify advanced echocardiography parameters for early identification of myocardial dysfunction during follow-up of patients with TM. METHODS: Forty TM patients who were 41 ± 5 years old were included in the study and divided into two groups according to cardiac magnetic resonance T2* results (Group 1: Τ2* > 25 ms, Group 2: Τ2* ≤ 25 ms). Liver T2* parameters were also measured. Conventional and deformational echocardiographic parameters were measured at baseline and approximately 2 years later. RESULTS: Thirty-two patients had Τ2* = 34 ± 4 ms (Group 1), and 8 had Τ2* = 17 ± 9 ms (Group 2). Blood consumption was 185 ± 60 and 199 ± 37 ml/kg/yr (p = 0.64), and liver T2* was 4 ± 5 and 17 ± 21 ms (p = 0.01) in Groups 1 and 2, respectively. At baseline, Group 1 had better left ventricular global longitudinal strain (GLS) (- 22 ± 3 vs. - 18 ± 5, p = 0.01) and similar left ventricular ejection fraction (LVEF) (62 ± 5% vs. 58 ± 10%, p = 0.086) than Group 2. At the 28 ± 11-month follow-up, LVEF, GLS, and T2* values in Group 1 (63 ± 3%, - 21 ± 3%, 34 ± 4 ms) and Group 2 (56 ± 11%, - 17 ± 4%, 17 ± 9 ms) did not change significantly compared to their corresponding baseline values. In 8 patients from Group 1, a worsening (> 15%) in LS (p = 0.001) was detected during follow-up, with a marginal reduction in LVEF. CONCLUSIONS: GLS seems to be an efficient echocardiographic parameter for detecting hemochromatosis-related cardiac dysfunction earlier than LVEF. It also seems to be affected by other factors (free radical oxygen, immunogenetic mechanisms or viral infections) in a minority of patients, underscoring the multifactorial etiology of cardiomyopathy.

Hemochromatosis and Hepatocellular Carcinoma Secondary to Immunoglobulin G4-Related Disease with Hepatopathy: A Case Report.

Immunoglobulin G4-related disease (IgG4-RD) is a recently characterized illness in which lymphocytes and plasma cells infiltrate various anatomical sites. IgG4-hepatopathy, a manifestation of IgG4-RD, is a broader term covering various patterns of liver injury. The clinical course, including the malignant potential of IgG4-RD, remains unclear. Here we report the first case of secondary hemochromatosis and hepatocellular carcinoma (HCC) developing from IgG4-hepatopathy. A 67-year-old man was admitted to our hospital for treatment of deteriorating glucose tolerance. Blood test results showed hypergammaglobulinemia, especially IgG4. He was readmitted 2 months later with dyspnea due to lung disease and pleural effusion, and elevated transaminase levels. He underwent liver and lung biopsies. IgG4-RD was diagnosed and he was treated with steroid therapy, which improved serum IgG4 levels and imaging abnormalities. A follow-up computed tomography (CT) scan conducted 38 months later revealed a tumor (diameter, 50 mm) in liver segments 7 and 8. The resected specimen revealed HCC and abundant siderosis in the background liver, indicating a diagnosis of hemochromatosis. IgG4-positive cells were scarce, probably because of corticosteroid therapy. In the present case, IgG4-RD was well controlled with prednisolone (PSL) and an immunosuppressive agent, and chronic hepatitis was not severe, even though the patient subsequently developed HCC. However, extensive siderosis consistent with hemochromatosis was unexpectedly noted. These findings suggest that secondary hemochromatosis and HCC developed during IgG4-RD with hepatopathy. We believe this case sheds light on IgG4-RD.

Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model.

COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.

Iron Through the Prism of Haematology.

Since the inception of the British Society for Haematology (BSH) 60 years ago, our increased scientific understanding of iron metabolism, together with clinical developments, have changed the way we diagnose and treat its disorders. In the UK, perhaps the most notable contributions relate to iron overload, some of which I will outline from personal experience. Diagnostically, this began with the identification of serum ferritin as a marker of iron overload and continued later with the application of MRI-based imaging techniques for iron and its distribution. Therapeutically, the first trials of both parenteral and oral chelation, which have radically changed the outcomes of transfusional iron-overloaded patients, took place in the UK and are now part of standard clinical practice. During this time, our scientific understanding of iron metabolism at a cellular and systemic level have advanced the diagnosis and treatment of inherited disorders of iron metabolism. There are potential novel applications related to our recent understanding of hepcidin metabolism and manipulation.

Endothelial Bone Morphogenetic Protein 2 (Bmp2) Knockout Exacerbates Hemochromatosis in Homeostatic Iron Regulator (Hfe) Knockout Mice but not Bmp6 Knockout Mice.

BACKGROUND AND AIMS: Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain. APPROACH AND RESULTS: We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes. CONCLUSIONS: These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.

Unsafe Deposits: Overlapping Cutaneous Manifestations of Porphyria Cutanea Tarda, Ochronosis, Hemochromatosis, and Argyria.

Cutaneous deposition disorders represent an array of conditions resulting from the accumulation of endogenous and exogenous substances within the skin. Many of the deposition diseases resemble each other and can also be confused with disorders not related to deposition. Porphyria cutanea tarda (PCT) results from dysfunction particularly in the fifth enzyme of the heme synthesis pathway, leading to increased skin fragility and bullae among other abnormalities. Ochronosis develops from alkaptonuria or exogenous sources, creating deposition of ocher-colored pigment in the skin. Hemochromatosis is a systemic disorder that can be inherited or acquired, altering skin pigmentation in more than 90% of patients. PCT can be an initial manifestation of hemochromatosis. Argyria is an acquired disorder of silver deposition that can also cause pigmentation similar to ochronosis. These uncommon but not rare disorders may resemble and be confused with each other in multiple ways.

Dietary and Sentinel Factors Leading to Hemochromatosis.

Although hereditary hemochromatosis is associated with the mutation of genes involved in iron transport and metabolism, secondary hemochromatosis is due to external factors, such as intended or unintended iron overload, hemolysis-linked iron exposure or other stress-impaired iron metabolism. The present review addresses diet-linked etiologies of hemochromatosis and their pathogenesis in the network of genes and nutrients. Although the mechanistic association to diet-linked etiologies can be complicated, the stress sentinels are pivotally involved in the pathological processes of secondary hemochromatosis in response to iron excess and other external stresses. Moreover, the mutations in these sentineling pathway-linked genes increase susceptibility to secondary hemochromatosis. Thus, the crosstalk between nutrients and genes would verify the complex procedures in the clinical outcomes of secondary hemochromatosis and chronic complications, such as malignancy. All of this evidence provides crucial insights into comprehensive clinical or nutritional interventions for hemochromatosis.

Major Issues of Care in Thalassemia Major Children Refugees.

Beta thalassemia major (ßTM) is the most common inherited hemoglobinopathy. Management essentially focuses on preventing and treating complications. Conventional treatment is based on a regular blood transfusion program, and chelation therapy. Management essentially focuses on preventing and treating complications. Severe complications of ßTM are very rarely seen in children in Europe. In the context of the migrant crisis, pediatricians will be confronted with the challenge of managing severe complicated ßTM. We report the case of 2 Syrian 10-year-old twin girls who arrived to France with numerous and severe complications of ßTM: hemochromatosis, alloimmunization, hypopituitarism, osteopenia… Their clinical management, which led to successful vital and functional improvement, is reported in this article.

Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI.

INTRODUCTION: Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals. Mutations in the HFE gene lead to excess iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is readily uptaken by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms greatly vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. MRI has emerged as the reference standard imaging modality for the detection and quantification of hepatic iron deposition, as ultrasound (US) is unable to detect iron overload and computed tomography (CT) findings are nonspecific and influenced by multiple confounding variables. If caught and treated early, HH disease progression can significantly be altered. Area covered: The data on Hemochromatosis, iron overload, and MRI were gathered by searching PubMed. Expert commentary: MRI is a great tool for diagnosis and management of iron overload. It is safe, effective, and a standard protocol should be included in diagnostic algorithms of future treatment guidelines.

IRON STORAGE DISEASE IN AFRICAN GREY PARROTS ( PSITTACUS ERITHACUS) EXPOSED TO A CARNIVOROUS DIET.

Within a 2-wk period, three African grey parrots ( Psittacus erithacus) presented for emergency treatment. All three parrots had depressed behavior, an inability to fly, and significant weight loss. Plasma chemistry abnormalities included severe hypoproteinemia and elevated liver enzymes in all parrots. Two of the parrots died, and histologic examination with hematoxylin and eosin and Prussian blue stains revealed severe hepatic iron storage. Quantitative analysis confirmed high hepatic iron concentrations. Iron accumulation was attributed to ingestion of a carnivorous bird diet or selectively eating too much fruit and vegetables high in ascorbic acid. Management entailed husbandry changes including switching the remaining parrots to a low-iron diet. Psittacine species exposed to carnivorous bird diets are at risk of developing iron storage disease.

[Diagnosis of haemochromatosis]. / Diagnostiek naar hemochromatose.

Interpretation of laboratory parameters in cases of haemochromatosis can be difficult. Here, we describe two patients with markedly elevated transferrin saturation and high ferritin levels. The first patient is a 51-year-old woman who had been complaining of fatigue, abdominal pain and arthritis for three years. Her liver enzymes were mildly elevated. Secondary causes of iron overload had been excluded. DNA investigation found a homozygous p.Cys282Tyr mutation in the HFE protein, consistent with hereditary haemochromatosis. The second patient is a 58-year-old man with general malaise and cholestatic liver injury. The p.Cys282Tyr and p.His63Asp mutations in the HFE protein could not be detected. Ultrasound of the liver revealed steatosis. The patient was a heavy drinker and a diagnosis of iron overload caused by alcoholic liver disease was made. Based on these case reports, we discuss the strategy to diagnose haemochromatosis and the background of associated laboratory tests.

Etiology of chronic liver diseases in the Northwest of Italy, 1998 through 2014.

AIM: To assess the etiology of chronic liver diseases (CLD) from 1998 to 2014 at the outpatient clinic of Gastroenterology of the main hospital in Northwest of Italy among those dedicated to hepatology. METHODS: A random sample of charts of patients referred to for increased liver enzymes between January 1998 and December 2006, and between January 2012 and December 2014 were reviewed. Etiology search included testing for hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatitis, primary biliary cirrhosis, Wilson's disease and hereditary hemocromatosis. A risky alcohol consumption was also considered. Non-alcoholic fatty liver disease (NAFLD) was diagnosed in patients with histological and/or ultrasound evidence of steatosis/steatohepatitis, and without other causes of CLD. RESULTS: The number of patients included was 1163. Of them, 528 (45%) had positivity for HCV and 85 (7%) for HBV. Among the virus-free patients, 417 (36%) had metabolic disorders whereas the remaining had history of alcohol abuse, less prevalent causes of CLD or concomitant conditions. In comparison to 1998-2000 (41%), a reduction of HCV alone-related cases was detected during the periods 2001-2003 (35%, OR = 0.75, 95%CI: 0.53-1.06), 2004-2006 (33%, OR = 0.70, 95%CI: 0.50-0.97) and 2012-2014 (31%, OR = 0.64, 95%CI: 0.46-0.91). On the contrary, in comparison to 1998-2000 (31%), metabolic-alone disorders increased in the period 2004-2006 (39%, OR = 1.37, 95%CI: 0.99-1.91) and 2012-2014 (41%, OR = 1.53, 95%CI: 1.09-2.16). The other etiologies remained stable. The increase of incidence of metabolic-alone etiology during the period 2004-2006 and 2012-2014 tended to be higher in older patients (≥ 50 years) compared to younger (P = 0.058). CONCLUSION: In the Northwest of Italy, during this study period, the prevalence of HCV infection decreased notably whereas that of NAFLD increased.

The Effects of Alcohol on Other Chronic Liver Diseases.

Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases.