Impact Of Acute-on-chronic Liver Failure And Decompensated Liver .

(2020) 18:10Nagel et al. Health and Quality of Life Outcomesstress [5]. The quality of life of relatives and caregiverswas assessed using the SF-36 questionnaire [9].EthicsThe study was conducted according to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision,2008). The study protocol was approved by the ethicscommittee of the Landesärztekammer RhinelandPalatine (Nr. 837.232.17 [11066]). Written informedconsent was obtained from every participant.Page 3 of 7CLDQ is severely impaired in patients with ACLFQuality of life of patients with ACLF and decompensatedcirrhosis was assessed by CLDQ. (Table 2 and 3). In patientswith acute-on-chronic liver failure quality of life was significantly impaired compared to patients with decompensatedliver cirrhosis (4,38 1,14 vs. 3,67 0,91; p value: 0,02). Inparticular burden from systematic symptoms (4,5 1,6 vs.3,3 1,3; p value: 0,004) and worries (4,5 1,3 vs. 3,6 1,2;p value 0,008) was higher in patients with ACLF.Patient’s quality of life is associated with degree of organfailureStatistical analysisThe statistical analyses were performed with SPSS Version23. Continuous variables are presented as means withstandard deviation. Categorial variables are presented asfrequencies and percentages. Categorial variables werecompared using Chi-Quadrat test or fisher’s exact test,and continuous variables were compared using student’sT–Test or Mann-Whitney U-Test. P Value below 0.05was considered to be statistically significant.The maximum Organ Failure Score during the inpatientstay was calculated for the patients (Table 4). The OFscore correlates with patients’ quality of life. There is asignificant correlation between quality of life issues suchas fatigue (r 0,294, p value 0,002), emotional function(r 0,270, p value: 0,003), worry (r 0,420, p value: 0,0001), activity (r 0,256, p value: 0,004) and systematic symptoms (r 0,358; p value: 0,003) with theOF score in ACLF patients.ResultsPatient baseline characteristicsA total of 63 patients were included. 21 patients hadACLF and 42 patients had decompensated liver cirrhosiswithout meeting the ACLF criteria. Alcohol liver cirrhosiswas the most common underlying cause of liver cirrhosis(21% for ACLF vs. 41% for decompensated liver cirrhosis)followed by NASH associated liver cirrhosis (10% forACLF vs. 16% for decompensated liver cirrhosis). Therewas no significant difference between ACLF and decompensated liver cirrhosis with respect to the etiology of livercirrhosis (P value: 0,7). Patients with ACLF had significantly higher MELD (15 6 vs. 22 7) and organ failurescores (7 1 vs. 10 2) than patients with decompensatedliver cirrhosis (P value: 0,001) (Table 1).The psychosocial burden and quality of life of closerelative is independent of the presence of an ACLFPsychosocial stress and quality of life of relatives were alsoassessed and compared between patients with decompensated cirrhosis and ACLF (Table 5). Interestingly, no significant differences were found in the investigated patientpopulation. There was no significant difference in both psychosocial stress and quality of life in caregivers measuredby physical, psychical, mental, and social strength. However,the univariate analysis showed a correlation with the age(OR: 0,35; p value: 0,049; 95%-CI: 0,69- 0,001) of theclose relatives, sodium of patients (OR: 0,87; p value: 0,04;95%-CI: 1,7 - 0,03) and the occurrence of hepatic encephalopathy (OR: 10,6; p value: 0,02; 95%-CI: 2,05-19,13).Table 1 Patient characteristics. The most common etiology was alcoholic liver cirrhosis (41% vs. 22%) in both groups followed byNASH (16% vs. 10%; p value 0,7). Impairment of liver function was higher in patients with ACLF measured by MELD Score (15 6 vs.22 7; p value 0,001) and Organ Failure Score (7 1 vs. 10 2; p value 0,001)ParameterDecompensated liver cirrhosis(N 42)Acute-on-chronic liver failure(N 21)Male Gender (N; %)25 (40%)13 (21%)0,9Age (years) (MEAN; SD)58 1458 100,9alcoholic (N; %)26 (41%)14 (22%)cryptogen/NASH (N; %)10 (16%)6 (10%)Viral (N; %)3 (5%)0 (0%)EtiologyP Value0,7cholestatic/ autoimmune (N; %)2 (3%)1 (2%)metabolic/hereditary (N; %)1 (2%)0 (0%)MELD (MEAN; SD)15 622 7 0,001Organ Failure Score (MEAN; SD)7 110 2 0,001

Nagel et al. Health and Quality of Life Outcomes(2020) 18:10Page 4 of 7Table 2 Shows the quality of life of patients with aspects of fatigue, emotional function, worries, abdominal symptoms, activity andsystemic symptoms assessed by CQLD. Patients with ACLF showed a significantly reduced quality of life in terms of worry (4,48 1,3vs. 3,57 1,2) and systemic symptoms (4,48 1,6 vs. 3,29 1,2)ParameterDecompensated liver cirrhosis(N 42)Acute-on-chronic liver failure(N 21)P ValueFatigue (MEAN; SD)3,98 1,123,76 1,090,5Emotional Function (MEAN; SD)4,24 1,143,67 1,070,06Worries (MEAN; SD)4,48 1,273,57 1,170,008Abdominal symptoms (MEAN; SD)4,43 1,43,9 1,220,2Activity (MEAN; SD)4,43 1,314,1 1,550,4Systemic symptoms (MEAN; SD)4,48 1,583,29 1,190,004Total Quality of Life (MEAN; SD)4,33 1,143,67 0,910,02The presence of ACLF or impaired liver function had no effect on the psychosocial burden of the close relatives. Incontrast, there was a clearly significant association with patient’s quality of life with psychosocial stress of relatives. Fatigue (OR: 6,5; p value: 0,0004; 95%-CI: 9,7- --3,2),emotional function (OR: 7,5; p value: 0,0001; 95%-CI: 10,2 - -4,6), worries (OR: 7,2; p value: 0,0001; 95%-CI: 9,6 - -4,8), abdominal symptoms (OR: 5,1; p value: 0,0002;95%-CI: 7,7 - -2,6) as well as activity (OR: 5,7; p value: 0,0001; 95%-CI: 8,1 - -3,2) and systematic symptoms(OR: 0,3; p value: 0,002; 95%-CI: 0,5 - 0,13) showed asignificant association with psychosocial burden in caregivers and close relatives (Table 6).DiscussionIn this prospective cohort study, the influence of acuteon chronic liver failure on the quality of life of patientsand their relatives was investigated for the first time. Patients with ACLF showed a significantly lower quality oflife compared to the control group. In particular, thesub-domains of worries and systematic symptoms weredecisive in patients with ACLF. That quality of life is animportant factor in patients with chronic liver diseases,which has been shown in several studies [2]. Patientswith decompensated liver cirrhosis show significantlyworse values for quality of life. In our collective the patients with ACLF showed a higher MELD value and thusa more impaired liver function than the comparisongroup. Interestingly, the Organ Failure Score also correlates with quality of life. All subdomains of quality of lifeexcept abdominal symptoms show a significant correlation with the OF score. The OF score covers renal, hepatic, respiratory, cognitive, cardio-circulatory andcoagulation functions. By definition, this function ismore often limited in patients with ACLF than in patients with decompensated liver cirrhosis. As a systemicdisease, ACLF has a much greater impact on the qualityof life of patients. This systematic disease is mainly responsible for the significant limitation of the subdomainof systematic symptoms. Often younger patients withpreviously unknown liver cirrhosis suffer from ACLF inTable 3 Shows the univariate analysis in patients with ACLF. Inaddition to clinical factors such as CHILD status (p value: 0,03),hepatorenal syndrome as a cause of decompensation (p value:0,007), duration of hospitalization (p value: 0,03) and intensivecare therapy (p value: 0,04), the analysis also showed aninfluence on patients’ quality of life. The partial aspect ofpatient’s worries shows a significant association with thepresence of ACLF (p value: 0,04)Table 4 Shows the correlation of the individual aspects of thepatients’ quality of life with the Organ Failure score. All partialaspects except abdominal symptoms like fatigue (r 0,294; pvalue: 0,02), emotional function (r 0,27; p value: 0,03), worries(r 0,42; p value: 0,001), activity (r 0,256; p value: 0,042)and systemic symptoms ( 0,358; p value: 0,003) showed asignificant correlation with organ failure scoreUnivariant analysis - ACLFParameterCorrelationP ValueParameterP ValueFatigue- 0,2940,02OR95% - CICorrelation with Organ Failure ScoreCHILD Status0,440,2110,9310,03Emotional function- 0,2700,03hepatorenal syndrome20,52314181,5960,007Worries- 0,420 0,001worries of patient1,79113328170,01Abdominal symptoms- 0,1520,2Duration of hospitalization0,940,8860,9940,03Activity- 0,2560,04ICU therapy0,160,0280,9110,04Systemic symptoms- 0,3580,003

Nagel et al. Health and Quality of Life Outcomes(2020) 18:10Page 5 of 7Table 5 Showed the quality of life of the relatives and the psychosocial burden. There is no difference between the quality of lifeand psychosocial burden of relatives of patients with ACLF or decompensated cirrhosisParameterDecompensated liver cirrhosis(N 42)Acute-on-chronic liver failure(N 21)P ValuePsychosocial burden of relatives (MEAN; SD)19,9 11,525,9 14,10,18physical strength of relatives (MEAN; SD)77,5 18,969,5 21,90,27mental strength of relatives (MEAN; SD)67,2 12,961,6 11,90,19social strength of relatives (MEAN; SD)68,4 15,265,4 19,30,62Environmental strength of relatives (MEAN; SD)77,5 14,870,6 16,40,21the sense of an initial diagnosis [10]. These patients haveoften not yet been able to deal adequately with their disease. In addition, many of these patients lack basic information about their disease. This is a possible cause ofthe reduced sub-domain of concern in these patients.These results have provided initial evidence that patientswith ACLF suffer from a significantly reduced quality oflife. In recent years awareness of impaired quality of lifein patients with chronic liver disease, in particular livercirrhosis has increased. The extent of the limitation ofquality of life is directly related to the severity of theunderlying liver disease [11, 12]. Especially in patientswith refractory ascites degree of quality of life impairment has been shown to provide valuable informationon 1-year mortality [3].Besides the reduced quality of life of the patients, wewere one of the first to show that the relatives of patients with ACLF suffer from a reduced quality of life.Both the psychological and physical strength of the relatives was reduced in our study. In addition, we were ableTable 6 Shows the univariate analysis of psychosocial burdenof relatives. Interestingly, there is a significant influence of thepatient’s age (p value: 0,05), sodium (p value: 0,04) and hepaticencephalopathy (p value: 0,02) on the psychosocial burden ofthe relative. In addition, all aspects of impaired quality of life ofpatients such as fatigue (p value: 0,0004), emotional function (pvalue: 0,00001), worries (p value: 0,00001), abdominalsymptoms (p value: 0,0002), patient activity (p value: 0,00005)and systemic symptoms (p value: 0,002) are associated withincreased psychosocial stress in relativesUnivariate analysis – psychosocial burden of relativesParameterOR95% - CIAge 0,35-0,690-0,001P ValueSodium-0,87 1704 0,030 0,04hepatic encephalopathy10,5920,54419,125 3179 0,00040,050,02fatigue of patient 6,52 9869Emotional function of patient 7,48 10,333 4622 0,0001worries of patient 7238 9618Abdominal symptoms of patients 5,14 7669 4847 0,0001 2611 0,0002Activity of patient 5,66 8126 3188 0,0001Systemic symptoms of patient 0,32 0,510 0,129 0,002to show that the psychosocial burden on the relatives ofpatients with ACLF is also significantly elevated. This reduced quality of life has an impact of the clinical courseof the patients. Frequently, relatives are the first whoregister initially subtle changes in patients, for examplein hepatic encephalopathy, and initiate first steps of therapy [13]. Studies on psychosocial stress of caregivers inchronic diseases such as dementia or ALS have shownthat the degree of psychosocial stress even correlateswith mortality in relatives and caregivers [14]. Investigations of psychosocial burden on relatives of patients withliver cirrhosis are rare. Bajaj et al. were able to show significant amounts of stress in relatives of patients withcirrhosis of the liver [6], especially if an episode of hepatic encephalopathy had preceded. In our study evenhigher levels of psychosocial stress were measured. Onthe one hand, this could be due to the fact that in ourstudy all patients were recruited during inpatient treatment for acute decompensation of liver cirrhosis andwere severely ill, with a significance percentage of patients with ACLF. Similar tendencies could be observedin all areas of quality of life of relatives. Our study provides early insights into the psychosocial burden and ondaily quality of life in caregivers and relatives of patientswith liver cirrhosis. So far to our knowledge noevidence-based interventions to support close relativesof patients with liver cirrhosis have been developed,however our data prove the need to not only care forthese patients but also consider the burden placed onclose relatives.And we were also able to show in our study that thequality of life of the patient is closely correlated with thepsychosocial stress of the relatives. All sub-domains of thequality of life showed a significant influence on the psychosocial load. Especially the limited activity, the worriesand the emotional function correlate with the psychosocial stress. It is known that especially cognitive defectsand reduction of vigilance, as in hepatic encephalopathy,have an influence on the psychosocial burden on relatives[15]. In our study the presence of hepatic encephalopathywas confirmed as an influencing factor to increase theburden on relatives. Hyponatremia is also a factor whichwas significantly associated with reduction of quality of

Nagel et al. Health and Quality of Life Outcomes(2020) 18:10Page 6 of 7life. Hyponatremia is often associated with advanced liverinsufficiency and reduced vigilance. The combination offrequent and increased physical symptoms as well as thesignificantly reduced quality of life in patients with ACLFhave a particularly strong influence on the quality of lifeand psychosocial stress of relatives.It must be said that this is a small cohort of patients.Although there is a clear trend towards a restricted quality of life among relatives, but without significance. Thesmall number of cases certainly plays a role here. Inaddition, patients with ACLF show significantly poorerliver function from the outset, so that this study shouldbe repeated on a larger collective with matching by liverfunction. Nevertheless, we were able to show first indications of quality of life and psychosocial stress in patientswith ACLF and their relatives. Influencing the quality oflife and psychosocial stress should be an elementary partof the therapy of this patient. In order to improve theprognosis of these patients, greater emphasis should beplaced on disease management and above all on trainingrelatives to prevent elementary complications.Ethics approval and consent to participateThe study was conducted according to the ethical guidelines of the 1975Declaration of Helsinki (6th revision, 2008). The study protocol was approvedby the ethics committee of the Landesärztekammer Rhineland-Palatine (Nr.837.232.17 [11066]). Written informed consent was obtained from everyparticipant.ConclusionPatients with acute-on-chronic liver failure suffer from asevere impairment in quality of life. This impairment isassociated with the severity of organ failure measured bythe Organ Failure Score. Close relatives and caregiversof patients with decompensated liver cirrhosis and ACLFsuffer from psychosocial stress and impaired quality oflife which is associated with severeness of impairment inpatients with liver cirrhosis. Future research shouldfocus not only on functional and psychosocial impairment in patients with liver cirrhosis but also on the development of evidence-based interventions to supportclose relatives of patients with liver cirrhosis.References1. Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J,Murray CJ, Naghavi M. Liver cirrhosis mortality in 187 countries between1980 and 2010: a systematic analysis. BMC Med. 2014;12:145.2. Janani K, Jain M, Vargese J, Srinivasan V, Harika K, Michael T, Venkataraman J.Health-related quality of life in liver cirrhosis patients using SF-36 and CLDQquestionnaires. Clin Exp Hepatol. 2018;4(4):232–9.3. Macdonald S, Jepsen P, Alrubaiy L, Watson H, Vilstrup H, Jalan R. 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Mindfulness-Based Stress Reduction TherapyImproves Patient and Caregiver-Reported Outcomes in Cirrhosis. Clin TranslGastroenterol. 2017;8(7):e108.8. Schulz KH, Kroencke S, Ewers H, Schulz H, Younossi ZM. The factorialstructure of the Chronic Liver Disease Questionnaire (CLDQ). Qual Life Res.2008;17(4):575–84.9. de Oliveira GR, Neto JF, de Camargo SM, ALG L, DCM E, Lucchetti G.Caregiving across the lifespan: comparing caregiver burden, mental health,and quality of life. Psychogeriatrics. 2015;15(2):123–32.10. Hernaez R, Solà E, Moreau R, Ginès P. Acute-on-chronic liver failure: anupdate. Gut. 2017;66(3):541–53.11. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, LoguercioC, Apolone G, Niero M, Abbiati R, I.S.G.f.q.o.l.i. cirrhosis. Factors associatedwith poor health-related quality of life of patients with cirrhosis.Gastroenterology. 2001;120(1):170–8.12. Martin LM, Sheridan MJ, Younossi ZM. The impact of liver disease on healthrelated quality of life: a review of the literature. Curr Gastroenterol Rep.2002;4(1):79–83.13. Künzler-Heule P, Beckmann S, Mahrer-Imhof R, Semela D, Händler-SchusterD. Being an informal caregiver for a relative with liver cirrhosis and overtAbbreviationsACLF: Acute on chronic liver failure; CLDQ: Chronic liver diseasequestionnaire; CLIF Consortium: Foundation for the study of chronic liverfailure; INR: International normalized ratio; OF Score: Organ failure score; SF36: Short form health surveyAcknowledgementsWe thank V. Weidner for excellent data collection.Authors’ contributionsPerformed research: MN. Contributed to acquisition of data: MN; Designedthe experiments and analyzed the data: MN, CL, JMS; JUM. Contributedreagents/materials/analysis tools: MN; PRG; MAW. Wrote the paper: MN; MNT. Statistical analysis: MN. All authors approved the final version of the manuscript and the authorship list. Guarantor of the article: MN-T.FundingThis work was not supported by any grant or funding source.Availability of data and materialsThe data supporting the conclusion of this article are includes within thearticle. Any queries regarding these data may be directed to thecorresponding author.Consent for publicationAuthors have agreed to submit it in its current form for consideration forpublication in the journal.Competing interestsThe authors declare that they have no competing interests.Author details1First Department of Medicine, University Medical Center Mainz of theJohannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz,Germany. 2Cirrhosis Center Mainz (CCM), University Medical Center of theJohannes Gutenberg-University Mainz, Mainz, Germany. 3LichtenbergResearch Group for Molecular Hepatocarcinogenesis, University MedicalCenter of the Johannes Gutenberg-University Mainz, Mainz, Germany.4Metabolic Liver Research Program, University Medical Center of theJ

Chronic liver disease is a relevant cause of morbidity and mortality worldwide. Every year, more than one mil-lion patients die worldwide as a result of liver cirrhosis [1]. In particular the acute-on-chronic liver failure is as-sociated with a bad outcome. Due to the high short-term mortality, acute-on-chronic liver failure is not only