Association of hereditary hemochromatosis with portal vein thrombosis: A national inpatient sample (2016-2020) analysis

Association of hereditary hemochromatosis with portal vein thrombosis: A national inpatient sample (2016-2020) analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of hereditary hemochromatosis with portal vein thrombosis: A national inpatient sample (2016-2020) analysis Himal Kharel, Nishan Babu Pokhrel, Zeni Kharel, Samikchhya Keshary Bhandari, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3819168/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hereditary hemochromatosis is a common inherited metabolic disorder of iron metabolism with variable penetrance. Portal vein thrombosis has several well-known causes including cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, and thrombophilia. It is unknown whether hereditary hemochromatosis is associated with portal vein thrombosis. A retrospective analysis of the NIS database from 2016 to 2020 was conducted using International Classification of Diseases (ICD-10) codes to identify hospitalizations with portal vein thrombosis. We used Fischer's exact test to compare proportions and the student's t-test to compare continuous variables. We used multivariate regression analysis to calculate the adjusted odds ratio after controlling for age, gender, primary payer, Charlson Comorbidity index, cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, history of past thrombosis, thrombophilia, end stage renal disease, obesity, smoking, and hyperlipidemia.There were 25805 hospitalizations with primary diagnosis of portal vein thrombosis. Multivariate logistic regression showed that hereditary hemochromatosis was independently associated with portal vein thrombosis (OR = 4.7, 95% CI = 1.15 to 19.35, p-value = 0.03) along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, history of thrombophilia, and end stage renal disease among other factors. Hereditary hemochromatosis portal vein thrombosis iron overload national inpatient sample Introduction Hereditary hemochromatosis(HH) has a prevalence of 1 in 220 to 250 people[ 1 ]. It is a common genetic disorder with variable penetrance. It is especially common in non-Hispanic whites of northern European origin. The clinical features of those affected include liver cirrhosis, diabetes mellitus, hypogonadism, cardiomyopathy, and arthropathy[ 1 ]. The lifetime risk of portal vein thrombosis in general population is estimated to be around 1%[ 2 ]. Portal vein thrombosis can be associated with increased risk of thrombotic and hemorrhagic complications ranging from. There are many well known risk factors of portal vein thrombosis including but not limited to, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, and intra-abdominal surgery[ 3 ]. Portal vein thrombosis Gill et al found that a standard deviation increase in ferritin was associated with significantly increased risk of venous thromboembolism with OR of 1.92[ 4 ]. It is unknown if hereditary hemochromatosis is independently associated with development of portal vein thrombosis. Data source We used the National Inpatient Sample (NIS) database from 2016 to 2020, which is a weighted database comprising 20% sample of all discharges[ 5 ]. It mainly consists of demographic, economic, and some clinical data. It is a part of the health care and cost utilization project (HCUP) and maintained by Agency of Healthcare Research Quality (AHRQ). Given the de-identified nature of patients’ information, institutional review board approval is not required. Variables and outcomes We used ICD-10 codes for portal vein thrombosis (I81) as the primary diagnosis. Secondary diagnosis included ICD-10 codes for cirrhosis(K7030, K7031, K7460, K745, K7469) myeloproliferative neoplasm(D471, D473), inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis)( K35200, K35201, K35209, K35211, K35211,K35219, K3530, K3531, K3532, K3533, K3580, K35890, K35891,K8500, K8501, K8502, K8510, K8512, K8520, K5720, K5721, K5730, K5731, K5732, K5733), intra-abdominal malignancy(C180, C181, C182, C183, C184, C185, C186, C187, C188, C189, C19, C20, C220, C250, C251, C252, C253, C254, C257, C258, C259), intra-abdominal surgery(0D, 0F), history of past thrombosis(Z86718), thrombophilia(D685,D686), end stage renal disease(N186), obesity(E66), smoking(F1721), and hyperlipidemia(E7800, E7801, E782, E783, E784, E785). The primary outcome included association between hereditary hemochromatosis expressed in odds ratio. Statistical analysis STATA version SE18.0 was used for statistical analysis. We used Fischer's exact test to compare proportions and the student's t-test to compare continuous variables. We used multivariate regression analysis to calculate the adjusted odds ratio after controlling for age, gender, primary payer, Charlson Comorbidity index, cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, history of past thrombosis, thrombophilia, end stage renal disease, obesity, smoking, and hyperlipidemia. Results Admission characteristics During 5-year period from 2016 to 2020, there were 25805 hospitalizations with a primary diagnosis of portal vein thrombosis. The mean age was 54.6 years (95% confidence interval 54.1–55.1). Out of them, 45.4% were female (95% confidence interval 44.1–46.8). The majority of patients were white (69.6%) followed by Asian (12.2%), and Black (12%). Most of the patients were on private insurance (40.4%) and Medicare (35.5%). The majority (92%) of patients had a Charlson co-morbidity index of greater than or equal to 3. Multivariate analysis Multivariate logistic regression showed that hereditary hemochromatosis was independently associated with portal vein thrombosis (OR = 4.7, 95% CI = 1.15 to 19.35, p-value = 0.03) along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, history of thrombophilia, and end stage renal disease among other factors. The findings are summarized in Table 1 . Table 1 Multivariate logistic regression findings Odds Ratio of Portal Vein Thrombosis 95% Confidence Interval P-value Risk factors Hereditary hemochromatosis 4.72 1.15–19.35 0.03 Cirrhosis 11.2 9.4–13.3 0.00 Myeloproliferative neoplasm 5.5 3.55–8.56 0.00 Inflammatory conditions of abdomen 2.5 1.8–3.4 0.00 History of abdominal malignancy 8.9 7.1–11.3 0.00 History of prior thrombosis 2.54 2–3.22 0.00 History of abdominal surgery 1.8 1.5–2.13 0.00 History of thrombophilia 8.8 6.9–11.2 0.00 End stage renal disease 0.14 0.05–0.35 0.00 Obesity 1.28 1.07–1.5 0.02 Smoking 1.1 0.9–1.3 0.29 Hyperlipidemia 0.72 0.6–0.86 0.00 Demographics Female 0.78 0.68–0.9 0.00 Age 1 0.99-1 0.9 Charlson Co-morbidity Index 1 1.21 0.94–1.5 0.13 2 0.97 0.72–1.31 0.88 > 3 1.38 1.08–1.7 0.01 Median Household Income 2nd Quartile 1.03 0.85–1.25 0.14 3rd Quartile 1.17 0.96–1.42 0.00 4th Quartile 1.09 0.89–1.34 0.00 Race Black 0.96 0.78–1.2 0.77 Hispanic 1.08 0.9–1.34 0.44 Asian 0.9 0.58–1.4 0.6 Native American 0.69 0.28–1.67 0.3 Other 1.40 1–1.96 0.05 Discussion Our study shows that Hereditary hemochromatosis is independently associated with increased risk of portal vein thrombosis along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, and history of thrombophilia among other factors. Of note, hemochromatosis is not a well known independent cause of portal vein thrombosis in studies so far. In a Swedish autopsy study of 24 000 autopsies, about 14% were found to have idiopathic portal vein thrombosis; and rest of them were found to be caused by cirrhosis, primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease or myeloproliferative disease[ 2 ]. To date we were able to find only a single case report from France where compound heterozygous C282Y/H63D hereditary hemochromatosis was found in a 49-year-old male presenting with idiopathic portal vein thrombosis and without cirrhosis[ 6 ]. A large-scale Mendelian Randomization study in 2019 concluded that iron overload increases risk of venous thromboembolism [OR 1.37 (1.14, 1.66)] [ 4 ] which was consistent with a case control study which showed dose-dependent relationship between hepcidin and risk of VTE[ 7 ]. Iron overload was found to increase thrombus formation after arterial injury, increase vascular ROS production, and impair endothelium-dependent vasorelaxation in mice[ 8 ]. In the same study, administration of ROS scavenger reversed the effect. Iron induced oxidative stress could decrease bioavailability of nitric oxide causing endothelial dysfunction and platelet activation[ 9 ] [ 10 ]. Given the susceptibility of fibrinogen to oxidation, exposure of fibrinogen to Fe 3+ promotes fibrin formation, promotes platelet aggregation, and causes less efficient plasminogen activation by tissue-type plasminogen activator[ 11 ] [ 12 ]. All these factors would explain the increased risk of thrombosis in setting of iron overload. In the setting of hereditary hemochromatosis, mutations in HFE gene appear to have some relation with factor V Leiden mutations. An observation study of a sample of unscreened patient with thrombosis by Xie et al. in 1998[ 13 ] showed that frequency of C282Y heterozygotes was significantly higher in factor V Leiden carriers than in factor V Leiden-negative patients or control populations. It is possible that a minor dysregulation of iron metabolism in the setting of presence of heterozygous state for factor V Leiden could have increased risk of thrombosis. In contrast, another study[ 14 ] in 1999 in 239 patients with venous thrombosis failed to show significantly increased frequency of C282Y heterozygotes in pts with FVL than without FVL, which would suggest that HFE C282Y is not an independent risk factor for thrombosis. However, it showed that among FVL positive patients, HFE C282Y was increased among patients with family history of thrombosis (RR 7.97, 95% CI 1.5–43.1). Similarly, a case control study by Brown et al.[ 15 ] did not find higher prevalence of C828Y allele in pts with thrombosis compared to those without thrombosis. Also, in pts with FVL positive status, the presence of C282Y heterozygosity was not significantly different in pts with thrombosis than without thrombosis. The strength of the study is the fact that we used large national database spanning 5 years. There were several limitations of our study. Firstly, given the retrospective nature of the study, there is a high risk of bias. Secondly, correlation is not equal to causation. Thirdly, due to the fact that national inpatient sample is an administrative database, it is subject to coding errors and mischaracterization of data. Declarations There are no conflicts of interest or competing interests. Ethical approval: Not applicable given this is a large publicly available database study Funding: None Competing interests: None Author contributions: HK and SKB came up with the idea and did the statistical analysis. The manuscript was completed by NBP, ZK, and TJ. CN proof read and added to the discussion. Data availability: Publicly available national inpatient sample database was used References B. R. Bacon, P. C. Adams, K. V. Kowdley, L. W. Powell, and A. S. Tavill, “Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases,” Hepatology , vol. 54, no. 1, pp. 328–343, 2011, doi: 10.1002/hep.24330. M. Ögren, D. Bergqvist, M. Björck, S. Acosta, H. Eriksson, and N. H. Sternby, “Portal vein thrombosis: Prevalence, patient characteristics and lifetime risk: A population study based on 23 796 consecutive autopsies,” World J Gastroenterol , vol. 12, no. 13, pp. 2115–2119, Apr. 2006, doi: 10.3748/wjg.v12.i13.2115. R. Quarrie and S. P. Stawicki, “Portal vein thrombosis: What surgeons need to know,” Int J Crit Illn Inj Sci , vol. 8, no. 2, pp. 73–77, 2018, doi: 10.4103/IJCIIS.IJCIIS_71_17. D. Gill et al. , “Effects of Genetically Determined Iron Status on Risk of Venous Thromboembolism and Carotid Atherosclerotic Disease: A Mendelian Randomization Study,” Journal of the American Heart Association , vol. 8, no. 15, p. e012994, Aug. 2019, doi: 10.1161/JAHA.119.012994. “HCUP-US NIS Overview.” Accessed: Dec. 19, 2023. [Online]. Available: https://hcup-us.ahrq.gov/nisoverview.jsp L. Delval, D. Brohée, P. Cauchie, M. Vanhaeverbeek, and P. Hilbert, “[Acute portal thrombosis revealing hereditary hemochromatosis: report of a case],” Rev Med Brux , vol. 23, no. 2, pp. 83–86, Apr. 2002. T. S. Ellingsen, J. Lappegård, T. Ueland, P. Aukrust, S. K. Brækkan, and J.-B. Hansen, “Plasma hepcidin is associated with future risk of venous thromboembolism,” Blood Adv , vol. 2, no. 11, pp. 1191–1197, May 2018, doi: 10.1182/bloodadvances.2018018465. S. M. Day et al. , “Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis,” Circulation , vol. 107, no. 20, pp. 2601–2606, May 2003, doi: 10.1161/01.CIR.0000066910.02844.D0. J. P. Cooke, “Does ADMA Cause Endothelial Dysfunction?,” Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 20, no. 9, pp. 2032–2037, Sep. 2000, doi: 10.1161/01.ATV.20.9.2032. G. Kenet et al. , “Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke,” Arterioscler Thromb Vasc Biol , vol. 19, no. 8, pp. 2017–2023, Aug. 1999, doi: 10.1161/01.atv.19.8.2017. Y. H. Feng and G. Hart, “In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions,” Cardiovasc Res , vol. 30, no. 2, pp. 255–261, Aug. 1995. G. R. Upchurch, N. Ramdev, M. T. Walsh, and J. Loscalzo, “Prothrombotic Consequences of the Oxidation of Fibrinogen and their Inhibition by Aspirin,” J Thromb Thrombolysis , vol. 5, no. 1, pp. 9–14, Jan. 1998, doi: 10.1023/A:1008859729045. Y. G. Xie, D. P. Lillicrap, and S. A. Taylor, “An association between the common hereditary hemochromatosis mutation and the factor V Leiden allele in a population with thrombosis,” Blood , vol. 92, no. 4, pp. 1461–1462, Aug. 1998. R. M. MacLean, G. P. Feeney, S. J. Bowley, D. J. Bowen, M. Worwood, and P. W. Collins, “Factor V Leiden and the common haemochromatosis mutation HFE C282Y: is there an association in familial venous thromboembolic disease?,” Br J Haematol , vol. 107, no. 1, pp. 210–212, Oct. 1999, doi: 10.1046/j.1365-2141.1999.01663.x. K. Brown, R. Luddington, S. A. Taylor, D. P. Lillicrap, and T. P. Baglin, “Risk of venous thromboembolism associated with the common hereditary haemochromatosis Hfe gene (C282Y) mutation,” Br J Haematol , vol. 105, no. 1, pp. 95–97, Apr. 1999. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3819168","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":267403649,"identity":"d34647f9-c97a-4966-8678-1dce9c3f569d","order_by":0,"name":"Himal Kharel","email":"data:image/png;base64,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","orcid":"","institution":"Rochester General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Himal","middleName":"","lastName":"Kharel","suffix":""},{"id":267403650,"identity":"098cc0c5-f227-486d-b213-eefc39f26faf","order_by":1,"name":"Nishan Babu Pokhrel","email":"","orcid":"","institution":"Norwalk Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nishan","middleName":"Babu","lastName":"Pokhrel","suffix":""},{"id":267403651,"identity":"109f9a65-9f62-406f-ada3-b7a17062e09f","order_by":2,"name":"Zeni Kharel","email":"","orcid":"","institution":"Rochester General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zeni","middleName":"","lastName":"Kharel","suffix":""},{"id":267403652,"identity":"8105ca87-2413-44d8-9cfb-004604432a5a","order_by":3,"name":"Samikchhya Keshary Bhandari","email":"","orcid":"","institution":"Tribhuvan University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Samikchhya","middleName":"Keshary","lastName":"Bhandari","suffix":""},{"id":267403654,"identity":"17c98f71-4c48-418d-a6f9-131c3d0654f0","order_by":4,"name":"Chengu Niu","email":"","orcid":"","institution":"Rochester General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chengu","middleName":"","lastName":"Niu","suffix":""},{"id":267403656,"identity":"b649b7d3-6706-442a-acc9-6ca87b7ca490","order_by":5,"name":"Tripti Jain","email":"","orcid":"","institution":"Rochester General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tripti","middleName":"","lastName":"Jain","suffix":""},{"id":267403657,"identity":"dd2825ff-5754-48d2-9d5c-cd7b8779bf0a","order_by":6,"name":"Aditya Sanjeevi","email":"","orcid":"","institution":"Rochester General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aditya","middleName":"","lastName":"Sanjeevi","suffix":""}],"badges":[],"createdAt":"2023-12-29 02:44:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3819168/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3819168/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52831328,"identity":"530eb26d-32f5-47d4-95f6-6d2179ff66a8","added_by":"auto","created_at":"2024-03-17 07:07:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":194945,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3819168/v1/075c427f-456e-4ef7-9c0b-34912ffd2f9b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of hereditary hemochromatosis with portal vein thrombosis: A national inpatient sample (2016-2020) analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHereditary hemochromatosis(HH) has a prevalence of 1 in 220 to 250 people[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is a common genetic disorder with variable penetrance. It is especially common in non-Hispanic whites of northern European origin. The clinical features of those affected include liver cirrhosis, diabetes mellitus, hypogonadism, cardiomyopathy, and arthropathy[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The lifetime risk of portal vein thrombosis in general population is estimated to be around 1%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Portal vein thrombosis can be associated with increased risk of thrombotic and hemorrhagic complications ranging from. There are many well known risk factors of portal vein thrombosis including but not limited to, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, and intra-abdominal surgery[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Portal vein thrombosis Gill et al found that a standard deviation increase in ferritin was associated with significantly increased risk of venous thromboembolism with OR of 1.92[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is unknown if hereditary hemochromatosis is independently associated with development of portal vein thrombosis.\u003c/p\u003e "},{"header":"Data source","content":"\u003cp\u003eWe used the National Inpatient Sample (NIS) database from 2016 to 2020, which is a weighted database comprising 20% sample of all discharges[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. It mainly consists of demographic, economic, and some clinical data. It is a part of the health care and cost utilization project (HCUP) and maintained by Agency of Healthcare Research Quality (AHRQ). Given the de-identified nature of patients’ information, institutional review board approval is not required.\u003c/p\u003e\u003cp\u003eVariables and outcomes\u003c/p\u003e\u003cp\u003eWe used ICD-10 codes for portal vein thrombosis (I81) as the primary diagnosis. Secondary diagnosis included ICD-10 codes for cirrhosis(K7030, K7031, K7460, K745, K7469) myeloproliferative neoplasm(D471, D473), inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis)( K35200, K35201, K35209, K35211, K35211,K35219, K3530, K3531, K3532, K3533, K3580, K35890, K35891,K8500, K8501, K8502, K8510, K8512, K8520, K5720, K5721, K5730, K5731, K5732, K5733), intra-abdominal malignancy(C180, C181, C182, C183, C184, C185, C186, C187, C188, C189, C19, C20, C220, C250, C251, C252, C253, C254, C257, C258, C259), intra-abdominal surgery(0D, 0F), history of past thrombosis(Z86718), thrombophilia(D685,D686), end stage renal disease(N186), obesity(E66), smoking(F1721), and hyperlipidemia(E7800, E7801, E782, E783, E784, E785). The primary outcome included association between hereditary hemochromatosis expressed in odds ratio.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eSTATA version SE18.0 was used for statistical analysis. We used Fischer's exact test to compare proportions and the student's t-test to compare continuous variables. We used multivariate regression analysis to calculate the adjusted odds ratio after controlling for age, gender, primary payer, Charlson Comorbidity index, cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, history of past thrombosis, thrombophilia, end stage renal disease, obesity, smoking, and hyperlipidemia.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAdmission characteristics\u003c/p\u003e \u003cp\u003eDuring 5-year period from 2016 to 2020, there were 25805 hospitalizations with a primary diagnosis of portal vein thrombosis. The mean age was 54.6 years (95% confidence interval 54.1\u0026ndash;55.1). Out of them, 45.4% were female (95% confidence interval 44.1\u0026ndash;46.8). The majority of patients were white (69.6%) followed by Asian (12.2%), and Black (12%). Most of the patients were on private insurance (40.4%) and Medicare (35.5%). The majority (92%) of patients had a Charlson co-morbidity index of greater than or equal to 3.\u003c/p\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003cp\u003eMultivariate logistic regression showed that hereditary hemochromatosis was independently associated with portal vein thrombosis (OR\u0026thinsp;=\u0026thinsp;4.7, 95% CI\u0026thinsp;=\u0026thinsp;1.15 to 19.35, p-value\u0026thinsp;=\u0026thinsp;0.03) along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, history of thrombophilia, and end stage renal disease among other factors. The findings are summarized in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate logistic regression findings\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds Ratio of Portal Vein Thrombosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% Confidence Interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eRisk factors\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHereditary hemochromatosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.15\u0026ndash;19.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4\u0026ndash;13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyeloproliferative neoplasm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.55\u0026ndash;8.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInflammatory conditions of abdomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026ndash;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of abdominal malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.1\u0026ndash;11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of prior thrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026ndash;3.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of abdominal surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u0026ndash;2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of thrombophilia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9\u0026ndash;11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnd stage renal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05\u0026ndash;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.07\u0026ndash;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u0026ndash;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026ndash;0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eDemographics\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.68\u0026ndash;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eCharlson Co-morbidity Index\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94\u0026ndash;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.72\u0026ndash;1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.08\u0026ndash;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eMedian Household Income\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2nd Quartile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.85\u0026ndash;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3rd Quartile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96\u0026ndash;1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4th Quartile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.89\u0026ndash;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eRace\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.78\u0026ndash;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u0026ndash;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.58\u0026ndash;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNative American\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.28\u0026ndash;1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u0026ndash;1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study shows that Hereditary hemochromatosis is independently associated with increased risk of portal vein thrombosis along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, and history of thrombophilia among other factors. Of note, hemochromatosis is not a well known independent cause of portal vein thrombosis in studies so far. In a Swedish autopsy study of 24 000 autopsies, about 14% were found to have idiopathic portal vein thrombosis; and rest of them were found to be caused by cirrhosis, primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease or myeloproliferative disease[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date we were able to find only a single case report from France where compound heterozygous C282Y/H63D hereditary hemochromatosis was found in a 49-year-old male presenting with idiopathic portal vein thrombosis and without cirrhosis[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA large-scale Mendelian Randomization study in 2019 concluded that iron overload increases risk of venous thromboembolism [OR 1.37 (1.14, 1.66)] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] which was consistent with a case control study which showed dose-dependent relationship between hepcidin and risk of VTE[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Iron overload was found to increase thrombus formation after arterial injury, increase vascular ROS production, and impair endothelium-dependent vasorelaxation in mice[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In the same study, administration of ROS scavenger reversed the effect. Iron induced oxidative stress could decrease bioavailability of nitric oxide causing endothelial dysfunction and platelet activation[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given the susceptibility of fibrinogen to oxidation, exposure of fibrinogen to Fe\u003csup\u003e3+\u003c/sup\u003e promotes fibrin formation, promotes platelet aggregation, and causes less efficient plasminogen activation by tissue-type plasminogen activator[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. All these factors would explain the increased risk of thrombosis in setting of iron overload.\u003c/p\u003e \u003cp\u003eIn the setting of hereditary hemochromatosis, mutations in HFE gene appear to have some relation with factor V Leiden mutations. An observation study of a sample of unscreened patient with thrombosis by Xie et al. in 1998[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] showed that frequency of C282Y heterozygotes was significantly higher in factor V Leiden carriers than in factor V Leiden-negative patients or control populations. It is possible that a minor dysregulation of iron metabolism in the setting of presence of heterozygous state for factor V Leiden could have increased risk of thrombosis. In contrast, another study[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] in 1999 in 239 patients with venous thrombosis failed to show significantly increased frequency of C282Y heterozygotes in pts with FVL than without FVL, which would suggest that HFE C282Y is not an independent risk factor for thrombosis. However, it showed that among FVL positive patients, HFE C282Y was increased among patients with family history of thrombosis (RR 7.97, 95% CI 1.5\u0026ndash;43.1). Similarly, a case control study by Brown et al.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] did not find higher prevalence of C828Y allele in pts with thrombosis compared to those without thrombosis. Also, in pts with FVL positive status, the presence of C282Y heterozygosity was not significantly different in pts with thrombosis than without thrombosis.\u003c/p\u003e \u003cp\u003eThe strength of the study is the fact that we used large national database spanning 5 years. There were several limitations of our study. Firstly, given the retrospective nature of the study, there is a high risk of bias. Secondly, correlation is not equal to causation. Thirdly, due to the fact that national inpatient sample is an administrative database, it is subject to coding errors and mischaracterization of data.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThere are no conflicts of interest or competing interests.\u003c/p\u003e\n\u003cp\u003eEthical approval: Not applicable given this is a large publicly available database study\u003c/p\u003e\n\u003cp\u003eFunding: None\u003c/p\u003e\n\u003cp\u003eCompeting interests: None\u003c/p\u003e\n\u003cp\u003eAuthor contributions: HK and SKB came up with the idea and did the statistical analysis. The manuscript was completed by NBP, ZK, and TJ. CN proof read and added to the discussion.\u003c/p\u003e\n\u003cp\u003eData availability: Publicly available national inpatient sample database was used\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eB. R. Bacon, P. C. Adams, K. V. Kowdley, L. W. Powell, and A. S. Tavill, \u0026ldquo;Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases,\u0026rdquo; \u003cem\u003eHepatology\u003c/em\u003e, vol. 54, no. 1, pp. 328\u0026ndash;343, 2011, doi: 10.1002/hep.24330.\u003c/li\u003e\n\u003cli\u003eM. \u0026Ouml;gren, D. Bergqvist, M. Bj\u0026ouml;rck, S. Acosta, H. Eriksson, and N. H. Sternby, \u0026ldquo;Portal vein thrombosis: Prevalence, patient characteristics and lifetime risk: A population study based on 23 796 consecutive autopsies,\u0026rdquo; \u003cem\u003eWorld J Gastroenterol\u003c/em\u003e, vol. 12, no. 13, pp. 2115\u0026ndash;2119, Apr. 2006, doi: 10.3748/wjg.v12.i13.2115.\u003c/li\u003e\n\u003cli\u003eR. Quarrie and S. P. Stawicki, \u0026ldquo;Portal vein thrombosis: What surgeons need to know,\u0026rdquo; \u003cem\u003eInt J Crit Illn Inj Sci\u003c/em\u003e, vol. 8, no. 2, pp. 73\u0026ndash;77, 2018, doi: 10.4103/IJCIIS.IJCIIS_71_17.\u003c/li\u003e\n\u003cli\u003eD. Gill \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Effects of Genetically Determined Iron Status on Risk of Venous Thromboembolism and Carotid Atherosclerotic Disease: A Mendelian Randomization Study,\u0026rdquo; \u003cem\u003eJournal of the American Heart Association\u003c/em\u003e, vol. 8, no. 15, p. e012994, Aug. 2019, doi: 10.1161/JAHA.119.012994.\u003c/li\u003e\n\u003cli\u003e\u0026ldquo;HCUP-US NIS Overview.\u0026rdquo; Accessed: Dec. 19, 2023. [Online]. Available: https://hcup-us.ahrq.gov/nisoverview.jsp\u003c/li\u003e\n\u003cli\u003eL. Delval, D. Broh\u0026eacute;e, P. Cauchie, M. Vanhaeverbeek, and P. Hilbert, \u0026ldquo;[Acute portal thrombosis revealing hereditary hemochromatosis: report of a case],\u0026rdquo; \u003cem\u003eRev Med Brux\u003c/em\u003e, vol. 23, no. 2, pp. 83\u0026ndash;86, Apr. 2002.\u003c/li\u003e\n\u003cli\u003eT. S. Ellingsen, J. Lappeg\u0026aring;rd, T. Ueland, P. Aukrust, S. K. Br\u0026aelig;kkan, and J.-B. Hansen, \u0026ldquo;Plasma hepcidin is associated with future risk of venous thromboembolism,\u0026rdquo; \u003cem\u003eBlood Adv\u003c/em\u003e, vol. 2, no. 11, pp. 1191\u0026ndash;1197, May 2018, doi: 10.1182/bloodadvances.2018018465.\u003c/li\u003e\n\u003cli\u003eS. M. Day \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis,\u0026rdquo; \u003cem\u003eCirculation\u003c/em\u003e, vol. 107, no. 20, pp. 2601\u0026ndash;2606, May 2003, doi: 10.1161/01.CIR.0000066910.02844.D0.\u003c/li\u003e\n\u003cli\u003eJ. P. Cooke, \u0026ldquo;Does ADMA Cause Endothelial Dysfunction?,\u0026rdquo; \u003cem\u003eArteriosclerosis, Thrombosis, and Vascular Biology\u003c/em\u003e, vol. 20, no. 9, pp. 2032\u0026ndash;2037, Sep. 2000, doi: 10.1161/01.ATV.20.9.2032.\u003c/li\u003e\n\u003cli\u003eG. Kenet \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke,\u0026rdquo; \u003cem\u003eArterioscler Thromb Vasc Biol\u003c/em\u003e, vol. 19, no. 8, pp. 2017\u0026ndash;2023, Aug. 1999, doi: 10.1161/01.atv.19.8.2017.\u003c/li\u003e\n\u003cli\u003eY. H. Feng and G. Hart, \u0026ldquo;In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions,\u0026rdquo; \u003cem\u003eCardiovasc Res\u003c/em\u003e, vol. 30, no. 2, pp. 255\u0026ndash;261, Aug. 1995.\u003c/li\u003e\n\u003cli\u003eG. R. Upchurch, N. Ramdev, M. T. Walsh, and J. Loscalzo, \u0026ldquo;Prothrombotic Consequences of the Oxidation of Fibrinogen and their Inhibition by Aspirin,\u0026rdquo; \u003cem\u003eJ Thromb Thrombolysis\u003c/em\u003e, vol. 5, no. 1, pp. 9\u0026ndash;14, Jan. 1998, doi: 10.1023/A:1008859729045.\u003c/li\u003e\n\u003cli\u003eY. G. Xie, D. P. Lillicrap, and S. A. Taylor, \u0026ldquo;An association between the common hereditary hemochromatosis mutation and the factor V Leiden allele in a population with thrombosis,\u0026rdquo; \u003cem\u003eBlood\u003c/em\u003e, vol. 92, no. 4, pp. 1461\u0026ndash;1462, Aug. 1998.\u003c/li\u003e\n\u003cli\u003eR. M. MacLean, G. P. Feeney, S. J. Bowley, D. J. Bowen, M. Worwood, and P. W. Collins, \u0026ldquo;Factor V Leiden and the common haemochromatosis mutation HFE C282Y: is there an association in familial venous thromboembolic disease?,\u0026rdquo; \u003cem\u003eBr J Haematol\u003c/em\u003e, vol. 107, no. 1, pp. 210\u0026ndash;212, Oct. 1999, doi: 10.1046/j.1365-2141.1999.01663.x.\u003c/li\u003e\n\u003cli\u003eK. Brown, R. Luddington, S. A. Taylor, D. P. Lillicrap, and T. P. Baglin, \u0026ldquo;Risk of venous thromboembolism associated with the common hereditary haemochromatosis Hfe gene (C282Y) mutation,\u0026rdquo; \u003cem\u003eBr J Haematol\u003c/em\u003e, vol. 105, no. 1, pp. 95\u0026ndash;97, Apr. 1999.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hereditary hemochromatosis, portal vein thrombosis, iron overload, national inpatient sample","lastPublishedDoi":"10.21203/rs.3.rs-3819168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3819168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHereditary hemochromatosis is a common inherited metabolic disorder of iron metabolism with variable penetrance. Portal vein thrombosis has several well-known causes including cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, and thrombophilia. It is unknown whether hereditary hemochromatosis is associated with portal vein thrombosis. A retrospective analysis of the NIS database from 2016 to 2020 was conducted using International Classification of Diseases (ICD-10) codes to identify hospitalizations with portal vein thrombosis. We used Fischer's exact test to compare proportions and the student's t-test to compare continuous variables. We used multivariate regression analysis to calculate the adjusted odds ratio after controlling for age, gender, primary payer, Charlson Comorbidity index, cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen (acute appendicitis, acute diverticulitis, and acute pancreatitis), intra-abdominal malignancy, intra-abdominal surgery, history of past thrombosis, thrombophilia, end stage renal disease, obesity, smoking, and hyperlipidemia.There were 25805 hospitalizations with primary diagnosis of portal vein thrombosis. Multivariate logistic regression showed that hereditary hemochromatosis was independently associated with portal vein thrombosis (OR\u0026thinsp;=\u0026thinsp;4.7, 95% CI\u0026thinsp;=\u0026thinsp;1.15 to 19.35, p-value\u0026thinsp;=\u0026thinsp;0.03) along with cirrhosis, myeloproliferative neoplasm, inflammatory conditions of abdomen, intra-abdominal malignancy, history of thrombosis, history of abdominal surgery, history of thrombophilia, and end stage renal disease among other factors.\u003c/p\u003e","manuscriptTitle":"Association of hereditary hemochromatosis with portal vein thrombosis: A national inpatient sample (2016-2020) analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-17 09:55:27","doi":"10.21203/rs.3.rs-3819168/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c13eb448-8cc5-4bdb-a798-cb23a401bd5b","owner":[],"postedDate":"January 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-17T06:59:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-17 09:55:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3819168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3819168","identity":"rs-3819168","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}