Acute-on-chronic liver failure: A complex clinical entity in patients with autoimmune hepatitis
2021; Elsevier BV; Volume: 75; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2021.06.035
ISSN1600-0641
AutoresAlessandro Granito, Paolo Muratori, Luigi Muratori,
Tópico(s)Liver Disease and Transplantation
ResumoIn their comprehensive and stimulating review, Moreau et al. report the distinctive features of "acute-on-chronic liver failure" (ACLF) based on different geographic definitions (European, North American, Chinese, Asian Pacific) and suggest that ACLF should be considered a unique clinical syndrome.[1]Moreau R. Gao B. Papp M. Bañares R. Kamath P.S. Acute-on-chronic liver failure: a distinct clinical syndrome.J Hepatol. 2021 Jul; 75: S27-S35Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar However, in discussing hallmarks, causes and precipitating factors of ACLF, they do not consider the case of autoimmune hepatitis (AIH), which can initiate as acute hepatitis in more than 40% of cases.[2]Muratori P. Carbone M. Stangos G. Perini L. Lalanne C. Ronca V. et al.Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: an Italian multicentre study.Dig Liver Dis. 2018; 50: 698-702Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar It is well recognized that AIH patients may develop ACLF either as hyperacute exacerbation of undiagnosed or misdiagnosed AIH, or in response to a second exogenous insult (viral, drug-induced, toxic) on typical AIH, possibly favored by long-term immunosuppression.3Zhang X. Chen P. Gao H. Hao S. Yang M. Zhao H. et al.Bacterial infection and predictors of mortality in patients with autoimmune liver disease-associated acute-on-chronic liver failure.Can J Gastroenterol Hepatol. 2018 Jan 28; 2018: 5108781Crossref PubMed Scopus (8) Google Scholar, 4Anand L. Choudhury A. Bihari C. Sharma B.C. Kumar M. Maiwall R. et al.Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.Hepatology. 2019; 70: 587-596Crossref PubMed Scopus (31) Google Scholar, 5Sharma S. Agarwal S. Gopi S. Anand A. Mohta S. Gunjan D. et al.Determinants of outcomes in autoimmune hepatitis presenting as acute on chronic liver failure without extrahepatic organ dysfunction upon treatment with steroids.J Clin Exp Hepatol. 2021; 11: 171-180Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar To mitigate the risk of ACLF in patients with AIH, international practice guidelines call for vaccination against HAV and HBV at the time of diagnosis and the prudent use of any additional medication.[6]European Association for the Study of the LiverEASL clinical practice guidelines: autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar,[7]Mack C.L. Adams D. Assis D.N. Kerkar N. Manns M.P. Mayo M.J. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (133) Google Scholar Nevertheless, these cautions are not uniformly effective due to the often subclinical asymptomatic course of AIH,[8]Muratori P. Lalanne C. Barbato E. Fabbri A. Cassani F. Lenzi M. et al.Features and progression of asymptomatic autoimmune hepatitis in Italy.Clin Gastroenterol Hepatol. 2016; 14: 139-146Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar uncertain adherence to recommended vaccinations, and medication restrictions. Available data on patients with AIH-related cirrhosis are heterogeneous and describe a dichotomy: optimal results with survival rates similar to that of patients without cirrhosis for some, dreadful outcomes for others, delaying or even precluding liver transplantation. In this regard, it is worth mentioning the rare published experiences of ACLF associated with AIH.3Zhang X. Chen P. Gao H. Hao S. Yang M. Zhao H. et al.Bacterial infection and predictors of mortality in patients with autoimmune liver disease-associated acute-on-chronic liver failure.Can J Gastroenterol Hepatol. 2018 Jan 28; 2018: 5108781Crossref PubMed Scopus (8) Google Scholar, 4Anand L. Choudhury A. Bihari C. Sharma B.C. Kumar M. Maiwall R. et al.Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.Hepatology. 2019; 70: 587-596Crossref PubMed Scopus (31) Google Scholar, 5Sharma S. Agarwal S. Gopi S. Anand A. Mohta S. Gunjan D. et al.Determinants of outcomes in autoimmune hepatitis presenting as acute on chronic liver failure without extrahepatic organ dysfunction upon treatment with steroids.J Clin Exp Hepatol. 2021; 11: 171-180Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar A small Chinese study showed that ACLF in autoimmune liver disease (40% with AIH) was associated with significant 28- and 90-day mortality rates (approximately 40% and 75%, respectively).[3]Zhang X. Chen P. Gao H. Hao S. Yang M. Zhao H. et al.Bacterial infection and predictors of mortality in patients with autoimmune liver disease-associated acute-on-chronic liver failure.Can J Gastroenterol Hepatol. 2018 Jan 28; 2018: 5108781Crossref PubMed Scopus (8) Google Scholar Of relevance, 76% of patients with ACLF already had a documented bacterial infection prior to hospital admission, the most common sites being the respiratory tract (42.5%) and peritoneum (22.5%). The study by Anand et al.[4]Anand L. Choudhury A. Bihari C. Sharma B.C. Kumar M. Maiwall R. et al.Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.Hepatology. 2019; 70: 587-596Crossref PubMed Scopus (31) Google Scholar failed to identify a precipitating factor in over 80% cases, and Sharma et al.[5]Sharma S. Agarwal S. Gopi S. Anand A. Mohta S. Gunjan D. et al.Determinants of outcomes in autoimmune hepatitis presenting as acute on chronic liver failure without extrahepatic organ dysfunction upon treatment with steroids.J Clin Exp Hepatol. 2021; 11: 171-180Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar documented in their report that more than half of their patients suffered an acute exacerbation as a consequence of tapering immunosuppression (Table 1).Table 1Studies assessing ACLF in patients with AIH.StudyAIH-ACLF patients, nACLF criteriaPrecipitating factorTreatmentTreatment response90-day survivalZhang et al. (2018)21APCCMI•76% of total ACLF patients had bacterial infectionNot reported@No specific ACLF treatment has been reported other than antibacterial agents.Not reported75%Anand et al. (2019)82APASL•83% no identifiable cause•10% DILI•7% viral infection34% patients received corticosteroidsˆ40 mg prednisolone daily for a period of 1 month, followed by tapering dose. The remaining patients (66%), with active sepsis, spontaneous bacterial peritonitis, history of active bleed, acute kidney injury, human immunodeficiency virus seropositivity, medically uncontrolled essential hypertension, were not considered for corticosteroid therapy.significantly improved 90-day survival°Patients who received steroids had significantly better 90-day survival (75%) compared to patients not receiving corticosteroids (48%) and without baseline sepsis (p = 0.09). The median length of ICU stay in the steroid group was significantly lower compared to those not receiving steroids (p <0.0001). In the steroid group, 18% died of sepsis, 7% patients developed hepatic encephalopathy followed by progressive liver failure. In non-steroid group, 22% patients died of progressive liver failure; 17% died of sepsis, and in the remaining 13% patients, the cause of death was not mentioned.75%°Patients who received steroids had significantly better 90-day survival (75%) compared to patients not receiving corticosteroids (48%) and without baseline sepsis (p = 0.09). The median length of ICU stay in the steroid group was significantly lower compared to those not receiving steroids (p <0.0001). In the steroid group, 18% died of sepsis, 7% patients developed hepatic encephalopathy followed by progressive liver failure. In non-steroid group, 22% patients died of progressive liver failure; 17% died of sepsis, and in the remaining 13% patients, the cause of death was not mentioned.Sharma et al. (2021)48APASL•52% AIH flare•4% DILI•4% HEV60% patients received corticosteroids69% patients required steroid discontinuation#Indications for discontinuation were infection in 60% of patients, followed by no improvement/deterioration in clinical/biochemical parameters in 40% of patients.55%ACLF, acute-on-chronic liver failure; AIH, autoimmune hepatitis; APASL, The Asian Pacific Association for the Study of the Liver; APCCMI, Asia-Pacific Congress of Clinical Microbiology and infection (13th Asia-Pacific congress of clinical microbiology and infection consensus guidelines for diagnosis and treatment of liver failure. Hepatobiliary & Pancreatic Diseases International 2013;12:346–354); DILI, drug-induced liver injury.@ No specific ACLF treatment has been reported other than antibacterial agents.ˆ 40 mg prednisolone daily for a period of 1 month, followed by tapering dose. The remaining patients (66%), with active sepsis, spontaneous bacterial peritonitis, history of active bleed, acute kidney injury, human immunodeficiency virus seropositivity, medically uncontrolled essential hypertension, were not considered for corticosteroid therapy.° Patients who received steroids had significantly better 90-day survival (75%) compared to patients not receiving corticosteroids (48%) and without baseline sepsis (p = 0.09). The median length of ICU stay in the steroid group was significantly lower compared to those not receiving steroids (p <0.0001). In the steroid group, 18% died of sepsis, 7% patients developed hepatic encephalopathy followed by progressive liver failure. In non-steroid group, 22% patients died of progressive liver failure; 17% died of sepsis, and in the remaining 13% patients, the cause of death was not mentioned.# Indications for discontinuation were infection in 60% of patients, followed by no improvement/deterioration in clinical/biochemical parameters in 40% of patients. Open table in a new tab ACLF, acute-on-chronic liver failure; AIH, autoimmune hepatitis; APASL, The Asian Pacific Association for the Study of the Liver; APCCMI, Asia-Pacific Congress of Clinical Microbiology and infection (13th Asia-Pacific congress of clinical microbiology and infection consensus guidelines for diagnosis and treatment of liver failure. Hepatobiliary & Pancreatic Diseases International 2013;12:346–354); DILI, drug-induced liver injury. The appropriate treatment for patients with AIH who develop ACLF remains a critical issue.[9]Rahim M.N. Miquel R. Heneghan M.A. Approach to the patient with acute severe autoimmune hepatitis.JHEP Rep. 2020; 2: 100149Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The finding of hepatic inflammatory activity in patients with cirrhosis necessitates steroid treatment, as failure to normalize histological inflammation is associated with progressive fibrosis and worse overall survival; however, the impact of immunosuppressive therapy on the overall outcome may be marginal at best and may increase the risk of drug-related side effects. International guidelines[6]European Association for the Study of the LiverEASL clinical practice guidelines: autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar,[7]Mack C.L. Adams D. Assis D.N. Kerkar N. Manns M.P. Mayo M.J. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (133) Google Scholar suggest treating all patients with cirrhosis and a certain degree of histological inflammation for at least 1 week. A further issue worth considering is that akin to patients with fulminant AIH, a significant proportion of patients with AIH who develop ACLF can be seronegative; therefore, to support the diagnosis, before initiating steroid treatment, histological assessment through the transjugular approach is strongly recommended when a severe coagulopathy is present.[4]Anand L. Choudhury A. Bihari C. Sharma B.C. Kumar M. Maiwall R. et al.Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.Hepatology. 2019; 70: 587-596Crossref PubMed Scopus (31) Google Scholar,[6]European Association for the Study of the LiverEASL clinical practice guidelines: autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar Even if poor liver function (high MELD/Child-Pugh scores) is associated with an unfavorable response to corticosteroid therapy, as a general recommendation, a short (1-2 weeks depending on clinical status and treatment response) trial of steroids (prednisone or prednisolone, 0.5–1 mg/kg daily in adults and up to 2 mg/kg in children) should be initiated when there is documented inflammatory activity based on liver biopsy results and when no active sepsis is detected.[7]Mack C.L. Adams D. Assis D.N. Kerkar N. Manns M.P. Mayo M.J. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (133) Google Scholar A recent study shows that the significant drop of the MELD score after the first 7 days of high-dose steroid treatment is typically observed in complete responders who will not need liver transplant.[10]Noguchi F. Chu P-s Yoshida A. Taniki N. Morikawa R. Hasegawa Y. et al.Early dynamics of MELD scores predict corticosteroid responsiveness to severe acute-onset autoimmune hepatitis.Clin Gastroenterol Hepatol. 2021 Jun 5; (S1542-3565(21)00609-1)Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This practical approach should be validated by international consortia in a multicenter study, to acquire knowledge on the treatment of this serious complication of AIH. The authors received no financial support to produce this manuscript. AG, PM, and LM analyzed and interpreted the patient data. AG was a major contributor in writing the manuscript. All authors read and approved the final manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.18 MB) Help with pdf files Multimedia component 1 Acute-on-chronic liver failure: A distinct clinical syndromeJournal of HepatologyVol. 75PreviewThere are different operating definitions for acute-on-chronic liver failure (ACLF) in different geographic regions. Consortia in Western countries have developed definitions that apply to patients with cirrhosis, while consortia in Asia have developed definitions that apply to patients with chronic liver diseases with or without cirrhosis. Investigators of the Chinese and Western Consortia believe that ACLF can be precipitated by acute insults that are intrahepatic (e.g. alcoholic hepatitis) or extrahepatic (e.g. Full-Text PDF
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