Simon C. Ling

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. Clinical practice guidelines are defined as “systematically developed statements to assist practitioner and patient decisions about appropriate heath care for specific clinical circumstances.”1 (All references are available in the Supporting Information.) These guidelines on autoimmune hepatitis provide a data-supported approach to the diagnosis and management of this disease. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines;2 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines;3 and (4) the experience of the authors in the specified topic. These recommendations, intended for use by physicians, suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting the recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation.4 The grading system applied to the recommendations has been adapted from the American College of Cardiology and the American Heart Association Practice Guidelines, and it is given below (Table 1). AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CYP1A2, cytochrome P450 1A2; HCV, hepatitis C virus; IBD, inflammatory bowel disease; IgG, immunoglobulin G; LKM-1, liver/kidney microsome type 1; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibodies. Autoimmune hepatitis (AIH) is a generally unresolving inflammation of the liver of unknown cause. A working model for its pathogenesis postulates that environmental triggers, a failure of immune tolerance mechanisms, and a genetic predisposition collaborate to induce a T cell–mediated immune attack upon liver antigens, leading to a progressive necroinflammatory and fibrotic process in the liver.5,6 Onset is frequently insidious with nonspecific symptoms such as fatigue, jaundice, nausea, abdominal pain, and arthralgias at presentation,7 but the clinical spectrum is wide, ranging from an asymptomatic presentation8,9 to an acute severe disease.10,11 The diagnosis is based on histologic abnormalities, characteristic clinical and laboratory findings, abnormal levels of serum globulins, and the presence of one or more characteristic autoantibodies.12-16 Women are affected more frequently than men (sex ratio, 3.6:1).17-19 and the disease is seen in all ethnic groups20-34 and at all ages.21,35-44 There are no robust epidemiological data on AIH in the United States. In Norway and Sweden, the mean incidence is 1 to 2 per 100,000 persons per year, and its point prevalence is 11 to 17 per 100,000 persons per year.45,46 A similar incidence and prevalence can be assumed for the Caucasian population of North America. Data on the natural progression of untreated disease are derived principally from experiences published prior to the widespread use of immunosuppressive agents for AIH and before the detection of the hepatitis C virus (HCV).47-54 These studies showed that as many as 40% of patients with untreated severe disease died within 6 months of diagnosis,47,49 and that survivors frequently developed cirrhosis, esophageal varices and subsequent hemorrhage.47,49,50,55 An acute onset of illness is common (∼40%),56-63 and an acute severe presentation, characterized by within of clinical is that or in with laboratory findings, and These studies to the of immunosuppressive as the in and an autoimmune pathogenesis of the disease. studies before the of be in studies and one can that of patients with Liver has as an for the and the patient and The for AIH and a system by an in and in (Table The clinical for the diagnosis are to or or AIH in the of The system developed as a by which to the of in clinical (Table and can be applied in by the The is in the and a can be before and (Table A of or or a of or AIH at A of has a of a of and of A of of has a of a of and a of A the of the system in with A system has been to clinical and is based on the presence and level of by serum immunoglobulin or and the of (Table In the system with and in the diagnosis of AIH, but it has to be in The diagnosis of AIH requires the presence of characteristic clinical and laboratory and the of that hepatitis and (Table The clinical an of and the use of to be The laboratory of the levels of serum alanine or aspartate or IgG, and and AIH can be asymptomatic in of patients are men and serum levels at than findings, including the of cirrhosis, are similar asymptomatic patients and as many as of asymptomatic patients the of asymptomatic patients be followed by an to for in disease In the level be a of biliary primary sclerosing than the which can be to in the the the presence or of in with The of AIH be including antinuclear smooth muscle to liver/kidney microsome type 1 and type 1 (Table be to disease and 1 and autoimmune liver that AIH primary biliary and Liver at is to the diagnosis and to the In acute of liver from of hepatitis is the and is is specific for AIH, and the of in the the and be The generally the In all but the is with or is and liver of this to hepatitis in The on the of the disease. to patients with an insidious patients with acute severe failure more and and but and The of the is by a and characterized by about the the and with a inflammatory and patients of AIH and such as PSC, PBC, or autoimmune a histologic such as or the presence of one of In the system can be to assist in diagnosis (Table The of or suggest or such as liver hepatitis or a and diagnosis of AIH by the system to the of serum of and of to or that liver There is no to and and histologic generally the the are a diagnosis can be by the presence of such as or liver ANA, SMA, and the for the diagnosis of AIH (Table In North American of patients with AIH ANA, SMA, or and are more in AIH patients and are by or They are in the United are by but be with this can be by to cytochrome the of are specific to and can the of the the diagnosis of AIH, the of the in the or in with disease clinical and In are of disease and can be to on an of is in in of for and SMA, and for are is in in the diagnosis of AIH, liver is by clinical The for is on of and This the detection of ANA, SMA, and but the presence of of an clinical such as to liver type 1 and to liver microsome type of the presence of the is with to and 1 (Table that be in patients the are and specific for and inflammatory bowel disease are frequently in patients with and can be the (Table with evidence that the of is within the this a more be (Table and as in AIH, to the and to a These are to as or is a (Table has been are in patients with AIH are for ANA, SMA, and but are more in with the are are specific for the diagnosis of autoimmune liver and detection patients with more severe disease and are available for The and in AIH are in an for the use of in the diagnosis of The use of in the diagnosis of in the of acute or hepatitis of cause. The for antinuclear smooth muscle to liver/kidney microsome type 1 and The of the one or more are the diagnosis of autoimmune hepatitis (AIH) or primary biliary be are are including for to liver liver type 1 the of the The of suggest including primary sclerosing or genetic with AIH been in ethnic The primary genetic is with the and of with disease clinical to and been AIH is a to be to subsequent of patients or for genetic is AIH be in patients with and patients the genetic autoimmune by a on that the of the autoimmune is a in and within the that of T has an of and and The liver with are cytochrome P450 in to to cytochrome P450 liver (Table This is the AIH that a of and genetic for the patient and are The diagnosis of AIH be clinical and laboratory or ALT, and serum or SMA, or and are and that can including and been (Table that or or be by the (Table In patients for in AIH is including at and be (Table In patients with AIH and the be by for the in the of AIH 1 and type been based on but been as clinical or A type has been as its is in type 1 AIH and in type 2 1 AIH is characterized by the presence of ANA, or and of AIH of patients are with a incidence and of patients are than and are at with autoimmune are common autoimmune and the of is in of to as that patients with severe AIH are to 2 AIH is characterized by the presence of patients with type 2 AIH are and serum immunoglobulin levels are for the of which be immune are progression to and an acute severe is of autoimmune hepatitis based on the presence of and 1 or and 2 can be to characterize the clinical or to in clinical be to type 2 and can and genetic that of and AIH can that each of These nonspecific can the The prevalence of AIH patients with to be the but this prevalence to in the system of the system in a review of patients with showed that and as and AIH, Clinical is to the of the disease and to the process AIH patients that suggest in about of AIH patients in the of biliary and presence the clinical or as as an The system can a diagnosis of in of AIH are acute and liver of that can of AIH and liver and and such as and can a that AIH with that generally of the an clinical has been with and with of AIH ethnic patients a of at than a of acute disease than patients patients with American patients are with severe liver North a of and disease at and patients are frequently men with progressive and quality of care are that be disease within AIH can an acute severe that can be for a or autoimmune hepatitis as acute liver can be in the inflammatory in of in can a on In disease can a and autoimmune are in with severe acute the be immune the liver Autoimmune and are the common with AIH in North American type and autoimmune are the common in AIH In with AIH, autoimmune sclerosing can be with or In with AIH and IBD, contrast biliary of are in of In with AIH but IBD, biliary are in of are immune the of studies be in patients with AIH and IBD, as as in and to months of In a of patients with and of AIH type 1 with sclerosing on The diagnosis of AIH be in all patients with acute or hepatitis of including patients with acute severe studies be to in has been no to with AIH and all with AIH and studies to that patients with serum levels of at the of the or more than in with a serum level more than a at 6 of or at to in of untreated patients and are with a of These laboratory and of disease at are for and symptoms with such as and are for of of disease (Table The natural of autoimmune hepatitis is in patients no or symptoms and in laboratory and been in and for and (Table with an asymptomatic patients and natural There are no guidelines that this population no is in asymptomatic patients with but patients versus and more than untreated asymptomatic patients with disease a than versus The of be the of the versus the autoimmune hepatitis can and a and to a point can be is in asymptomatic in are to the to a are at for and with cirrhosis, or or and (Table is in patients laboratory or of liver with or benefit from and an of and can and of with or severe be for a benefit before and be in patients with severe below or below or of (Table The for in are similar to in (Table The disease process in to be more severe at than seen in of in diagnosis or immune such as autoimmune sclerosing than of at and the of the disease in are seen in The in and that in diagnosis and the at the of with evidence of inflammatory are to all in which the diagnosis of AIH has been be the diagnosis of autoimmune hepatitis or the for the are in in or the patient be to a before be in patients with serum or levels than at in with a serum level at of or (Table be in patients symptoms and laboratory and but the be and the of to a prior to (Table be in patients with or no disease or cirrhosis, but patients to be followed months (Table be in patients with or to the disease is severe and progressive and for the can be (Table be in patients with a severe below or below or of (Table be in at the of diagnosis of are in severe AIH (Table or a of in with is in the United or which is in (Table be to an level to a from be by every are and by been to The is of the or The of and is with a of than the versus and it is the preferred can the of to but this is to or the of In is preferred is appropriate as the in with severe a of are or patients with and with (Table The is appropriate in patients be for at 6 months or are at for including and with or (Table for and and in be at 6 for and be based on an of of the and be as appropriate to the a and The of agents such as be appropriate for on be for disease by and of the and patients from liver disease patients with AIH be hepatitis virus and hepatitis A virus be as as before is of been in than in and to the of There been no in with autoimmune but of 17 or more the of similar to in (Table the severe disease at presentation, the to with with or is generally in of liver is months of in is the in all reported for and it is in a of to (Table In a to has been in of a is of the of or on and use of or for all is with as has been in but the to for of A as for with autoimmune hepatitis to a more and be evidence of to or in be with with and to within in with or as in or a of with and to within in with The is and in can be of (Table be with in in with or (Table on be for disease at and for disease a and appropriate agents such as and be has been no or to has been The and of the with each be to the patient prior to the of (Table including and in of patients 2 of of the (Table with and are but it is than with are the common for in autoimmune is in of patients of and of or with and of in autoimmune hepatitis and (Table of patients with or which its The of in patients with autoimmune hepatitis is and the the of is or the is An but of is a with and that The has been reported in autoimmune has the in patients with inflammatory bowel The of is and the is failure (Table The of in patients with autoimmune hepatitis is and the of severe is 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before and the be in with liver disease and of are at for with of are at for of the population has a severe and all patients with a of this experience with but in at the of and the level of with of the The of severe the of in and the to by and for in or the of than of of The of with be with the patient prior to (Table be the of in and be in patients has a by the and it be in patients of AIH be by 2 prior to and by serum or levels at for at months be in patients with before or in is or (Table There is no or of The of can be based on a that is with a or on a that is to the and patients be given the to a that is of (Table of in the serum AST, and levels within 2 of laboratory and liver in than and the of 2 clinical and laboratory by of the laboratory serum or ALT, and and of liver inflammation liver is the and the of (Table The of is laboratory before of the of by to to patients and of patients laboratory prior to the of the in studies of the of be in studies as or of of in patients is 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Funding for the development of this Practice Guideline and Guidance was provided by the American Association for the Study of Liver Diseases. Potential conflict of interest: Dr. Mack consults for Albireo. Dr. Kerkar advises High Tide and received royalties from Elsevier. Dr. Manns consults for, is on the speakers' bureau for, and received grants from Falk. He consults for and received grants from Novartis. Dr. Vierling advises and received grants from CymaBay, Enanta, Genkyotex, Intercept, Lilly, Novartis, and TaiwanJ. He advises Arena, BioIncept, Blade, and GlaxoSmithKline and received grants from Allergan and NGM. What's New Since 2010 Guidelines? Histological features of NAFLD are present in 17%‐30% of adult patients with AIH, and concurrent NAFLD may influence response to therapy. Diagnostic scoring systems should be used only to support clinical judgment in challenging cases of AIH and to define AIH cohorts for clinical studies. Immune checkpoint inhibitors have been associated with immune‐mediated liver injury and are frequently steroid‐responsive, but the liver injury lacks autoantibodies and typical histological features of AIH. Elastography may be used to assess the stages of hepatic fibrosis noninvasively. Testing for TPMT activity prior to AZA treatment is encouraged in all patients. Budesonide and AZA or predniso(lo)ne and AZA are recommended as first‐line AIH treatments in children and adults who do not have cirrhosis, acute severe hepatitis, or ALF. AZA can be continued throughout pregnancy, whereas the use of MMF is contraindicated in pregnancy. Liver tissue examination prior to drug withdrawal in individuals with ≥2 years of biochemical remission is preferred but not mandatory in adults and required in children. MMF or TAC can be used as second‐line treatment in children and adults with AIH who have failed to respond to first‐line therapy. Patients with acute severe AIH should receive predniso(lo)ne followed by LT if no improvement within 2 weeks, whereas patients with AIH and ALF should be evaluated directly for LT. Glucocorticoids can be discontinued after LT and patients monitored for recurrence of AIH. Purpose and Scope The objectives of this document are to provide guidance in the diagnosis and management of autoimmune hepatitis (AIH) based on current evidence and expert opinion and to present guidelines to clinically relevant questions based on systematic reviews of the literature and the quality of evidence.1 This practice guideline/guidance constitutes an update of the guidelines on AIH published in 2010 by the American Association for the Study of Liver Diseases (AASLD).2 It updates the epidemiology, diagnosis, management, and outcomes of AIH in adults and children. The document is divided into "guideline recommendations" and "guidance statements." Guideline recommendations were based on evidence derived from systematic reviews of the medical literature and supported, if appropriate, by meta‐analyses. The systematic reviews and meta‐analyses were conducted independently by the Mayo Clinic Evidence‐Based Practice Center. Findings were analyzed and interpreted by a multidisciplinary panel of experts, including both content and methodology experts, who rated the quality of evidence and determined the strength of each recommendation. The quality of clinical evidence was determined by its source (e.g., randomized controlled trial or observational study), and the strength of the recommendation was determined by assessing the quality of evidence, balance of benefits and harms, patient values and preferences, and use of resources and costs. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to categorize each recommendation as strong or conditional (Table 1).3 Details of the methodology, systematic reviews, and meta‐analyses are published separately. The guideline recommendations focus on pertinent management issues for which sufficient evidence was available to render a recommendation. They address glucocorticoid and azathioprine therapy as first‐line management, second‐line medications after failure of first‐line therapy, and maintenance management after liver transplantation (LT; see Supporting Table S1 for patient/intervention/comparison/outcome questions related to systematic reviews). Table 1 - GRADE Assessment of Clinical Studies Study Design Rating Quality Strength Determinants Strength and Implications of Recommendation Randomized controlled trial High Quality of evidence Strong Moderate Balance of benefits and harms Most people would want course Most people should take course Can be adapted as policy in most cases Low Patient values and preferences Observational Very low Resources and costs Conditional Feasibility Many people would select course Requires decision aids and shared decision‐making Debatable policy choice Acessibility Equity Quality downgrades: selection bias, inconsistency, imprecision, indirectness, publication bias. Quality upgrades: large effect, very large effect, dose–response gradient, confounders produce no effect. "Guidance statements" were developed by consensus of an expert panel based on formal review and analysis of the published literature on the topic. The quality (level) of evidence and the strength of each guidance statement were not formally rated for the guidance statements. "Guidance statements" were used to address topics for which a sufficient number of randomized controlled trials were not available to justify a systematic review and meta‐analysis. The "guidance statements" and "guideline recommendations" were also reviewed by members of the AIH Association, a 501(c)(3) nonprofit organization, in order to incorporate patient and public perspectives. "Guidance statements" and "guideline recommendations" are intended to provide health care practitioners with updated information and rigorously assessed, evidence‐based recommendations. They are intended to aid, not supersede, clinical judgment. For ease of reading this AIH guidance/guidelines document, a glossary of definitions is provided in Table 2. Table 2 - Definitions of AIH and Its Treatment Outcomes Condition Definition AIH Characteristic histologic abnormalities (lymphoplasmacytic interface hepatitis), elevated AST, ALT, and total IgG and the presence of one or more characteristic autoantibodies Inactive cirrhosis Absence of inflammatory infiltrates in both portal tracts and fibrous bands in cirrhosis Acute severe AIH Jaundice, INR > 1.5 < 2, no encephalopathy; no previously recognized liver disease370 ALF INR ≥ 2; hepatic encephalopathy within 26 weeks of onset of illness; no previously recognized liver disease100 Biochemical remission Normalization of serum AST, ALT, and IgG* levels Histological remission Absence of inflammation in liver tissue after treatment Treatment failure Worsening laboratory or histological findings despite compliance with standard therapy Incomplete response Improvement of laboratory and histological findings that are insufficient to satisfy criteria for remission Relapse Exacerbation of disease activity after induction of remission and drug withdrawal (or nonadherence) Treatment intolerance Inability to continue maintenance therapy due to drug‐related side effects *Patients with cirrhosis in biochemical remission may have persistent elevation of IgG. AIH is an immune‐mediated inflammatory liver disease of uncertain cause which affects all ages, both genders, and all ethnicities. Patients may be asymptomatic, be chronically ill, or present with acute liver failure (ALF); and the diagnosis must be considered in all patients with acute or chronic liver inflammation, including patients with graft dysfunction after LT. AIH does not have a signature diagnostic feature, and the diagnosis requires the presence of a constellation of typical features which can vary between patients with the same disease and can occur in other liver diseases. Progression to advanced hepatic fibrosis, cirrhosis, death from liver failure, or LT are possible outcomes. Treatment with immunosuppressive agents has been life‐saving, but management regimens may be long‐term, associated with serious side effects, and variably effective. Background Epidemiology AIH occurs at all ages and within all ethnic groups, and its manifestations appear to vary by race and ethnicity. Alaskan Natives have a high frequency of icteric AIH at presentation, Hispanics more commonly present with cirrhosis, and African Americans have accelerated progression of disease and a higher rate of recurrence after LT compared to other races.5 Female predominance occurs in adults (71%‐95% women)7 and children (60%‐76% girls).13 Early epidemiological reports suggested that the onset of AIH had age peaks at 10‐30 and 40‐60 years, but the findings may have been influenced by referral bias.17 Older peak ages at onset (>60 years) have been reported in Denmark11 and New Zealand.10 The estimated incidence of AIH varies worldwide depending on the region and the age at onset. Incidence rates in adults range from 0.67 (southern Israel) to 2 cases per 100,000 person‐years (Canterbury region of New Zealand).10 Pediatric incidences are lower, ranging from 0.23 (Canada)16 to 0.4 per 100,000 person‐years (United States).15 Over the past few decades there has been a near 50% increase in incidence in Spain, Denmark, Sweden, and the Netherlands.11 The prevalence of AIH in adults ranges from 4 (Singapore) to 42.9 (Alaska natives) per 100,000 persons.17 The prevalence in children ranges from 2.4 (non‐native Canadian children)26 and 3 per 100,000 persons (United States)15 to 9.9 per 100,000 persons (native Canadian children).17 Genetic Predispositions In common with other autoimmune diseases, the primary genetic associations in AIH involve major histocompatibility complex loci. Human leukocyte antigen (HLA) associations cluster within the conserved 8.1 ancestral haplotype which defines the alleles carried by most Caucasians27 and results from linkage disequilibrium within HLA class I, II, and III loci: HLA‐A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*03:01, DRB1*04:01, DRB1*13:01, DRB3*01:01, DQA1*05:01, DQB1*02:01.28HLA‐DRB1*03:01 haplotypes associated with AIH are the result of additional genetic recombinations. AIH also has non‐HLA genetic associations, but the odds ratios (ORs) for risk of AIH are far lower than those for HLA alleles. Susceptibility for AIH has been associated with genetic polymorphisms encoding cytotoxic T lymphocyte antigen‐4 (CTLA‐4),33 tumor necrosis factor‐alpha (TNF‐α),34 Fas (cluster of differentiation 95 [CD95] or apoptosis antigen‐1),36 vitamin D receptor,38 signal transducer and activator of transcription 4,40 transforming growth factor‐beta 1,41 macrophage migration inhibitory factor,42 SH2B adapter protein 3,43 caspase recruitment domain family member 10,43 and the interleukin‐23 (IL‐23) receptor.44 Dysfunctional products of genetic variants or deficient levels of gene product may disrupt homeostatic mechanisms that affect the proliferation and survival of autoreactive T and B cells, regulate cytokine production, and modulate inflammatory and immune responses. AIH is a complex genetic disease that requires interplay among genetic, epigenetic, immunologic, and environmental factors. A rare exception is AIH associated with an autosomal recessive mutation in the autoimmune regulator gene on chromosome 21q22.3, which has been associated with autoimmune polyglandular syndrome type 1 (APS‐1).45 Environmental exposures play greater roles than genetics in shaping the immune repertoire, and specific environmental factors, such as viral infections or xenobiotic exposures, can act as environmental triggers for loss of self‐tolerance to autoantigens in persons genetically susceptible to AIH.46 Pathogenesis Autoreactive CD4 and CD8 T cells break self‐tolerance to hepatic autoantigens as the result of environmental triggers and inability of autoantigen‐specific natural T regulatory cells (nTregs) and inducible T regulatory cells (iTregs) to prevent autoreactivity48 (Fig. 1). Concurrently, in the absence of effective B regulatory cell (Breg) inhibition, autoreactive B cells produce autoantibodies.51 Peptide autoantigens are presented by class II and class I HLA alleles to autoreactive T‐cell receptors on CD4 T helper (Th) cells and CD8 cytotoxic T lymphocytes (CTLs), respectively. Binding of different autoantigens to B‐cell receptors initiates secretion of specific autoantibodies.Figure 1: Current concepts of the immunopathogenesis of AIH. Current knowledge supports a multistep working model of the immunopathogenesis of AIH, in which a break in self‐tolerance to hepatocyte autoantigens initiates immunological responses causing progressive hepatic necroinflammation and fibrogenesis.50 In the first step, thymic autoantigen‐specific nTregs are incapable of preventing immune responses to hepatic autoantigens during hepatic or systemic immune responses to environmental triggers, such as viral infections or xenobiotics. In the second step, professional antigen‐presenting cells (APCs) present autoantigenic peptides to autoreactive α/β T cell receptors (TCRs) on naive CD4+ Th cells, and CD8+ T cells and APCs activate MAIT cells by presenting bacterially processed vitamin B antigens to MAIT cell TCRs.54 Costimulation is a crucial third step, which induces expression of T‐cell genes required for proliferation, differentiation, and maturation of autoantigen‐specific CD4+ Th subsets (e.g., Th1, Th2, Th3, Th9, Th17, iTregs, Tr1, Tfh cells) and both CD8+ CTLs and CD8+ Tregs. In the fourth step, secretion of specific cytokines by subsets of CD4+ Th cells produces a variety of immunological sequelae, including CD4+ Th2 cytokine stimulation of B‐cell autoantibody production, CD4+ Tfh‐cell activation of B cells into antibody‐secreting plasma cells, Treg stimulation of Breg development through IL‐35 mechanisms and cytokine‐activated macrophages, and CD4+ Th17 cell–mediated pathogenic cytotoxicity. The fifth step is the cumulative failure of CD4+ and CD8+ Tregs and Bregs to control autoantigen‐specific effector mechanisms causing hepatic injury.53 Moreover, exposure of CD4+ iTregs to specific cytokines can transform them from regulatory cells into pathogenic CD4+ Th17 cells.52 The sixth step is the generation of complex portal inflammatory infiltrates of effector cells that cause cytotoxicity of periportal and lobular hepatocytes. Necroinflammatory destruction of hepatocytes results in activation of periportal stellate cells, which amplify local immune responses through contact‐dependent and independent mechanisms and cause progressive portal fibrosis, culminating in cirrhosis in the absence of effective immunosuppressive therapy. Abbreviations: Ag, antigen; IFN, interferon; TGF, transforming growth factor.The composition of the local cytokine milieu dictates CD4 Th cells to differentiate into Th1, Th2, Th9, Th17, iTregs, and T follicular helper (Tfh) cell subsets in the presence of costimulatory signaling.50 CD4 Th1 cells secrete cytokines that promote proliferation of autoantigen‐specific CD8 CTLs and activation of macrophages. CD4 Th2 cytokines augment immunoglobulin production by B cells, while cytokines produced by Tfh cells induce their conversion to immunoglobulin G (IgG)–secreting plasma cells. CD4 Th17 cells intensify inflammation and tissue injury. Autoantigen‐specific iTregs can down‐regulate the proliferation and functions of all CD4 Th subtypes, and inadequate numbers and/or dysfunction of CD4 iTregs may play a key role in AIH.52 Cytokine‐mediated transformation of CD4 iTregs into pathogenic CD4 Th17 cells also promotes perpetuation of AIH. Low doses of IL‐2 preferentially stimulate proliferation and function of CD4 iTregs, while high doses promote production of other pathogenic CD4 Th subsets. Mucosal invariant T (MAIT) cells that react with bacterially processed vitamin B antigens presented by major histocompatibility complex class I–related molecules congregate in the peribiliary region in AIH.54 MAIT cells can express characteristics of CD4 Th1 and Th17 cells, and they may transform CD4 iTregs into proinflammatory CD4 Th17 cells. Inflammatory infiltrates composed of CD4 Th subsets, CD8 CTLs, MAIT cells, B cells, plasma cells, and innate immune cells, including natural killer (NK) and NK T cells and activated macrophages, can accumulate within the portal tracts. Adhesion molecules and chemokines mediate transendothelial migration of immune cells into tissues.50 Extension of inflammation into periportal hepatocytes (interface hepatitis) and lobular hepatitis causes apoptosis of hepatocytes and fibrogenesis in untreated patients with AIH. Uptake and processing of immune complexes of autoantigen and immunoglobulin by antigen‐presenting cells greatly increases activation of autoantigen‐specific CD8 CTLs, and autoantibodies may enhance CD8 CTL cytotoxicity of hepatocytes. Diagnosis Diagnostic Requisites and Subtypes The diagnosis of AIH is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (elevated serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels and increased serum IgG concentration), and the presence of one or more characteristic autoantibodies.2 AIH lacks a signature diagnostic marker, and the diagnosis requires characteristic features and the exclusion of other diseases that may resemble it (e.g., viral hepatitis, drug‐induced liver injury, Wilson's disease, hereditary hemochromatosis).56 There are two types of AIH, based on the specific autoantibodies that are present. Type 1 is characterized by antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA)/anti‐actin antibodies, and type 2 is characterized by antibodies to liver kidney microsome type 1 (anti‐LKM1), usually in the absence of ANA and SMA.57 The characteristic clinical features of these two types are presented in Table 3. In addition, up to 20% of AIH cases are negative for ANA, SMA, and LKM1 autoantibodies, despite the presence of other characteristic features of AIH (seronegative AIH). If seronegative AIH is suspected, other autoantibodies may be sought, as indicated in Table 4 and Fig. 2. Classification of AIH into types assists in management and aids in predicting outcomes in children, but it may be less informative in adults.58 Table 3 - Characteristic Features of Type 1 and Type 2 AIH Features Type 1 AIH Type 2 AIH Frequency US adults, 96%61 US children, 9%‐12%14 UK children, 38%13 Age at presentation Peripubertal and adults Usually under 14 years153 Mode of presentation Chronic symptoms common Acute onset (~40%) Ascites or GI bleeding rare Acute liver failure possible555 Asymptomatic in 25%‐34% Relapse frequent108 Acute in 25%‐75% Acute severe in 2%‐6% Laboratory features Hypergammaglobulinemia IgA levels may be reduced153 Autoantibodies ANA Anti‐LKM1 SMA, anti‐actin [Anti‐LC1, Anti‐LKM3] SLA Concurrent immune diseases Autoimmune thyroiditis Autoimmune thyroiditis Rheumatic diseases Diabetes mellitus IBD Vitiligo Autoimmune overlap with PSC (ASC in children) Common in children Rare Atypical pANCA‐positive Atypical pANCA‐negative Overlap with PBC Seen in adults (not children) Not reported Cirrhosis at presentation Rare after drug withdrawal usually Abbreviations: serum immunoglobulin Table 4 - Autoantibodies in the Diagnosis of AIH Diagnostic ANA Type 1 Type 1 LKM1 Type 2 SLA Type 1 after with Type 1 Type 1 Type 1 family Type 2 Type 2 of overlap Type 1 Abbreviations: autoimmune Diagnostic for the of AIH after exclusion of and diseases. ANA and should be in adults and antibodies to LKM1 should be if ANA and are ANA, SMA, and LKM1 should be in all patients at presentation The findings of the liver support the diagnosis of AIH or that an overlap AIH with or The absence of ANA, SMA, and LKM1 additional that can antibodies to tissue and for one of these autoantibodies support the diagnosis of AIH or other including disease Abbreviations: tissue ANA, SMA, and the for the diagnosis of AIH (Table ANA are in of American adults with AIH at presentation, are present in and are present in of patients with AIH have ANA, SMA, or as an at and have ANA can also occur as an in primary chronic hepatitis chronic hepatitis B liver disease and chronic liver disease and can occur as an in PSC chronic hepatitis and chronic liver disease ANA and are concurrent in of liver diseases of AIH, and the diagnostic for AIH from to if two autoantibodies are at Anti‐LKM1 are commonly in the absence of ANA and SMA, and this has their after first for ANA and (Fig. have a low for AIH in American adults and their after first the absence of ANA and is in these patients. Anti‐LKM1 are in of and Canadian children with and of ANA, SMA, and are usually at in adults and children disease and treatment but they are not of disease activity or treatment to liver antigen are present in of patients with type 1 AIH, and they have high for the (Table have been the of AIH in of and they have been associated with severe disease and after drug Atypical antibodies are frequently present in patients with type 1 AIH but they diagnostic in overlap and liver may be the only autoantibodies are a of SMA, and they are present in of patients with AIH and (Table to is an that is present in of patients with AIH and of patients with to anti‐actin and has been associated with severe acute AIH, treatment and to liver type 1 are present in of patients with and they occur in children with severe liver (Table are present in of patients with type 2 and may be in seronegative and have not been rigorously in the should be and with the clinical may be depending on results of the and in with the diagnostic (Fig. Histological Findings The diagnosis of AIH be liver and histological hepatitis is the histological of AIH, by plasma cell in and lobular hepatitis in necrosis is also in and it occurs with frequency in patients with and is the of one cell into with both cells to is present in of patients with AIH, and hepatocyte are present in (Fig. of the histological findings is specific for AIH, but the findings of interface hepatitis with portal or cells into the and are considered typical of Histological features characteristic of AIH. inflammatory of the portal and interface hepatitis of the portal and cell predominance in a portal inflammatory and of a and A hepatocyte and of hepatocytes and are of of of is present in of adults at presentation, in the as as in of Cirrhosis in of adults with necrosis or The histological examination at presentation is to or concurrent the of inflammatory and the of plasma cells may be present in patients with but the clinical of this Histological findings of are present in 17%‐30% of patients with and liver tissue examination may patients with AIH and who are at increased risk of and The histological features of AIH with ALF in the and of is present in plasma inflammatory in hepatic necrosis in and in of patients with ALF have two or all of these Diagnostic The diagnostic scoring system of the Autoimmune was by an panel in in and in Table The scoring system has greater for AIH compared to the scoring system whereas the scoring system has and clinical judgment as the The diagnostic scoring system is for patients with complex or whereas the scoring system is most for typical of patients with the scoring system should be considered the system a low In children, a of to the of the criteria a of and a of In that were associated with seronegative AIH. The diagnostic scoring system can be to children and lower autoantibody than in adults as diagnostic of the serum for the serum in the with the serum or may the of the scoring system for children by the of to the and scoring systems of by

This is a comprehensive guidance on the diagnosis, evaluation, and management of ascites and hepatorenal syndrome (HRS) in patients with chronic liver disease from the American Association for the Study of Liver Diseases (AASLD). It replaces the prior AASLD guideline on the same topic published in 2012 (Table 1).(1) Because this guidance represents an update covering nearly a decade, numerous changes are made. Instead of enumerating the individual changes, the following list represents noticeable revisions: This AASLD Guidance provides a data-supported approach to the management of ascites and HRS. It differs from the AASLD Guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence, and strength of the recommendations. In contrast, this Guidance was developed by consensus of an expert panel and provides guidance statements based on comprehensive review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee. The AASLD Practice Guidelines Committee chose to perform a Guidance on this topic because a sufficient number of randomized controlled trials were not available to support meaningful systematic reviews and meta-analyses. Hepatic decompensation, defined by ascites, hepatic encephalopathy, and portal hypertensive gastrointestinal bleeding, is an important landmark in the natural history of cirrhosis.(2) Ascites is commonly the first decompensation-defining event, with 5%-10% of patients with compensated cirrhosis developing ascites per year.(3) The development of ascites is associated with a reduction in 5-year survival from 80% to 30%,(4) which is due in part to patients with ascites being prone to additional complications, such as bacterial infections, electrolyte abnormalities, HRS, and nutritional imbalances, and, consequently, further clinical decline.(5) Patients with cirrhosis who develop clinically significant ascites and related complications should be considered for referral for liver transplantation (LT) evaluation and, when appropriate, palliative care.(6) HRS is a late complication of cirrhosis that accounted for 3.2% of all hospital discharges related to cirrhosis according to a 2012 study based on a large inpatient health care database of patients representative of community hospitals in the United States.(4) Moreover, the number of HRS discharges in the United States has increased significantly in the past 2 decades.(7) HRS was also associated with high inpatient mortality (~46%) as well as longer lengths of stay and higher costs of hospitalizations compared with cirrhosis discharges without HRS. Figure 1 summarizes the key steps in the pathogenesis of ascites and related complications discussed in this document. From the perspective of the management of ascites, pathogenetic events of importance are renal sodium retention, arterial underfilling, and portal hypertension, which may be mitigated by diuretics, albumin infusion, and portal decompressive procedures, respectively.(8, 9) More recently, the advent of vasopressin receptor antagonists provided further insights on the contribution of water retention in the pathogenesis of ascites.(10) Recent reviews provide more detailed discussion of the pathogenesis of ascites.(11-13) HRS is a functional renal failure resulting from hemodynamic changes occurring in patients with ascites and portal hypertension.(14) The primary pathophysiologic mechanism of HRS is reduced renal perfusion secondary to renal vasoconstriction mediated by increased activities of the sympathetic, renin-angiotensin-aldosterone, and vasopressin systems,(5) which may be further aggravated by decreased cardiac output in patients with cirrhosis-associated cardiomyopathy. In addition, systemic inflammation that is common among patients with decompensated cirrhosis may trigger immune-mediated renal injury.(15) Finally, emerging evidence suggests that renal autoregulation, a natural defense mechanism to maintain renal blood flow, is impaired in patients with cirrhosis, predisposing them to additional direct hemodynamic renal injury.(16) Together, structural kidney damage can follow severe and/or repeated episodes of such renal events.(17, 18) Although cirrhosis is the most common cause of ascites in the Western world, other potential causes should be considered, including malignancy, heart failure, tuberculosis, and pancreatic disease. The initial evaluation of ascites should include history, physical examination, abdominal doppler ultrasound, laboratory assessment of liver and renal function, serum and urine electrolytes, and a diagnostic paracentesis for analysis of the ascitic fluid (Fig. 2; Tables 2-4).(19, 20) In evaluating the etiology of ascites, the serum albumin ascites gradient is calculated by subtracting the ascitic fluid albumin from the serum albumin in simultaneously obtained samples.(21) A serum albumin ascites gradient ≥1.1 g/dL is highly suggestive of portal hypertension, usually caused by liver disease with an accuracy of approximately 97%, whereas a serum albumin ascites gradient <1.1 g/dL suggests other causes of ascites (Table 4). In contrast, a high ascitic fluid protein (>2.5 g/dL) supports a cardiac source for ascites.(22) Other tests of the ascitic fluid, such as amylase, cytology, or culture for mycobacteria, are not routinely indicated but should be guided by the patient's clinical context. In patients with cirrhosis, ascites can be graded according to the amount of fluid accumulated in the abdominal cavity and classified according to response to treatment (Table 5).(19) No treatment is recommended for grade 1 ascites, as there is no evidence that it improves patient outcomes. Response to therapy and subsequent outcome in patients with grade 2 or 3 ascites depends on several factors such as the underlying cause of cirrhosis; feasibility and effectiveness of therapy to alter the natural course of cirrhosis; presence of superimposed complications such as renal failure, hyponatremia, and spontaneous bacterial peritonitis (SBP); and adherence of the patient to dietary sodium restriction and diuretics. Moderate dietary sodium restriction (2 g or 90 mmol/day) should be prescribed to achieve a negative sodium balance and net fluid loss. Fluid restriction is not indicated unless hyponatremia is present. Patient education for sodium restriction is essential to maximize adherence while avoiding malnutrition and sarcopenia.(23-25) Instructions about a sodium-restricted diet should include advice on sodium contents of preprepared meals, avoiding adding salt to cooked meals, and guarding against nutritional deficiency.(23) A formal consultation with a dietician should be considered. In most patients with cirrhosis presenting with ascites, dietary sodium restriction alone is insufficient and diuretic therapy is necessary. The patient should be made aware that daily monitoring of body weight, preferably at the same time of the day, is essential in assessing the efficacy of diuretics and preventing their adverse effects. The peritoneal membrane's ability to reabsorb ascites from the abdominal cavity is limited to approximately 500 mL per day. Thus, in a patient without peripheral edema, weight loss exceeding 0.5 kg per day may result in plasma volume contraction, predisposing the patient to renal failure and hyponatremia. In those with edema, weight loss up to 1 kg/day may be tolerated.(19, 26) In addition, patients should understand the need for laboratory monitoring (e.g., serum electrolyte concentrations), particularly during the first weeks of treatment. Assessment of 24-hour urinary sodium excretion may be useful to guide therapy; in the absence of renal dysfunction, sodium excretion lower than the intake (e.g., 80 mmol/day) indicates an insufficient diuretic dose. Persistent ascites despite adequate urinary sodium excretion indicates dietary indiscretion. When a 24-hour urine collection is not feasible, a random "spot" urine sodium concentration that is greater than the potassium (K) concentration correlates well with 24-hour urine sodium excretion.(27, 28) When the spot urine sodium (Na)/K ratio is >1, the patient should be losing fluid weight,(28) and, if not, dietary noncompliance should be suspected. If the spot urine Na/K ratio is ≤1, there is insufficient natriuresis, and an increase in diuretics should be considered. Aldosterone antagonists (e.g., spironolactone) and loop diuretics (e.g., furosemide, torsemide, bumetanide) are the mainstay of diuretic treatment of cirrhotic ascites.(29, 30) Two studies addressing the best way to use these diuretics showed that for the first episode of ascites, treatment with aldosterone antagonists alone generated an adequate response with few side effects,(29, 30) whereas those with long-standing ascites responded better to a combined diuretic treatment.(31) The recommended initial dose of spironolactone is 100 mg/day, which can be progressively increased up to 400 mg/day. Spironolactone and its active metabolites have a long half-life; the full effect of a dose change may not be seen for up to 3 days. When the dose is increased, it should be done cautiously and in a stepwise fashion, with an interval of at least 72 hours. The dose of furosemide (initially 40 mg/day) may be progressively increased, according to the response and tolerability toward 160 mg/day, which is the generally accepted threshold to determine medical treatment refractoriness.(19, 26) Torsemide or bumetanide may improve natriuresis in patients with a suboptimal response to furosemide.(32) Patients with chronic kidney disease (CKD) in general are treated with higher doses of loop diuretics and lower doses of aldosterone antagonists. When ascites is adequately mobilized, attempts should be made to taper the diuretics to the lowest dosages to maintain minimal or no ascites. Adverse effects of diuretic therapy may occur in 20% and 40% of patients with cirrhosis and ascites (Table 6).(23) Painful gynecomastia can be caused or exacerbated by spironolactone, which may respond to switching to amiloride or eplerenone(33, 34); see Table 6 for conversion doses. Muscle cramps are common in patients with liver disease, particularly in patients on diuretic treatment for ascites, and adversely influence the quality of life.(35) The exact mechanisms by which they occur remain unclear; however, besides the correction of electrolyte alterations (e.g., hypokalemia and hypomagnesemia), muscle cramps may respond to medications, such as baclofen (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day)(36) and albumin (20-40 g/week).(35) Other drugs such as orphenadrine(37) and methocarbamol(38) have been proposed for muscle cramps in patients with cirrhosis. Finally, quinidine at a dose of 400 mg/day for 4 weeks in patients with cirrhosis was more effective than placebo against painful muscle cramps; however, toxicities such as diarrhea in about one-third of cases requiring treatment withdrawal may limit its use.(39) For patients presenting with tense ascites, large-volume paracentesis (LVP) combined with hyperoncotic human albumin is the initial treatment of choice, even in the presence of hyponatremia.(40, 41) Patients with massive peripheral edema may require a second paracentesis shortly after the first because a rapid shift of fluid may occur from interstitial tissue to the abdominal cavity.(19, 26, 40, 42) After LVP and a significant reduction in the intra-abdominal pressure, diuretics can be instituted, which may eliminate or reduce the frequency of paracentesis.(43) More detailed discussion about LVP is found in the section on refractory ascites (RA). Given the hemodynamic abnormalities in patients with cirrhosis and ascites, medications that may further reduce effective arterial volume and renal perfusion should be avoided. The most commonly encountered example is nonsteroidal anti-inflammatory drugs, which may precipitate hyponatremia, diuretic refractoriness, and acute kidney injury (AKI).(44) The angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, α1-adrenergic blockers, and dipyridamole should also be avoided.(45-48) Similarly, all potential nephrotoxins should be avoided in patients with cirrhosis and ascites. Aminoglycoside antibiotics should be avoided whenever possible in the treatment of bacterial infections.(49) Finally, in patients with cirrhosis and ascites, the use of IV contrast media is not contraindicated(50); however, caution needs to be exercised in patients with impaired renal function. Albumin, the most abundant serum protein, is the main component that generates the oncotic pressure. In addition, albumin has a multitude of other functions, including ligand binding, anti-inflammatory, antioxidant, and endothelial stabilizing effects.(51-53) Recently, long-term albumin administration to patients with decompensated cirrhosis has been studied.(54, 55) In the ANSWER study, 431 patients with diuretic-responsive ascites were randomized to either standard medical treatment or standard medical treatment plus 40 g of albumin twice a week for the initial 2 weeks and then 40 g once a week for 18 months. A significantly better overall survival was seen in patients receiving albumin, with a 38% reduction in mortality.(54) In the MACTH study, 173 patients with ascites listed for LT were randomized to receive standard medical treatment plus 40 g of albumin every 15 days and an α1-receptor agonist, midodrine (15-30 mg/day depending on the response), or standard medical treatment plus placebo. Despite some improvement in parameters reflecting improved effective plasma volume, no difference was observed in the complication rates or death during 12 months of follow-up.(55) Thus, the discrepant results between the two trials point to the need for further studies to address the role of albumin as well as cost-effectiveness(56) in the management of ascites. Given the complexity of medical care of patients with cirrhosis and ascites, the use of a multidisciplinary team is likely beneficial but has not been studied extensively. A model of specialized care has been proposed: an integrated team including hepatologists, dedicated nurses, physicians in training, and diagnostic facilities improved 12-month survival and reduced the rate of hospitalization for liver-related complications in outpatients with cirrhosis and ascites compared with standard practice.(57) RA occurs in approximately 5%-10% of all patients with cirrhosis and ascites and is associated with poor survival of 50% at 6 months.(58) RA is defined as ascites that cannot be mobilized or recurs after LVP despite dietary sodium restriction and diuretic therapy.(19) Thus, RA is further divided into (1) diuretic resistant (i.e., persistent ascites despite maximal doses of diuretics) and (2) diuretic intractable, in which side effects of diuretics preclude the use of maximum doses (Table 7).(59) Recurrent ascites, which is defined as ascites that recurs at least three times within 1 year despite dietary sodium restriction and diuretic therapy, may be a forerunner of RA.(59) Figure 3 outlines the suggested treatment algorithm for RA management. Diuretic-resistant ascites Because of the lack of response to dietary sodium restriction and maximal doses of diuretics Diuretic-intractable ascites Because of the development of diuretic-induced complications* that precludes the use of effective doses of diuretics Fails sodium restriction Fails maximum doses of diuretics Both for at least 1 week Lack of treatment response Early recurrence of ascites *Diuretic-induced complications Dietary sodium restriction is important in the management of patients at all stages of ascites, including those with recurrent or refractory ascites, as it lowers the rate of ascites accumulation. Frequent review of a food diary can help identify high-sodium food items if the patient is reaccumulating ascites rapidly. Some patients who have been labeled as having RA may reduce their ascites once they adhere to a low-sodium diet. This is especially true in patients who excrete approximately 80 mmol of sodium in their urine per day.(28) Fluid restriction in a patient with cirrhosis and RA is difficult to enforce and is often impractical. These patients' daily urine output is usually less than 1 L, making it virtually impossible to achieve a negative fluid balance by restricting fluid intake to less than the urine output. The serum sodium concentration at which fluid restriction should be instituted has not been well defined(60) but is recommended when serum sodium is ≤125 mmol/L or its onset is rapid (see the section on hyponatremia). In patients who have diuretic-resistant ascites, the continued use of diuretics is ineffective while predisposing patients to complications, especially renal impairment. Furthermore, loop diuretics have a sigmoidal dose-response curve, which means that once the ceiling dose is reached, further increase in doses will not increase renal sodium excretion. For patients with liver cirrhosis, this ceiling dose is reduced compared with healthy controls.(61) In patients with diuretic intractable ascites, there are no data as to whether diuretic doses lower than those that have produced side effects should be used once the side effects have abated. Chronic albumin infusion in patients with cirrhosis and RA was evaluated in a cohort of 70 participants, 45 of whom received 20 g of albumin twice weekly.(62) There was a significant reduction in the 24-month hospital admissions for complications of cirrhosis and mortality.(62) These results suggest that the use of albumin is generally safe and may be beneficial in patients with RA, but randomized controlled trials are needed to support these findings. The dose of albumin used may be critical in achieving positive results.(63) LVP, arbitrarily defined as a paracentesis of >5 L, has been shown to be safe and effective in the management of RA. When done repeatedly, LVP has a lower incidence of electrolyte abnormalities, renal dysfunction, and hemodynamic disturbance with similar survival compared with continued diuretic use.(40) In patients undergoing LVP, the use of albumin is crucial to prevent a further reduction of effective arterial blood volume, which may precipitate postparacentesis circulatory dysfunction (PPCD). The clinical manifestations of PPCD include renal impairment, including HRS, dilutional hyponatremia, hepatic encephalopathy, and death.(64, 65) Albumin infusion is particularly important if more than 5 L of ascites are removed to prevent the development of PPCD.(28, 66) Paracenteses of a smaller volume are not associated with significant hemodynamic changes,(67) and albumin infusion may not be required. Although there has not been a dose-response study on albumin use with LVP, the administration of 6-8 g of albumin per liter of ascites removed has been recommended.(19) For example, after the fifth liter, approximately 40 g of albumin should be infused, and after 8 L removal, the amount of albumin given should be approximately 64 g. It has been held that there is no limit for the amount of ascites that can be removed in a single session, provided an appropriate amount of albumin is administered. However, the risk of PPCD increases with >8 L of fluid evacuated in one single session. A recent study showed that by limiting the LVP volume to <8 L per session and providing a higher than recommended dose of albumin (9.0 ± 2.5 g per liter of ascites removed), renal function and survival may be better preserved over a mean period of 2 years despite the development of PPCD in 40% of patients.(68) In patients with hemodynamic instability (systolic blood hyponatremia sodium and/or the presence of albumin infusion should be considered for paracentesis of a smaller LVP is a safe even in the presence of In a study that patients with an ratio of and a of of patients minimal after time or is not a for is of factors or may include patients with or and In the may be considered, particularly if there is history of prior Given its ability to reduce the portal in patients with RA has been shown to be better than repeated LVP in the of with in patients with RA is in recent including a This may be especially true for patients with for Liver those who received a smaller and those who a response to with of reduction of portal with of the volume to the systemic the the effective blood In there is of the over at which a significant occurs with of it is important to patients' that the of ascites is not and patients should be on a sodium-restricted diet ascites is adequately is recommended about the use of diuretics as diuretics reduce the volume, which may the of the effective arterial blood volume and the volume effects of ascites approximately 80% of patients will their ascites with Patients who to despite a at 12 months should be for LT of may be related to the the or the presence of a which are discussed in in the AASLD guidance on the In patients with RA undergoing with have the incidence of dysfunction The of in the management of depends on the of the function after the is of the in patients with a has however, long-term has been suggested in patients who received for dysfunction and in patients with a as studies may should be considered in patients with persistent or recurrent ascites even if the is Patient and for is of critical importance for a In patients with high of are poor to receive a risk factors (e.g., and patients to more complications and hepatic per may not survival after for with a smaller than have been associated with lower incidence of hepatic without the efficacy on ascites A recent study suggests that at an of natural history as those with recurrent result in side effects and improved survival when compared with The survival of was significantly better than in patients who received LVP, albumin, and diuretics. There was also no difference in the incidence of hepatic during However, this of will need to be in a randomized controlled it can be For patients who are not the and efficacy of peritoneal remain to be The studies published are of in which the bacterial rate was The risk and are even less for for whom LVP a treatment The ascites is an that ascites from the peritoneal cavity into the the of ascites by of an was to reduce paracentesis with improvement in quality of and nutritional the is not available in Patients who have RA and significant liver dysfunction that precludes should be considered for Patients who have RA but preserved liver function may be the as patients with ascites may an additional mortality risk to especially in patients is patients with RA also have hyponatremia, which is by the the hemodynamic abnormalities of decompensated cirrhosis will weeks to months to Patients may to have ascites for some time in the period and will need to stay on a sodium-restricted diet of ascites. are the standard of care for the of in patients with cirrhosis and portal More recently, the use of was found to be associated with a higher of and survival in decompensated cirrhosis, including patients with and Other that showed no of use on or on even in patients with severe liver dysfunction and those with liver These results to the of the that were useful during a of period in the natural history of that use be It is important to that of the studies are randomized controlled In the randomized controlled in patients with compensated cirrhosis, the use of was associated with a reduced incidence of ascites, that the use of in the of cirrhosis is the adequately randomized controlled studies such as survival are needed in patients with decompensated cirrhosis. For can caution the use of in patients with RA, especially in those with hemodynamic abnormalities as indicated by blood hyponatremia with serum sodium or serum of be if circulatory dysfunction improves with improvement of these defined as a serum concentration is in nearly of patients with cirrhosis and ascites, with over a fifth having serum patients with cirrhosis, ascites, and hyponatremia have however, and hyponatremia should be considered. hyponatremia can occur because of poor intake or from urinary or gastrointestinal related to an of diuretic or hyponatremia is among patients with cirrhosis unless there is a such as syndrome of medications (e.g., and severe or of hyponatremia, in patients with cirrhosis, from muscle and to and in hyponatremia is associated with reduced edema and improved quality of and The of hyponatremia with cirrhosis is graded as and severe hyponatremia often not require management from monitoring and water however, patients with hyponatremia, or severe hyponatremia, and LT may require management. of hemodynamic as cirrhosis (Fig. Patients with cirrhosis and serum are at increased risk for developing hepatic HRS and and they have a higher and patients with hyponatremia may be at increased risk of these This the of serum into the liver in the United States in to LT for patients with of hyponatremia in cirrhotic ascites depends on

BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).