Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.

[1]  Ja-june Jang,et al.  Hepatic steatosis is associated with intrahepatic cholestasis and transient hyperbilirubinemia during regeneration after living donor liver transplantation , 2006, Transplant international : official journal of the European Society for Organ Transplantation.

[2]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[3]  B. Neuschwander‐Tetri,et al.  Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial , 2009, Hepatology.

[4]  I. Kamel,et al.  Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study , 2011, BMJ : British Medical Journal.

[5]  A. Duchini,et al.  ROUX-EN-Y GASTRIC BYPASS FOR RECURRENT NONALCOHOLIC STEATOHEPATITIS IN LIVER TRANSPLANT RECIPIENTS WITH MORBID OBESITY , 2001, Transplantation.

[6]  S. Sookoian,et al.  Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease , 2011, Hepatology.

[7]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[8]  Joel Z Stengel,et al.  Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. , 2011, Gastroenterology.

[9]  H. Cortez‐Pinto,et al.  Hepatic histology in obese patients undergoing bariatric surgery. , 2006, Journal of hepatology.

[10]  M. Kaplan,et al.  Evaluation of abnormal liver-enzyme results in asymptomatic patients. , 2000, The New England journal of medicine.

[11]  J. Sallis,et al.  Physical Activity Recommendations, Exercise Intensity, and Histological Severity of Nonalcoholic Fatty Liver Disease , 2011, The American Journal of Gastroenterology.

[12]  J. Trotter Thin chance for fat people (to become living donors) , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[13]  J. Perkins Saying “yes” to obese living liver donors: Short‐term intensive treatment for donors with hepatic steatosis in living‐donor liver transplantation. Nakamuta M, Morizono S, Soejiima Y, Yoshizumi T, Aishima S, Takasugi S, et al. Transplantation 2005;80:608–612. , 2006, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[14]  A. Madan,et al.  Laparoscopic Roux-en-Y Gastric Bypass is Safe and Feasible after Orthotopic Liver Transplantation , 2005, Obesity surgery.

[15]  D. Torres,et al.  A Pilot Study Using Simvastatin in the Treatment of Nonalcoholic Steatohepatitis: A Randomized Placebo-controlled Trial , 2009, Journal of clinical gastroenterology.

[16]  K. Cusi,et al.  Corrigendum:The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association , 2012, The American Journal of Gastroenterology.

[17]  K. Hasegawa,et al.  Living donor liver transplantation for non‐alcoholic steatohepatitis: A single center experience , 2014, Hepatology research : the official journal of the Japan Society of Hepatology.

[18]  S. Ikramuddin,et al.  Gastric bypass after liver transplantation , 2013, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[19]  M. Charlton Nonalcoholic fatty liver disease: a review of current understanding and future impact. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[20]  P. Fontes,et al.  Outcome After Liver Transplantation for NASH Cirrhosis , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  K. Batts,et al.  Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases. , 2000, Transplantation.

[22]  J. Torres,et al.  Sleeve Gastrectomy as Treatment for Severe Obesity after Orthotopic Liver Transplantation , 2007, Obesity surgery.

[23]  D. Pessayre,et al.  Mitochondrial injury in steatohepatitis , 2004, European journal of gastroenterology & hepatology.

[24]  K. Jauch,et al.  Effect of graft steatosis on liver function and organ survival after liver transplantation. , 2008, American journal of surgery.

[25]  C. Rosen,et al.  Evaluation of the donor liver for living donor liver transplantation , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[26]  J. Crowley,et al.  The Selenium and Vitamin E Cancer Prevention Trial (SELECT) , 2011 .

[27]  Roberto Pastor-Barriuso,et al.  Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality , 2005, Annals of Internal Medicine.

[28]  G. Marchesini,et al.  Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome , 2003, Hepatology.

[29]  C. Alessandri,et al.  Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis. , 2013, The Cochrane database of systematic reviews.

[30]  R. Carithers,et al.  Practice Guidelines : Evaluation of the Patient for Liver Transplantation , 2005 .

[31]  D. S̆timac,et al.  Nonalcoholic Fatty Liver Disease/Steatohepatitis: Epidemiology, Pathogenesis, Clinical Presentation and Treatment , 2012, Digestive Diseases.

[32]  A. McCullough,et al.  Pathogenesis of non-alcoholic steatohepatitis: human data. , 2007, Clinics in liver disease.

[33]  V. Mazzaferro,et al.  Milan multicenter experience in liver transplantation for hepatocellular carcinoma. , 1994, Transplantation proceedings.

[34]  G. Marchesini,et al.  A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease , 2005, The American Journal of Gastroenterology.

[35]  S. Saadeh Nonalcoholic Fatty liver disease and obesity. , 2007, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[36]  K. Batts,et al.  Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[37]  M. Stegall,et al.  Risk factors for primary dysfunction after liver transplantation--a multivariate analysis. , 1993, Transplantation.

[38]  L. Burgart,et al.  Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial , 2004, Hepatology.

[39]  I. Shimomura,et al.  Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[40]  Erland Erdmann,et al.  Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial , 2005, The Lancet.

[41]  G. Aithal,et al.  Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. , 2008, Gastroenterology.

[42]  C. Wai,et al.  Prevalence and clinical associations of posttransplant fatty liver disease , 2007, Liver international : official journal of the International Association for the Study of the Liver.

[43]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[44]  P. Thuluvath,et al.  Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States , 2002, Hepatology.

[45]  E. Schiff,et al.  Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease , 2009, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[46]  A. Lentsch,et al.  Clinical review of nonalcoholic steatohepatitis in liver surgery and transplantation. , 2010, Journal of the American College of Surgeons.

[47]  G. Avey,et al.  NAFLD Recurrence in Liver Transplant Recipients , 2011, Transplantation.

[48]  L. Rubbia‐Brandt,et al.  Non-Alcoholic Fatty Liver Disease in Liver Transplant Recipients: Another Story of “Seed and Soil” , 2010, American Journal of Gastroenterology.

[49]  S. Fan,et al.  Retracted: Fat‐Derived Hormone Adiponectin Combined with FTY720 Significantly Improves Small‐for‐Size Fatty Liver Graft Survival , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[50]  Katherine M Flegal,et al.  Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. , 2012, JAMA.

[51]  P. Thuluvath,et al.  Steroid avoidance in liver transplantation: Meta‐analysis and meta‐regression of randomized trials , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[52]  J. Dixon,et al.  Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. , 2001, Gastroenterology.

[53]  Z. Younossi,et al.  Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[54]  S. Sanderson,et al.  The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. , 2005, Journal of hepatology.

[55]  M. Holmqvist,et al.  Long‐term follow‐up of patients with NAFLD and elevated liver enzymes , 2006, Hepatology.

[56]  Natalie J Torok,et al.  De novo nonalcoholic fatty liver disease after liver transplantation , 2007, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[57]  K. Kasturi,et al.  Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[58]  C. Ryan,et al.  One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation , 2002, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[59]  R. Wolfe,et al.  Chronic renal failure after transplantation of a nonrenal organ. , 2003, The New England journal of medicine.

[60]  B. Neuschwander‐Tetri,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[61]  S. Nissen,et al.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. , 2007, The New England journal of medicine.

[62]  J. Hardies,et al.  A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. , 2006, The New England journal of medicine.

[63]  Christopher D. Williams,et al.  Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis , 2012, Hepatology.

[64]  R. Fisher,et al.  Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[65]  J. Bradley,et al.  Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. , 2005, Critical reviews in oncology/hematology.

[66]  J. Ludwig,et al.  Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. , 1980, Mayo Clinic proceedings.

[67]  W. Jochum,et al.  Use of Severely Steatotic Grafts in Liver Transplantation: A Matched Case-Control Study , 2007, Annals of surgery.

[68]  D. Reeds,et al.  Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. , 2009, Gastroenterology.

[69]  S. Caldwell,et al.  Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease , 1999, Hepatology.

[70]  R. Malthaner,et al.  Cyclosporin versus tacrolimus for liver transplanted patients. , 2006, The Cochrane database of systematic reviews.

[71]  C. Buechler,et al.  Adiponectin, a key adipokine in obesity related liver diseases. , 2011, World journal of gastroenterology.

[72]  D. Modan-Moses,et al.  Leptin and transplantation: pieces are still missing in the puzzle. , 2002, The Israel Medical Association journal : IMAJ.

[73]  A. Feldstein,et al.  Hepatic Lipid Partitioning and Liver Damage in Nonalcoholic Fatty Liver Disease , 2009, Journal of Biological Chemistry.

[74]  R. Green,et al.  Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. , 2011, Annals of hepatology.

[75]  V. Paradis,et al.  High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: A potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis , 2001, Hepatology.

[76]  R. Gish,et al.  De Novo Non‐Alcoholic Fatty Liver Disease Following Orthotopic Liver Transplantation , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[77]  T. Berg,et al.  High‐dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double‐blind, randomized, placebo‐controlled trial , 2010, Hepatology.

[78]  B. Banas,et al.  Calcineurin inhibitor minimization protocols in liver transplantation , 2009, Transplant international : official journal of the European Society for Organ Transplantation.

[79]  R. Wiesner,et al.  Combined Liver Transplantation and Gastric Sleeve Resection for Patients With Medically Complicated Obesity and End‐Stage Liver Disease , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[80]  K. Kaita,et al.  Fatty Infiltration of Liver in Hyperlipidemic Patients , 2000, Digestive Diseases and Sciences.

[81]  P. Angulo,et al.  Nonalcoholic fatty liver disease. , 2002, Revista de gastroenterologia de Mexico.

[82]  K. Cusi,et al.  Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. , 2012, Gastroenterology.

[83]  S. Knechtle,et al.  The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. , 1991, Transplantation.

[84]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[85]  E. Fassio,et al.  Natural history of nonalcoholic steathepatitis: A longitudinal study of repeat liver biopsies , 2004, Hepatology.

[86]  R. N. Macsween,et al.  Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? , 2002, Journal of clinical pathology.

[87]  S. Tueche Diabetes mellitus after liver transplant new etiologic clues and cornerstones for understanding. , 2003, Transplantation proceedings.