Assessing the liver to predict outcomes in heart transplantation
2015; Elsevier BV; Volume: 34; Issue: 7 Linguagem: Inglês
10.1016/j.healun.2015.04.002
ISSN1557-3117
Autores Tópico(s)Mechanical Circulatory Support Devices
ResumoIs life worth living? It all depends on the liver.William James (1842–1910)American philosopher and psychologist For highly selected patients with progressive heart failure symptoms and worsening clinical status, cardiac transplantation remains the standard of care for treatment of advanced heart disease.1Hunt S.A. Haddad F. The changing face of heart transplantation.J Am Coll Cardiol. 2008; 52: 587-598Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar Guidelines for selecting patients for heart transplant include absolute and relative contraindications,2Mancini D. Lietz K. Selection of cardiac transplantation candidates in 2010.Circulation. 2010; 122: 173-183Crossref PubMed Scopus (237) Google Scholar, 3Mehra M.R. Kobashigawa J. Starling R. et al.Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006.J Heart Lung Transplant. 2006; 25: 1024-1042Abstract Full Text Full Text PDF PubMed Scopus (768) Google Scholar which may vary from center to center and across regions and countries. Definitions of severe or irreversible organ dysfunction have been proposed (Table 1), but specific criteria must be evaluated in the context of individual patient disease trajectory, including the presence or absence of inotropic or mechanical circulatory support. Much is known about the prevalence and effect of renal dysfunction in the setting of advanced heart failure,4Metra M. Cotter G. Gheorghiade M. Dei C.L. Voors A.A. The role of the kidney in heart failure.Eur Heart J. 2012; 33: 2135-2142Crossref PubMed Scopus (184) Google Scholar but the understanding of cardiohepatic interactions remains less clear.Table 1Definitions of Severe or Irreversible Organ DysfunctionaAdapted from Givertz MM, Heart transplantation. In: Nabel EG, editor. Scientific American Medicine. Hamilton, Ontario: Decker Intellectual Properties, 2014. See also, Scientific American Medicine, available at: http://www.sciammedicine.com; accessed March 29, 2015.Organ systemAbsolute contraindicationsRelative contraindicationsRenalStage 4 or 5 chronic kidney diseaseCreatinine clearance between 20 and 30 ml/minSignificant proteinuriaPulmonaryFEV1 < 1.0 literFVC, TLC, or Dlco < 40% to 50% predictedRecent pulmonary embolismHepaticCirrhosis proven on biopsy specimenTotal bilirubin >2.5 to 3.0 mg/dlChronic active HBV or HCV infectionNeurologicMulti-infarct dementiaMuscular dystrophyNon-disabling stroke or recent seizuresGastroenterologicActive peptic ulcer disease or gastrointestinal bleedingDlco, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HBV, hepatitis B virus; HCV, hepatitis C virus; TLC, total lung capacity.a Adapted from Givertz MM, Heart transplantation. In: Nabel EG, editor. Scientific American Medicine. Hamilton, Ontario: Decker Intellectual Properties, 2014. See also, Scientific American Medicine, available at: http://www.sciammedicine.com; accessed March 29, 2015. Open table in a new tab Dlco, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HBV, hepatitis B virus; HCV, hepatitis C virus; TLC, total lung capacity. In the setting of cardiogenic shock, Samsky et al5Samsky M.D. Patel C.B. DeWald T.A. et al.Cardiohepatic interactions in heart failure: an overview and clinical implications.J Am Coll Cardiol. 2013; 61: 2397-2405Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar postulate that acute cardiogenic liver injury is linked to a combination of hepatic congestion from elevated hepatic venous pressure and impaired perfusion (i.e., both are required). Chronic passive congestion (or “congestive hepatopathy”), however, may be associated with advanced biventricular heart failure, restrictive cardiomyopathy, and/or severe tricuspid regurgitation and presents with more subtle signs and symptoms. In the middle are patients admitted with acute decompensated heart failure in whom symptoms and laboratory abnormalities may be confused with primary gastrointestinal or hepatobiliary conditions. Cardiohepatic interactions, whatever the cause, may have overlapping pathology that may be silent with current imaging (Table 2).Table 2Clinicopathologic Correlations in Advanced Heart and Liver DiseaseHepatic injurySigns and symptomsLaboratory assessmentsPathologyAcute cardiogenic liver injuryWeakness and apathyMarkedly elevated LDH, followed by ALT/ASTHemorrhagic centrilobular necrosisConfusionElevated bilirubinMild biliary stasisTremorElevated INRLack of regenerative activity or fibrosisAcute decompensated heart failureAbdominal bloatingElevated alkaline phosphataseCholestasisNausea and anorexiaMild-moderately elevated ALT/ASTSinusoidal dilationBridging fibrosis or cirrhosisaIn advanced cases.Chronic passive congestionAbdominal bloatingMildly elevated ALT/ASTCentrilobular necrosisAscites and lower extremity edemabMay be absent, especially in younger patients.Elevated alkaline phosphatase, bilirubin and GGTCholestasisDecreased albuminMinimal portal inflammationBridging fibrosis or cirrhosisaIn advanced cases.ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; INR, international normalized ratio; LDH, lactate dehydrogenase.a In advanced cases.b May be absent, especially in younger patients. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; INR, international normalized ratio; LDH, lactate dehydrogenase. During the past 10 years, the prognostic importance of acute and chronic liver dysfunction in patients with advanced heart disease has been illuminated. Most of the studies, however, have focused on easily accessible, routine laboratory investigations. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, total bilirubin was a strong independent predictor of worsening heart failure and all-cause mortality.6Allen L.A. Felker G.M. Pocock S. et al.CHARM Investigators. Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.Eur J Heart Fail. 2009; 11: 170-177Crossref PubMed Scopus (306) Google Scholar More recent data from Poelzl et al7Poelzl G. Ess M. Mussner-Seeber C. Pachinger O. Frick M. Ulmer H. Liver dysfunction in chronic heart failure: prevalence, characteristics and prognostic significance.Eur J Clin Invest. 2012; 42: 153-163Crossref PubMed Scopus (126) Google Scholar demonstrate that other markers of cholestasis (e.g., alkaline phosphatase and γ-glutamyl transferase), but not transaminases, predict transplant-free survival in ambulatory heart failure patients. In patients with acute heart failure, baseline, and in-hospital changes in albumin (decrease) and total bilirubin (increase) provide additional prognostic information.8Ambrosy A.P. Vaduganathan M. Huffman M.D. et al.EVEREST trial investigators. Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial.Eur J Heart Fail. 2012; 14: 302-311Crossref PubMed Scopus (144) Google Scholar Similarly, hyperbilirubinemia and hypoalbuminemia predict right ventricular failure after left ventricular assist device (VAD) implantation and adverse outcomes after transplant. Several investigators have assessed the effect of the Model for End-Stage Liver Disease (MELD) and MELD without international normalized ratio (MELD-XI) scores on heart failure, VAD, and post-transplant outcomes. This scoring system, originally developed in patients with hepatic cirrhosis waiting for a liver transplant, incorporates hepatic, renal, systemic inflammatory, and nutritional data. Not surprisingly, this multimarker approach independently predicts adverse outcomes in patients with chronic heart failure9Kim M.S. Kato T.S. Farr M. et al.Hepatic dysfunction in ambulatory patients with heart failure: application of the MELD scoring system for outcome prediction.J Am Coll Cardiol. 2013; 61: 2253-2261Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar as well as peri-operative bleeding and post-operative morbidity and mortality in VAD10Yang J.A. Kato T.S. Shulman B.P. et al.Liver dysfunction as a predictor of outcomes in patients with advanced heart failure requiring ventricular assist device support: use of the model of end-stage liver disease (MELD) and MELD excluding INR (MELD-XI) scoring system.J Heart Lung Transplant. 2012; 31: 601-610Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar and transplant patients.11Chokshi A. Cheema F.H. Schaefle K.J. et al.Hepatic dysfunction and survival after orthotopic heart transplantation: application of the MELD scoring system for outcome prediction.J Heart Lung Transplant. 2012; 31: 591-600Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Moreover, improved MELD scores may be observed during VAD support or after transplant and indicate enhanced prognosis. Unfortunately, none of these laboratory parameters takes into account structural abnormalities of the liver, including the extent and severity of fibrosis. Although static or functional imaging studies, such as ultrasound, computed tomography, and liver-spleen scan, may identify hepatic cirrhosis in some patients, the overall sensitivity of non-invasive imaging is poor. Analysis of a specimen from a liver biopsy, whether performed by the transvenous, transcutaneous, or open route, remains the gold standard. To determine the clinical predictors of hepatic fibrosis in patients with advanced heart failure, Gelow et al12Gelow J.M. Desai A.S. Hochberg C.P. Glickman J.N. Givertz M.M. Fang J.C. Clinical predictors of hepatic fibrosis in chronic advanced heart failure.Circ Heart Fail. 2010; 3: 59-64Crossref PubMed Scopus (64) Google Scholar identified 59 patients from whom liver tissue was obtained during evaluation for VAD or transplant. Nearly 80% had some degree of fibrosis on blinded pathologic review, with approximately 50% meeting criteria for severe (grade 3 or 4) fibrosis. Notably, advanced heart failure patients with hepatic fibrosis had worse renal function, more severe tricuspid regurgitation, and greater obstructive or mixed liver function test abnormalities. Abnormal abdominal imaging was inadequate to identify or rule out fibrosis, with a sensitivity of 30% and negative predictive value of 21%, respectively. No outcomes information was provided. In the current issue of The Journal of Heart and Lung Transplantation, Farr et al13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar extend these data by determining the prognostic value of liver biopsy in patients evaluated for heart transplant. During a 13-year period, approximately 1,200 patients underwent cardiac transplantation at Columbia University. Advanced liver disease was suspected in 68 of these patients (5.3%), and they underwent liver biopsy. Retrospectively, they were assigned a standard fibrosis score (0–4) along with a novel liver risk score [(fibrosis + 1) × MELD-XI]. This highly-selected biopsy group was more than 40% non-Caucasian, with nearly 50% having “other” etiologies of heart failure, including congenital heart disease and restrictive or infiltrative cardiomyopathies. Of the study cohort, 52 patients were listed for transplant and 36 received an allograft, with 27 (75%) surviving longer than 1 year. Post-transplant survivors had lower MELD-XI and liver risk scores, whereas patients who died after transplant had more allograft dysfunction, longer ventilator times, and more severe bleeding. In a multivariable analysis, the MELD-XI score before transplant and the liver risk score during evaluation were independent predictors of 1-year death. The novelty of the liver risk score is its ability to combine structural (e.g., fibrosis) and functional (e.g., total bilirubin, creatinine) abnormalities of advanced heart disease associated with end-organ dysfunction. Similar to previous findings,12Gelow J.M. Desai A.S. Hochberg C.P. Glickman J.N. Givertz M.M. Fang J.C. Clinical predictors of hepatic fibrosis in chronic advanced heart failure.Circ Heart Fail. 2010; 3: 59-64Crossref PubMed Scopus (64) Google Scholar other liver function tests and imaging studies were not able to differentiate patients with no to mild vs moderate to severe fibrosis. The major limitation of retrospective studies assessing the presence and prognostic significance of hepatic fibrosis is the high likelihood of selection bias. In the study by Farr et al,13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar the need for liver biopsy was “based on a history of liver disease, including viral hepatitis, NAFLD [non-alcoholic fatty liver disease], alcoholism and congestive hepatopathy or cardiac cirrhosis.” For consistency, all patients underwent a transjugular liver biopsy. The indications and techniques were even more mixed in the study by Gelow et al12Gelow J.M. Desai A.S. Hochberg C.P. Glickman J.N. Givertz M.M. Fang J.C. Clinical predictors of hepatic fibrosis in chronic advanced heart failure.Circ Heart Fail. 2010; 3: 59-64Crossref PubMed Scopus (64) Google Scholar and included specimens obtained from the transjugular approach during the pre-transplant evaluation, at the time of VAD implantation (due to operator suspicion), and at autopsy before or after VAD or transplant. Farr et al13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar acknowledge this limitation along with the small numbers, single-center design, and lack of prospective validation. An additional concern is the potential sampling error of transjugular liver biopsy. In a related report in this issue of The Journal of Heart and Lung Transplantation, Wu et al14Wu F.M. Jonas M.M. Opotowsky A.R. et al.Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes.J Heart Lung Transplant. 2015; 34: 883-891Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar describe hepatic fibrosis and clinical outcomes in 68 adults and children with Fontan circulation. This retrospective record review identified patients with congenital heart disease and a history of Fontan surgery who underwent liver biopsies “for clinical reasons,” including heart failure (47%), ascites (32%), and hepatitis C (15%). Despite normal hepatic vein pressure gradients, 78% of patients had advanced (grade 3 or 4) centrilobular fibrosis, 31% had advanced portal fibrosis, and 15% had cirrhosis. Contrary to the data of Farr et al,13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar there was no correlation between death and histologic findings. With regard to sampling error, specimens from biopsies obtained through a transjugular approach were more fragmented than those obtained through a transcutaneous approach. Furthermore, among autopsy cases, the distribution of fibrosis was patchy, with areas of more marked fibrosis and areas of relative sparing. Inter-reader variability of liver pathology has not been adequately assessed in patients with advanced heart failure, and refinement of hepatic fibrosis scoring has only recently been proposed.15Dai D.F. Swanson P.E. Krieger E.V. Liou I.W. Carithers R.L. Yeh M.M. Congestive hepatic fibrosis score: a novel histologic assessment of clinical severity.Mod Pathol. 2014; 27: 1552-1558Crossref PubMed Scopus (67) Google Scholar The current studies13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 14Wu F.M. Jonas M.M. Opotowsky A.R. et al.Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes.J Heart Lung Transplant. 2015; 34: 883-891Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar raise several important questions that should direct future investigation. Liver biopsy is an invasive procedure that is unlikely to become a routine part of the pre-transplant evaluation. Novel imaging strategies to assess fibrosis, including transient elastography and diffusion-weighted magnetic resonance imaging, have been validated in critically ill non-cardiac patients16Koch A. Horn A. Duckers H, et al. Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU.Crit Care. 2011; 15: R266Crossref PubMed Scopus (52) Google Scholar and may help to risk stratify patients with severe heart failure. Likewise, novel biomarkers of hepatic fibrosis and apoptosis, including fibroblast growth factor-23, Toll-like receptor 4, and epitopes of hepatic cytokeratin-18,17Prie D. Forand A. Francoz C. et al.Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list.PloS One. 2013; 8: e66182Crossref PubMed Scopus (42) Google Scholar, 18Herzer K. Kneiseler G. Bechmann L.P. et al.Onset of heart failure determines the hepatic cell death pattern.Ann Hepatol. 2011; 10: 174-179PubMed Google Scholar, 19Rockey D.C. Bell P.D. Hill J.A. Fibrosis: a common pathway to organ injury and failure.N Engl J Med. 2015; 372: 1138-1149Crossref PubMed Scopus (709) Google Scholar may help target appropriate candidates for liver biopsy. For patients found to have moderate to severe fibrosis, mechanical circulatory support could provide a bridge to recovery of hepatic function,20Demirozu Z.T. Hernandez R. Mallidi H.R. et al.HeartMate II left ventricular assist device implantation in patients with advanced hepatic dysfunction.J Card Surg. 2014; 29: 419-423Crossref PubMed Scopus (13) Google Scholar although data are lacking on reversal of biopsy findings. Heart transplant alone has also been shown to ameliorate laboratory abnormalities—but not the pathology—associated with congestive hepatopathy.11Chokshi A. Cheema F.H. Schaefle K.J. et al.Hepatic dysfunction and survival after orthotopic heart transplantation: application of the MELD scoring system for outcome prediction.J Heart Lung Transplant. 2012; 31: 591-600Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 21Dichtl W. Vogel W. Dunst K.M. et al.Cardiac hepatopathy before and after heart transplantation.Transpl Int. 2005; 18: 697-702Crossref PubMed Scopus (73) Google Scholar Although most adult heart transplant programs will exclude for transplant patients with cirrhosis proven on the biopsy specimen, there may be special populations, such as younger Fontan patients, that can achieve good short-term and possibly longer-term outcomes.22Simpson K.E. Esmaeeli A. Khanna G. et al.Liver cirrhosis in Fontan patients does not affect 1-year post-heart transplant mortality or markers of liver function.J Heart Lung Transplant. 2014; 33: 170-177Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Notably, in the study by Wu et al,14Wu F.M. Jonas M.M. Opotowsky A.R. et al.Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes.J Heart Lung Transplant. 2015; 34: 883-891Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar the pathologic findings did not correlate with outcomes. While awaiting additional data, a more systematic approach to evaluating liver disease during the heart transplant evaluation is needed. Programs should be encouraged to implement quality initiatives in which contemporary laboratory and imaging data, including transient elastography, are prospectively collected and combined with clinical information to target high-risk patients for biopsy (Figure 1). Alternative options are available for those found to have advanced liver disease, as defined by Farr et al.13Farr M. Mitchell J. Lippel M. et al.Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.J Heart Lung Transplant. 2015; 34: 873-882Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Recent single-center23Atluri P. Gaffey A. Howard J. et al.Combined heart and liver transplantation can be safely performed with excellent short- and long-term results.Ann Thorac Surg. 2014; 98: 858-862Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and registry24Cannon R.M. Hughes M.G. Jones C.M. Eng M. Marvin M.R. A review of the United States experience with combined heart-liver transplantation.Transpl Int. 2012; 25: 1223-1228Crossref PubMed Scopus (84) Google Scholar data suggest that combined heart and liver transplantation is highly feasible and associated with excellent short-term and long-term survival (up to 87% at 1 year and 83% at 5 years). In addition, similar to findings in combined heart-kidney transplant, less rejection23Atluri P. Gaffey A. Howard J. et al.Combined heart and liver transplantation can be safely performed with excellent short- and long-term results.Ann Thorac Surg. 2014; 98: 858-862Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and early attenuation of cardiac allograft vasculopathy25Topilsky Y. Raichlin E. Hasin T. et al.Combined heart and liver transplant attenuates cardiac allograft vasculopathy compared with isolated heart transplantation.Transplantation. 2013; 95: 859-865Crossref PubMed Scopus (27) Google Scholar have been observed. Whether this is due to enhanced immunologic protection or differences in immunosuppressive therapy requires further study. Specific diagnoses (e.g., amyloidosis) may be particularly suited for dual-organ transplant, but these patients should be referred to specialized centers. Finally, although destination VAD therapy may offer an acceptable medium-term or long-term solution for patients with end-stage heart disease complicated by cirrhosis, higher perioperative morbidity (e.g., vasoplegia, bleeding) and mortality should be anticipated. This author does not have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomesThe Journal of Heart and Lung TransplantationVol. 34Issue 7PreviewThe Fontan operation redirects venous blood flow directly to the pulmonary circulation in subjects with single ventricle anatomy. Congestive hepatopathy and cirrhosis have been described in subjects with Fontan circulation, but the prevalence of and predictors for liver disease remain unknown. Full-Text PDF Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunctionThe Journal of Heart and Lung TransplantationVol. 34Issue 7PreviewFunctional and structural liver abnormalities may be found in patients with advanced heart failure (HF). The Model of End-Stage Liver Disease Excluding INR (MELD-XI) score allows functional risk stratification of HF patients on and off anti-coagulation awaiting heart transplantation (HTx), but these scores may improve or worsen depending on bridging therapies and during time on the waiting list. Liver biopsy is sometimes performed to assess for severity of fibrosis. Uncertainty remains whether biopsy in addition to MELD-XI improves prediction of adverse outcomes in patients evaluated for HTx. Full-Text PDF
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