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Preventive Strategies for Nonalcoholic Fatty Liver Disease After Liver Transplantation

  • Narendra S. Choudhary
    Affiliations
    Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
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  • Sanjiv Saigal
    Correspondence
    Address for correspondence: Sanjiv Saigal, Director, Hepatology & Liver Transplant, Medanta Institute of Digestive & Hepatobiliary Sciences &Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurgaon, PIN 122001, India.
    Affiliations
    Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
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      Post-transplant nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) is common and can be recurrent or de novo. The available data suggest that progression of fibrosis is accelerated in these patients compared to NASH in general population. The long-term data suggest more risk of metabolic syndrome and associated metabolic comorbidities and cardiovascular disease in these patients. The current review focuses on prevalence and prevention/treatment of post-transplant NAFLD or NASH.

      Keywords

      After liver transplantation, recurrent or de novo nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) is a common finding. It is called recurrent when baseline disease was NASH-related cirrhosis and called de novo when pretransplant liver disease was something other than NASH.
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      The available data show that both recurrent and de novo NAFLD/NASH are common.
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • et al.
      Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease.
      • Malik S.M.
      • Devera M.E.
      • Fontes P.
      • et al.
      Recurrent disease following liver transplantation for nonalcoholic steatohepatitis cirrhosis.
      • Yalamanchili K.
      • Saadeh S.
      • Klintmalm G.B.
      • et al.
      Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.
      • Dureja P.
      • Mellinger J.
      • Agni R.
      • et al.
      NAFLD recurrence in liver transplant recipients.
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      • Contos M.J.
      • Cales W.
      • Sterling R.K.
      • et al.
      Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.
      • Kim H.
      • Lee K.
      • Lee K.W.
      • et al.
      Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation.
      • Dumortier J.
      • Giostra E.
      • Belbouab S.
      • et al.
      Non-alcoholic fatty liver disease in liver transplant recipients: another story of ‘‘seed and soil”.
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • et al.
      Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.
      Liver transplantation cures the liver disease (cirrhosis); however, it does not cure metabolic risk of a given patient. In fact, there is a rise in metabolic risk factors after liver transplantation. Metabolic syndrome occurs in 43–58% of patients after liver transplantation (LT).
      • Bianchi G.
      • Marchesini G.
      • Marzocchi R.
      • et al.
      Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression.
      • Choudhary N.S.
      • Saigal S.
      • Saraf N.
      • et al.
      Sarcopenic obesity with metabolicsyndrome: a newly recognized entity following living donor liver transplantation.
      • Laryea M.
      • Watt K.D.
      • Molinari M.
      • et al.
      Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events.
      • Pagadala M.
      • Dasarathy S.
      • Eghtesad B.
      • McCullough A.J.
      Posttransplant metabolic syndrome: an epidemic waiting to happen.
      A study from our center in north India showed a 53% prevalence of metabolic syndrome after LT; there was significant rise of body mass index and triglycerides. The prevalence of hypertension increased from 18% pre-LT to 39% after transplantation, and prevalence of diabetes increased from 20% pre-LT to 56% after transplantation.
      • Choudhary N.S.
      • Saigal S.
      • Saraf N.
      • et al.
      Sarcopenic obesity with metabolicsyndrome: a newly recognized entity following living donor liver transplantation.
      Various factors contributing to this higher risk of metabolic syndrome include weight gain and impact of immunosuppression agents combined with diet, lifestyle, and genetic susceptibility of a patient. All these factors lead to higher incidence of diabetes, hypertension, dyslipidemia, and metabolic syndrome after liver transplantation. The immunosuppression agents affect multiple aspects of metabolic syndrome. Corticosteroids and calcineurin inhibitors cause hyperglycemia, hypertension, and dyslipidemia. Steroids cause weight gain. Mammalian target of rapamycin inhibitors cause dyslipidemia.
      • Watt K.D.
      Metabolic syndrome: is immunosuppression to blame?.
      • Kappus M.
      • Abdelmalek M.
      De novo and recurrence of nonalcoholic steatohepatitis after liver transplantation.
      • Choudhary N.S.
      • Saigal S.
      • Shukla R.
      • et al.
      Current status of immunosuppression in liver transplantation.
      It should be noted that mycophenolate is devoid of these metabolic side effects.
      • Choudhary N.S.
      • Saigal S.
      • Shukla R.
      • et al.
      Current status of immunosuppression in liver transplantation.
      This higher risk of metabolic syndrome after transplantation manifest as post-transplantation NAFLD/NASH, cardiovascular events and possibly associated with malignancies also.
      • Pais R.
      • Barritt 4th, A.S.
      • Calmus Y.
      • et al.
      NAFLD and liver transplantation: current burden and expected challenges.
      The presence of rs738409-G allele of PNPLA3 gene and donor graft steatosis also predispose to post-transplant development of NAFLD/NASH.
      • Gitto S.
      • Marra F.
      • De Maria N.
      • et al.
      Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times.
      Thus, post-transplant patients are predisposed to metabolic syndrome and having NAFLD/NASH.

      Prevalence of post-transplant NAFLD/NASH

      Several studies have looked at recurrent and de novo NAFLD/NASH after LT, and clinically relevant randomly selected studies are shown in Table 1. Data suggest that patients with NASH as pretransplant etiology have higher prevalence of NAFLD/NASH after liver transplantation. Yalamanchili
      • Yalamanchili K.
      • Saadeh S.
      • Klintmalm G.B.
      • et al.
      Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.
      et al. studied 257 patients with NASH (n = 18) or cryptogenic cirrhosis (CC, n = 239) and showed that 45% of NASH and 23% of CC had recurrent disease at a follow-up of 5 years, P = 0.007. El Atrache
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      et al. studied 83 patients with NASH/CC and showed a 24% prevalence of NASH at 1.5 years after LT. Narayanan et al.
      • Narayanan P.
      • Mara K.
      • Izzy M.
      • et al.
      Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation.
      showed that recurrent NAFLD was present in 77.6% of patients compared to 44.7% of non-NASH patients. Vallin et al. showed that recurrent NAFLD was more common than de novo NAFLD/NASH. Patients with recurrent NAFLD had higher histologic severity at all time points than patients with de novo NAFLD.
      • Vallin M.
      • Guillaud O.
      • Boillot O.
      • Hervieu V.
      • Scoazec J.Y.
      • Dumortier J.
      Recurrent or denovo nonalcoholic fatty liver disease after liver transplantation: natural history based on liver biopsy analysis.
      Several studies have also looked at de novo NAFLD/NASH. A meta-analysis of 12 studies that included 2166 patients showed a 26% pooled prevalence of de novo NAFLD that ranged from 14.7% to 52% across included studies. Fibrosis was reported in 3.3%–52% of patients, and NASH was reported from 1 to 32%. It should be noted that some of the studies had reported only fibrosis; thus, reported prevalence of NASH is lower than reported prevalence of fibrosis. The highest prevalence of de novo NAFLD was found in patients with alcoholic cirrhosis (37%) and cryptogenic cirrhosis (35%) and in patients taking tacrolimus (26%).
      • Losurdo G.
      • Castellaneta A.
      • Rendina M.
      • Carparelli S.
      • Leandro G.
      • Di Leo A.
      Systematic review with meta-analysis: de novo nonalcoholic fatty liver disease in liver-transplanted patients.
      Table 1NAFLD/NASH After Liver Transplantation.
      Authorref.N, baseline diseaseRecurrent or de novo NAFLD/NASHFibrosis/comments
      Bhagat
      • Bhagat V.
      • Mindikoglu A.L.
      • Nudo C.G.
      • et al.
      Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease.
      64 NASH33% NASH, none in the control group (alcoholic), mean time of biopsies not providedNone had ≥F3 fibrosis
      Malik
      • Malik S.M.
      • Devera M.E.
      • Fontes P.
      • et al.
      Recurrent disease following liver transplantation for nonalcoholic steatohepatitis cirrhosis.
      98 NASHNAFLD 70%, NASH 25%, at a mean of 18 months18% had ≥F2 fibrosis
      Yalamanchili
      • Yalamanchili K.
      • Saadeh S.
      • Klintmalm G.B.
      • et al.
      Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.
      Total 257, NASH (18) or CC (239)45% of NASH, 23% CC had NAFLD at 5 years, NASH in 4%5% at 5 years; 10% at 10 years, ≥F3
      Dureja
      • Dureja P.
      • Mellinger J.
      • Agni R.
      • et al.
      NAFLD recurrence in liver transplant recipients.
      88, NASH/CC39% NAFLD and 28% NASH, average time of biopsy was 11.9 months after transplant9% had ≥F2 fibrosis 3 patients had stage 3 or 4 fibrosis
      El Atrache
      • El Atrache M.M.
      • Abouljoud M.S.
      • Divine G.
      • et al.
      Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.
      83, NASH/CC24% NASH at 18.2 ± 14 months, Recurrence was significantly associated with NASH (33%) compared with CC (14%)3 allograft failure due to NASH recurrence, all had ≥F3 fibrosis
      Contos
      • Contos M.J.
      • Cales W.
      • Sterling R.K.
      • et al.
      Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.
      30, NASH/CC100% steatosis by 5 years as compared with only 25% in the control group, 10% NASH1 had bridging fibrosis
      Kim
      • Kim H.
      • Lee K.
      • Lee K.W.
      • et al.
      Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation.
      156 non-NASHDe novo NAFLD in 45 (27%), 6.7% NASH, mean period of 35.4 months between LT and biopsy4.4% (F2) of NAFLD
      Duormortier
      • Dumortier J.
      • Giostra E.
      • Belbouab S.
      • et al.
      Non-alcoholic fatty liver disease in liver transplant recipients: another story of ‘‘seed and soil”.
      421 non-NASHDe novo NAFLD 31%, 3.8% NASH, biopsy at median 40 monthsCirrhosis or extensive fibrosis in 3 patients (2.25%), at 38, 95, and 108 months
      Bhati
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • et al.
      Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.
      103 NASH34 had liver biopsy at a median follow up of 47 (23–95) months, NAFLD in 88.2%, 41.2% had NASHBridging fibrosis was noted in 20.6%
      CC, cryptogenic cirrhosis, NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease.
      The recent International Liver Transplant Society consensus document suggests that recurrent NAFLD/NASH may be different from de novo disease. Recurrent disease is more common and may progress more rapidly (moderate quality of evidence and moderate strength of recommendation).
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.

      Implications of post-LT NAFLD/NASH

      Post-transplant NASH may have different natural history than pretransplant NASH. Several studies have shown that these patients have significant fibrosis at a short time after transplantation as shown in Table 1. A meta-analysis in pretransplant (patients with NASH) has shown that one-stage fibrosis progression takes 7 years in NASH. This meta-analysis also showed that progression to NASH or fibrosis might happen in nonalcoholic fatty liver also, although the rate of fibrosis progression was slower compared to NASH.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      As shown in table 1, multiple studies have shown that a significant degree of fibrosis may occur in patients with recurrent or de novo NAFLD/NASH after few years only in liver transplant recipients. The recent International Liver Transplant Society consensus document addresses one important question: does recurrent or de novo NASH negatively affects patient and graft survival? The current data have not shown any clear association between recurrent or de novo NAFLD/NASH and patient or graft survival; however, quality of evidence is low and strength of recommendation is weak. It is suggested that data on long-term graft and patient survival are needed, and additional clinical end points should include cardiovascular events, renal disease, and malignancy.
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      This bias towards limited clinical importance of post-LT NAFLD/NASH is created by short-term studies that have shown similar outcomes in NASH and non-NASH patients. Recently, three studies have looked at long-term follow-up of these patients. Bhati et al. studied 103 patients of NASH as pretransplant etiology; 34 had a liver biopsy at a median follow-up of 47 (23–95) months after transplantation. Biopsy showed recurrent NAFLD in 88.2%, 41.2% had NASH, and bridging fibrosis was noted in 20.6% of patients. A total of 56 patients had transient elastography at a median follow-up of 75 (40–146) months, which showed steatosis in 49 (87.5%). The advanced fibrosis was present in 26.8%, and 5.4% of these had suggestion of cirrhosis.
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • et al.
      Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.
      A total of 32 patients died, with leading cause of mortality as cancer and infections (25% each) followed by cardiovascular disease in 21.9%; 9% of deaths were due to graft cirrhosis.
      • Bhati C.
      • Idowu M.O.
      • Sanyal A.J.
      • et al.
      Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.
      The second study was a retrospective analysis by Narayanan et al.
      • Narayanan P.
      • Mara K.
      • Izzy M.
      • et al.
      Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation.
      that included 588 patient transplanted from 1999 to 2006. NAFLD was present in 77.6% recurrent and in 44.7% of non-NASH recipients at 10 years. The risk factor for post-LT NAFLD included female gender, a diagnosis of hepatitis C, and time-dependent body mass index. The author showed that underlying NASH was associated with cardiovascular events with a hazard ratio of 2.04 (1.37–3.04), P < 0.001.
      • Narayanan P.
      • Mara K.
      • Izzy M.
      • et al.
      Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation.
      The third study by Gitto et al.
      • Gitto S.
      • de Maria N.
      • di Benedetto F.
      • et al.
      De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients.
      compared 43 patients with de novo NAFLD to 151 patients without NAFLD. These patients underwent liver transplantation between 2001 and 2005 and were followed up till 2016. NAFLD appeared at a mean follow-up of 55 months. The patients with de novo NAFLD had significantly higher prevalence of diabetes mellitus (51.2% versus 30.5%), obesity (48.8% vs 9.9%), and metabolic syndrome (74.4% vs 29.8%). Cardiovascular events occurred in 34.9% in NAFLD versus 7.9% in other group; also de novo solid neoplasm occurred more commonly in the de novo NAFLD group (30.2% vs 11.9%). The de novo NAFLD was an independent predictor of mortality.
      • Gitto S.
      • de Maria N.
      • di Benedetto F.
      • et al.
      De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients.
      Although both NAFLD/NASH and cardiovascular disease are associated with metabolic syndrome, several potential links make NAFLD/NASH an independent (of metabolic risk factors) risk factor for CVD.
      • Fargion S.
      • Porzio M.
      • Fracanzani A.L.
      Nonalcoholic fatty liver disease and vascular disease: state-of-the-art.
      • DeFilippis A.P.
      • Blaha M.J.
      • Martin S.S.
      • et al.
      Nonalcoholic fatty liver disease and serum lipoproteins: the Multi-Ethnic Study of Atherosclerosis.
      • Alkhouri N.
      • Tamimi T.A.
      • Yerian L.
      • Lopez R.
      • Zein N.N.
      • Feldstein A.E.
      The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk.
      • Matsuzawa Y.
      • Funahashi T.
      • Kihara S.
      • Shimomura I.
      Adiponectin and metabolic syndrome.
      • Tripodi A.
      • Fracanzani A.L.
      • Primignani M.
      • et al.
      Procoagulant imbalance in patients with non-alcoholic fatty liver disease.
      These possible links causing atherosclerosis acceleration include atherogenic dyslipidemia, chronic inflammation, oxidative stress, and imbalance of procoagulant and anticoagulant factors. Atherogenic dyslipidemia include high triglycerides, low high-density lipoprotein, and small dense and oxidized low-density lipoprotein (LDL). It is possible that all these contribute to higher cardiovascular events in post-LT patients with NAFLD/NASH similar to higher risk in non-LT population with NASH. Multiple studies and meta-analysis have shown that patients with NAFLD/NASH and NASH-related cirrhosis have higher risk of coronary artery disease and coronary events before or after liver transplantation.
      • Choudhary N.S.
      • Duseja A.
      Screening of cardiovascular disease in nonalcoholic fatty liver disease.
      • Kapuria D.
      • Takyar V.K.
      • Etzion O.
      • Sorana P.
      • O’keffe J.H.
      • Koh C.
      Association of hepatic steatosis with subclinical atherosclerosis: systematic review and meta-analysis.
      • Wu S.
      • Wu F.
      • Ding Y.
      • Hou J.
      • Bi J.
      • Zhang Z.
      Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis.
      • Kadayifci A.
      • Tan V.
      • Ursell P.C.
      • Merriman R.B.
      • Bass N.M.
      Clinical and pathologic risk factors for atherosclerosis in cirrhosis: a comparison between NASH-related cirrhosis and cirrhosis due to other aetiologies.
      • Kalaitzakis E.
      • Björnsson E.
      Coronary artery disease in liver cirrhosis: does the aetiology of liver disease matter?.
      • Vanwagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      However, current literature does not support any particular algorithm to screen these patients in absence of prospective and good quality data.
      • Choudhary N.S.
      • Duseja A.
      Screening of cardiovascular disease in nonalcoholic fatty liver disease.

      Prevention of post-transplantation NAFLD/NASH

      Prevention of post-LT NAFLD/NASH includes avoidance of weight gain and promotion of weight loss.
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      • Lucey M.R.
      • Terrault N.
      • Ojo L.
      • et al.
      Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      Table 2 summarizes management of metabolic risk factors. Patients with morbid obesity can be considered for bariatric surgery, although literature is limited.
      • Al-Nowaylati A.R.
      • Al-Haddad B.J.
      • Dorman R.B.
      • et al.
      Gastric bypass after liver transplantation.
      • Lin M.Y.
      • Tavakol M.M.
      • Sarin A.
      • et al.
      Safety and feasibility of sleeve gastrectomy in morbidly obese patients following liver transplantation.
      Cardiovascular screening programs are encouraged based on individual risk.
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      Immunosuppression protocol of short-term and low-dose steroid is preferred in these patients (moderate quality of evidence and moderate strength of recommendation).
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      No pharmacological agent has been tried for fatty liver in this population.
      Table 2Management of Metabolic Risk Factors, Based on References
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      • Lucey M.R.
      • Terrault N.
      • Ojo L.
      • et al.
      Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      .
      ParameterManagement
      Low-density lipoprotein >100 mg/dLLifestyle modification, diet changes

      Statins± addition of ezetimibe if not controlled by diet and lifestyle
      Higher triglyceridesFibric acid derivatives, fish oils
      Diabetes mellitusTarget HbA1c < 7% by lifestyle changes and medications, insulin is preferred when patient is on high doses of steroids
      HypertensionTreatment target: blood pressure 130/80 mm Hg, amlodipine/nifedipine may be preferred as these agents counteract real vasoconstrictor effect of calcineurin inhibitors, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers preferred in presence of chronic kidney disease, diabetes/proteinuria, heart failure with monitoring for hyperkalemia, beta blockers may be used in patients with coronary artery disease or heart failure
      Figure 1 describes a flowchart for issues faced in patients with NAFLD that affect outcomes in patients with NAFLD before and after liver transplantation. As NAFLD is associated with cardiovascular disease (including coronary artery disease) and chronic kidney disease,
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      • Fussner L.A.
      • Charlton M.R.
      • Heimbach J.K.
      • et al.
      The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
      • Papademetriou M.
      • Athyros V.G.
      • Geladari E.
      • Doumas M.
      • Tsioufis C.
      • Papademetriou V.
      The Co-existence of NASH and chronic kidney disease boosts cardiovascular risk: are there any common therapeutic options?.
      these diseases have an impact on short-term and long-term morbidity and mortality.
      • Vanwagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      All patients with NAFLD as etiology of cirrhosis should have detailed cardiac assessment to rule out coronary artery disease as presence of NAFLD should decrease threshold for angiography.
      • Hogan B.J.
      • Gonsalkorala E.
      • Heneghan M.A.
      Evaluation of coronary artery disease in potential liver transplant recipients.
      Figure 1
      Figure 1Issues in patients with NAFLD undergoing liver transplantation, tacrolimus to cyclosporine (if poor glycemic control, grade 2, and level B evidence). NAFLD, nonalcoholic fatty liver disease.
      Preoperatively, all patients should have measurement of serum creatinine, urinalysis, quantitative protein measurement, and renal ultrasound as these patients may have chronic kidney disease. Serum creatinine tends to overestimate GFR in cirrhosis. Pre-LT GFR influences selection of immunosuppression after LT. Table 3 summarizes prevention measures for NAFLD in the liver transplantation setting. Regular monitoring is important to detect disease recurrence and assess graft function. It is important to monitor and treat patients for features of the metabolic syndrome. Immunosuppression should be tailored according to the individual's risk of rejection, presence of renal impairment, and presence of liver cancer. Tacrolimus is generally preferred over cyclosporine in general but is associated with more risk of diabetes. Table 4 describes immunosuppression modification for metabolic syndrome/NAFLD after liver transplantation. Steroid-free immunosuppression is shown to be associated with less hypertension, diabetes, and cholesterol levels with no impact on graft loss or survival.
      • Segev D.L.
      • Sozio S.M.
      • Shin E.J.
      • et al.
      Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials.
      • Castedal M.
      • Skoglund C.
      • Axelson C.
      • Bennet W.
      Steroid-free immunosuppression with low-dose tacrolimus is safe and significantly reduces the incidence of new-onset diabetes mellitus following liver transplantation.
      Thus, steroids avoidance and minimization of calcineurin inhibitors may reduce the risk of post-transplant metabolic syndrome, but prospective studies are needed. As the greatest weight gain occurs in the first year following LT, the dietary interventions should be implemented early after LT and patients should be asked for regular exercise. Counseling regarding post-LT NAFLD and associated comorbidities may be helpful.
      Table 3Prevention of NAFLD in Liver Transplantation Setting.
      Pretransplantation measuresPost-transplantation measures
      • Careful evaluation of patient's cardiovascular risk factors
      • Renal protective strategies for patients with renal dysfunction
      • Assessing patients who are overweight
      • Be vigilant for sarcopenic obesity
      • Maintain moderate glycemic control
      • Choosing an appropriate immunosuppression regimen
      • Diet
      • Exercise
      • Be vigilant for development of the metabolic syndrome postoperatively
      • Close attention to glycemic control
      Table 4Prevention of Metabolic Risk Factors: Immunosuppression Modification (References
      • Germani G.
      • Laryea M.
      • Rubbia-Brandt L.
      • et al.
      Management of recurrent and de novo NAFLD/NASH after liver transplantation.
      • Lucey M.R.
      • Terrault N.
      • Ojo L.
      • et al.
      Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      ).
      Risk factorIS modification
      DiabetesSteroid short-term only/avoidance

      Tacrolimus to cyclosporine (if poor glycemic control, grade 2, level B evidence)
      HypertensionMinimization of steroids and calcineurin inhibitors
      Refractory hyperlipidemiaCyclosporin conversion to tacrolimus

      Calcineurin inhibitor reduction and addition of mycophenolate

      mTORi discontinuation (weak recommendations)

      Summary

      Both recurrent and de novo NAFLD/NASH are common after LT and are derived by several factors that increase risk of metabolic syndrome in these patients. Recurrent NAFLD is more common than de novo NAFLD. There is suggestion of accelerated fibrosis progression in these patients. While short-term studies have shown almost similar outcome to patients with other etiologies, long-term studies are needed. A careful attention to diet, lifestyle, and prevention of weight gain or promoting weight loss and management of metabolic comorbidities may help to prevent morbidity associated to post-LT NAFLD/NASH. Primary emphasis should be on control of diabetes, cardiovascular status, dyslipidemia, obesity, and renal parameters. Following transplant, judicious immunosuppression and early steroid withdrawal play a key role. Adherence to dietary and exercise regimens is pivotal in NAFLD prevention after transplantation.

      Conflicts of interest and funding

      The authors have none to declare.

      Acknowledgments

      The authors thank Mr. Yogesh Saini (research coordinator).

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