Diagnosis Of Hemochromatosis Research Articles

CME Laboratory 63/Answers: Diagnostics of Iron Metabolism

CME Laboratory 63/Answers: Diagnostics of Iron Metabolism Abstract. Abstract: Iron deficiency is common and affects the course of many chronic diseases. The diagnosis of absolute and manifest iron deficiency anemia can be easily made by measuring hemoglobin and serum ferritin levels. In inflammatory diseases, the diagnosis can be facilitated by additional laboratory parameters such as soluble transferrin receptor. In several chronic diseases like cardiac or renal failure, different and higher thresholds for serum ferritin apply depending on the disease and stage, sometimes with additional consideration of transferrin saturation. Transferrin saturation is also important for the diagnosis of hemochromatosis. In patients with transferrin saturation >45 %, diagnosis usually requires evidence of homozygosity for the C282Y mutation in the HFE gene.

Magnetic resonance imaging of neonatal hemochromatosis.

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently resulting in fetal loss or neonatal death. It is thought that most cases of neonatal hemochromatosis are caused by gestational alloimmune liver disease (GALD), with neonatal hemochromatosis being a phenotype of GALD rather than a disease process. Extrahepatic siderosis in the pancreas, myocardium, thyroid and minor salivary gland is a characteristic feature of neonatal hemochromatosis. There is also sparing of the reticuloendothelial system with no iron deposition in the spleen. Hepatic and extrahepatic siderosis seen in neonatal hemochromatosis is from iron dysregulation secondary to liver damage rather than iron deposition causing the liver damage. The presence of extrahepatic siderosis in the pancreas and thyroid is diagnostic of neonatal hemochromatosis and can be detected noninvasively by multi-echo gradient recalled echo (GRE) T2*-weighted sequence of MRI within hours of birth. This helps to expedite the treatment in the form of intravenous immunoglobulin and exchange transfusion, which improves the survival in these babies. The finding of hepatic siderosis is nonspecific and does not help in the diagnosis of neonatal hemochromatosis because it is seen with other causes of advanced liver disease.

Analysis of the left atrial function using two dimensional strain in patients with recent diagnosis of hereditary hemochromatosis

Abstract Funding Acknowledgements Type of funding sources: None. Background. Hereditary hemochromatosis (HH) is a genetic condition associated with a systemic iron overload caused by a reduction in the concentration of the iron regulatory hormone hepcidin or the hepcidin-ferroportin complex activity. Heart failure is the leading cause of death. It has been demonstrated early stages of systolic and diastolic left ventricular dysfunction in previous studies. The main function of the left atrium (LA) is to modulate the left ventricular filling through the reservoir, conduct and bump phases. Purpose. To compare the LA function between asymptomatic and recently diagnosed HH patients and a control group using two-dimensional speckle tracking. Methods. In this prospective study, 30 patients with HH (90% males, 47 ± 18 years old) and 30 healthy controls with a normal echo stress test (85% males, 45 ± 13 years old) were included. A conventional echocardiogram was performed. LA strain, LA strain rate and LA volumetric parameters during the reservoir, conduit and bump phases were studied according to the current recommendations. The LA stiffness index was calculated by using the ratio between E/e´ ratio and LA strain during the reservoir phase. Results. LA volume was similar in both groups (36,5 ± 10 ml vs 32,3 ± 6,5 ml; p = 0.09). No differences were observed in LA ejection fraction (EF) (57.5 ± 10% vs 60 ± 5%; p = 0.32), LA passive EF (35 ± 12% vs 36 ± 9%; p = 0.82) or LA bump function (34 ± 11% vs 36 ± 9.9%; p = 0.41) between both groups. On the contrary, the HH group had lower LA reservoir strain (31.5 ± 6.5% vs 38.3 ± 7.9%; p = 0.002) and during the conduct phase (18 ± 7% vs 23.3 ± 6.4%; p = 0.01) than the control group. The LA stiffness index was significantly higher in the HH group (25.5 ± 9.1 vs 19.5 ± 6.4; p = 0.01). Conclusion. Early abnormalities in the LA function could be detected by using two-dimensional speckle tracking study despite no evidence of changes in atrial size or volumetric parameters. Abstract Figure.

A Case of Secondary Hemochromatosis

A 28-year-old woman with a history of transfusion-dependent thalassemia major who did not receive any iron-chelating agent presented with symptoms of iron overload with marked diffuse increased liver density. Eventually, the diagnosis of secondary hemochromatosis was done based on the aforementioned history, laboratory, and imaging findings.

Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy

Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. To estimate the incidence of primary hepatic carcinoma and death by HFE variant status. Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018. Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants. Two linked co-primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex. A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .20) were not statistically significant. Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.

S3508 A Rare Case of Juvenile Hemochromatosis

INTRODUCTION: Juvenile hemochromatosis is a rare phenomenon seen in patients who have a severe overload of iron in the first three decades in life. It is the most severe form of hereditary hemochromatosis and can cause further clinical complications of cardiomyopathy, hypogonadism, and liver fibrosis. The disease process can progress and cause signs of fatal heart failure. Both male and female populations are equally represented. Lab studies usually reveal elevated serum ferritin and transferrin saturation and gene transformation for HFE mutation is often positive. Phlebotomy is pursued in order to achieve iron depletion which greatly reduces morbidity and mortality. We present a 19 year old male who arrived at an outpatient hematologist office for evaluation of his fatigue. CASE DESCRIPTION/METHODS: This is a 19 year African American old male with no PMH history who arrived at an outpatient hematologist office after having routine blood work for his symptoms of fatigue. Referral labs indicated a ferritin of 1322 associated with an elevated total bilirubin of 3.5 and direct bilirubin that was mostly indirect. On physical examination, the patient had mild scleral icterus but a benign examination. Outpatient lab work revealed a total bilirubin of 5.2, direct bilirubin less than 0.2, Combs test negative, ferritin 1301, haptoglobin at 18. Hemoglobin electrophoresis showed a decreased MCV secondary to a beta thalassemia trait. A hemochromatosis DNA analysis revealed that the patient had a homozygous trait of C2827 locus further indicating a diagnosis of hemochromatosis. A MRI of the liver demonstrated increased iron overload and tiny gallstones. The patient proceeded with an outpatient cholecystectomy and liver biopsy. He was started on a regular phlebotomy program every 2 weeks with the goal of getting his serum ferritin level below 100. DISCUSSION: Juvenile hemochromatosis is a rare inherited autosomal recessive manner. Juvenile hemochromatosis shares numerous features with adult hemochromatosis, but iron deposition occurs at an accelerated rate. It is important to note that there is no gender disparity. Clinicians should refer to an outpatient hepatologist for further management and seek early treatment with phlebotomy as it can prevent and even reverse secondary complications of organ damage. In our particular case, the patient was identified early in the disease course and significantly improved his outcomes.

SAT-354 Isolated Hypoparathyroidism: A Rare Initial Manifestation of Hereditary Hemochromatosis (HH)

Background:We present a case of hypoparathyroidism diagnosed in a patient as initial manifestation of hereditary hemochromatosis. As per our literature search, it is very rarely reported as an isolated abnormality in HH.Case:A 27 year old male with history of seizure disorder, well controlled on Oxcarbazepine, referred for evaluation of chronic hypocalcemia. His PMH includes cerebral palsy, with good functional capacity and mild cognitive impairment. He denied muscle spasm, perioral numbness, bone pain, muscle weakness or fracture. He was taking calcium carbonate 600mg bid and vitamin D 50,000 IU q2monthly.There was no family history of any Ca disorders. Physical exam was unremarkable.Laboratory evaluation revealed Ca levels ranging from 7.6 to 8.5mg/dl with intact PTH values ranging from 11 to 22pg/ml. His ionized calcium was also low. Patient’s 24 hr urinary Ca was 122mg/24hrs. In this case, he did initially have hypomagnesemia and vitamin d deficiency, which could potentially explain low calcium. But even after supplementing Vitamin D and Mg, patient’s Ca remained low. His kidney function was normal. Hemoglobin was in range of 14-15g/dl. To further evaluate the cause of hypoparathyroidism, iron saturation and iron levels were also sent. His iron saturation % was high at 89% with iron level of 286 ug/dl. His ferritin was 224 ng/ml and TIBC was 265 ug/dl. A sample was sent for genetic analysis to rule out hemochromatosis. Homozygous mutations in C282Y gene were found. A diagnosis of hereditary hemochromatosis was made. His other entire hormonal axis was intact. In this case, patient’s hypoparathyroidism is likely an initial manifestation of his HH.Discussion:Hereditary Hemochromatosis (HH) is a genetic disease characterized by an excessive (unregulated) entry of iron into the bloodstream with increased iron deposition in the parenchymal cells of a variety of organs leading to their failure. A defect in the hemochromatosis gene (HFE) is the most common form of HH, also known as the classic form or type 1 HH, where the principal mutation is represented by a substitution of tyrosine for cysteine at position 282 of the HFE gene (C282Y) as seen in our case. According to the genetic forms, the clinical manifestation usually ranges from simple biochemical abnormalities to severe organ damage and disease such as liver cirrhosis, arthritis, DM, cardiomyopathy and hypogonadism.There are reports of hypoparathyroidism from iron overload seen in thalassemia patients and patients who receive long term blood transfusions. In our literature review, this is the first documented case of HH initially manifesting as hypoparathyroidism. As HH is not uncommon in Caucasians, the work up for hemochromatosis as a possible cause of endocrinopathies should be kept in the differential diagnosis. It will help in early diagnosis & treatment which can reverse the effects of the disease leading to better outcomes.

Polycythemia and Anemia in Hereditary Hemochromatosis

IntroductionHereditary hemochromatosis is a syndrome of dysregulated iron homeostasis resulting in the excessive deposition of iron. Hemochromatosis causes pulmonary, pancreatic, and hepatic dysfunction, all of which are risk factors for anemia in the general population. Conversely, iron overload states are thought to predispose to polycythemia. The effect of the homozygosity and heterozygosity of hereditary hemochromatosis-associated genes on hemoglobin levels has not been sufficiently studied.Materials and methodsWe conducted a retrospective cohort study at West Virginia University of all patients who underwent HFE gene analysis and carried the diagnosis of hemochromatosis. Charts were reviewed to identify relevant variables and the patients’ clinical course.ResultsA total of 213 patients were included with 143 male participants (67.13%). The mean age was 53.6 years (SD: 15.2). A total of 108 patients were homozygous for the C282Y mutation. The prevalence of baseline characteristics are as follows: tobacco use 46.3%, chronic obstructive pulmonary disease 16.4%, malignancy 20.1%, cirrhosis 16.8%, anticoagulant use 6.5%, and chronic renal insufficiency 13.1%. The mean hemoglobin of the population was 15.0 mg/dL (SD 2.21). Anemia was seen in 23 patients (10.80%) and 59 patients (27.6%) had polycythemia.Concurrent malignancy and the presence of chronic renal insufficiency were significantly associated with anemia in both the univariate and multivariate analysis (p-values < 0.001). Patients with homozygosity for C282Y were more likely to receive phlebotomy as compared to other patients. Serum ferritin was not associated with anemia or polycythemia on multivariate analyses (p-values 0.197 and 0.105, respectively).ConclusionDespite the high prevalence of comorbidities that are known risk factors for anemia in the general population, few patients with hereditary hemochromatosis develop anemia. Female patients with hereditary hemochromatosis are relatively protected against polycythemia, affecting only one-fourth of all patients with hemochromatosis, with most patients’ serum hemoglobin reported within normal limits.

The Allele Frequency of the HFE gene mutation H63D (rs1799945) and Its Relationship to a Hereditary Hemochromatosis Diagnosis in Metabolic Nutrition Students at Virginia Tech

Hereditary hemochromatosis (HH) is a disease that causes excess iron absorption from the diet. This excess iron can be stored in the liver, skin, heart, pancreas, and joints, and then can lead to other health conditions, as the human body has no way of actively excreting iron. The human hemochromatosis protein (HFE protein) is encoded by the HFE gene, and mutations in this gene can lead to a dysfunction of the protein resulting in HH or iron overload later in adulthood. The objective of this study was to analyze the mutant allele frequency and the penetrance of the H63D mutation (SNP rs1799945) of the HFE gene in a cohort of Virginia Tech students. This study had a total of 69 participants. Fifty-two participants provided saliva samples, genomic data from 23andMe®, and surveys with phenotypic information. Of these, 6 were genotyped using the RFLP technique and served as controls for genotype confirmation. An additional 17 participants provided saliva samples, but did not provide 23andMe® data; genomic DNA from these participants were genotyped using the RFLP technique. Our results showed that although none of the participants had been diagnosed with HH, the mutant allele frequency of this population was 13.04%. In conclusion, as HH is usually diagnosed in older adults, we could not identify any students with a phenotype of HH, even though we could detect the mutant allele. This data suggests that affordable and accessible genetic ancestry and health kits such as the 23andMe® kit, could provide an efficient way to identify, prevent, and manage HH and other genetic diseases before symptoms arise. KEYWORDS: Hereditary Hemochromatosis; Iron Absorption; Single Nucleotide Polymorphism; Restriction Fragment Length Polymorphism; College Student Population; 23andMe®; Population Analysis; Survey Results

Diagnosis and management of hereditary haemochromatosis.

Hereditary haemochromatosis, one of the most common genetic disorders in the United States, can produce systemic iron deposition leading to end-organ failure and death if untreated. The diagnosis of this condition can be challenging as elevated serum ferritin may be seen in a variety of conditions, including acute and chronic liver disease, a range of systemic inflammatory states, and both primary and secondary iron overload syndromes. Appropriate and timely diagnosis of haemochromatosis is paramount as simple interventions, such as phlebotomy, can prevent or reverse organ damage from iron overload. The recognition of other aetiologies of elevated ferritin is also vital to ensure that appropriate intervention is provided and phlebotomy only utilized in patients who require it. In this review, we summarize the existing data on the work up and management of hereditary haemochromatosis and present a practical algorithm for the diagnosis and management of this disease.

What's Important and New in Hemochromatosis?

Major advances in the understanding of genetic iron overload have led to a clarification of the nosology and terminology of the related diseases. The term hemochromatosis should be reserved to the entities where iron overload is related to hepcidin deficiency or hepcidin resistance. The diagnosis of hemochromatosis is non-invasive, based on clinical examination, blood investigations and, whenever possible, magnetic resonance imaging. Phlebotomies remain the mainstay of the treatment, but new therapeutic approaches should, in the future, constitute a valuable advance, hopefully both as an adjunct to bleeding in the induction phase and as its replacement in the maintenance phase. The goal of the present review is to update the terminology of hemochromatosis in light of major pathophysiological advances, and the main features of its diagnostic and therapeutic approaches.

Hemochromatosis International: therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr homozygous genotype

Hereditary hemochromatosis is a kind of hereditary metabolic liver disorders. It is caused by mutations in genes related to hemochromatosis, which leads to over deposition of iron in the liver, pancreas, skin, hypophysis, gonad and other organs and tissues of the whole body and is manifested as cirrhosis, diabetes, skin pigmentation, and low libido. Physicians of our country have inadequate understanding and familiarity with this disorder. Both the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases have issued guidelines for the diagnosis and treatment of hemochromatosis, but these two guidelines are complicated and difficult for Chinese clinical physician to comprehend. In 2018, Hepatology International published therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr homozygous genotype developed by Hemochromatosis International, these recommendations were objective, simple, and practical. We believe the above-mentioned guideline is understandable and helpful for clinicians and patients without medical education background. Therefore, herein the recommendations are translated into Chinese language, with a view to being able to be clinical work guide for the majority of Chinese hepatologists.

Health Care Utilization and Economic Burdens of Hemochromatosis in the United States: A Population-Based Claims Study.

Little is known about the health care burden of hemochromatosis in the United States, despite its increased morbidity and mortality due to associated advanced liver diseases. To evaluate the health care utilization and economic burdens of hemochromatosis in the United States using real-world claims data. We performed a case-control analysis of adult participants in the Truven Health MarketScan Commercial Claims database from 2010 to 2015. 37,092 hemochromatosis cases were matched 1:1 by demographics and comorbidities to hemochromatosis-free controls with chronic liver disease using propensity scores. Total and service-specific health care parameters were quantified for the 12 months following versus the 12 months before the first date of hemochromatosis diagnosis and over the 12 months following a randomly selected date for controls. Incremental differences in health care burdens between cases and controls were examined using Wilcoxon signed rank tests and McNemar tests for continuous and dichotomous measures, respectively. Adjusted multivariable regression analyses using generalized linear models were used to compare the health care burdens for cases with controls. In comparison with the year before, the 12 months following first hemochromatosis diagnoses had a higher total number of claims per patient (34.37 vs. 29.99; P < 0.0001) and an increase in the per-patient total health care costs ($20,023 vs. $16,905; P < 0.0001). After hemochromatosis diagnosis, health care costs were 2%, 8%, 23%, and 43% higher for inpatient admissions, emergency department visits, outpatient visits, and pharmaceutical prescriptions, compared respectively with the 12 months before diagnosis. In the 12 months following the index date, hemochromatosis cases incurred $2,732 more in total unadjusted costs compared with controls. Compared with controls, cases had adjusted incident rate ratio (IRR) 1.26 (95% CI = 1.30-1.77) times the total number of claims (IRR = 1.40, 95% CI = 1.38-1.43) more outpatient visits and IRR = 1.10 (95% CI = 1.08-1.11) excess pharmaceutical claims. Compared with controls, cases had significantly higher adjusted mean health care costs for inpatient services ($6,484 vs. $7,854), outpatient services ($7,032 vs. $11,005), and pharmaceutical claims ($2,520 vs. $2,822; all P values < 0.05). The annual health care costs among type 2 diabetes, hypertension, arthritis, and chronic kidney disease (CKD) patients with hemochromatosis were $6,968, $7,424, $2,967, and $43,847, respectively, higher than type 2 diabetes, hypertension, arthritis, and CKD patients without hemochromatosis (P < 0.0001). Hemochromatosis in the United States is associated with significant health care utilization and economic burdens driven by outpatient visits, pharmaceutical claims, and a high number of comorbidities DISCLOSURES: No outside funding supported this study. The authors have no relevant financial or other relationships to disclose. An abstract containing some of the results from this study was accepted for the American Association for the Study of Liver Diseases Meeting; November 9-13, 2018; San Francisco, CA.

Ferroportin Disease Caused by a Heterozygous Variant p.Cys326Phe in the SLC40A1 Gene and the Efficacy of Therapeutic Phlebotomy in Children.

Therapeutic phlebotomy is recommended for treating hereditary hemochromatosis. However, the procedure and its efficacy for children remain unclear. We describe a young female patient with ferroportin disease, which was confirmed from excess iron deposition within hepatocytes and by identifying a heterozygous variant p.Cys326Phe in SLC40A1. She had been followed without phlebotomy. Liver histology at age 13 years revealed iron deposition progression. Phlebotomy was initiated and her iron markers and imaging findings improved without severe adverse effects. Therapeutic phlebotomy for children is effective and well-tolerated and should be considered as early as possible after a hemochromatosis diagnosis.

PF500 A NEW FTL GENE MUTATION RESPONSIBLE FOR HYPOFERRITINEMIA WITHOUT IRON DEFICIENCY

Background:Serum ferritin (sFt), is widely considered the best test to assess iron deficiency, as it reflects tissue iron storage. A decrease in sFt is an early indicator of a lack of iron in the body and precedes the decrease of serum iron and the onset of iron deficiency anemia. We present an exceptional case of hypoferritinemia, without anemia or associated iron deficiency. Repeated injections of intravenous iron to the patient led to severe iron overload.Aims:Case report: A 34‐year‐old woman was referred to our Center for investigation of iron overload. She reported that three years ago a biological assessment to investigate asthenia revealed very low sFt (1 μg/L). The CBC showed no anemia nor microcytosis. The patient had previously received oral iron supplementation for 8 years because of this low sFt. She was given IV iron and received 18 injections in 15 months. Following these injections, ferritin normalized (69 μg/L), but transferrin saturation (TSat) was measured at 96%. The patient consulted a few months later for severe asthenia, anorexia, weight loss and dyspnoea and was hospitalized. Liver iron concentration (LIC) measured by MRI was 190 μmol/g (N &lt;36 μmol/g). The diagnosis of secondary haemochromatosis was given and phlebotomies were started. When we saw the patient for second opinion, she already had 9 phlebotomies. Iron parameters showed a SFt at 2 μg/L, serum iron at 31.48 μmol/L and TSat at 92%. Hemoglobin (Hb) levels were normal at 128 g/L with a MCV at 98 fL. Due to a poor clinical tolerance of the phlebotomies, oral iron chelation was proposed. The patient reported that her father, mother, two sisters, and one brother also had unexplained hypoferritinemia and had received iron supplementation.Methods:After informed written consent, Sanger sequencing of the 5’UTR and exon 1 of the FTL (ferritin light chain) gene and NGS analysis of a panel of genes involved in hereditary iron overload (BMP6, HAMP, HFE, HJV, SLC40A1, TRF2) were performed.Results:An undescribed mutation of the FTL gene (c.92A&gt; G or p.Y31C), was identified at the homozygous state. A mutation of the BMP6 gene (c: 337C&gt; G or p.Gln133Glu) in the heterozygous state was also observed. This already described mutation is associated with a decrease expression of hepcidin and is thought to promote iron overload. However, hepcidin was measured 3 times at normal values in our patient.Summary/Conclusion:The mutation identified in the FTL gene is localized in the region involved in L ferritin secretion. Two hypotheses could account for the hypoferritinemia presented by the patient. It could be a lack of serum secretion of the L‐ferritin chain, despite normal tissue iron stores, or a modification of the recognition site by the antibodies used for ferritin assays (immunological). In order to explore these hypotheses, a study of family segregation and different assay techniques for ferritin were investigated. In addition, the BMP6 gene mutation could have played an aggravating cofactor role, favouring the occurrence of acquired iron overload in this patient. This case illustrates the importance of a pragmatic attitude in the presence of any discrepancies among iron parameters. This isolated hypoferritinemia without anemia or other evidence of iron deficiency, was not an indication of IV iron treatment, which led to iron overload and serious complications in the patient.

A short report: reflective testing in the diagnosis of hereditary haemochromatosis: results of a short retrospective study.

Reflective addition of iron studies to elevated ferritin results can be a useful first step towards making a diagnosis of haemochromatosis; however, the criteria for doing so are poorly defined and the efficiency of different stages of this process are not well documented. We studied the efficiency of current practice at York Teaching Hospitals NHS Foundation Trust with the aim to identify areas for improvement. Data were gathered from the laboratory database on the number of iron studies and subsequent interpretive comments reflectively added by laboratory staff during an eight-month period. Reflective addition of iron was based on individual practice of the reporter. Standardised interpretive comments were added to suggest HFE genotyping when both the ferritin and transferrin saturation were raised. The number of patients successfully followed up and found to have pathological HFE gene mutations was used to evaluate efficiency. A total of 2651 raised ferritin results were reported during the evaluation period, which resulted in the reflective addition of 381 iron studies and 43 interpretive comments by the duty biochemists. This led to 33 requests for HFE genotyping and the identification of 13 individuals with pathological mutations. The number of iron studies reflectively added to diagnose one patient (NND) was found to be 29.3. Reflective addition of iron studies and interpretive comments can assist in the early detection of patients with hereditary haemochromatosis. Better guidance for laboratory staff undertaking reflective testing and for general practitioners facilitating patient follow-up may increase the efficiency of this diagnostic process.

Value of liver biopsy in the diagnosis of hereditary hemochromatosis

The paper gives an update on the pathogenesis and main clinical manifestations of primary (hereditary) hemochromatosis and its diagnostic methods. It emphasizes the importance of genetic research in the diagnosis of the disease. Its clinical manifestations are associated with iron deposition in organs, such as the liver, pancreas, joints, skin, and heart. The paper points out the importance of liver biopsy using Perls' reaction for the diagnosis of liver damage with the development of fibrosis, cirrhosis, and cancer as the main cause of death in patients with hereditary hemochromatosis and presents the results of examining liver biopsy specimens in patients with hemochromatosis.

Clinical case of hereditary hemochromatosis

The article presents a clinical case demonstrating the difficulties of timely diagnosis of hereditary hemochromatosis, presents data on modern diagnosis and approaches to the treatment of the disease according to existing clinical guidelines. The described clinical case of hereditary hemochromatosis is associated with a homozygous mutation of C282Y in HFE gene in a 58-year-old patient and his twin brother. Initially, signs of iron deposition in the liver were found on MRI of the abdominal cavity. In laboratory analyses, the patient was found to have an increased level of serum iron - 40 µmol/l and ferritin - 1340 ng/ml. Subsequently, the investigation of HFE gene mutations was carried out and a mutation of C282Y in homozygous form (genotype A/A) was found, which is a molecular genetic confirmation of hereditary hemochromatosis of type 1. At the same time, the patient's twin brother at the targeted examination had the serum iron level of 36 µmol/l, the ferritin level of 600 ng/ml, and also the mutation of HFE gene, the allelic variant of A/A. The results of liver fibroelastometry of the patient correlate with the degree of fibrosis F1 by Metavir scale. Timely started therapeutic phlebotomies led to improved clinical and laboratory parameters of iron metabolism while maintaining normal levels of red blood cells and hemoglobin.

Chronic iron overload causing haemochromatosis and hepatopathy in 21 horses and one donkey.

Iron toxicosis is rarely reported in horses and chronic excessive oral iron intake has not been reported to cause clinical symptoms in equids. This case series describes 21 genetically unrelated horses and one donkey with chronic iron overload causing haemochromatosis and hepatopathy. Case series. All equids showing clinical signs compatible with chronic liver disease presented to Utrecht University and diagnosed with iron overload and haemochromatosis based on histopathological evaluation of liver tissue and/or blood transferrin saturation levels of >80% and proof of excess dietary iron intake due to excess iron content in drinking water were included. This study included 22 equids. All tested animals (n=19) had transferrin saturation >80% and 21 of 22 had increased gamma-glutamyltransferase (γGT). Ultrasonography revealed rounded liver margins in five out of six horses and increased echogenicity in 4/6. Histological examination of liver tissue of 12 animals showed hepatitis, fibrosis and haemosiderin accumulation in macrophages and hepatocytes. Post-mortem examination also revealed haemosiderin accumulation in other organs in all seven examined animals. High iron content in drinking water was identified as the source of iron overload in all cases. All animals were housed under the same conditions for a minimum of 9years prior to diagnosis of haemochromatosis. Of 22 animals, 13 survived until 1 January 2018, ranging from 17 to 79months post diagnosis. Histology of liver tissue was not available for 10 of 22 cases. Chronic iron overload can lead to haemochromatosis and hepatopathy in equids. Development of disease is slow and clinical signs are nonspecific. Long-term excessive iron intake in equids should be avoided. If animals drink from natural water sources, it is important to test the water for iron content. The Summary is available in Spanish - see Supporting Information.

Higher age at diagnosis of hemochromatosis is the strongest predictor of the occurrence of hepatocellular carcinoma in the Swiss hemochromatosis cohort: A prospective longitudinal observational study.

Hereditary hemochromatosis (HH) is the most common genetic disease in Caucasians which is characterized by an increased intestinal iron absorption, resulting into a progressive accumulation of iron in organs including liver, heart, and pancreas, leading to their progressive dysfunction. Hepatocellular carcinoma (HCC) is a long-term complication of HH, which contributes to increased mortality.We evaluated the risk factors of HCC in a prospective cohort of Swiss hemochromatosis patients with a long-term follow-up.We included 147 patients with the mean age at diagnosis of 48 years, in whom 70% were men. Overall, 9% of the patients developed HCC during the mean follow-up time of 14 years (range 1–40 years). Patients with HCC had higher age at diagnosis (61 ± 11 vs 47 ± 13 years, P = .003), more frequently liver cirrhosis on biopsy (90% vs 37.5%, P = .004), and higher serum ferritin levels [3704 (Q1:2025, Q3:4463) vs 1338 (Q1:691, Q3:2468) μg/L, P < .001], they needed more iron removed by phlebotomy until its depletion [8.9 (Q1:7.2, Q3:10.1) vs 3.8 (Q1:1.6, Q3:8.9) g, P = .029], compared to non-HCC patients. After adjustment for possible confounders, only higher age at diagnosis remained significantly associated with HCC development (odds ratio 1.19, 95% CI 0.056–0.397, P = .001, per year).Higher age at diagnosis showed the strongest association with the occurrence of HCC in Swiss hemochromatosis patients. Patients who were diagnosed at a higher age and with a high iron overload (serum ferritin levels >1000 μg/L) require regular screening even if they have no liver cirrhosis.