Gestational alloimmune liver disease with alpha thalassaemia in a neonate.

A term baby presented with cholestatic jaundice since birth. She was diagnosed as gestational alloimmune liver disease-neonatal haemochromatosis (GALD-NH) on evaluation. The baby received intravenous immunoglobulin (IVIG) and recovered gradually from the illness. She was also diagnosed with alpha thalassaemia during the course of evaluation, confirmed by genetic testing. NH is a very rare disorder that results in fetal loss or neonatal death due to liver failure. NH is now known to be a phenotypic expression of GALD. Worldwide, NH is seen in less than one in a million pregnancies. The mortality rate of GALD has traditionally been around 80% with almost all babies needing liver transplantation, with advent of maternal and neonatal IVIG treatment, this has reduced significantly. There is no reported case of GALD-NH treated successfully with IVIG from India. Here, we report an interesting case of GALD-NH with alpha thalassaemia.

CONCURRENT IRON OVERLOAD AND NEOPLASIA IN LESCHENAULT'S ROUSETTES (ROUSETTUS LESCHENAULTII): A CASE SERIES.

This case series investigates a cluster of deaths in a captive colony of Leschenault's rousettes (Rousettus leschenaultii). Six of seven bats that died between March and September 2021 were diagnosed postmortem with both iron overload (IO) and neoplasia, neither of which have previously been reported in this species. Iron status was assessed via hepatic histopathological grading, hepatic iron concentration, and, in two cases, serum iron concentration. On histopathological grading, all cases had hemochromatosis except one, which had hemosiderosis. Hepatic iron concentrations did not correlate with histopathological grading. Neoplasms in these six bats included hepatocellular carcinoma (HCC; 4), bronchioloalveolar adenocarcinoma (1), pancreatic adenocarcinoma (1), and sarcoma of the spleen and stomach (1). One bat had two neoplasms (HCC and sarcoma of the spleen and stomach). One additional case of HCC in 2018 was identified on retrospective case review. Etiology was investigated to the extent possible in a clinical setting. Nutritional analysis and drinking water testing found oral iron intake within acceptable bounds; however, dietary vitamin C was potentially excessive and may have contributed to IO. Panhepadnavirus PCR testing of liver tissue was negative for all bats. A species-associated susceptibility to IO, as seen in Egyptian fruit bats (Rousettus aegyptiacus), is possible. The high incidence of HCC is suspected to be related to IO; other differentials include viral infection. Causes or contributing factors were not definitively identified for the other neoplasms seen but could include age, inherited risk (given a high level of inbreeding), or an oncogenic virus. Pending further research in this species, it is recommended that keepers of Leschenault's rousettes offer conservative amounts of vitamin C and iron (as for Egyptian fruit bats), submit for postmortem examination any euthanized or found dead, and share records of similar cases.

Coinheritance of hereditary spherocytosis with haemochromatosis: next-generation sequencing reveals.

We report the case of a man in his 50s with extravascular haemolysis, fluctuating indirect hyperbilirubinaemia, elevated transferrin saturation with hyperferritinaemia and normal liver enzymes. Spherocytes were detected in a blood smear and a mutation of unknown significance, c.1626+1G>A p.?, in intron 13 of the SLC4A1 gene, was identified by next-generation sequencing (NGS). The same mutation was found in his daughter, who presented with similar laboratory changes, confirming the diagnosis of hereditary spherocytosis. Abdominal MRI showed hepatosplenomegaly with hepatic iron overload. In this context of haemolysis (without anaemia) and iron overload, a diagnosis of haemochromatosis was presumed. NGS confirmed the presence of the variants p.(His63Asp) and p.(Cys282Tyr) in heterozygosity in the HFE gene. We report this case for the rarity of co-existing two haematological diseases counteracting each other.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Is iron overload associated with worse outcomes in patients with chronic liver disease undergoing liver transplantation?

Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.

An Iron-chelating Agent Improved the Cardiac Function in a Patient with Severe Heart Failure Due to Hereditary Hemochromatosis.

A 24-year-old man was admitted to our hospital because of severe heart failure. Although he was treated with diuretics and positive inotropic agents, his heart failure progressed. An endomyocardial biopsy revealed iron deposition in his myocytes. Finally, he was diagnosed with hereditary hemochromatosis. After starting administration of an iron-chelating agent in addition to conventional treatment for heart failure, his condition improved. We should consider hemochromatosis in heart failure patients with severe right ventricular dysfunction in addition to left ventricular dysfunction.

Hereditary hemochromatosis with homozygous C282Y HFE mutation: possible clinical model to assess effects of elevated reactive oxygen species on the development of cardiovascular disease.

Hereditary hemochromatosis with the homozygous C282Y HFE mutation (HH-282H) is a genetic condition which causes iron overload (IO) and elevated reactive oxygen species (ROS) secondary to the IO. Interestingly, even after successful iron removal therapy, HH-282H subjects demonstrate chronically elevated ROS. Raised ROS are also associated with the development of multiple cardiovascular diseases and HH-282H subjects may be at risk to develop these complications. In this narrative review, we consider HH-282H subjects as a clinical model for assessing the contribution of elevated ROS to the development of cardiovascular diseases in subjects with fewer confounding clinical risk factors as compared to other disease conditions with high ROS. We identify HH-282H subjects as a potentially unique clinical model to assess the impact of chronically elevated ROS on the development of cardiovascular disease and to serve as a clinical model to detect effective interventions for anti-ROS therapy.

Striking Cholestatic Giant Cell Hepatitis Resulting in Fulminant Liver Failure After Garcinia Cambogia Use.

Garcinia cambogia, a weight control herbal, can cause mild liver toxicity with nonspecific histologic changes. Herein, we reported a case of herbal-induced fulminant cholestatic giant cell hepatitis due to garcinia cambogia use. A 65-year-old woman with breast cancer treated 18 years earlier was admitted for obstructive jaundice for 2 weeks. She started using garcinia cambogia 3 months ago for weight loss. Physical exam showed scleral icterus. Serum studies excluded Wilson's disease, systemic infection including COVID-19 (coronavirus disease 2019), autoimmune hepatitis, and metabolic or toxicologic causes. An urgent liver biopsy showed severe giant cell hepatitis in absence of HSV-1/2, cytomegalovirus, HBsAg and HBcAg (immunostain), and EBV (in situ hybridization). Despite supportive therapy, the patient developed grade 2-3 hepatic encephalopathy and necessitated liver transplant. The explanted liver was markedly atrophy, in which the most striking histologic finding was diffuse distribution of multinucleated giant hepatocytes with syncytial pattern in a background of extensive zone-1 accentuated, geographic, hemorrhagic, confluent hepatocytic necrosis, along with remarkable hepatocytic and canalicular cholestasis. Marked hepatocellular and sinusoidal iron orverload present. The patient recovered uneventfully.

A Matched-Cohort Analysis of Outcomes in Patients with Hereditary Hemochromatosis After Anterior Cervical Discectomy and Fusion.

BACKGROUND: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder. This disease affects gut iron transport, leading to iron overload, which affects immune function, coagulation mechanics, and bone health. Within the spine, HH contributes to decreased bone mineral density and accelerated intervertebral disc degeneration. The purpose of this study was to discover the differences in the rates of common 90-day postoperative complications and 1-year and 2-year surgical outcomes in patients with and without HH after anterior cervical discectomy and fusion (ACDF). METHODS: Using the PearlDiver database, patients with active diagnoses of HH before ACDF were matched to patients without HH using a 1:5 ratio on the basis of age, sex, body mass index, and comorbidities. Postoperative complications were assessed at 90 days, and 1-year and 2-year surgical outcomes were assessed. All outcomes and complications were analyzed using multivariate logistic regression with significance achieved at P < 0.05. RESULTS: Patients with HH had significantly higher rates of 1-year and 2-year reoperation rates compared with patients without HH (29.19% vs. 3.94% and 37.1% vs. 5.93%, respectively; P < 0.001). The rates of 90-day postoperative complications significantly increased in patients with HH including dysphagia, pneumonia, cerebrovascular accident, deep vein thrombosis, acute kidney injury, urinary tract infection, hyponatremia, surgical site infection, iatrogenic deformity, emergency department visit, and hospital readmission. CONCLUSIONS: Patients with HH undergoing ACDF showed increased 90-day postoperative complications and significantly increased rates of 1-year and 2-year reoperation compared with patients without HH. These findings suggest that iron overload may contribute to adverse outcomes in patients with HH undergoing 1-level and 2-level ACDF.

Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis.

PURPOSE: Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. METHODS: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. RESULTS: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. CONCLUSION: We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.

Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.

Exploring the Association between Hemochromatosis and Lower-Limb Venous Disease.

OBJECTIVE: Chronic venous disease is a circulatory system dysfunction that has the potential to lead to venous leg ulceration. Although research on the influence of specific gene variants on chronic venous disease has been limited, a few studies have reported an association between hemochromatosis and chronic venous disease. However, no studies have looked at the prevalence of lower-limb venous disease and leg ulcers in people with hemochromatosis. This study aimed to review the existing literature for any association between venous disease and hemochromatosis and investigate the prevalence of venous disease and leg ulcers in people with hemochromatosis. METHODS: Scoping systematic literature review and cross-sectional study surveying people with hemochromatosis. RESULTS: This scoping systematic literature review included nine articles and indicated a link between hemochromatosis and venous disease/leg ulcers, although further studies are needed to support this link. Analysis of survey results from people with hemochromatosis found a 9.2% prevalence of leg ulcers in those with self-reported hemochromatosis, considerably higher than the 1% to 3% expected, suggesting that hemochromatosis gene variants may be associated with the pathogenesis of chronic venous disease and leg ulcers. CONCLUSIONS: This is the first known study to complete a review of the literature regarding hemochromatosis and venous leg ulcers and document the association between hemochromatosis and venous disease/leg ulcers. There is a lack of research in this area and hence limited evidence to guide practice.

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial.

BACKGROUND: Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. METHODS: This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. FINDINGS: Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 µmol/L (95% CI 18·6 to 30·6), 20·1 µmol/L (14·8 to 25·3), 11·9 µmol/L (9·2 to 14·7), 22·5 µmol/L (15·9 to 29·1), and 19·0 µmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 µg/L (52·2 to 114.4), 65·5 µg/L (32·1 to 98·9), 62·8 µg/L (33·8 to 91·9), 150·0 µg/L (86·6 to 213.3), and 94·3 µg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. INTERPRETATION: Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. FUNDING: Protagonist Therapeutics.

A "Mix and Match" in Hemochromatosis-A Case Report and Literature Focus on the Liver.

Hemochromatosis is a genetic disorder characterized by increased iron storage in various organs with progressive multisystemic damage. Despite the reports dating back to 1865, the diagnosis of hemochromatosis poses a challenge to clinicians due to its non-specific symptoms and indolent course causing significant delay in disease recognition. The key organ that is affected by iron overload is the liver, suffering from fibrosis, cirrhosis or hepatocellular carcinoma, complications that can be prevented via early diagnosis and treatment. This review aims to draw attention to the pitfalls in diagnosing hemochromatosis. We present a case with multiorgan complaints, abnormal iron markers and a consistent genetic result. We then examine the relevant literature and discuss hemochromatosis subtypes and liver involvement, including transplant outcome and treatment options. In summary, hemochromatosis remains difficult to diagnose due to its symptom heterogeneity and rarity; thus, further education for practitioners of all disciplines is useful in facilitating its early recognition and management.