High Red Cell Distribution Width and Low Absolute Lymphocyte Count Associate With Subsequent Mortality in HCV Infection
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Background: Hepatitis-C virus (HCV) chronic infection can lead to cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, cardiovascular disease (CVD), and mortality. Transient Elastography (TE) is used to non-invasively assess fibrosis. Whether immune monitoring provides additive prognostic value is not established. Increased red-cell distribution width (RDW) and decreased absolute lymphocyte count (ALC) predict mortality in those without liver disease. Whether these relationships remain during HCV infection is unknown.
Materials and Methods: A retrospective cohort of 1,715 single-site VA Liver Clinic patients receiving Transient Elastography (TE) 2014-2019 to evaluate HCV-associated liver damage were evaluated for RDW and ALC in relation to traditional parameters of cardiovascular risk, liver health, development of HCC, and mortality.
Results: The cohort was 97% male, 55% African American, 26% with diabetes mellitus, 67% with hypertension, and 66% with tobacco use. After TE, 3% were subsequently diagnosed with HCC, and 12% (n=208) died. Most deaths (n=189) were due to non-liver causes. The TE score associated with prevalent CVD positively correlated with atherosclerotic cardiovascular disease (ASCVD) 10-Year Risk Score, age, RDW, and negatively correlated with ALC. Patients with anisocytosis (RDW above 14%) or lymphopenia (ALC level under 1.2x109/L) had greater subsequent all-cause mortality, even after adjusting for age, TE score, and comorbidities. TE score, and to a modest degree RDW, were associated with subsequent liver-associated mortality, while TE score, RDW, and ALC were each independently associated with non-liver cause of death.
Conclusion: Widely available mortality calculators generally require multiple pieces of clinical information. RDW and ALC, parameters collected on a single laboratory test that is commonly performed, prior to HCV therapy may be pragmatic markers of long-term risk of mortality.
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El-Serag HB, Rudolph KL. Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis. Gastroenterology. 2007;132(7):2557–2576. doi: 10.1053/j.gastro.2007.04.061. PMID: 17570226
Collaboration GB of DC. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018 Nov 1;4(11):1553–1568. doi: 10.1001/jamaoncol.2018.2706.
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485–1491. doi: 10.1200/JCO.2008.20.7753.
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. Elsevier Inc.; 2012;142(6):1264-1273.e1. doi: 10.1053/j.gastro.2011.12.061. PMID: 22537432
Babiker A, Jeudy J, Kligerman S, Khambaty M, Shah A, Bagchi S. Risk of Cardiovascular Disease Due to Chronic Hepatitis C Infection: A Review. J Clin Transl Hepatol. 2017;5(4):1–20. doi: 10.14218/jcth.2017.00021.
Lou YF, Wang MY, Mao WL. Clinical usefulness of measuring red blood cell distribution width in patients with hepatitis B. PLoS ONE. 2012;7(5). doi: 10.1371/journal.pone.0037644. PMID: 22649548
Karagoz E, Ulcay A, Tanoglu A, Kara M, Turhan V, Erdem H, Oncul O, Gorenek L. Clinical usefulness of mean platelet volume and red blood cell distribution width to platelet ratio for predicting the severity of hepatic fibrosis in chronic hepatitis B virus patients. Eur J Gastroenterol Hepatol. 2014;26(12).
Wang H, Xu H, Wang X, Wu R, Gao X, Jin Q, Niu J. Red Blood Cell Distribution Width to Platelet Ratio is Related to Histologic Severity of Primary Biliary Cirrhosis. Medicine (Baltimore). 2016;95(11).
Yang W, Huang H, Wang Y, Yu X, Yang Z. High red blood cell distribution width is closely associated with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2014;26(2).
Zidar DA, Al-Kindi SG, Liu Y, Krieger NI, Perzynski AT, Osnard M, Nmai C, Anthony DD, Lederman MM, Freeman ML, Bonomo RA, Simon DI, Dalton JE. Association of Lymphopenia With Risk of Mortality Among Adults in the US General Population. JAMA Netw Open. 2019 Dec 2;2(12):e1916526–e1916526. doi: 10.1001/jamanetworkopen.2019.16526.
Silzle T, Blum S, Schuler E, Kaivers J, Rudelius M, Hildebrandt B, Gattermann N, Haas R, Germing U. Lymphopenia at diagnosis is highly prevalent in myelodysplastic syndromes and has an independent negative prognostic value in IPSS-R-low-risk patients. Blood Cancer J. 2019;9(8):63. doi: 10.1038/s41408-019-0223-7.
Kust D, Lucijanic M, Urch K, Samija I, Celap I, Kruljac I, Prpic M, Lucijanic I, Matesa N, Bolanca A. Clinical and prognostic significance of anisocytosis measured as a red cell distribution width in patients with colorectal cancer. QJM Int J Med. 2017 Jun 1;110(6):361–367. doi: 10.1093/qjmed/hcw223.
McGovern BH, Golan Y, Lopez M, Pratt D, Lawton A, Moore G, Epstein M, Knox TA. The Impact of Cirrhosis on CD4+ T Cell Counts in HIV-Seronegative Patients. Clin Infect Dis. 2007 Feb 1;44(3):431–437. doi: 10.1086/509580.
Sandrin L, Fourquet B, Hasquenoph J-M, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29(12):1705–1713. doi: 10.1016/j.ultrasmedbio.2003.07.001.
Lim JK, Flamm SL, Singh S, Falck-Ytter YT, Gerson L, Hirano I, Nguyen GC, Rubenstein JH, Smalley WE, Stollman N, Sultan S, Vege SS, Wani SB, Weinberg D, Yang YX. American Gastroenterological Association Institute Guideline on the Role of Elastography in the Evaluation of Liver Fibrosis. Gastroenterology. 2017;152(6):1536–1543. doi: 10.1053/j.gastro.2017.03.017. PMID: 28442119
Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. Elsevier, Inc; 2018;16(1):27-38.e4. doi: 10.1016/j.cgh.2017.04.038. PMID: 28479504
Facciorusso A, Del Prete V, Turco A, Buccino RV, Nacchiero MC, Muscatiello N. Long-term liver stiffness assessment in hepatitis C virus patients undergoing antiviral therapy: Results from a 5-year cohort study. J Gastroenterol Hepatol. 2018;33(4):942–949. doi: 10.1111/jgh.14008.
Arima Y, Kawabe N, Hashimoto S, Harata M, Nitta Y, Murao M, Nakano T, Shimazaki H, Kobayashi K, Ichino N, Osakabe K, Nishikawa T, Okumura A, Ishikawa T, Yoshioka K. Reduction of liver stiffness by interferon treatment in the patients with chronic hepatitis C. Hepatol Res. 2010;40(4):383–392. doi: 10.1111/j.1872-034X.2009.00618.x.
Chekuri S, Nickerson J, Bichoupan K, Sefcik R, Doobay K, Chang S, DelBello D, Harty A, Dieterich DT, Perumalswami P V., Branch AD. Liver stiffness decreases rapidly in response to successful hepatitis C treatment and then plateaus. PLoS ONE. 2016;11(7):1–14. doi: 10.1371/journal.pone.0159413. PMID: 27442255
Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, Xuan SY. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: An updated meta-analysis. Hepatology. 2011;53(3):726–736. doi: 10.1002/hep.24105.
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, Sulkowski MS, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–1325. doi: 10.1002/hep.21178. PMID: 16729309
Chen L, Lu XY, Zhu CQ. Prognostic value of albumin-red cell distribution width score in patients with severe community-acquired pneumonia. Ann Palliat Med. 2020 May;9(3):759-765. doi: 10.21037/apm.2020.04.22. Epub 2020 Apr 18. PMID: 32312071.
Evans TC, Jehle D. The red blood cell distribution width. J Emerg Med. 1991;9:71–74. doi: 10.1016/0736-4679(91)90592-4.
Al-Kindi SG, Zidar DA, McComsey GA, Longenecker CT. Association of anisocytosis with markers of immune activation and exhaustion in treated hiv. Pathog Immun. 2017;2(1):138–150. doi: 10.20411/pai.v2i1.199.
Mohamed OSD, Azmy GJ, Elfadl EMA. Clinical significance of red blood cell distribution width in systemic lupus erythematosus patients. Egypt Rheumatol Rehabil. 2020;47(1):38. doi: 10.1186/s43166-020-00037-y.
Ma C, Wang X, Zhao R. Associations of lymphocyte percentage and red blood cell distribution width with risk of lung cancer. J Int Med Res. 2019;47(7):3099–3108. doi: 10.1177/0300060519850417. PMID: 31167586
Higgins JM, Foy BH, Carlson JCT, Reinertsen E, Padros I. Valls R, Pallares Lopez R, Palanques-Tost E, Mow C, Westover MB, Aguirre AD. Association of Red Blood Cell Distribution Width with Mortality Risk in Hospitalized Adults with SARS-CoV-2 Infection. JAMA Netw Open. 2020;3(9):1–13. doi: 10.1001/jamanetworkopen.2020.22058. PMID: 32965501
Afghahi A, Purington N, Han SS, Desai M, Pierson E, Mathur MB, Seto T, Thompson CA, Rigdon J, Telli ML, Badve SS, Curtis CN, West RB, Horst K, Gomez SL, Ford JM, Sledge GW, Kurian AW. Higher absolute lymphocyte counts predict lower mortality from early-stage triple-negative breast cancer. Clin Cancer Res. 2018;24(12):2851–2858. doi: 10.1158/1078-0432.CCR-17-1323. PMID: 29581131
Vicente Conesa MA, Garcia-Martinez E, Gonzalez Billalabeitia E, Chaves Benito A, Garcia Garcia T, Vicente Garcia V, Ayala de la Peña F. Predictive value of peripheral blood lymphocyte count in breast cancer patients treated with primary chemotherapy. The Breast. 2012;21(4):468–474. doi: 10.1016/j.breast.2011.11.002.
Drewry A, Samra N, Skrupky L, Fuller B, Compton S, Hotchkiss R. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42(5):383–391. doi: 10.1097/SHK.0000000000000234. PMID: 25051284
Matos LC, Batista P, Monteiro N, Ribeiro J, Cipriano MA, Henriques P, Girão F, Carvalho A. Lymphocyte subsets in alcoholic liver disease. World J Hepatol. 2013;5(2):46–55. doi: 10.4254/wjh.v5.i2.46. PMID: 23646229
Fernández-Ruiz M, López-Medrano F, Romo EM, Allende LM, Meneu JC, Fundora-Suárez Y, San-Juan R, Lizasoain M, Paz-Artal E, Aguado JM. Pretransplant lymphocyte count predicts the incidence of infection during the first two years after liver transplantation. Liver Transpl. 2009;15(10):1209–1216. doi: 10.1002/lt.21833.
Wang M, Li C, Wen TF, Peng W, Chen LP. Postoperative low absolute lymphocyte counts may predict poor outcomes of hepatocellular carcinoma after liver resection. Chin Med J (Engl). 2016;129(5):536–541. doi: 10.4103/0366-6999.176982. PMID: 26904987
Nagai S, Yoshida A, Kohno K, Altshuler D, Nakamura M, Brown KA, Abouljoud MS, Moonka D. Peritransplant absolute lymphocyte count as a predictive factor for advanced recurrence of hepatitis C after liver transplantation. Hepatology. 2014;59(1):35–45. doi: 10.1002/hep.26536.
Petta S, Maida M, Macaluso FS, Barbara M, Licata A, Craxì A, Cammà C. Hepatitis C Virus Infection Is Associated with Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. Gastroenterology. Elsevier, Inc; 2016;150(1):145-155.e4. doi: 10.1053/j.gastro.2015.09.007.
Badawi A, Di Giuseppe G, Arora P. Cardiovascular disease risk in patients with hepatitis C infection: Results from two general population health surveys in Canada and the United States (2007-2017). PLoS ONE. Public Library of Science; 2018 Dec 12;13(12):e0208839.
Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology. 2002;122(6):1609–1619. doi: 10.1053/gast.2002.33411.
Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodés J. Clinical management of hepatocellular carcinoma. Conclusions of the barcelona-2000 EASL conference. J Hepatol. 2001;35(3):421–430. doi: 10.1016/S0168-8278(01)00130-1.