Diagnosis Of Hemochromatosis Research Articles

Chinese guidelines for the diagnosis and treatment of hereditary hemochromatosis

Hereditary hemochromatosis is an iron overload disease caused by mutations in iron-regulating genes, resulting in excessive iron deposition in organs such as the liver, heart, skin, pancreas, and gonads, leading to corresponding multi-system damage. This condition is relatively common in European and American populations, primarily caused by mutations in the HFE gene; however, it is rare in China and other Asian countries, almost exclusively due to mutations in non-HFE genes. Clinical features include unexplained chronic hepatitis or cirrhosis, accompanied by elevated serum ferritin and/or increased transferrin saturation. MRI shows iron deposition in the liver, liver biopsy reveals iron accumulation in hepatocytes, and genetic testing facilitate the diagnosis of this disease. Repeated phlebotomy is the first-line therapy for this condition. For those who cannot tolerate phlebotomy, iron chelation therapy may be used, and patients who progress to end-stage liver disease will require liver transplantation. To assist clinicians in making informed decisions on the diagnosis and treatment of hereditary hemochromatosis, the Chinese Society of Hepatology, Chinese Medical Association has invited experts from clinical medicine, molecular genetics, pathology, imaging, and methodology to systematically summarize the advancement in this field and collaboratively develop the current guidelines.

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

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. 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. 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. Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Self-Sustainability with Therapeutic Phlebotomy, a Solution to the National Blood Crisis?

CONCLUSION Hereditary hemochromatosis (HH) is a genetic condition associated with iron overload in the human body. The mainstay of treatment remains therapeutic phlebotomy. On August 1st, 2022, the American Red Cross approved using blood obtained from therapeutic phlebotomy for transfusion. While normal individuals can donate blood only as often as once in 56 days, individuals with HH can have phlebotomy as often as once weekly. Utilizing the blood collected from these patients could be a significant resource to mitigate the shortage of blood needed for transfusion. We aimed to quantify the number of units of blood removed by therapeutic phlebotomy from individuals with HH and assess its potential contribution to total units of blood required in a community hospital for two years (2021 and 2022). We retrospectively reviewed electronic medical records of adult individuals who underwent therapeutic phlebotomy at Saint Vincent Hospital between January 1, 2021, and December 31, 2022. Patients with hereditary hemochromatosis were identified based on a positive genetic test for HFE gene mutations. We collected data including gender, race, age at diagnosis, and the number of units of blood removed from patients during the study period. The total number of units transfused in the in-patient care services and operating room was obtained. A descriptive statistic was performed using R version 4.2.2 statistics software. A total of 112 patients received therapeutic phlebotomy over two years (2021 and 2022) of whom 65% (N=73) had a diagnosis of HH. A majority of the patients were males (60%, 44/73) and were non-Hispanic/Latino (85%, 62/73). The mean age at diagnosis of HH was 62 [standard deviation (SD): 17] years. The median number of units of blood removed by phlebotomy per patient with HH was 3 (2-5), the annual distribution is as displayed in Table 1. A total of 504 units of whole blood was removed through therapeutic phlebotomy from 73 patients during the study period. The total requirement for blood transfusion across all the departments in the hospital was 6065 units (2,733 units in 2021 and 3,332 units in 2022). The total number of units removed through therapeutic phlebotomy in HH patients represented 8.31% (504/6065 Units) and 82.49% (504/611 Units) of total units of blood requirement for the entire hospital and operating room respectively (Table 2). The units of blood removed through therapeutic phlebotomy of patients with HH, could potentially help sustain 8.31% of total blood requirement of the hospital. Primarily, over 82% of the demand from the operating room could be fulfilled if the entirety of the blood from therapeutic phlebotomy were to be transfused. Overcoming technical challenges in utilizing the blood from therapeutic phlebotomy for transfusion in routine clinical practice could help mitigate the national blood crisis and aid in self-sustainability of blood products at a community level. Our study highlights the need for broader efforts to create awareness and incentivizing re-utilization of blood obtained from therapeutic phlebotomy.

Screening for Hereditary Hemochromatosis in Newly Referred Diabetes Mellitus

AimsHereditary hemochromatosis (HH) is the most common inherited disease in European populations. It is particularly common in people of Irish heritage, approximately 2% of whom will be at risk of iron overload as a result of human homoeostatic iron regulator protein (HFE) gene mutations. We aimed to evaluate the utility of screening for HH in newly referred patients with DM of Irish heritage in a prospective study. MethodsOf 575 patients newly referred between March 2018 and March 2021, 556 attended for blood testing, to include fasting transferrin saturations, prior to their first clinic visit. Patients with elevated transferrin saturations were further screened for hereditary hemochromatosis (HH) with HFE gene analysis. ResultsTransferrin saturations were elevated in 13 of 556 patients (2.3%), 3 of whom had a preexisting diagnosis of HH. Of the remaining 10 patients, 7 had HFE gene mutations suggestive of HH (2 C282Y homozygous, 3 C282Y/H63D compound heterozygous, and 2 H63D homozygous), 1 was a HH carrier (C282Y heterozygous), and 2 had normal genetics. ConclusionsThe prevalence of HH of 1.8% in this screened DM population is lower than the reported incidence of HH in the Irish population, suggesting a limited utility of routine screening for HH in newly referred patients with DM.

PO-05-164 IMPACT OF ARRHYTHMIAS IN PATIENTS WITH HEMOCHROMATOSIS: A NATIONAL INPATIENT SAMPLE (NIS) ANALYSIS

Hemochromatosis is a relatively rare genetic disease that results in restrictive cardiomyopathy caused by the deposition of iron. Iron has a higher affinity to deposit in the conduction system of the heart resulting in a lower threshold for developing arrhythmias. We sought to assess the data on the burden of arrhythmias in hospitalized patients with hemochromatosis. To study the impact of arrythmia in a special study cohort i.e. adults with hemochromatosis The national inpatient sample (NIS) from 2018-2020 was queried for adult patients (age>18 yrs) admitted with a secondary diagnosis of hemochromatosis. These patients were stratified for arrhythmias [atrial fibrillation (AF), atrial flutters, SVTs, heart blocks (first degree, second degree, complete heart blocks [CHB], ventricular tachycardia (VT), and fibrillation(VF)]. Baseline risk factors and cardiac complications were compared. Multiple regression analysis was performed using mortality as the primary outcome. Results were further validated with propensity-matched analysis. A total of 141755 adult patients hospitalized from 2018-2020 had hemochromatosis with a mean age of 55 years. Of these, 33.84% were females and 16.59% had an underlying arrhythmia. In the cohort of hemochromatosis, patients with concurrent arrhythmias had a higher prevalence of diabetes mellitus (27.67% vs 18.55%; P<0.0001), hyperlipidemia (41.08% vs 22.83%; P<0.0002), tobacco abuse (30.5% vs 24.05%; P<0.0001) and obesity than those without arrhythmias (14.77% vs 10.98%; P<0.0001). The prevalence of valvular abnormalities (36.39% vs 24.55%; P<0.0001), old myocardial infarction (6.91% vs 3.25%; P<0.0001), and coronary artery disease (28.06% vs 10.68%; P< 0.0001) was also significantly higher in these patients. Multivariate regression analysis revealed higher odds of mortality with AF, VF, and VT in adult patients with hemochromatosis (Table 1). Propensity-matched analysis confirmed these findings. (Table 2) The odds of mortality were not significant with CHB in these patients. Hemochromatosis portends worse outcomes with arrhythmias compared to without it. Arrhythmias in hemochromatosis should be better managed to improve patient outcomes. Further studies are warranted to determine the pathogenesis of arrhythmias in patients with hemochromatosis to develop therapeutics and mitigate complications.

Juvenile Hemochromatosis With Non-transfused Hemolytic Anemia Caused by a De Novo PIEZO1 Gene Mutation.

Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-transfused hemolytic anemia in children and young adults.

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.

Abstract 13476: Prevalence of Hemochromatosis in Non-Rheumatic Valvular Heart Disease and Its Effect on Prognosis: A National Cohort Analysis

Background Hemochromatosis can lead to heart failure, starting as restrictive cardiomyopathy and resulting in dilated cardiomyopathy if not treated. There is limited literature regarding whether hemochromatosis has an impact on the prognosis of non-rheumatic valvular heart disease (NRVHD). We aimed to establish the prevalence of hemochromatosis in NRVHD patients and its prognostic implications. Methods A retrospective cohort analysis was conducted with National Inpatient Sample 2016-2019. Primary outcome was the effect of hemochromatosis on prognosis of patients with NRVHD. Secondary outcomes were the independent predictors of mortality which were calculated with multivariate logistic regression analysis. Results 120,425 patients had a diagnosis of hemochromatosis with a prevalence of 0.085%, out of these 3.82% (n=4595) had NRVHD. Mean age was 65.4 years, 59% patients were males, 75% were white, and 18% were black. For individual valvular involvement, we observed that aortic valve was affected in 1.84% patients (n=2210), mitral valve in 1.82% patients (n=2195), tricuspid valve in 0.4% patients (n=485) and pulmonic valve in 0.13% patients (n=155). Hemochromatosis was associated with significantly lower odds of mortality of 53% in patients with non-rheumatic (NR) aortic valve disease (OR 0.47, CI 0.22 - 0.99, p=0.04). This association of hemochromatosis with reduction in mortality was not seen in patients with NR mitral (OR 0.49, p=0.06), tricuspid (OR 0.76, p=0.6), or pulmonary valve disease. The independent predictors of mortality in patients with hemochromatosis and NRVHD were acute liver failure (OR 5.4, p=0.05) and female gender (OR 3.7, p=0.02). Among the patients with hemochromatosis and NR aortic valve disease 8.3% underwent transcatheter while 6.1% underwent surgical aortic valve replacement. Conclusions Prevalence of hemochromatosis with co-morbid NRVHD is 3.82%. The independent predictors of mortality in this patient population are acute liver failure and female gender. Hemochromatosis is associated with 53% lower odds of mortality in patients with NR aortic valve disease. Extensive research and further studies are required to explore the possible causes for the observed reduced mortality.

Current German Guidelines on Diagnosis and Treatment of Secondary Hemochromatosis in Patients with Congenital Anemias.

Adequate diagnosis and treatment of secondary hemochromatosis in patients with congenital anemias is important for reducing long-term mortality and morbidity as for improving patients' quality of life. Due to the strong migration movements during recent years, the number of patients in Germany suffering from hemoglobinopathies as some of the most relevant disorders in the context of iron overload (IOL) has increased enormously. Many of these patients had received inadequate medical care in their countries of origin prior to migration, including diagnosis and treatment of IOL. In parallel, various medical developments and achievements took place, including the expansion of stem cell transplant as curative therapeutic option and the introduction of gene therapy for patients with hemoglobinopathies. Diagnostic tools to assess both liver and heart IOL became available at more sites in Germany. Overall experience with iron elimination therapy either as monotherapy or as combination of different chelators increased. All these aspects were considered during revision of the consensus-based guideline on the diagnosis and treatment of secondary IOL in patients with congenital anemias (AWMF Reg. No. 025/029). Here, we briefly summarize the procedure for the revision of the guideline, provide a brief overview of innovations as compared to the previous version dated from 2015, and finally present the consensus recommendations adopted in the current version.

MAGNETIC RESONANCE IMAGING R2* AS A METHOD TO MONITOR IRON OVERLOAD IN PATIENTS UNDERGOING THERAPEUTIC PHLEBOTOMY FOR HEREDITARY HEMOCHROMATOSIS

: to determine if there was a reduction in liver iron overload due to therapeutic phlebotomy as a treatment for iron overload in patients with hereditary hemochromatosis. : Through a retrospective observational study, we analyzed Magnetic Resonance imaging (MRI) R2* of 5 patients, before and after phlebotomy treatment, who are in medical follow-up for hereditary hemochromatosis. Data were collected from a hospital database and included patients with the diagnosis of hereditary hemochromatosis, with two MRI R2* (one before and one after treatment with phlebotomy), and with serum ferritin and transferrin saturation (TS) data collected in a period next to each MRI. The mean number of phlebotomies between MRIs was seven for each patient. The mean interval between MRIs was 25.6 months (maximum of 66 and minimum of 12). On the first MRI, four patients presented liver iron overload (80%) and 1 did not (20%); the iron overload was severe in all four patients. On the second MRI, all patients with iron overload in the first showed a large reduction to mild overload in the deposits. The only patient who did not have it continued without an iron deposit in the liver. No patient had pancreatic iron deposits at the first or second MRI. One patient initially presented a splenic deposit (20%), which was not evidenced in the second. One liver (20%) had mild hepatic steatosis at the first MRI, which remained mild at the second. No patient developed steatosis during the study period. The mean serum ferritin on the first MRI period was 521.1 (minimum of 139 and maximum of 1000); over the second MRI, the average was 218.4 (minimum of 83 and maximum of 401). All patients showed a reduction in serum ferritin between images. The average reduction was 46.8% (minimum of 5.0% and maximum of 86.5%). The average TS in the first MRI period was 38.35% (minimum of 23% and maximum of 53%) and in the second, 37.47% (minimum of 25% and maximum of 42%). Three patients (60%) had an increase in TS, despite a decrease in serum ferritin. All patients had values within the normal range for ALT and AST in the study period. : Liver iron overload is one of the most serious complications of hereditary hemochromatosis since it is one of the main iron storage organs and the first one to show iron overload. It mayslowly lead to irreversible hepatic damage, such as cirrhosis, or even hepatocellular carcinoma, in addition to multiple organ complications. Measurement of the liver concentration of iron may guide physicians to have better decisions regarding when to initiate or stop therapeutic phlebotomy as a therapy in hereditary hemochromatosis. MRI R2* can be used for detection and quantification of liver iron content, being proposed as a non-invasive method to guide therapy. However, the exact correlation between liver iron content, number, and interval of phlebotomies prescribed, and laboratory findings are not yet well established. : Periodic phlebotomy demonstrated to be an efficient way to reduce body overload, especially liver deposits, as seen in MRI R2* images. In agreement with the literature, the liver accumulates iron before other abdominal organs, such as the pancreas and spleen. Serum ferritin appears to be a better marker for liver iron overload reduction in patients undergoing phlebotomy for hereditary hemochromatosis than transferrin saturation.

Hemochromatosis Mimicked Gaucher Disease: Role of Hyperferritinemia in Evaluation of a Clinical Case.

Simple SummaryIn this paper, we describe the problem of diagnostic delay in Gaucher disease through the evaluation of a clinical case and how some clinical–instrumental parameters, such as hyperferritinemia should trigger an alarm bell in clinicians, inducing the clinical suspicion of Gaucher disease. In the described case of a 38-year-old man, the first diagnosis of hemochromatosis was updated to type 1 Gaucher disease years later. Analysis of the clinical case showed that the first diagnosis of hemochromatosis had been made almost exclusively based on a finding of high levels of ferritin and splenomegaly. Type 1 Gaucher disease and hereditary hemochromatosis show common clinical features, such as asthenia, joint pain, splenomegaly and hyperferritinemia. For this reason, in the presence of “unexplained hyperferritinemia” it is necessary to consider Gaucher disease in differential diagnosis, even if few typical signs and symptoms of the disease are present. The combination of a careful clinical history with simple first-level investigations may be sufficient to make differential diagnosis, also including rare conditions, such as Gaucher disease. Misdiagnosis and delayed diagnosis in metabolic diseases can lead to irreversible organ damage and a delayed start of specific therapy for these patients.Gaucher disease is a disorder of lysosomes caused by a functional defect of the glucocerebrosidase enzyme. The disease is mainly due to mutations in the GBA1 gene, which determines the gradual storage of glucosylceramide substrate in the patient’s macrophages. In this paper, we describe the case of a 38-year-old man who clinically presented with hyperferritinemia, thrombocytopenia, leukopenia, anemia and mild splenomegaly; a diagnosis of hemochromatosis was made 10 years earlier. Re-evaluation of the clinical case led to a suspicion of Gaucher disease, which was confirmed by enzymatic analysis, which was found to be below the normal range, and genetic evaluation, which identified compound heterozygosity N370S/RecNciI. We know that patients suffering from Gaucher disease can also have high ferritin levels. Even if the mechanism underlying the changes in iron metabolism is not yet elucidated, the chronic mild inflammatory state present in these patients probably causes the storage of ferritin in macrophages, resulting in hyperferritinemia. Therefore, in the presence of few typical signs and symptoms of the disease should raise an alarm bell in the clinicians, inducing clinical suspicion of Gaucher disease. Misdiagnosis and diagnostic delay in metabolic diseases could cause irreversible organ damage and delay the start of specific therapy for these patients.

T246 HFE genotype and allele frequencies in the Balearic islands for the diagnosis of hemochromatosis

T246 HFE genotype and allele frequencies in the Balearic islands for the diagnosis of hemochromatosis

20-Year-Old Man With Elevated Liver Tests

20-Year-Old Man With Elevated Liver Tests

Abdominal pain and cirrhosis at diagnosis of hemochromatosis: Analysis of 219 referred probands with HFE p.C282Y homozygosity and a literature review.

BackgroundIn hemochromatosis, causes of abdominal pain and its associations with cirrhosis are poorly understood.MethodsWe retrospectively compared characteristics of referred hemochromatosis probands with HFE p.C282Y homozygosity with/without biopsy-proven cirrhosis: sex, age, diabetes, heavy alcohol consumption, abdominal pain/tenderness, hepatomegaly, splenomegaly, non-alcoholic fatty liver disease, chronic viral hepatitis, ascites, transferrin saturation (TS), serum ferritin (SF), and iron removed by phlebotomy (QFe). We performed logistic regression on cirrhosis using characteristics identified in univariate comparisons. We performed computerized and manual searches to identify hemochromatosis case series and compiled prevalence data on cirrhosis and abdominal pain and causes of abdominal pain.ResultsOf 219 probands, 57.1% were men. Mean age was 48±13 y. In 22 probands with cirrhosis, proportions of men, mean age, prevalences of heavy alcohol consumption, abdominal pain, abdominal tenderness, hepatomegaly, splenomegaly, and chronic viral hepatitis, and median TS, SF, and QFe were significantly greater than in probands without cirrhosis. Regression analysis revealed three associations with cirrhosis: abdominal pain (p = 0.0292; odds ratio 9.8 (95% CI: 1.2, 76.9)); chronic viral hepatitis (p = 0.0153; 11.5 (95% CI: 1.6, 83.3)); and QFe (p = 0.0009; 1.2 (95% CI: 1.1, 1.3)). Of eight probands with abdominal pain, five had cirrhosis and four had diabetes. One proband each with abdominal pain had heavy alcohol consumption, chronic viral hepatitis B, hepatic sarcoidosis, hepatocellular carcinoma, and chronic cholecystitis, cholelithiasis, and sigmoid diverticulitis. Abdominal pain was alleviated after phlebotomy alone in four probands. In 12 previous reports (1935–2011), there was a negative correlation of cirrhosis prevalence and publication year (p = 0.0033). In 11 previous reports (1935–1996), a positive association of abdominal pain prevalence and publication year was not significant (p = 0.0802).ConclusionsAbdominal pain, chronic viral hepatitis, and QFe are significantly associated with cirrhosis in referred hemochromatosis probands with HFE p.C282Y homozygosity. Iron-related and non-iron-related factors contribute to the occurrence of abdominal pain.

S2901 Yersinia enterocolitica Liver Abscesses as an Atypical Presentation of Hereditary Hemochromatosis

Introduction: Hereditary hemochromatosis typically presents with organ dysfunction due to iron overload. Yersinia enterocolitica is an iron-utilizing microbe which hereditary hemochromatosis patients are predisposed to. We present an atypical presentation of hereditary hemochromatosis that was uncovered by liver abscesses caused by yersinia enterocolitica. This case highlights the importance of considering hereditary hemochromatosis in the setting of yersinia enterocolitica infection. Case Description/Methods: A 75 year old male with a PMH of diabetes mellitus, congestive heart failure, and complete heart block presented two months after pacemaker placement with nausea, anorexia, and subjective fevers. Physical exam was benign from a gastrointestinal standpoint. CT abdomen and pelvis showed multiple hepatic lesions. Biopsy confirmed abscess, and cultures grew yersinia enterocolitica. Initial ferritin was elevated above 4500. Blood cultures remained negative. Treatment with ceftriaxone and metronidazole was complicated by severe sepsis before resolution of abscesses were confirmed by CT. Post-infection, repeat ferritin remained elevated over 1000 with transferrin saturation elevated above 79%. Genetic testing confirmed homozygous C282Y gene mutations. The patient was advised to follow-up for possible phlebotomy. Discussion: Our case highlights that liver abscesses due to yersinia enterocolitica should provoke an investigation for hereditary hemochromatosis. Hereditary hemochromatosis likely contributed to multiple disease processes in our patient including heart failure, conduction disturbances, and diabetes mellitus. Early diagnosis of hereditary hemochromatosis has the potential to avoid later disease complications in patients and their families.Figure 1.: CT scan of liver abscesses from yersinia enterocolitica infection.

Correlation of genotype and phenotype in 32 patients with hereditary hemochromatosis in China

BackgroundHereditary hemochromatosis (HH) is widely recognized and clinical manifestations of hemochromatosis-related (HFE-related) HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis.MethodsPeripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed.ResultsOf the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous + heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3 + 10delGTT + SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis (p = 0.007). The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups (p = 0.01). Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH. The incidence of cirrhosis (p = 0.011), cardiac involvement (p = 0.042), diabetes (p = 0.035) and hypogonadism (p = 0.020) was statistically significant in the four groups. However, due to the limited sample size, the pairwise comparison showed no significant difference.ConclusionsThis is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.

Idiopathic Hemochromatosis Presenting As a Sicca Syndrome. A Case Report and Review of the Literature

Hemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism, the most common allele being the C282Y allele in the HFE gene. Despite the increased awareness of Hemochromatosis, the disease is commonly under diagnosed. Symptoms of hemochromatosis can be non-specific and are related to iron deposition within various body organs. Clinical findings seen in fully established disease include liver cirrhosis, cardiomyopathy, hypogonadism, diabetes mellitus and skin pigmentation (bronze diabetes). In early stages, the disease is either asymptomatic or could present with weakness, fatigue and joint pains. Other rare manifestations include night sweats, movement disorders, including chorea and parkinsonism, as well as non-specific GI symptoms.We present a case of a 35-year-old gentleman who was following in the outpatient clinic with the complaints of fatigue, dry eyes, dry mouth and throat for the past several years. He also reported hand tremors, occasional low back, knee and ankle pain without stiffness, since childhood. He had a medical history of Raynaud syndrome treated with Nifedipine. Physical examination was consistent with dry mucus membranes and dry mouth. Patient workup revealed positive ANA, borderline low level of C3 and C4, normal ESR, CRP, TSH and negative serologies for Sjogren's A and B antibodies. Patient's excessive dryness was clinically diagnosed as Sicca syndrome and was treated with artificial tears and hydroxychloroquine which helped with the dryness, however the fatigue persisted.Few years later, he developed worsening of his hand tremors and developed transient unsteadiness with no focal weakness or sensory symptoms. He also developed right upper quadrant pain with tenderness. U/s abdomen and Ct scan were unremarkable. Further work up revealed slight elevation of liver enzymes with normal bilirubin. He had no history of alcohol use and hepatitis serologies were negative. Iron studies were ordered, which showed marked elevation of ferritin and iron saturation was found to be 61%. Genetic analysis showed that he was a carrier of a hemochromatosis-associated alleles C282Y/H63D. A diagnosis of hemochromatosis was confirmed by liver biopsy which showed heavy iron deposition. Patient received treatment with maintenance phlebotomies and has remained well without evidence of disease progression.Our patient had a long standing constellation of nonspecific symptoms including hand tremors, arthralgia, sicca like symptoms, which were misdiagnosed as Sicca syndrome. On review of the literature, only a handful of cases have been reported describing the initial presentation of idiopathic hemochromatosis as Sicca syndrome. Our case emphasizes the importance of early recognition of rare presenting features of this disease. It also underlines whether there is an association between these two distinct diseases, which needs to be further explored. DisclosuresNo relevant conflicts of interest to declare.

Hémochromatoses

AbstractHemochromatoses benefit from a great clarification of their nosology thanks to the consideration of the mechanism underlying the development of iron overload. Thus, the mechanistic common denominator is hepcidin deficiency which, by stimulating the cellular iron export activity of ferroportin in the duodenum and the spleen, leads to a cascade: hyper-sideremia, appearance of non-transferrin bound iron that first targets the liver, and exerts cellular toxicity damaging key organs and corresponding to the development of hemochromatosis, that is source of morbidity and mortality. In the Caucasian subject, hemochromatosis linked to the HFE gene is by far the most frequent. Non HFE-related hemochromatoses are rare but multi-ethnic and often severe. The contribution of biology is major for the understanding of the pathophysiology (role of hypo-hepcidinemia), for the diagnosis (coefficient of transferrin saturation, ferritinemia) including the etiological identification (genetic tests), and for the therapeutic follow-up (importance of ferritinemia and possibly in the future of hepcidinemia). The diagnosis of hemochromatosis has become totally non-invasive (based on clinical, biological and imaging techniques) and its therapy, which remains based on phlebotomies, should in the future call for innovative approaches aimed at restoring normal iron metabolism.

The late diagnosis of hemochromatosis in the patient with chronic hepatitis B and kidney damage Clinical Case Report

A late diagnosis of secondary hemochromatosis was made to a 38-year-old man with chronic hepatitis B, who after poisoning with alcohol surrogate (which was a year ago) had episodes of macrohematuria with signs of acute kidney damage, which required treatment in the ICU and hemodialysis sessions, after which kidney function was restored. In August 2020, the patient had a contact with a COVID-19 patient, but upon admission to the hospital, the results of tests for COVID-19 were negative. During the examination in our department, after the exclusion of the urological disease, the diagnosis of interstitial nephritis of toxic etiology, hemolytic anemia, chronic viral hepatitis B was made. Then in-depth study of iron metabolism, bone marrow, and MRI of parenchymal organs revealed secondary hemochromatosis.

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.