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Xie LD, Kong XM, Shen JX, Wang TL, Ma J, Zhang YF, Chen XP. Novel compound heterozygous mutations in the hemojuvelin gene in a juvenile hemochromatosis patient: A case report. World J Clin Cases 2024; 12:3961-3970. [PMID: 38994316 PMCID: PMC11235419 DOI: 10.12998/wjcc.v12.i19.3961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/08/2024] [Accepted: 05/20/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND Juvenile hemochromatosis (JH) is an early-onset, rare autosomal recessive disorder of iron overload observed worldwide that leads to damage in multiple organs. Pathogenic mutations in the hemojuvelin (HJV) gene are the major cause of JH. CASE SUMMARY A 34-year-old male Chinese patient presented with liver fibrosis, diabetes, hypogonadotropic hypogonadism, hypophysis hypothyroidism, and skin hyperpigmentation. Biochemical test revealed a markedly elevated serum ferritin level of 4329 μg/L and a transferrin saturation rate of 95.4%. Targeted exome sequencing and Sanger sequencing revealed that the proband had a novel mutation c.863G>A (p.R288Q) in the HJV gene which was transmitted from his father, and two known mutations, c.18G>C (p.Q6H) and c.962_963delGCinsAA (p.C321*) in cis, which were inherited from his mother. The p.R288W mutation was previously reported to be pathogenic for hemochromatosis, which strongly supported the pathogenicity of p.R288Q reported for the first time in this case. After 72 wk of intensive phlebotomy therapy, the patient achieved a reduction in serum ferritin to 160.5 μg/L. The patient's clinical symptoms demonstrated a notable improvement. CONCLUSION This study highlights the importance of screening for hemochromatosis in patients with diabetes and hypogonadotropic hypogonadism. It also suggests that long-term active phlebotomy could efficiently improve the prognosis in severe JH.
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Affiliation(s)
- Ling-Ding Xie
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Mu Kong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jing-Xia Shen
- Department of Tumor Radiotherapy and Chemotherapy, Qian’an People’s Hospital, Qian’an 064400, Hebei Province, China
| | - Tai-Ling Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jing Ma
- Department of Endocrinology, Aksu First People's Hospital, Aksu Region 843000, Xinjiang Uygur Autonomous Region, China
| | - Yun-Fen Zhang
- Department of Metabolic Diseases, Qian’an Traditional Chinese Medical Hospital, Qian’an 064400, Hebei Province, China
| | - Xiao-Ping Chen
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
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Szczerbinska A, Kasztelan-Szczerbinska B, Rycyk-Bojarzynska A, Kocki J, Cichoz-Lach H. Hemochromatosis-How Not to Overlook and Properly Manage "Iron People"-A Review. J Clin Med 2024; 13:3660. [PMID: 38999226 PMCID: PMC11242024 DOI: 10.3390/jcm13133660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Hemochromatosis (HC) is the main genetic disorder of iron overload and is regarded as metal-related human toxicosis. HC may result from HFE and rare non-HFE gene mutations, causing hepcidin deficiency or, sporadically, hepcidin resistance. This review focuses on HFE-related HC. The illness presents a strong biochemical penetrance, but its prevalence is low. Unfortunately, the majority of patients with HC remain undiagnosed at their disease-curable stage. The main aim of HC management is to prevent iron overload in its early phase and remove excess iron from the body by phlebotomy in its late stage. Raising global awareness of HC among health staff, teaching them how not to overlook early HC manifestations, and paying attention to careful patient monitoring remain critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.
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Affiliation(s)
- Agnieszka Szczerbinska
- Faculty of Medicine, Medical University of Warsaw, 61 Zwirki i Wigury Street, 02-091 Warsaw, Poland
| | - Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Anna Rycyk-Bojarzynska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Janusz Kocki
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Street, 20-080 Lublin, Poland;
| | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
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Olynyk JK, St. Pierre TG, Chen J, Frazer DM, Ramm LE, Ramm GA. Extrahepatic Iron Loading Associates With the Propensity to Develop Advanced Hepatic Fibrosis in Hemochromatosis. GASTRO HEP ADVANCES 2024; 3:454-460. [PMID: 39131712 PMCID: PMC11307999 DOI: 10.1016/j.gastha.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/22/2024] [Indexed: 08/13/2024]
Abstract
Background and Aims Hemostatic iron regulator-hemochromatosis can result in progressive iron-loading and advanced hepatic fibrosis in some individuals. We studied total body and hepatic iron loading to determine whether the distribution of iron-loading influences the risk of advanced fibrosis. Methods One hundred thirty-eight men and 66 women with hemochromatosis who underwent liver biopsy for staging of hepatic fibrosis had evaluation of hepatic iron concentration (HIC), hepatic iron index (HIC/age), total body iron stores (mobilizable iron), and mobilizable iron/HIC ratio (a marker of total body iron relative to hepatic iron). The potential impact of liver volume on mobilizable iron stores was assessed using magnetic resonance imaging in a separate cohort of 19 newly diagnosed individuals with hemochromatosis. Results Of 204 biopsied subjects, 41 had advanced fibrosis and exhibited 60% greater accumulation of mobilizable iron relative to HIC (mean 0.070 ± 0.008 g Fe/[μmol Fe/g]) compared with 163 subjects with low-grade fibrosis (mean 0.044 ± 0.002 g Fe/[μmol Fe/g], P < .0001). Linear regression modeling confirmed a discrete advanced hepatic fibrosis phenotype associated with greater mobilizable iron stores relative to HIC. The ratios of the upper to lower 95% limits of the distributions of liver volumes and the mobilizable iron/HIC ratios were 2.7 (95% confidence interval 2.3-3.0) and 9.7 (95% confidence interval 8.0-11.7), respectively, indicating that the distribution of liver volumes is not sufficiently wide to explain the variability in mobilizable iron/HIC ratios, suggesting that significant extrahepatic iron loading is present in those with advanced hepatic fibrosis. Conclusion Advanced hepatic fibrosis develops in hemostatic iron regulator-hemochromatosis individuals who also have excessive extrahepatic mobilizable iron stores.
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Affiliation(s)
- John K. Olynyk
- Curtin Medical School, Curtin University, Bentley, Western Australia, Australia
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Timothy G. St. Pierre
- School of Physics, Mathematics, and Computing, University of Western Australia, Crawley, Western Australia, Australia
| | - James Chen
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - David M. Frazer
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- School of Biomedical Sciences, Queensland University of Technology, Gardens Point, Queensland, Australia
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
| | - Louise E. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Grant A. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
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Crawford DHG, Ramm GA, Bridle KR, Nicoll AJ, Delatycki MB, Olynyk JK. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int 2023; 17:522-541. [PMID: 37067673 DOI: 10.1007/s12072-023-10510-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/28/2023] [Indexed: 04/18/2023]
Affiliation(s)
- Darrell H G Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Gallipoli Medical Research Foundation, Brisbane, Australia
| | - Grant A Ramm
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Kim R Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Australia.
- Gallipoli Medical Research Foundation, Brisbane, Australia.
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, Box Hill, VIC, Australia
- Monash University, Melbourne, VIC, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, VIC, Australia
- The University of Melbourne, Melbourne, VIC, Australia
- Victorian Clinical Genetics Services, Parkville, VIC, Australia
| | - John K Olynyk
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, WA, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
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Affiliation(s)
- John K Olynyk
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
| | - Grant A Ramm
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
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Therkildsen R, Dahl EE, Schiødt FV. Hereditary hemochromatosis: data from a single center Copenhagen cohort. Scand J Gastroenterol 2022; 57:972-977. [PMID: 35249441 DOI: 10.1080/00365521.2022.2042591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES We aimed to describe a cohort of hereditary hemochromatosis (HH) patients from a single urban center in Copenhagen. METHODS Retrospectively, data from patients with HH from the years 2009-2020 were collected. RESULTS A total of 203 patients was recorded. Males constituted 65.0% of the patients. Homozygous HH (HHH)/compound heterozygous HH (CHH) accounted for 69.4%/30.6%. HHH patients had significantly higher ferritin and transferrin saturation (TS) levels at debut than CHH patients. Fifty-five HHH patients (39.0%) had ferritin >1000 ug/L versus 9 (14.5%) in the CHH group (p < .001). Age at debut did not differ between female and male patients. Ferritin (but not TS) levels were significantly higher in male patients. The proportion of patients with ferritin >1000 did not differ between males and females. One-hundred patients (49.3%) had one or more symptoms at the time of diagnosis; arthralgias of the metacarpophalangeal joints and/or ankles (n = 46 (22.7%)), fatigue (n = 67 (33.0%)) and decreased libido (n = 20 (9.9%)). The proportion of patients with symptoms did not differ between HHH and CHH or between male and female patients. Severe organ complications (cardiomyopathy, late onset type 1 diabetes or cirrhosis) were present in 14 patients (6.9%). CONCLUSIONS We report a high proportion of compound HH, constituting almost one-third of patients. We found that the proportion of patients with symptoms did not differ between HHH and CHH and recommend that CHH should be treated and examined in the same way as HHH.
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Affiliation(s)
- Rikke Therkildsen
- Division of Gastroenterology, Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, NV, Denmark
| | - Eva Efsen Dahl
- Division of Gastroenterology, Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, NV, Denmark
| | - Frank Vinholt Schiødt
- Division of Gastroenterology, Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, NV, Denmark
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Barton JC, Barton JC, Patel N, McLaren GD. Abdominal pain and cirrhosis at diagnosis of hemochromatosis: Analysis of 219 referred probands with HFE p.C282Y homozygosity and a literature review. PLoS One 2021; 16:e0261690. [PMID: 34932603 PMCID: PMC8691644 DOI: 10.1371/journal.pone.0261690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 12/07/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND In hemochromatosis, causes of abdominal pain and its associations with cirrhosis are poorly understood. METHODS We 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. RESULTS Of 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). CONCLUSIONS Abdominal 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.
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Affiliation(s)
- James C. Barton
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America
- Southern Iron Disorders Center, Birmingham, AL, United States of America
- * E-mail:
| | - J. Clayborn Barton
- Southern Iron Disorders Center, Birmingham, AL, United States of America
| | - Neha Patel
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, United States of America
| | - Gordon D. McLaren
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, United States of America
- Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA, United States of America
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Bardou-Jacquet E, Morandeau E, Anderson GJ, Ramm GA, Ramm LE, Morcet J, Bouzille G, Dixon J, Clouston AD, Lainé F, Turlin B, Powell LW, Deugnier YM. Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE. Clin Gastroenterol Hepatol 2020; 18:1851-1857. [PMID: 31622736 DOI: 10.1016/j.cgh.2019.10.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/20/2019] [Accepted: 10/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment. METHODS We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence. RESULTS At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09; 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16; 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07; 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1; 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08; 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer. CONCLUSIONS In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced.
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Affiliation(s)
- Edouard Bardou-Jacquet
- University of Rennes, CHU Rennes, INSERM, CIC 1414, Liver Disease Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France.
| | | | - Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | | | | | - Jeannette Dixon
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Andrew D Clouston
- Faculty of Health Sciences, University of Queensland, Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Fabrice Lainé
- CHU Rennes, INSERM, Liver Disease Department, CIC 1414, Rennes, France
| | - Bruno Turlin
- University of Rennes, CHU Rennes, INSERM, Pathology Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
| | - Lawrie W Powell
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Yves M Deugnier
- University of Rennes, CHU Rennes, INSERM, CIC 1414, Liver Disease Department, French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
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Chin J, Powell LW, Ramm LE, Ayonrinde OT, Ramm GA, Olynyk JK. Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis. Sci Rep 2019; 9:20234. [PMID: 31882912 PMCID: PMC6934689 DOI: 10.1038/s41598-019-56732-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/03/2019] [Indexed: 01/02/2023] Open
Abstract
Development of advanced hepatic fibrosis in HFE Hemochromatosis (HH) is influenced by hepatic iron concentration (HIC) and age. In patients with HH, it is important to assess the likelihood of cirrhosis and thus the need for confirmatory liver biopsy. Therapeutic phlebotomy also provides an estimate of mobilisable iron stores. We determined whether mobilisable iron stores may predict the presence of advanced fibrosis. Retrospective analysis of 137 male and 65 female HH subjects was undertaken. Biochemical, histological and phlebotomy data were available on all subjects. The mean values of HIC, HIC × [age], mobilisable iron, mobilisable iron × [age] and serum ferritin in the cohort were higher in the group with advanced fibrosis. HIC had an optimum sensitivity and specificity of 73% for the diagnosis of advanced liver fibrosis, with a cut-off HIC level of 200 µmol/g (AUROC 0.83, p < 0.0001). AUROC for HIC was greater in females (0.93) than males (0.79). Mobilisable iron had an optimum sensitivity and specificity both of 83% at a cut-off of 9.6 g for the prediction of advanced fibrosis in all subjects (AUROC 0.92, p < 0.0001). Mobilisable iron stores provide a simple, clinically useful indication of the risk of advanced fibrosis and should routinely be considered.
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Affiliation(s)
- Justin Chin
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia.
| | - Lawrie W Powell
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Oyekoya T Ayonrinde
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
| | - Grant A Ramm
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - John K Olynyk
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
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Elsaid MI, John T, Li Y, Koduru S, Ali SZ, Catalano C, Narayanan N, Rustgi VK. Health Care Utilization and Economic Burdens of Hemochromatosis in the United States: A Population-Based Claims Study. J Manag Care Spec Pharm 2019; 25:1377-1386. [PMID: 31778618 PMCID: PMC10397675 DOI: 10.18553/jmcp.2019.25.12.1377] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND 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. OBJECTIVE To evaluate the health care utilization and economic burdens of hemochromatosis in the United States using real-world claims data. METHODS 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. RESULTS 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). CONCLUSIONS 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.
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Affiliation(s)
- Mohamed I. Elsaid
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Tina John
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - You Li
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Sobha Koduru
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Saima Z. Ali
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Carolyn Catalano
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Navaneeth Narayanan
- Department of Pharmacy Practice, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey, Piscataway, and Division of Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Vinod K. Rustgi
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
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Abstract
Hereditary hemochromatosis (HH) is one of the most common genetic disorders among persons of northern European descent. There have been recent advances in the diagnosis, management, and treatment of HH. The availability of molecular diagnostic testing for HH has made possible confirmation of the diagnosis for most patients. Several genotype-phenotype correlation studies have clarified the differences in clinical features between patients with the C282Y homozygous genotypes and other HFE mutation patterns. The increasing use of noninvasive tests such as MRI T2* has made quantification of hepatic iron deposition easier and eliminated the need for liver biopsy in most patients. Serum ferritin of <1,000 ng/mL at diagnosis remains an important diagnostic test to identify patients with a low risk of advanced hepatic fibrosis and should be used routinely as part of the initial diagnostic evaluation. Genetic testing for other types of HH is available but is expensive and generally not useful in most clinical settings. Serum ferritin may be elevated among patients with nonalcoholic fatty liver disease and in those with alcoholic liver disease. These diagnoses are more common than HH among patients with elevated serum ferritin who are not C282Y homozygotes or C282Y/H63D compound heterozygotes. A secondary cause for liver disease should be excluded among patients with suspected iron overload who are not C282Y homozygotes. Phlebotomy remains the mainstay of therapy, but emerging novel therapies such as new chelating agents may have a role for selected patients.
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12
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Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Ahmed Aboubakr A, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G, Salh S, Mostafa T, Mogawer S, Sadek SE, Saber MM, Ezelarab H, Mahmoud AA, Sultan S, El Kassas M, Kamal E, ElSayed NM, Moussa S. Managing diabetes and liver disease association. Arab J Gastroenterol 2018; 19:166-179. [PMID: 30420265 DOI: 10.1016/j.ajg.2018.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/26/2018] [Indexed: 02/05/2023]
Abstract
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
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Affiliation(s)
- Abd Elkhalek Hamed
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt.
| | - Medhat Elsahar
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Police Medical Academy, Egypt
| | | | | | | | | | - Ashraf Ahmed Aboubakr
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | | | - Reda Elwakil
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Ain Shams University, Egypt
| | - Gamal Esmat
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Kasr Al Aini, Egypt
| | - Samira Salh
- Department of Pharmacy, Cairo University, Egypt
| | | | | | - Sameh Emil Sadek
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | - Maha M Saber
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Hanan Ezelarab
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Asem Ashraf Mahmoud
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | - Ehab Kamal
- Medical Department, National Research Centre, Egypt
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Barton JC, McLaren CE, Chen WP, Ramm GA, Anderson GJ, Powell LW, Subramaniam VN, Adams PC, Phatak PD, Gurrin LC, Phillips JD, Parker CJ, Emond MJ, McLaren GD. Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes. Ann Hepatol 2018; 17:871-879. [PMID: 30145563 PMCID: PMC6368858 DOI: 10.5604/01.3001.0012.3169] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.
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Affiliation(s)
- James C. Barton
- Southern Iron Disorders Center, Birmingham, AL, USA
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Wen-pin Chen
- Chao Family Comprehensive Cancer Center, lrvine, CA, USA
| | - Grant A. Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gregory J. Anderson
- Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane St. Lucia, QLD, Australia
| | - Lawrie W Powell
- Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane St. Lucia, QLD, Australia
- Royal Brisbane & Women’s Hospital, Herston, QLD, Australia
| | - V. Nathan Subramaniam
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Paul C. Adams
- Department of Medicine, London Health Sciences Centre, London, ONT, Canada
| | | | - Lyle C. Gurrin
- Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - John D. Phillips
- Departments of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Charles J. Parker
- Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Mary J. Emond
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Gordon D. McLaren
- Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
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Golfeyz S, Lewis S, Weisberg IS. Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert Rev Gastroenterol Hepatol 2018; 12:767-778. [PMID: 29966105 DOI: 10.1080/17474124.2018.1496016] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals. Mutations in the HFE gene lead to excess iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is readily uptaken by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms greatly vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. MRI has emerged as the reference standard imaging modality for the detection and quantification of hepatic iron deposition, as ultrasound (US) is unable to detect iron overload and computed tomography (CT) findings are nonspecific and influenced by multiple confounding variables. If caught and treated early, HH disease progression can significantly be altered. Area covered: The data on Hemochromatosis, iron overload, and MRI were gathered by searching PubMed. Expert commentary: MRI is a great tool for diagnosis and management of iron overload. It is safe, effective, and a standard protocol should be included in diagnostic algorithms of future treatment guidelines.
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Affiliation(s)
- Shmuel Golfeyz
- a Department of Internal Medicine , Mount Sinai Beth Israel , New York , NY , USA
| | - Sara Lewis
- b Department of Radiology , Icahn School of Medicine at Mount Sinai , New York , NY , USA.,c Translational and Molecular Imaging Institute , Icahn School of Medicine at Mount Sinai , New York , NY , USA
| | - Ilan S Weisberg
- d Department of Digestive Diseases and Hepatology , Mount Sinai Beth Israel , New York , NY , USA
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15
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Abstract
Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.
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Affiliation(s)
- Pierre Brissot
- INSERM, Univ. Rennes, INRA, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
| | - Antonello Pietrangelo
- Division of Internal Medicine 2 and Center for Haemochromatosis, University Hospital of Modena, Modena, Italy
| | - Paul C. Adams
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Barbara de Graaff
- Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | | | - Olivier Loréal
- INSERM, Univ. Rennes, INRA, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
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16
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Lin H, Fu C, Kannengiesser S, Cheng S, Shen J, Dong H, Yan F. Quantitative analysis of hepatic iron in patients suspected of coexisting iron overload and steatosis using multi-echo single-voxel magnetic resonance spectroscopy: Comparison with fat-saturated multi-echo gradient echo sequence. J Magn Reson Imaging 2018. [PMID: 29513377 DOI: 10.1002/jmri.25967] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The coexistence of hepatic iron and fat is common in patients with hyperferritinemia, which plays an interactive and aggressive role in the progression of diseases (fibrosis, cirrhosis, and hepatocellular carcinomas). PURPOSE To evaluate a modified high-speed T2 -corrected multi-echo, single voxel spectroscopy sequence (HISTOV) for liver iron concentration (LIC) quantification in patients with hyperferritinemia, with simultaneous fat fraction (FF) estimation. STUDY TYPE Retrospective cohort study. POPULATION Thirty-eight patients with hyperferritinemia were enrolled. FIELD STRENGTH/SEQUENCE HISTOV, a fat-saturated multi-echo gradient echo (GRE) sequence, and a spin echo sequence (FerriScan) were performed at 1.5T. ASSESSMENT R2 of the water signal and FF were calculated with HISTOV, and R2* values were derived from the GRE sequence, with R2 and LIC from FerriScan serving as the references. STATISTICAL TESTS Linear regression, correlation analyses, receiver operating characteristic analyses, and Bland-Altman analyses were conducted. RESULTS Abnormal hepatic iron load was detected in 32/38 patients, of whom 10/32 had coexisting steatosis. Strong correlation was found between R2* and FerriScan-LIC (R2 = 0.861), and between HISTOV-R2_ water and FerriScan-R2 (R2 = 0.889). Furthermore, HISTOV-R2_ water was not correlated with HISTOV-FF. The area under the curve (AUC) for HISTOV-R2_ water was 0.974, 0.971, and 1, corresponding to clinical FerriScan-LIC thresholds of 1.8, 3.2, and 7.0 mg/g dw, respectively. No significant difference in the AUC was found between HISTOV-R2_ water and R2* at any of the LIC thresholds, with P-values of 0.42, 0.37, and 1, respectively. HISTOV-LIC showed excellent agreement with FerriScan-LIC, with a mean bias of 0.00 ± 1.18 mg/g dw, whereas the mean bias between GRE-LIC and FerriScan-LIC was 0.53 ± 1.49 mg/g dw. DATA CONCLUSION HISTOV is useful for the quantification and grading of liver iron overload in patients with hyperferritinemia, particularly in cases with coexisting steatosis. HISTOV-LIC showed no systematic bias compared with FerriScan-LIC, making it a promising alternative for iron quantification. LEVEL OF EVIDENCE 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018.
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Affiliation(s)
- Huimin Lin
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Caixia Fu
- Application Development, Siemens Shenzhen Magnetic Resonance Ltd, Shenzhen, China
| | | | - Shu Cheng
- Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Shen
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haipeng Dong
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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17
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Lin H, Wei H, He N, Fu C, Cheng S, Shen J, Wang B, Yan X, Liu C, Yan F. Quantitative susceptibility mapping in combination with water-fat separation for simultaneous liver iron and fat fraction quantification. Eur Radiol 2018; 28:3494-3504. [PMID: 29470640 DOI: 10.1007/s00330-017-5263-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 12/08/2017] [Accepted: 12/20/2017] [Indexed: 12/21/2022]
Abstract
PURPOSES To evaluate the feasibility of simultaneous quantification of liver iron concentration (LIC) and fat fraction (FF) using water-fat separation and quantitative susceptibility mapping (QSM). METHODS Forty-five patients suspected of liver iron overload (LIO) were included. A volumetric interpolated breath-hold examination sequence for QSM and FF, a fat-saturated gradient echo sequence for R2*, a spin echo sequence for LIC measurements and MRS analyses for FF (FF-MRS) were performed. Magnetic susceptibility and FF were calculated using a water-fat separation method (FF-MRI). Correlation and receiver operating characteristic analyses were performed. RESULTS Magnetic susceptibility showed strong correlation with LIC (rs=0.918). The optimal susceptibility cut-off values were 0.34, 0.63, 1.29 and 2.23 ppm corresponding to LIC thresholds of 1.8, 3.2, 7.0 and 15.0 mg/g dry weight. The area under the curve (AUC) were 0.948, 0.970, 1 and 1, respectively. No difference in AUC was found between susceptibility and R2* at all LIC thresholds. Correlation was found between FF-MRI and FF-MRS (R2=0.910). CONCLUSIONS QSM has a high diagnostic performance for LIC quantification, similar to that of R2*. FF-MRI provides simultaneous fat quantification. Findings suggest QSM in combination with water-fat separation has potential value for evaluating LIO, especially in cases with coexisting steatosis. KEY POINTS • Magnetic susceptibility showed strong correlation with LIC (r s =0.918). • QSM showed high diagnostic performance for LIC, similar to that of R 2* . • Simultaneously estimated FF-MRI showed strong correlation with MR-Spectroscopy-based FF (R 2 =0.910). • QSM combining water-fat separation has quantitative value for LIO with coexisted steatosis.
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Affiliation(s)
- Huimin Lin
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, NO. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Hongjiang Wei
- Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA
| | - Naying He
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, NO. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Caixia Fu
- Application Development, Siemens Shenzhen Magnetic Resonance Ltd., Shenzhen, China
| | - Shu Cheng
- Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Shen
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, NO. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Baisong Wang
- Department of Biological Statistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Yan
- MR Collaboration NE Asia, Siemens Healthcare, Shanghai, China
| | - Chunlei Liu
- Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.,Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, NO. 197 Ruijin Er Road, Shanghai, 200025, China.
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18
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Brissot P, Cavey T, Ropert M, Gaboriau F, Loréal O. Hemochromatosis: a model of metal-related human toxicosis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:2007-2013. [PMID: 27628916 DOI: 10.1007/s11356-016-7576-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 09/01/2016] [Indexed: 06/06/2023]
Abstract
Many environmental agents, such as excessive alcohol intake, xenobiotics, and virus, are able to damage the human body, targeting especially the liver. Metal excess may also assault the liver. Thus, chronic iron overload may cause, especially when associated with cofactors, diffuse organ damage that is a source of significant morbidity and mortality. Iron excess can be either of acquired (mostly transfusional) or of genetic origin. Hemochromatosis is the archetype of genetic iron overload diseases and represents a serious health problem. A better understanding of iron metabolism has deeply modified the hemochromatosis field which today benefits from much more efficient diagnostic and therapeutic approaches.
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Affiliation(s)
- Pierre Brissot
- Hepatology, Faculty of Medicine, University of Rennes1, 2, avenue Pr. Léon BERNARD, 35043, Rennes, France.
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France.
- Inserm-UMR 991, University of Rennes1, Rennes, France.
| | - Thibault Cavey
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France
- Inserm-UMR 991, University of Rennes1, Rennes, France
| | - Martine Ropert
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France
- Inserm-UMR 991, University of Rennes1, Rennes, France
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Wood MJ, Crawford DHG, Wockner LF, Powell LW, Ramm GA. Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis. Liver Int 2017; 37:1382-1388. [PMID: 28231420 DOI: 10.1111/liv.13395] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 02/16/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis. METHODS We identified 291 C282Y HFE-homozygous patients who had undergone liver biopsy for histological fibrosis staging and measurement of HIC. Ordinal logistic regression determined the best model for fibrosis stage not including serum ferritin. Then, serum ferritin was introduced into this model to assess whether the predictive power of the model was significantly increased and to evaluate the effect on other predictors of fibrosis. RESULTS Ordinal logistic regression analyses without serum ferritin demonstrated that log HIC (OR 2.89; P < .001), male gender (OR 2.93; P = .005), alcohol consumption (g/day) (OR 1.01; P = .004), steatosis (OR 2.86; P = .01), arthritis (OR 2.46; P = .01) predicted increasing fibrosis stage (n=217). Addition of serum ferritin in multivariate analysis substantially improved the predictive power of the model (χ2 = 37.15; P < .01) and was highly predictive of fibrosis stage (OR 5.44; P < .001). Inclusion of serum ferritin in this model rendered the effects of HIC, gender, alcohol and steatosis to non-significance. CONCLUSIONS In haemochromatosis, serum ferritin is a better predictor of fibrosis stage than HIC, gender, steatosis and alcohol. These data support a hypothesis that ferritin may play a role in fibrosis rather than simply acting as a passive indicator of iron storage.
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Affiliation(s)
- Marnie J Wood
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Darrell H G Crawford
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Greenslopes Hospital, The Gallipoli Medical Research Foundation, Brisbane, Queensland, Australia
| | - Leesa F Wockner
- Biostatistics Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Lawrie W Powell
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Centre for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital and the University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis. Redox Biol 2016; 11:157-169. [PMID: 27936457 PMCID: PMC5149069 DOI: 10.1016/j.redox.2016.11.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 11/16/2016] [Accepted: 11/28/2016] [Indexed: 12/18/2022] Open
Abstract
Background and Aims In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/- mice (an established model of human HFE-hemochromatosis). Methods Wild-type, Nrf2-/-, Hfe-/- and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12–18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Results Despite the parenchymal iron accumulation, Hfe-/- mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. Conclusions The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.
Despite the parenchymal iron overload, single Hfe-/- mice present no liver injury. Hfe and Nrf2 double knockout mice develop liver fibrosis with aging. Fibrosis is triggered by iron-related hepatocellular death (sideronecrosis). Nrf2 genetic disruption increases susceptibility to oxidative/electrophilic stress. NRF2 status is a potential determinant of liver injury in hemochromatosis.
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Abstract
Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases.
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Affiliation(s)
- Christine C Hsu
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19146, USA
| | - Kris V Kowdley
- Swedish Liver Care Network, Swedish Medical Center, 1124 Columbia Street, Suite 600, Seattle, WA 98104, USA.
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22
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Kokil GR, Veedu RN, Ramm GA, Prins JB, Parekh HS. Type 2 diabetes mellitus: limitations of conventional therapies and intervention with nucleic acid-based therapeutics. Chem Rev 2015; 115:4719-43. [PMID: 25918949 DOI: 10.1021/cr5002832] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Ganesh R Kokil
- †School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Rakesh N Veedu
- §Center for Comparative Genomics, Murdoch University, 90 South Street, Murdoch, WA 6150, Australia.,∥Western Australian Neuroscience Research Institute, Perth, WA 6150, Australia.,‡School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane QLD 4072 Australia
| | - Grant A Ramm
- ⊥The Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.,#Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, QLD 4006, Australia
| | - Johannes B Prins
- ∇Mater Research Institute, The University of Queensland, Brisbane, QLD 4101, Australia
| | - Harendra S Parekh
- †School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Brisbane, QLD 4102, Australia
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23
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Powell LW. A career forged in iron. Hepatology 2015; 61:4-14. [PMID: 25043645 DOI: 10.1002/hep.27293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 06/27/2014] [Indexed: 12/07/2022]
Affiliation(s)
- Lawrie W Powell
- The Center for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital, and The University of Queensland Center for Clinical Research, Brisbane, Queensland, Australia
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24
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Pretorius E, Bester J, Vermeulen N, Lipinski B, Gericke GS, Kell DB. Profound morphological changes in the erythrocytes and fibrin networks of patients with hemochromatosis or with hyperferritinemia, and their normalization by iron chelators and other agents. PLoS One 2014; 9:e85271. [PMID: 24416376 PMCID: PMC3887013 DOI: 10.1371/journal.pone.0085271] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 11/25/2013] [Indexed: 12/22/2022] Open
Abstract
It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise.
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Affiliation(s)
- Etheresia Pretorius
- Department of Physiology, University of Pretoria, Arcadia, South Africa
- * E-mail:
| | - Janette Bester
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Natasha Vermeulen
- Department of Physiology, University of Pretoria, Arcadia, South Africa
| | - Boguslaw Lipinski
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | | | - Douglas B. Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, Lancs, United Kingdom
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25
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Wood MJ, Powell LW, Dixon JL, Subramaniam VN, Ramm GA. Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis. World J Gastroenterol 2013; 19:9366-9376. [PMID: 24409064 PMCID: PMC3882410 DOI: 10.3748/wjg.v19.i48.9366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 08/23/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.
METHODS: A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied, with all subjects having liver biopsy data and DNA available for testing. This study assessed the association of eight single nucleotide polymorphisms (SNPs) in a total of six genes including toll-like receptor 4 (TLR4), transforming growth factor-beta (TGF-β), oxoguanine DNA glycosylase, monocyte chemoattractant protein 1, chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity. Genotyping was performed using high resolution melt analysis and sequencing. The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.
RESULTS: There were significant associations between the cofactors of male gender (P = 0.0001), increasing age (P = 0.006), alcohol consumption (P = 0.0001), steatosis (P = 0.03), hepatic iron concentration (P < 0.0001) and the presence of hepatic fibrosis. Of the candidate gene polymorphisms studied, none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors. We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied. Importantly, in this large, well characterised cohort of patients there was no association between SNPs for TGF-β or TLR4 and the presence of fibrosis, cirrhosis or increasing fibrosis stage in multivariate analysis.
CONCLUSION: In our large, well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.
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26
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Diabetes mellitus at the time of diagnosis of cirrhosis is associated with higher incidence of spontaneous bacterial peritonitis, but not with increased mortality. Clin Sci (Lond) 2013; 125:341-8. [PMID: 23566037 DOI: 10.1042/cs20120596] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
DM (diabetes mellitus) is present in 20-40% of patients with liver cirrhosis, but its prognostic impact is unclear. Therefore, in the present study, we investigated whether the presence of DM in patients with cirrhosis was associated with increased mortality, and/or with increased incidence of SBP (spontaneous bacterial peritonitis). We reviewed medical and laboratory data of 230 patients with cirrhosis from the period 2001-2011, for whom data were complete in n=226. Follow-up for the outcomes mortality and SBP was performed until May 2012, with only 13 patients lost to follow-up. DM was present at baseline in 78 patients (35%). Median follow-up was 6.2 (interquartile range, 3.1-9.3) years, during which 118 patients died [47 out of 78 with DM (60%), and 71 out of 148 without DM (48%)]. The presence of DM at baseline was not associated with increased mortality after adjustment for age {HR (hazard ratio), 1.00 [95% CI (confidence interval), 0.67-1.50]}. Further adjustment for sex, aetiology of cirrhosis, platelet count and the Child-Pugh or MELD (model for end-stage liver disease) score did not change this finding. During follow-up, 37 patients developed incident SBP (19 with DM and 18 without DM). DM at baseline was associated with incident SBP, even after adjustment for age, sex, aetiology, platelet count and the Child-Pugh [HR, 2.39 (95% CI, 1.10-5.18)] or MELD score [HR, 2.50 (95% CI, 1.16-5.40)]. In conclusion, the presence of DM at baseline in patients with cirrhosis was associated with an increased risk of SBP, which may represent an increased susceptibility to infections. On the other hand, DM was not clearly associated with increased mortality in these patients.
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27
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Abstract
Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. This can result in elevated serum ferritin, iron deposition in various organs and ultimately end-organ damage, although there is incomplete biochemical and clinical penetrance and variable phenotypic expression of the HFE mutation in hereditary hemochromatosis. An elevated SF >1000 mg/l [corrected] is associated with an increased risk of cirrhosis and mortality in C282Y homozygotes.Conversely, a SF <1000 µg/l is associated with a very low likelihood of cirrhosis, making liver biopsy unnecessary among C282Y homozygotes in the absence of concomitant risk factors for liver disease. Phlebotomy remains the mainstay of treatment and new treatments being studied include erythrocytapheresis and 'mini-hepcidins'. Iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers, possibly supporting iron depletion in these patients.
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Affiliation(s)
- Pushpjeet Kanwar
- Liver Center for Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
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28
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Abstract
In addition to directly causing liver disease, alcohol consumption is a common comorbid condition with other chronic liver diseases and may exacerbate liver injury, particularly in nonalcoholic fatty liver disease, chronic viral hepatitis, hereditary hemochromatosis, and autoimmune liver diseases. This synergism can result in increased hepatic inflammation and accelerated rates of fibrosis, with more rapid and earlier development of cirrhosis, and also increase the risk for liver cancer and death from liver disease.
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Affiliation(s)
- Maximilian Lee
- Liver Center of Excellence, Virginia Mason Medical Center, 1100 Ninth Avenue, Seattle, WA 98101, USA
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