Hypoalbuminemia: an underestimated, vital characteristic of hospitalized COVID-19 positive patients?

Abstract

The COVID-19 pandemic has led to the greatest worldwide health crisis in decades. The number of infected patients with severe SARS-CoV-2 (COVID-19) disease has overwhelmed the capacity of almost all health care systems around world. Hypoalbuminemia has now been reported in patients with severe disease seeking help in the emergency room because of COVID-19 infection. In the past, hypoalbuminemia was considered to be a negative prognostic marker, not only in patients with chronic liver disease, but also in patients with SARS and MERS infections. Albumin is the major serum protein synthesized by the liver. A low serum albumin level is an ominous clinical sign. Introduction of amino acids to a patient’s diet is of fundamental importance to hepatic albumin synthesis in different clinical situations. This highlights the importance of nutritional support during the early phases of COVID-19-infection. Furthermore, albumin synthesis in the hepatocyte is downregulated at a pretranslational level by the direct interaction of the major acute-phase cytokines which are released into the circulation during the cytokine “storm” induced by the viral effects on the lungs. Both mechanisms contribute to severe hypoalbuminemia which, combined with massive fluid losses due to the fever, is responsible for severe hypovolemia and shock commonly observed in patients with COVID-19 in critical care settings.

Keywords

Severe acute respiratory syndrome cornonavirus 2 / SARS-CoV-2 / COVID-19 / albumin synthesis / nutrition / acute-phase reaction / cytokines / liver / extrahepatic organs

References

[1] Wang Y,Liu W,Zhang L.Discovery of a subgenotype of human coronavirus NL63 associated with severe lower respiratory tract infection in China, 2018..Emerg Microbes Infect2020;9:246-55 PMCID:PMC7034077

[2] Zhou F,Du R,Liu Y.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study..Lancet2020;395:1054-62

[3] Huang C,Li X,Zhao J.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China..Lancet2020;395:497-506 PMCID:PMC7159299

[4] Shi H,Jiang N,Alwalid O.Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study..Lancet Infect Dis2020;20:425-34 PMCID:PMC7159053

[5] Chen T,Chen H,Yang D.Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study..BMJ2020;368:m1091 PMCID:PMC7190011

[6] Wang D,Hu C,Liu X.Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China..JAMA2020;323:1061-9 PMCID:PMC7042881

[7] Zhu N,Wang W,Yang B.A novel coronavirus from patients with pneumonia in China, 2019..N Engl J Med2020;382:727-33 PMCID:PMC7092803

[8] Li Q,Wu P,Zhou L.Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia..N Engl J Med2020;382:1199-1207 PMCID:PMC7121484

[9] Liu Y,Zhang C,Wang F.Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury..Sci China Life Sci2020;63:364-74 PMCID:PMC7088566

[10] Zhang Y,Zhang S,Cao W.Coagulopathy and antiphosphlipid antibodies in Patients with COVID-19..N Engl J Med2020;382:e38 PMCID:PMC7161262

[11] Liu CL,Peng MJ,Lin RL.Clinical and laboratory features of severe acute respiratory syndrome vis-a-vis onset of fever..Chest2004;126:509-17 PMCID:PMC7094461

[12] Leong HN,Lim HH,Tan C.SARS in Singapore--predictors of disease severity..Ann Acad Med Singapore2006;35:326-31

[13] Ko JH,Lee JY,Cho SY.Predictive factors for pneumonia development and progression to respiratory failure in MERS-CoV infected patients..J Infection2016;73:468-75 PMCID:PMC7112644

[14] Leem AY,Kim YS,Won S.Incidence and risk of chronic obstructive pulmonary disease in a Korean community-based cohort..Int J Chron Obstruct Pulmon Dis2018;13:509-17 PMCID:PMC5804735

[15] Zhang J,Jia X,Hu K.Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China..Clin Microbiol Infect2020;Epub ahead of print. doi: 10.1016/j.cmi.2020.04.012 PMCID:PMC7159868

[16] Gong J,Qiu X,Chen Y.A tool to early predict severe corona virus disease 2019 (COVID-19) : a multicenter study using the risk nomogram in Wuhan and Guangdong, China..Clin Infect Dis2020;Epub ahead of print. doi: 10.1093/cid/ciaa443 PMCID:PMC7184338

[17] Cohn EJ,Strong LE,Armstrong SH.Chemical, clinical, and immunological studies on the products of human plasma fractionation. I. the characterization of the protein fractions of human plasma..J Clin Invest1944;23:417-32 PMCID:PMC435357

[18] Scatchard G,Brown A.Chemical,clinical and immunological studies on the products of human plasma fractonation. VI. The osmotic pressure of plasma and of serum albumin..J Clin Investt1944;23:458-64 PMCID:PMC435362

[19] Post J.Serum proteins in relation to liver disorders..Bull N Y Acad Med1943;19:815-30 PMCID:PMC1934020

[20] Thorn GW,Davemport VD.Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXI. The use of salt-poor concentrated human serum albumin solution in the treatment of hepatic cirrhosis..J Clin Invest1946;25:304-23 PMCID:PMC435567

[21] Kunkel HG,Ahrens EH,Hoagland CL.The use of concentrated human serum albumin in the tretment of cirrhosis oft he liver..J Clin Invest1948;27:305-19 PMCID:PMC438869

[22] Wilkinson P.The effect of repeated albumin infusions in patients with cirrhosis..Lancet1962;2:1125-9

[23] Gentilini P,Di Fiore G,Buzzelli G.Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial..J Hepatol1999;30:639-45

[24] Caraceni P,Angeli P,Neri S.Long-term albumin administration in decompensated cirrhosis (ANSWER):an open label randomized trial..Lancet2018;391:2417-29

[25] Patek AJ,Colcher H,Earle DP.The effects of intravenous injection of concentrated human serum albumin upon blood plasma,ascites and renal functions in three patients with cirrhosis oft he liver..J Clin Invest1948;27:135-44

[26] Schindler C.Albumin substitution improves urinary sodium excretion and diuresis in patients with liver cirrhosis and refractory ascites..J Hepatol1999;31:1132

[27] Schindler C.Humanalbumingaben zur Verbesserung der renalen Ausscheidungsfunktion bei Patienten mit therapierefractärem Aszites-Ein Erfahrungsbericht..Leber Magen Darm1999;4:183-7

[28] Nolte W.Albumin for refractory ascites..Gastroenterology2003;125:1283-4

[29] Trotter J,Everson GT.Chronic albumin infusions to achieve diuresis in patients with ascites who are not candidates for transjugular intrahepatic portosystemic shunt(TIPS)..Dig Dis Sci2005;50:1356-60

[30] Bajaj JS,O’Leary JG,Wong F.The impact of albumin use on resolution of hyponatremia in hospitalized patients with cirrhosis..Am J Gastroenterol2018;113:1339

[31] Bai Z,Yoshida EM,Guo X.Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis..Aging (Albany NY)2019;11:8502-25 PMCID:PMC6814610

[32] Kaplan DE,Aytaman A,Fox R.Development and performance of an algorithm to estimate the child-turcotte-pugh score from a national electronic healthcare database..Clin Gastroenterol Hepatol2015;13:2333-41.e1-6 PMCID:PMC4655141

[33] Alberino F,Amodio P,Di Pascoli L.Nutrition and survival in patients with liver cirrhosis..Nutrition2001;17:445-50

[34] Paine CH,Pichler RH.Albumin in cirrhosis: more than a colloid..Curr Treat Options Gastroenterol2019;17:231-43

[35] Wujtewicz M,Aszkiełowicz A,Piwowarczyk S.COVID-19 - what should anaethesiologists and intensivists know about it?.Anaesthesiol Intensive Ther2020;52:34-41

[36] Alhazzani W,Arabi YM,Gong MN.Surviving sepsis campaign:Guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)..Intensive Care Med2020;46:854-87 PMCID:PMC7101866

[37] Elmaouhoub A,Ramadori G.Kinetics of albumin- and alpha-fetoprotein-production during rat liver development..Histochem Cell Biol2007;128:431-43

[38] Fanali G,Trezza V,Fasano M.Human serum albumin: from bench to bedside..Mol Aspects Med2012;33:209-90

[39] Lin L,Zhang Z,Zhang Z.Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection..Gut2020;69:997-1001

[40] Lechien JR,De Siati DR,Le Bon SD.Olfactory and gustatory dysfunctions as clinical presentation of mild-to-moderate forms of the coronavirus disease(COVID-19): a multicenter European study..Eur Arch Otorhinolaryngol2020;1-11 PMCID:PMC7134551

[41] Lovato A.Clinical presentation of COVID-19: a systematic review focusing on upper airway symptoms..Ear Nose Throat J2020;145561320920762

[42] Russell B,Rigg A,Papa S.Anosmia and ageusia are emerging as symptoms in patients with COVID-19: what does the current evidence say?.Ecancermedicalscience2020;14:ed98 PMCID:PMC7134577

[43] Baker T,Petersen DB,Khalid K.Essential care of critical illness must not be forgotten in the COVID-19 pandemic..Lancet2020;395:1253-4

[44] Dreher M,Bickenbach J,Hartmann B.Charakteristik von 50 hospitalisierten COVID-19-Patienten mit und ohne ARDS..Deutch Arztebl Int2020;117:271-8

[45] Ramadori G.Cytokines and the hepatic acute-phase response..Semin Liver Dis1999;19:141-55

[46] Buckley MM,Devlin M,Rae MG.Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague-Dawley rats..Exp Physiol2016;101:1477-91

[47] Goto J,Harii N,Yanagisawa M.Usefulness of a real-time bowel sound analysis system in patients with severe sepsis (pilot study)..J Artif Organs2015;18:86-91

[48] Groves HT,Moffatt MF,Tregoning JS.Respiratory Viral Infection Alters the Gut Microbiota by Inducing Inappetence..mBio2020;11:e03236-19 PMCID:PMC7029140

[49] Ramadori G,Dinarello CA,Colten HR.Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1..J Exp Med1985;162:930-42 PMCID:PMC2187799

[50] Ahmad G,Ramadori P,Batusic DS.Changes of hepatic lactoferrin gene expression in two mouse models of the acute phase reaction..Int J Biochem Cell Biol2011;43:1822-32

[51] Sultan S,Ahmad S,Bianchi A.LIPOCALIN-2 is a major acute-phase protein in a rat and mouse model of sterile abscess..Shock2012;37:191-6

[52] Sheikh N,Ramadori G.Changes of gene-expression of iron regulatory proteins during turpentin-oil induced acute-phase response in the rat..Lab Invest2007;87:713-25

[53] Sheikh N,Dudas J,Neubauer K.Hepcidin and hemojuvelin gene expression in rat liver damage: in vivo and in vitro studies..Am J Physiol Gastrointest Liver Physiol2006;291:G482-90

[54] Christiansen H,Saile B,Rave-Fränk M.x-Irradiation in rat liver: consequent upregulation of hepcidin and downregulation of hemojuvelin and ferroportin-1 gene expression..Radiology2007;242:189-97

[55] Moriconi F,Ramadori P,Sheikh N.Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver..Lab Invest2009;89:1252-60

[56] Sheikh N,Dudas J.Cytokine-induced neutrophil chemoattractant-1 is released by the noninjured liver in a rat acute-phase model..Lab Invest2006;86:800-14

[57] Ramadori P,Ahmad G,Ramadori G.Hepatic changes of erythropoietin gene expression in a rat model of acute-phase response..Liver Int2010;30:55-64

[58] Tron K,Dudas J,Kietzmann T.Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6..Lab Invest2005;85:376-87

[59] Krause A,Mägert HJ,Forssmann WG.LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity..FEBS Lett2000;480:147-50

[60] Ruot B,Rambourdin F,Capitan P.Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis..Am J Physiol Endocrinol Metab2000;279:E244-51

[61] Flaim KE,Peavy DE,Jefferson LS.The role of amino acids in the regulation of protein synthesis in perfused rat liver. II. Effects of amino acid deficiency on peptide chain initiation, polysomal aggregation, and distribution of albumin mRNA..J Biol Chem1982;257:2939-46

[62] Lee JL,Lee RW.Serum albumin and prealbumin in calorically restricted, nondiseased individuals: a systematic review..Am J Med2015;128:1023.e1-22

[63] Ramadori G,Colten HR.Expression and regulation of the murine serum amyloid A (SAA) gene in extrahepatic sites..J Immunol1985;135:3645-7

[64] Perez L.Acute phase protein response to viral infection and vaccination..Arch Biochem Biophys2019;671:196-202 PMCID:PMC7094616

[65] Zhou Y,Tian J.Risk factors associated with disease progression in a cohort of patients infected with the 2019 novel coronavirus..Ann Palliat Med2020;9:428-36

[66] Chen L,Bao L.Convalescent plasma as a potential therapy for COVID-19..Lancet Infect Dis2020;20:398-400 PMCID:PMC7128218

[67] Shen C,Zhao F,Li J.Treatment of 5 critically ill patients with COVID-19 with convalescent plasma..JAMA2020;323:1582-9 PMCID:PMC7101507

[68] Duan K,Li C,Yu T.Effectivness of convalescent plasma therapy in severe COVID-19 patients..Proc Natl Acad Sci2020;117:9490-6 PMCID:PMC7196837

[69] Zhang B,Tan T,Dong Y.Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection..Chest2020;Epub ahead of print. doi: 10.1016/j.chest.2020.03.039 PMCID:PMC7101507

[70] Bloch EM,Casadevall A,Shaz B.Deployment of convalescent plasma fro prevention and treatment of COVID-19..J Clin Invest2020;Epub ahead of print. doi: 10.1172/JCI138745

[71] Roback JD.Convalescent plasma to treat COVID-19: possibilities and challenges..JAMA.2020;Epub ahead of print. doi: 10.1001/jama.2020.4940