- Email: [email protected]
Nonalcoholic Fatty Liver Disease and Liver Transplantation
Nonalcoholic Fatty Liver Disease and Liver Tra n s p l a n t a t i o n Tuan Pham, MDa, Travis B. Dick, Michael R. Charlton, MD, FRCPc,*
PharmD, MBA, BCPS
b
,
KEYWORDS Nonalcoholic fatty liver disease Liver transplantation The metabolic syndrome Nonalcoholic steatohepatitis KEY POINTS Nonalcoholic fatty liver disease (NAFLD) is on a trajectory to become the most common indication for liver transplantation. Although features of NAFLD are common after liver transplantation for nonalcoholic steatohepatitis (NASH), recurrence of NASH with progressive fibrosis is unusual. Management of obesity and components of the metabolic syndrome are essential in achieving optimal posttransplant outcomes. Minimization of immunosuppression is a cornerstone of posttransplant management of patients undergoing liver transplantation for NAFLD.
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a complication of obesity1,2 and is widely considered to be the hepatic manifestation of the metabolic syndrome. It is a frequent cause of chronic liver disease in the United States with a changing prevalence mirroring the rising obesity trend.3–5 NAFLD has a variable natural history, but in some patients can progress to nonalcoholic steatohepatitis (NASH) with progressive fibrosis and eventual complications of cirrhosis, including liver failure and hepatocellular carcinoma.6–8 NASH is also thought to be the underlying etiology for cryptogenic cirrhosis in patients with features of the metabolic syndrome.6 Compared with the general population, patients with NASH have an increased risk for cardiovascular-related death, Disclosures: Drs T.B. Dick and T. Pham have nothing to disclose. Dr M.R. Charlton has received research support from Gilead Sciences, Merck, and Janssen. a Division of Gastroenterology and Hepatology, University of Utah, 30 N 1900 E, Salt Lake City, UT 84132, USA; b Department of Pharmacy, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84107-5701, USA; c Hepatology and Liver Transplantation, Intermountain Transplant Center, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84107-5701, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 20 (2016) 403–417 http://dx.doi.org/10.1016/j.cld.2015.10.014 1089-3261/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
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liver-related death,9 overall mortality, and death in association with hepatocellular carcinoma.10 The significant impact on mortality, magnified by the growing prevalence of the disease, has led to NASH being the third most common indication for liver transplantation, with a trajectory to become the most common (Fig. 1).11 Aside from its role in causing primary liver disease, concomitant NAFLD has been linked with a greater severity of liver disease in patients with chronic hepatitis C infection,12 as well as treatment failure in patients with chronic hepatitis B infection.13 Furthermore, the increasing prevalence of NAFLD in the population at large may lead to a reduced pool of suitable donor organs, because moderate to severe steatosis in the donor organ can significantly impact allograft viability.14 Taken in sum, the ever-growing burden and far-reaching impact of NAFLD underscores the need for evolving new considerations in liver transplant management. This article reviews these considerations as well as our current understanding of the physiology and management of patients with NASH before and after liver transplantation. NONALCOHOLIC FATTY LIVER DISEASE AND PRE LIVER TRANSPLANT CONSIDERATIONS
The median wait-list time has increased over recent years along with the number of candidates removed from the list for being too sick to undergo liver transplantation.15 The increased frequency of medical comorbidities in patients with NAFLD make them especially susceptible to being delisted or dying while awaiting surgery.16 Recognition of these comorbidities and their respective impact is essential for improving pretransplant survivorship, in addition to minimizing posttransplant complications. Impact of Weight and Body Composition
An increased body mass index (BMI) in cirrhosis can lead to an increased rate of clinical decompensation and risk of dying or being delisted while awaiting
Fig. 1. Longitudinal trends in the frequency of indications for liver transplantation in the United States are shown for 2002 through 2014. Nonalcoholic steatohepatitis (NASH) and cryptogenic cirrhosis (CC) have been combined to account for the high frequency of NASH as a cause of cryptogenic cirrhosis. Alcoholic liver disease (ALD) has also had a surge as an indication for liver transplantation. HCV, hepatitis C virus. (Data from Scientific Registry of Transplant Recipients.)
NAFLD and Liver Transplantation
liver transplantation.16,17 Conversely, weight reduction can lead to an improvement in the histologic features of NASH.18 In the posttransplant setting, Nair and colleagues19 demonstrated through a large scale analysis of the United Network for Organ Sharing database that patients with class III obesity (BMI 40 kg/m2) at the time of transplant have significantly higher rates of posttransplant primary graft nonfunction and mortality at 1 and 2 years. This same study also noted increased mortality at 5 years posttransplant in recipients with class II obesity (BMI >35 kg/m2). These observations may have been confounded by the presence of ascites. After correcting for ascites, a large, prospective, multicenter study found BMI does not confer any independent risk of mortality or allograft failure.20 Hakeem and colleagues21 also confirmed a lack of correlation between BMI corrected for ascites and posttransplant graft and patient survival, although the authors did note a significant increase in postoperative complications and greater duration of hospital stay in overweight and obese patients compared with those with normal weight (BMI 18–25 kg/m2). By extension, weight reduction should have important implications for pretransplant survivorship as well as reducing postoperative morbidity and mortality. Overnutrition and obesity, the primary effectors of NAFLD, are also strongly associated with sarcopenia through shared mechanisms such as insulin resistance, physical inactivity, chronic inflammation, vitamin D deficiency, and oxidative stress.22,23 Tandon and colleagues24 found sarcopenia to be highly prevalent (41%) and predictive of mortality (hazard ratio, 2.36; 95% CI, 1.23–4.53) in patients awaiting liver transplantation. In situations of refractory ascites and hyponatremia where a conventional Model for End-stage Liver Disease (MELD) score underestimates death,25 the addition of a sarcopenic index to MELD significantly improves pretransplant prognostication.26 Furthermore, patients with sarcopenia have a higher risk of posttransplant infection, longer postoperative hospitalizations, and unclear risk for posttransplant death.27–29 Several tools have been described for evaluating sarcopenia and malnutrition, including skeletal muscle mass on imaging, strength testing on functional assessments, and anthropomorphic measurements. Of these, abdominal imaging with computed tomography has been the most studied with regards to relevant clinical outcomes in the pretransplant and posttransplant populations, and is considered the gold standard despite concerns for operationalization beyond clinical research.24,26,29,30 The reproducibility of measurements and high likelihood of use within a liver transplant program make abdominal computed tomography a good candidate tool for concomitant sarcopenia management. Other promising modalities include dual energy x-ray absorptiometry,22 bioelectrical impedance analysis,31 hand-grip strength,32 and triceps skinfold thickness.33 Regardless of the diagnostic test, recognition and reversing sarcopenia has been associated with a survival benefit.34 Because sarcopenia has been linked to protein malnutrition and physical inactivity in patients with advanced liver disease, the mainstays of treatment to date have focused on caloric/amino acid supplementation and increased physical activity. A moderate exercise regimen, such as walking 5000 steps per day in combination with respective energy and protein intakes of 35 to 40 kcal/kg of body weight per day and 1.2 to 1.5 g/kg of body weight per day, can increase musculoskeletal mass in patients with compensated cirrhosis.31 In those patients with compensated cirrhosis and concomitant obesity, exercise for weight loss in combination with total caloric restriction and branched chain amino acid supplementation has been advocated. Owing to the inherent exercise intolerance associated with decompensated liver disease, a primary nutritional strategy of branched chain amino acid and caloric supplementation may be the best option for treating sarcopenia.35
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Chronic Kidney Disease
A recent metaanalysis by Musso and colleagues36 demonstrated an increased prevalence (odds ratio [OR], 2.12; 95% CI, 1.69–2.66) and incidence (HR, 1.79; 95% CI, 1.65–1.95) of chronic kidney disease (CKD) in patients with NAFLD. Worsening NAFLD severity was associated with a higher prevalence and incidence of CKD, with the highest prevalence (OR, 5.20; 95% CI, 3.14–8.61) and incidence (HR, 3.29; 95% CI, 2.30–4.71) seen in cases of more advanced fibrosis. The effect of this seems to be an increase in NASH-related cirrhosis as an indication for simultaneous liver–kidney transplantation based on an analysis of the United Network for Organ Sharing database during the years 2002 to 2011.37 This study also observed a lesser 5-year liver graft (HR, 2.50; 95% CI, 1.10–5.80), kidney graft (HR, 2.30; 95% CI, 1.10–5.10), and patient (HR, 2.20; 95% CI, 1.02–5.79) survival for NASH patients in comparison with transplantation for other causes of cirrhosis. This observation is supported by several studies demonstrating a direct impact on allograft and patient survival by the presence of renal insufficiency at the time of transplant38,39 and by NASH itself.40 The relationship between CKD and posttransplant outcomes highlight the need for improved recognition. Direct measurement of the glomerular filtration rate (GFR) with exogenous markers of clearance such as inulin, iothalamate, or iohexol is considered the gold standard for assessing renal function. However, the cost and complexity of these techniques typically preclude their routine use at many transplant centers. Owing to ease of testing and availability, serum creatinine is widely used for estimating GFR. Current consensus recommendations for simultaneous liver–kidney transplant evaluation endorse the use of serum creatinine in the Modified Diet in Renal Disease equation to estimate renal function.41 However, concern for conventional serum creatinine levels underestimating GFR in patients with cirrhosis and sarcopenia has driven efforts to evaluate other markers in this population. Cystatin C is a low-molecularweight protein filtered by the kidneys that has been shown to improve estimated GFR over serum creatinine.42 In 1 study by Mindikoglu and colleagues,43 a new equation developed by the Chronic Kidney Epidemiology Collaboration (CKD-EPI) using both serum creatinine and cystatin C (CKD-EPI creatinine-cystatin C equation) was found to be more accurate for estimating GFR compared with conventional creatininebased equations such as creatinine clearance, the Cockcroft-Gault equation, and the Modified Diet in Renal Disease equation. Cystatin C has also been demonstrated to outperform MELD regardless of the severity of ascites and in the presence of significant renal dysfunction (GFR <60 mL/min/1.73 m2).44 Future efforts should further validate the use of cystatin C–containing equations for better predicting pretransplant mortality, posttransplant renal disease, and need for simultaneous liver–kidney transplants. Cardiovascular Disease
The shared association with the metabolic syndrome leads to a high concurrence of atherosclerotic disease in patients with NAFLD. In a NAFLD cohort of 129 patients, Ekstedt and colleagues45 found a 15.5% rate of cardiovascular-related mortality during a mean follow-up of 13.7 years. Another cross-sectional study of 250 patients after at an outpatient diabetes clinic found a higher prevalence of overt coronary, cerebrovascular, and peripheral vascular disease in patients with NAFLD compared with those without (10.8% vs 1.1%; 37.3% vs 5.5%, 24.5% vs 2.5% respectively; P<.001).46 NAFLD, independent of the metabolic syndrome, has been highly associated with subclinical atherosclerotic disease as well.47 Current recommendations from the American Association for the Study of Liver Diseases advocate noninvasive testing with dobutamine stress echocardiography in
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patients with traditional cardiac risk factors (chronic smokers, age >50 years, and a clinical or family history of heart disease or diabetes), followed by coronary angiography if preliminary screening is abnormal or inconclusive. However, noninvasive testing modalities such as dobutamine stress echocardiography and single photon emission computed tomography–technetium-99m–sestamibi imaging have poor sensitivity in detecting coronary artery disease in cirrhotic patients.48,49 They are even less likely to detect subclinical atherosclerosis, although the presence of such may still carry implications for postoperative cardiovascular events.50 Based on the poor sensitivity of noninvasive testing, Raval and colleagues51 advocated for proceeding directly to coronary angiography in patients with known coronary artery disease, diabetes mellitus, or 2 or more other cardiovascular risk factors. However, although cardiac catheterization can be performed in patients with end-stage liver disease despite coagulopathy, there remains an increased risk for major bleeding complications and pseudoaneurysms. As such, current consensus recommendations from the American Heart Association and American College of Cardiology do not recommend routine angiography in the absence of symptoms; noninvasive testing can be considered in the presence of 3 or more relevant risk factors (diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, age >60 years, tobacco use, hypertension, and dyslipidemia).52 Given these constraints, serum biomarkers may have a role in supplementing a risk stratification scheme for predicting postoperative cardiovascular complications. Data from Cross et al53 found that, among other cardiovascular risk factors (age, diabetes, history of cardiovascular disease), a serum troponin I level of greater than 0.07 was also predictive of post liver transplant cardiac events (HR, 2.00; P 5 .023). Although this lends credence to the usefulness of serum biomarkers in predicting relevant cardiovascular events, more evidence is needed before use of biomarkers can be routinely incorporated into decision-making schemes for tempering coronary artery evaluation or transplant eligibility.
NONALCOHOLIC FATTY LIVER DISEASE AND POST LIVER TRANSPLANT CONSIDERATIONS Transplant Outcomes
Published center outcomes for NAFLD-related liver disease have varied widely. Heuer and colleagues54 analyzed data from 432 consecutive patients transplanted between 2007 and 2011, of which 40 patients had underlying NASH. They found that 25% of their NASH patients died within the first month from cardiogenic shock and infectious complications, and had a 1-year survival rate of 42%. A large number of these patients (22%) had a BMI of greater than 35 kg/m2 at the time of surgery. Barritt and colleagues55 demonstrated that patients transplanted for NAFLD had an increased risk for death with adjusted hazard ratios of 8.96, 1.49, and 1.05, respectively, at 30 days, 1 year, and 3 years posttransplant. However, in a larger cohort followed for 10 years, Bhagat and colleagues56 found no difference in survival (P 5 .17) or graft failure (P 5 .40) compared with those transplanted for alcoholic liver disease. Vanwagner and colleagues57 also found no difference in patient, graft, or cardiovascular mortality between patients transplanted for NASH and alcohol related cirrhosis during a 12-month or longer follow-up, but the authors did note that NASH patients were more likely to have the metabolic syndrome at the time of transplantation and to experience a cardiovascular event within the first postoperative year (OR, 4.12; 95% CI, 1.91–8.90). Results from large registry studies portray more comparable posttransplant outcomes. Quillin and colleagues58 queried the Ohio Solid Organ Transplantation
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Consortium and examined a total of 2356 patients transplanted for NASH, hepatitis C virus, and alcoholic liver disease. They found no difference in survival among the 3 groups at 30 days and 1 year posttransplantation; patients with NASH had improved survival at 3 and 5 years posttransplantation, as well as graft survival compared with those with hepatitis C virus liver disease. An analysis of 35,781 adult patients from the Scientific Registry of Transplant Recipients who underwent primary liver transplant from 2001 to 2009, showed similar 1- and 3-year survival rates between those transplanted for NASH (84% and 78%, respectively) compared with non-NASH indications (87% and 78%, respectively; P 5 .67).11 The most common causes of long-term mortality are malignancy, cardiovascular disease, infections, and renal insufficiency (Fig. 2). Data encompassing 53,738 patients demonstrated 1-, 3-, and 5-year survival rates of 87.6%, 82.2%, and 76.7% respectively for NASH, which was in turn found to be superior to the survival of patients transplanted for hepatocellular carcinoma, hepatitis C infection, and alcoholic liver disease among others.59 On balance, based on the results of analyses of large, prospective registries, short- and medium-term morbidity notwithstanding, posttransplant mortality and graft loss seems to be comparable for patients undergoing liver transplantation for other indications. Recurrence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis
Although features of NAFLD are common after liver transplantation for NASH, recurrence of NASH with progressive fibrosis is unusual. In contrast, simple steatosis (grade 2) is very common, occurring in two-thirds of recipients in the first postoperative year, a frequency that is significantly more frequent than observed in other indications.60 The prevalence of steatohepatitis is also high, occurring in about one-half of transplant recipients with NASH by the second postoperative year. NASH with a
Fig. 2. The frequency of nonhepatic causes of mortality among liver transplant recipients, including those with nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis are shown. Malignancy, infections, cardiovascular disease, and renal insufficiency, all exacerbated by the metabolic syndrome and immunosuppression, are common causes of mortality at 1 and 12 years posttransplantation. Recurrence of NASH is an unusual cause of mortality. CV, cardiovascular.
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fibrosis stage of 2 or greater occurs in only 5% of recipients by postoperative year 5,60 with cirrhosis occurring in only 2% to 3% of NASH recipients in the medium term.61 Recurrence of NASH is thus much less aggressive than recurrence of hepatitis C virus. An important exception to the low frequency of progressive fibrosing NASH in liver transplant recipients are patients with hypopituitarism, who frequently experience rapid recurrence of NASH and advanced fibrosis and graft loss, commonly associated with hepatopulmonary syndrome. Recurrence of NASH and hepatopulmonary syndrome has been reported to be responsive to growth hormone supplementation in patients with hypopituitarism.62 Posttransplant Imaging and Liver Biopsies
The low frequency of clinically important recurrence of NASH reduces the yield of routine or protocol based liver biopsies to screen for recurrence of disease. A combination of normal alanine aminotransferase (<40 IU/L) and an ultrasound examination that is negative for hepatic steatosis has been reported to have a 100% negative predictive value for recurrence of NASH.62 Liver biopsies should only be considered in patients with steatosis on ultrasound and/or persistently elevated transaminases. In the nontransplant setting, MR elastography has emerged as a dynamic, sensitive, and specific tool for screening for and determining the amount of fibrosis secondary to NASH.63,64 APPROACH TO RECURRENCE OF NONALCOHOLIC FATTY LIVER DISEASE AND NONALCOHOLIC STEATOHEPATITIS AFTER LIVER TRANSPLANTATION
An algorithm for an overall approach to the posttransplant management of patients undergoing liver transplantation for NASH is presented in Fig. 3. There are, as of yet, no Food and Drug Administration–approved therapies for NASH. Although weight loss has been shown to attenuate the histologic features of NASH in the nontransplant setting,65 the impact of chronic fatigue and the metabolic effects of immunosuppression make sustained reduction of weight difficult for the majority of liver transplant recipients, who more typically develop progressively increasing BMIs after liver transplantation. Difficulties with weight reduction aside, optimized weight and nutrition are cornerstones of the approach to posttransplant NASH because even modest reductions in BMI, for example, a reduction of 20% to 40%, can produce improvement in transaminases and histologic features of NASH.66–69 Pharmacologic Considerations
Glycemic control is an important consideration in patients with NASH who have type 2 diabetes mellitus; even in the absence of weight loss, metformin has been reported to improve the histologic features of NASH.70 Alternatively, vitamin E (800 IU/d a-tocopherol) was superior to both pioglitazone and placebo in improving histologic features of NASH in patients with type 2 diabetes mellitus in a large, multicenter study.71 Longer term vitamin E use is associated with an increased risk of tumors (eg, prostate cancer) and cardiovascular disease and should therefore not be used in the long periods, for example, for longer than 1 year. Pioglitazone use is associated with weight gain71 and has a signal for potential hepatotoxicity.72 The weight gain associated with thiazolidinediones may, in the medium and long term, negate their modest reported histologic benefits. For these reasons, we suggest that vitamin E (800 IU/d of a-tocopherol) be considered in all patients with histologically proven recurrence of NASH. Pioglitazone should only be considered in patients with recurrence of NASH and who have type 2 diabetes mellitus. Growth hormone therapy should be considered for patients with NASH secondary to hypopituitarism after liver transplantation.62
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Liver Transplantation for NASH or CC: •Annual screen for features of metabolic syndrome •Mediterranean diet (including 60 mL/d extra virgin olive oil) • ≥2 cups/d filtered coffee •Nutrition consultation
Any of: •Elevated transaminase(s) •Steatosis on U/S •Hypopituitarism •Abnormal liver stiffness on MR elastography
Consider Liver Biopsy
Reevaluate in 1 y
NASH No NASH Nutrition consultation Vitamin E (800 IU/d) Metformin or TZD if T2DM Growth hormone if hypopituitarism
Fig. 3. An algorithm for the general management of patients who undergo liver transplantation for nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis (CC) is shown. Features of the metabolic syndrome are common and are a common source of morbidity and mortality. The low frequency of progressive recurrence of NASH mandates a selective approach to obtaining liver biopsies. T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione; U/S, ultrasonography.
Key considerations in prescribing immunosuppression and pharmacotherapy of the metabolic syndrome are presented in Table 1. For further information see, Hameed B, Terrault N: Emerging Therapies for Nonalcoholic Fatty Liver Disease, in this issue. Dietary Considerations Cholesterol
There is overwhelming evidence that cholesterol is a key lipotoxic trigger for NASH. Mechanisms of cholesterol lipotoxicity include sensitization of hepatocytes to tumor necrosis factor-a and Fas,73 depletion of mitochondrial glutathione with subsequent loss of mitochondrial membrane function, ultimately leading to cytochrome C translocation to the cytosol.74,75 The importance of cholesterol-induced glutathione depletion is further implied by the observation that supplementation of mitochondrial glutathione restores mitochondrial function and attenuates the histologic features of NASH.74 Increases in hepatic and hepatocyte mitochondrial cholesterol have been a highly reproducible finding in animal models of NASH.73,76–78 In the absence of an approved pharmacotherapy and based on the substantial evidence implicating dietary cholesterol as a lipotoxic trigger for NASH, dietary cholesterol intake should be minimized routinely in patients with fatty liver disease, including liver transplant recipients.
Table 1 Immunosuppression and pharmacotherapy of the metabolic syndrome
Drug
HMG-CoA Reductase Inhibitors (Statins)
Metformin
Thiazolidinediones ACEi
No drug–drug No drug–drug Increase interactions interactions in HMG-CoA reductase inhibitor concentrations Antiproliferative Mycophenolate No drug–drug Case report interaction of increased anemia with rosiglitazone No drug–drug mTORi Everolimus No clinically Sirolimus interactions significant interactions
CNI
Tacrolimus Cyclosporine
ARB
Increased risk of elevated serum creatinine and serum potassium
No drug–drug interactions
Increased risk of angioedema
CCB
PPI
Increase in CNI CNI exposure concentrations can increase
No drug–drug No drug–drug interactions interactions
Decreased mycophenolate concentrations
No drug–drug Increase interactions in mTORi concentrations
NAFLD and Liver Transplantation
CNI can inhibit the metabolism of most statins. The safest combination with CNI is pravastatin owing to its metabolism being less dependent upon CYP3A4. Reduction of other statin doses may be necessary and monitoring of myotoxicity is important. mTORi can cause angioedema and risk is increased with concomitant administration of ACEi. There is no metabolic drug–drug interaction described in the literature. CNI vasoconstrict the afferent arteriole and both ACEi and ARBs vasodilate the efferent renal arteriole. Concomitant administration may result in decreased renal perfusion causing an elevated serum creatinine. Both agents can lead to hyperkalemia owing to this mechanism and the CNI’s ability to induce distal renal tubular acidosis. Combination therapy has been used safely, but judicious monitoring of renal function is imperative. Both dihydropyridine and nondihydropyridine CCB inhibit CYP3A metabolism of CNI and increase CNI whole blood concentrations. Dihydropyridine CCB in combination with CNI are not routinely clinically significant. Nondihydropyridine CCB, both verapamil and diltiazem, are potent inhibitors and usually require dose adjustments of CNI when initiating, titrating, or discontinuing these agents. Nondihydropyridine CCB, both verapamil and diltiazem, potently inhibit the metabolism of both mTORi. Empiric dose adjustments of the mTORi are warranted when initiating, titrating, or discontinuing these agents. Dihydropyridine CCB can inhibit metabolism of mTORi but are generally not clinically significant. PPI, particularly omeprazole and lansoprazole, can increase concentrations of CNI by potentially inhibiting CYP3A4 metabolism of tacrolimus, particularly in those that are poor or intermediate metabolizers at CYP2C19. Coadministration of mycophenolate mofetil with PPI, particularly lansoprazole and pantoprazole, can reduce exposure of mycophenolate. Increased gastric pH may contribute to decreased mycophenolate solubility. Pantoprazole administered with mycophenolic acid in healthy volunteers did not alter pharmacokinetics of a single dose of mycophenolic acid. Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor antagonists; CCB, calcium channel blockers; CNI, calcineurin inhibitor; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; mTORi, mammalian target of rapamycin inhibitors; PPI, proton pump inhibitors.
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Coffee
Empiric pharmacotherapy of NAFLD with insulin-sensitizing agents or vitamin E is of marginal benefit (at best) and confers substantial risk (eg, weight gain). Several nonpharmacologic interventions have, however, emerged as beneficial for obesity and for reducing histologic severity and impact in NAFLD. The most compelling evidence is for coffee consumption; 2 to 4 cups of coffee consumed daily has been associated with improved histologic features of NAFLD and a reduction in the severity of components of the metabolic syndrome. Regardless of mechanism, coffee consumption is associated independently with a 12% decrease in mortality when compared with no coffee consumption.79 The benefit seems to be greatest with filtered coffee rather than consumption of espresso or tea.80 Consumption of 2 or more cups of coffee per day is also associated with decreased rates of hepatic fibrosis for patients with chronic liver diseases,81 including NASH.82 Although cause and effect is not established, a systematic review reported improved serum transaminases, decreased frequency of progression to cirrhosis and HCC, and lowered overall mortality in association with regular coffee consumption.83 Although multiple components of coffee may contribute to the beneficial effects, coffee polyphenols and caffeine have been demonstrated to have antioxidant effects,84 downregulate transforming growth factor-beta1 and SMAD2/3, increase peroxisome proliferator activated receptorgamma receptor expression,85 and to decrease activation of hepatic stellate cells.86,87 Based on the substantial sum of these observations, recipients with obesity and/or NAFLD should be encouraged to consume 2 or more cups of coffee per day. Mediterranean diet and olive oil
A Mediterranean diet is defined by a diet composed of primarily fruits, vegetables, whole grains, legumes, and nuts and replacement of butter with extra virgin olive oil. Herbs and spices replace salt to flavor foods. Red meat is largely replaced by fish and poultry, which are eaten at least twice a week. A large (n 5 7447), prospective study in which diets were supplemented with extra virgin olive oil (w60 mL/d) versus no supplementation of olive oil, observed that olive oil supplementation reduced the incidence of major cardiovascular events by 30%.80 The hazard ratio for all-cause mortality was 0.70 (95% CI, 0.54–0.92) for the group assigned to a Mediterranean diet with extra virgin olive oil when compared with the control group in multivariate analysis. Olive oil also has specific benefits in patients with NAFLD, reducing hepatic steatosis and improving inflammatory markers.88–90 On the basis of these observations and in the absence of any risk associated with consumption of extra virgin olive oil, we recommend a Mediterranean diet, including approximately 60 mL/d of olive oil for liver transplant recipients. REFERENCES
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23. Kim TN, Park MS, Lim KI, et al. Relationships between sarcopenic obesity and insulin resistance, Inflammation, and vitamin D status: the Korean Sarcopenic Obesity Study. Clin Endocrinol (Oxf) 2013;78:525–32. 24. Tandon P, Ney M, Irwin I, et al. Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value. Liver Transpl 2012;18:1209–16. 25. Heuman DM, Abou-Assi SG, Habib A, et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology 2004;40:802–10. 26. Durand F, Buyse S, Francoz C, et al. Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography. J Hepatol 2014;60:1151–7. 27. Englesebe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg 2010;211:271–8. 28. Krell RW, Kaul DR, Martin AR, et al. Association between sarcopenia and the risk of serious infection among adults undergoing liver transplantation. Liver Transpl 2013;19:1396–402. 29. Montano-Loza AJ, Meza-Junco J, Baracos VE, et al. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl 2014;20:640–8. 30. Abellan van Kan G, Houles M, Vellas B. Identifying sarcopenia. Curr Opin Clin Nutr Metab Care 2012;15:436–41. 31. Hayahi F, Matsumoto Y, Momoki C, et al. Physical inactivity and insufficient dietary intake are associated with the frequency of sarcopenia in patients with compensated viral liver cirrhosis. Hepatol Res 2013;43:1264–75. 32. Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients. Nutrition 2005;21:113–7. 33. Figueiredo F, Dickson ER, Pasha TM, et al. Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease. Liver Transpl 2000;6:575–81. 34. Tsien C, Shah SN, McCullough AJ, et al. Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent. Eur J Gastroenterol Hepatol 2013;25:85–93. 35. Toshikuni N, Arisawa T, Tsutsumi M. Nutrition and exercise in the management of liver cirrhosis. World J Gastroenterol 2014;20:7286–97. 36. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014;11:e1001680. 37. Singal AK, Salameh H, Kuo YF, et al. Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology. Transplantation 2014;98:216–21. 38. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35:1179–85. 39. Giusto M, Berenquer M, Merkel C, et al. Chronic kidney disease after liver transplantation: pretransplantation risk factors and predictors during follow-up. Transplantation 2013;95:1148–53. 40. Houlihan DD, Armstrong MJ, Davidov Y, et al. Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens? Liver Transpl 2011;17:1292–8.
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41. Nadim MK, Sung RS, Davis CL, et al. Simultaneous liver-kidney transplantation summit: current state and future directions. Am J Transplant 2012;12:2901–8. 42. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20–9. 43. Mindikoglu AL, Dowling TC, Weir MR, et al. Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis. Hepatology 2014;59:1532–42. 44. De Souza V, Hadj-Aissa A, Dolomanova O, et al. Creatinine- versus cystatin C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis. Hepatology 2014;59:1522–31. 45. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865–73. 46. Targher G, Bertolini L, Padovani R, et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J Hepatol 2010;53:713–8. 47. Oni ET, Agatston AS, Blaha MJ, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013;230:258–67. 48. Harrinstein ME, Flaherty JD, Ansari AH, et al. Predictive value of dobutamine stress echocardiography for coronary artery disease detection in liver transplant candidates. Am J Transplant 2008;8:1523–8. 49. Davidson CJ, Gheorghiade MI, Flaherty JD, et al. Predictive value of stress myocardial perfusion imaging in liver transplant candidates. Am J Cardiol 2002;89:359–60. 50. Rubin DA, Schulman DS, Edwards TD, et al. Myocardial ischemia after orthotopic liver transplantation. Am J Cardiol 1994;74:53–6. 51. Raval Z, Harrinstein ME, Skaro AI, et al. Cardiovascular risk assessment of the liver transplant candidate. Cardiology 2011;58:223–31. 52. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates. J Am Coll Cardiol 2012;60:434–80. 53. Cross E, Watt KD, Pedersen R, et al. Predictors of cardiovascular events after liver transplantation: a role for pretransplant serum troponin levels. Liver Transpl 2011;17:23–31. 54. Heuer M, Kaiser GM, Kahraman A, et al. Liver transplantation in nonalcoholic steatohepatitis is associated with mortality and post-transplant complications: a single-center experience. Digestion 2012;86:107–13. 55. Barritt AS, Dellon ES, Kozlowski T, et al. The influence of nonalcoholic fatty liver disease and its associated comorbidities on liver transplant outcomes. J Clin Gastroenterol 2011;45:372–8. 56. Bhagat V, Mindikoglu AL, Nudo CG, et al. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transpl 2009;15:1814–20. 57. VanWagner LB, Bhave M, Te HS, et al. Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology 2012;56:1741–50. 58. Quillin RC, Wilson GC, Sutton JM, et al. Increasing prevalence of nonalcoholic steatohepatitis as an indication for liver transplantation. Surgery 2014;156: 1049–56. 59. Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl 2012;18:29–37.
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60. Maor-Kendler Y, Batts KP, Burgart LJ, et al. Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases. Transplantation 2000;70:292–7. 61. Dumortier J, Giostra E, Belbouab S, et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil”. Am J Gastroenterol 2010; 105:613–20. 62. Singal AW, Watt KD, Heimbach JH, et al. Recurrence of metabolic syndrome and non-alcoholic steatohepatitis after liver transplantation – a comparative analysis. Hepatology 2012;53(Suppl):636. 63. Loomba R, Wolfson T, Ang B, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 2014;60:1920–8. 64. Loomba R, Sirlin CB, Ang B, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61:1239–50. 65. Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997;27:103–7. 66. Vajro P, Fontanella A, Perna C, et al. Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr 1994;125:239–41. 67. Drenick EJ, Simmons F, Murphy JF. Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small-bowel bypass. N Engl J Med 1970; 282:829–34. 68. Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004;53:413–9. 69. Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6:1396–402. 70. Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000;6:998–1003. 71. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–85. 72. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004;39:188–96. 73. Mari M, Caballero F, Colell A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 2006;4:185–98. 74. Caballero F, Fernandez A, Matı´as N, et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem 2010;285:18528–36. 75. Mari M, Morales A, Colell A, et al. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009;11:2685–700. 76. Mari M, Colell A, Morales A, et al. Mechanism of mitochondrial glutathionedependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 2008;134:1507–20. 77. Charlton M, Krishnan A, Viker K, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2011;301:G825–34. 78. Wouters K, van Gorp PJ, Bieghs V, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008;48:474–86.
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79. Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012;366:1891–904. 80. Anty R, Marjoux S, Iannelli A, et al. Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J Hepatol 2012;57: 1090–6. 81. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010;51:201–9. 82. Molloy JW, Calcagno CJ, Williams CD, et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 2012;55:429–36. 83. Saab S, Mallam D, Cox GA 2nd, et al. Impact of coffee on liver diseases: a systematic review. Liver Int 2014;34:495–504. 84. Kalthoff S, Ehmer U, Freiberg N, et al. Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 2010;139:1699–710. 85. Gressner OA, Lahme B, Rehbein K, et al. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol 2008;49: 758–67. 86. Shim SG, Jun DW, Kim EK, et al. Caffeine attenuates liver fibrosis via defective adhesion of hepatic stellate cells in cirrhotic model. J Gastroenterol Hepatol 2013;28:1877–84. 87. Estruch R, Ros E, Salas-Salvado´ J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90. 88. Buettner R, Ascher M, Ga¨bele E, et al. Olive oil attenuates the cholesterolinduced development of nonalcoholic steatohepatitis despite increased insulin resistance in a rodent model. Horm Metab Res 2013;45:795–801. 89. Kruse M, von Loeffelholz C, Hoffmann D, et al. Dietary rapeseed/canola-oil supplementation reduces serum lipids and liver enzymes and alters postprandial inflammatory responses in adipose tissue compared to olive-oil supplementation in obese men. Mol Nutr Food Res 2015;59:507–19. 90. Hernandez R, Martinez-Lara E, Can˜uelo A, et al. Steatosis recovery after treatment with a balanced sunflower or olive oil-based diet: involvement of perisinusoidal stellate cells. World J Gastroenterol 2005;11:7480–5.
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PharmD, MBA, BCPS
b
,
KEYWORDS Nonalcoholic fatty liver disease Liver transplantation The metabolic syndrome Nonalcoholic steatohepatitis KEY POINTS Nonalcoholic fatty liver disease (NAFLD) is on a trajectory to become the most common indication for liver transplantation. Although features of NAFLD are common after liver transplantation for nonalcoholic steatohepatitis (NASH), recurrence of NASH with progressive fibrosis is unusual. Management of obesity and components of the metabolic syndrome are essential in achieving optimal posttransplant outcomes. Minimization of immunosuppression is a cornerstone of posttransplant management of patients undergoing liver transplantation for NAFLD.
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a complication of obesity1,2 and is widely considered to be the hepatic manifestation of the metabolic syndrome. It is a frequent cause of chronic liver disease in the United States with a changing prevalence mirroring the rising obesity trend.3–5 NAFLD has a variable natural history, but in some patients can progress to nonalcoholic steatohepatitis (NASH) with progressive fibrosis and eventual complications of cirrhosis, including liver failure and hepatocellular carcinoma.6–8 NASH is also thought to be the underlying etiology for cryptogenic cirrhosis in patients with features of the metabolic syndrome.6 Compared with the general population, patients with NASH have an increased risk for cardiovascular-related death, Disclosures: Drs T.B. Dick and T. Pham have nothing to disclose. Dr M.R. Charlton has received research support from Gilead Sciences, Merck, and Janssen. a Division of Gastroenterology and Hepatology, University of Utah, 30 N 1900 E, Salt Lake City, UT 84132, USA; b Department of Pharmacy, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84107-5701, USA; c Hepatology and Liver Transplantation, Intermountain Transplant Center, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84107-5701, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 20 (2016) 403–417 http://dx.doi.org/10.1016/j.cld.2015.10.014 1089-3261/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
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liver-related death,9 overall mortality, and death in association with hepatocellular carcinoma.10 The significant impact on mortality, magnified by the growing prevalence of the disease, has led to NASH being the third most common indication for liver transplantation, with a trajectory to become the most common (Fig. 1).11 Aside from its role in causing primary liver disease, concomitant NAFLD has been linked with a greater severity of liver disease in patients with chronic hepatitis C infection,12 as well as treatment failure in patients with chronic hepatitis B infection.13 Furthermore, the increasing prevalence of NAFLD in the population at large may lead to a reduced pool of suitable donor organs, because moderate to severe steatosis in the donor organ can significantly impact allograft viability.14 Taken in sum, the ever-growing burden and far-reaching impact of NAFLD underscores the need for evolving new considerations in liver transplant management. This article reviews these considerations as well as our current understanding of the physiology and management of patients with NASH before and after liver transplantation. NONALCOHOLIC FATTY LIVER DISEASE AND PRE LIVER TRANSPLANT CONSIDERATIONS
The median wait-list time has increased over recent years along with the number of candidates removed from the list for being too sick to undergo liver transplantation.15 The increased frequency of medical comorbidities in patients with NAFLD make them especially susceptible to being delisted or dying while awaiting surgery.16 Recognition of these comorbidities and their respective impact is essential for improving pretransplant survivorship, in addition to minimizing posttransplant complications. Impact of Weight and Body Composition
An increased body mass index (BMI) in cirrhosis can lead to an increased rate of clinical decompensation and risk of dying or being delisted while awaiting
Fig. 1. Longitudinal trends in the frequency of indications for liver transplantation in the United States are shown for 2002 through 2014. Nonalcoholic steatohepatitis (NASH) and cryptogenic cirrhosis (CC) have been combined to account for the high frequency of NASH as a cause of cryptogenic cirrhosis. Alcoholic liver disease (ALD) has also had a surge as an indication for liver transplantation. HCV, hepatitis C virus. (Data from Scientific Registry of Transplant Recipients.)
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liver transplantation.16,17 Conversely, weight reduction can lead to an improvement in the histologic features of NASH.18 In the posttransplant setting, Nair and colleagues19 demonstrated through a large scale analysis of the United Network for Organ Sharing database that patients with class III obesity (BMI 40 kg/m2) at the time of transplant have significantly higher rates of posttransplant primary graft nonfunction and mortality at 1 and 2 years. This same study also noted increased mortality at 5 years posttransplant in recipients with class II obesity (BMI >35 kg/m2). These observations may have been confounded by the presence of ascites. After correcting for ascites, a large, prospective, multicenter study found BMI does not confer any independent risk of mortality or allograft failure.20 Hakeem and colleagues21 also confirmed a lack of correlation between BMI corrected for ascites and posttransplant graft and patient survival, although the authors did note a significant increase in postoperative complications and greater duration of hospital stay in overweight and obese patients compared with those with normal weight (BMI 18–25 kg/m2). By extension, weight reduction should have important implications for pretransplant survivorship as well as reducing postoperative morbidity and mortality. Overnutrition and obesity, the primary effectors of NAFLD, are also strongly associated with sarcopenia through shared mechanisms such as insulin resistance, physical inactivity, chronic inflammation, vitamin D deficiency, and oxidative stress.22,23 Tandon and colleagues24 found sarcopenia to be highly prevalent (41%) and predictive of mortality (hazard ratio, 2.36; 95% CI, 1.23–4.53) in patients awaiting liver transplantation. In situations of refractory ascites and hyponatremia where a conventional Model for End-stage Liver Disease (MELD) score underestimates death,25 the addition of a sarcopenic index to MELD significantly improves pretransplant prognostication.26 Furthermore, patients with sarcopenia have a higher risk of posttransplant infection, longer postoperative hospitalizations, and unclear risk for posttransplant death.27–29 Several tools have been described for evaluating sarcopenia and malnutrition, including skeletal muscle mass on imaging, strength testing on functional assessments, and anthropomorphic measurements. Of these, abdominal imaging with computed tomography has been the most studied with regards to relevant clinical outcomes in the pretransplant and posttransplant populations, and is considered the gold standard despite concerns for operationalization beyond clinical research.24,26,29,30 The reproducibility of measurements and high likelihood of use within a liver transplant program make abdominal computed tomography a good candidate tool for concomitant sarcopenia management. Other promising modalities include dual energy x-ray absorptiometry,22 bioelectrical impedance analysis,31 hand-grip strength,32 and triceps skinfold thickness.33 Regardless of the diagnostic test, recognition and reversing sarcopenia has been associated with a survival benefit.34 Because sarcopenia has been linked to protein malnutrition and physical inactivity in patients with advanced liver disease, the mainstays of treatment to date have focused on caloric/amino acid supplementation and increased physical activity. A moderate exercise regimen, such as walking 5000 steps per day in combination with respective energy and protein intakes of 35 to 40 kcal/kg of body weight per day and 1.2 to 1.5 g/kg of body weight per day, can increase musculoskeletal mass in patients with compensated cirrhosis.31 In those patients with compensated cirrhosis and concomitant obesity, exercise for weight loss in combination with total caloric restriction and branched chain amino acid supplementation has been advocated. Owing to the inherent exercise intolerance associated with decompensated liver disease, a primary nutritional strategy of branched chain amino acid and caloric supplementation may be the best option for treating sarcopenia.35
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Chronic Kidney Disease
A recent metaanalysis by Musso and colleagues36 demonstrated an increased prevalence (odds ratio [OR], 2.12; 95% CI, 1.69–2.66) and incidence (HR, 1.79; 95% CI, 1.65–1.95) of chronic kidney disease (CKD) in patients with NAFLD. Worsening NAFLD severity was associated with a higher prevalence and incidence of CKD, with the highest prevalence (OR, 5.20; 95% CI, 3.14–8.61) and incidence (HR, 3.29; 95% CI, 2.30–4.71) seen in cases of more advanced fibrosis. The effect of this seems to be an increase in NASH-related cirrhosis as an indication for simultaneous liver–kidney transplantation based on an analysis of the United Network for Organ Sharing database during the years 2002 to 2011.37 This study also observed a lesser 5-year liver graft (HR, 2.50; 95% CI, 1.10–5.80), kidney graft (HR, 2.30; 95% CI, 1.10–5.10), and patient (HR, 2.20; 95% CI, 1.02–5.79) survival for NASH patients in comparison with transplantation for other causes of cirrhosis. This observation is supported by several studies demonstrating a direct impact on allograft and patient survival by the presence of renal insufficiency at the time of transplant38,39 and by NASH itself.40 The relationship between CKD and posttransplant outcomes highlight the need for improved recognition. Direct measurement of the glomerular filtration rate (GFR) with exogenous markers of clearance such as inulin, iothalamate, or iohexol is considered the gold standard for assessing renal function. However, the cost and complexity of these techniques typically preclude their routine use at many transplant centers. Owing to ease of testing and availability, serum creatinine is widely used for estimating GFR. Current consensus recommendations for simultaneous liver–kidney transplant evaluation endorse the use of serum creatinine in the Modified Diet in Renal Disease equation to estimate renal function.41 However, concern for conventional serum creatinine levels underestimating GFR in patients with cirrhosis and sarcopenia has driven efforts to evaluate other markers in this population. Cystatin C is a low-molecularweight protein filtered by the kidneys that has been shown to improve estimated GFR over serum creatinine.42 In 1 study by Mindikoglu and colleagues,43 a new equation developed by the Chronic Kidney Epidemiology Collaboration (CKD-EPI) using both serum creatinine and cystatin C (CKD-EPI creatinine-cystatin C equation) was found to be more accurate for estimating GFR compared with conventional creatininebased equations such as creatinine clearance, the Cockcroft-Gault equation, and the Modified Diet in Renal Disease equation. Cystatin C has also been demonstrated to outperform MELD regardless of the severity of ascites and in the presence of significant renal dysfunction (GFR <60 mL/min/1.73 m2).44 Future efforts should further validate the use of cystatin C–containing equations for better predicting pretransplant mortality, posttransplant renal disease, and need for simultaneous liver–kidney transplants. Cardiovascular Disease
The shared association with the metabolic syndrome leads to a high concurrence of atherosclerotic disease in patients with NAFLD. In a NAFLD cohort of 129 patients, Ekstedt and colleagues45 found a 15.5% rate of cardiovascular-related mortality during a mean follow-up of 13.7 years. Another cross-sectional study of 250 patients after at an outpatient diabetes clinic found a higher prevalence of overt coronary, cerebrovascular, and peripheral vascular disease in patients with NAFLD compared with those without (10.8% vs 1.1%; 37.3% vs 5.5%, 24.5% vs 2.5% respectively; P<.001).46 NAFLD, independent of the metabolic syndrome, has been highly associated with subclinical atherosclerotic disease as well.47 Current recommendations from the American Association for the Study of Liver Diseases advocate noninvasive testing with dobutamine stress echocardiography in
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patients with traditional cardiac risk factors (chronic smokers, age >50 years, and a clinical or family history of heart disease or diabetes), followed by coronary angiography if preliminary screening is abnormal or inconclusive. However, noninvasive testing modalities such as dobutamine stress echocardiography and single photon emission computed tomography–technetium-99m–sestamibi imaging have poor sensitivity in detecting coronary artery disease in cirrhotic patients.48,49 They are even less likely to detect subclinical atherosclerosis, although the presence of such may still carry implications for postoperative cardiovascular events.50 Based on the poor sensitivity of noninvasive testing, Raval and colleagues51 advocated for proceeding directly to coronary angiography in patients with known coronary artery disease, diabetes mellitus, or 2 or more other cardiovascular risk factors. However, although cardiac catheterization can be performed in patients with end-stage liver disease despite coagulopathy, there remains an increased risk for major bleeding complications and pseudoaneurysms. As such, current consensus recommendations from the American Heart Association and American College of Cardiology do not recommend routine angiography in the absence of symptoms; noninvasive testing can be considered in the presence of 3 or more relevant risk factors (diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, age >60 years, tobacco use, hypertension, and dyslipidemia).52 Given these constraints, serum biomarkers may have a role in supplementing a risk stratification scheme for predicting postoperative cardiovascular complications. Data from Cross et al53 found that, among other cardiovascular risk factors (age, diabetes, history of cardiovascular disease), a serum troponin I level of greater than 0.07 was also predictive of post liver transplant cardiac events (HR, 2.00; P 5 .023). Although this lends credence to the usefulness of serum biomarkers in predicting relevant cardiovascular events, more evidence is needed before use of biomarkers can be routinely incorporated into decision-making schemes for tempering coronary artery evaluation or transplant eligibility.
NONALCOHOLIC FATTY LIVER DISEASE AND POST LIVER TRANSPLANT CONSIDERATIONS Transplant Outcomes
Published center outcomes for NAFLD-related liver disease have varied widely. Heuer and colleagues54 analyzed data from 432 consecutive patients transplanted between 2007 and 2011, of which 40 patients had underlying NASH. They found that 25% of their NASH patients died within the first month from cardiogenic shock and infectious complications, and had a 1-year survival rate of 42%. A large number of these patients (22%) had a BMI of greater than 35 kg/m2 at the time of surgery. Barritt and colleagues55 demonstrated that patients transplanted for NAFLD had an increased risk for death with adjusted hazard ratios of 8.96, 1.49, and 1.05, respectively, at 30 days, 1 year, and 3 years posttransplant. However, in a larger cohort followed for 10 years, Bhagat and colleagues56 found no difference in survival (P 5 .17) or graft failure (P 5 .40) compared with those transplanted for alcoholic liver disease. Vanwagner and colleagues57 also found no difference in patient, graft, or cardiovascular mortality between patients transplanted for NASH and alcohol related cirrhosis during a 12-month or longer follow-up, but the authors did note that NASH patients were more likely to have the metabolic syndrome at the time of transplantation and to experience a cardiovascular event within the first postoperative year (OR, 4.12; 95% CI, 1.91–8.90). Results from large registry studies portray more comparable posttransplant outcomes. Quillin and colleagues58 queried the Ohio Solid Organ Transplantation
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Consortium and examined a total of 2356 patients transplanted for NASH, hepatitis C virus, and alcoholic liver disease. They found no difference in survival among the 3 groups at 30 days and 1 year posttransplantation; patients with NASH had improved survival at 3 and 5 years posttransplantation, as well as graft survival compared with those with hepatitis C virus liver disease. An analysis of 35,781 adult patients from the Scientific Registry of Transplant Recipients who underwent primary liver transplant from 2001 to 2009, showed similar 1- and 3-year survival rates between those transplanted for NASH (84% and 78%, respectively) compared with non-NASH indications (87% and 78%, respectively; P 5 .67).11 The most common causes of long-term mortality are malignancy, cardiovascular disease, infections, and renal insufficiency (Fig. 2). Data encompassing 53,738 patients demonstrated 1-, 3-, and 5-year survival rates of 87.6%, 82.2%, and 76.7% respectively for NASH, which was in turn found to be superior to the survival of patients transplanted for hepatocellular carcinoma, hepatitis C infection, and alcoholic liver disease among others.59 On balance, based on the results of analyses of large, prospective registries, short- and medium-term morbidity notwithstanding, posttransplant mortality and graft loss seems to be comparable for patients undergoing liver transplantation for other indications. Recurrence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis
Although features of NAFLD are common after liver transplantation for NASH, recurrence of NASH with progressive fibrosis is unusual. In contrast, simple steatosis (grade 2) is very common, occurring in two-thirds of recipients in the first postoperative year, a frequency that is significantly more frequent than observed in other indications.60 The prevalence of steatohepatitis is also high, occurring in about one-half of transplant recipients with NASH by the second postoperative year. NASH with a
Fig. 2. The frequency of nonhepatic causes of mortality among liver transplant recipients, including those with nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis are shown. Malignancy, infections, cardiovascular disease, and renal insufficiency, all exacerbated by the metabolic syndrome and immunosuppression, are common causes of mortality at 1 and 12 years posttransplantation. Recurrence of NASH is an unusual cause of mortality. CV, cardiovascular.
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fibrosis stage of 2 or greater occurs in only 5% of recipients by postoperative year 5,60 with cirrhosis occurring in only 2% to 3% of NASH recipients in the medium term.61 Recurrence of NASH is thus much less aggressive than recurrence of hepatitis C virus. An important exception to the low frequency of progressive fibrosing NASH in liver transplant recipients are patients with hypopituitarism, who frequently experience rapid recurrence of NASH and advanced fibrosis and graft loss, commonly associated with hepatopulmonary syndrome. Recurrence of NASH and hepatopulmonary syndrome has been reported to be responsive to growth hormone supplementation in patients with hypopituitarism.62 Posttransplant Imaging and Liver Biopsies
The low frequency of clinically important recurrence of NASH reduces the yield of routine or protocol based liver biopsies to screen for recurrence of disease. A combination of normal alanine aminotransferase (<40 IU/L) and an ultrasound examination that is negative for hepatic steatosis has been reported to have a 100% negative predictive value for recurrence of NASH.62 Liver biopsies should only be considered in patients with steatosis on ultrasound and/or persistently elevated transaminases. In the nontransplant setting, MR elastography has emerged as a dynamic, sensitive, and specific tool for screening for and determining the amount of fibrosis secondary to NASH.63,64 APPROACH TO RECURRENCE OF NONALCOHOLIC FATTY LIVER DISEASE AND NONALCOHOLIC STEATOHEPATITIS AFTER LIVER TRANSPLANTATION
An algorithm for an overall approach to the posttransplant management of patients undergoing liver transplantation for NASH is presented in Fig. 3. There are, as of yet, no Food and Drug Administration–approved therapies for NASH. Although weight loss has been shown to attenuate the histologic features of NASH in the nontransplant setting,65 the impact of chronic fatigue and the metabolic effects of immunosuppression make sustained reduction of weight difficult for the majority of liver transplant recipients, who more typically develop progressively increasing BMIs after liver transplantation. Difficulties with weight reduction aside, optimized weight and nutrition are cornerstones of the approach to posttransplant NASH because even modest reductions in BMI, for example, a reduction of 20% to 40%, can produce improvement in transaminases and histologic features of NASH.66–69 Pharmacologic Considerations
Glycemic control is an important consideration in patients with NASH who have type 2 diabetes mellitus; even in the absence of weight loss, metformin has been reported to improve the histologic features of NASH.70 Alternatively, vitamin E (800 IU/d a-tocopherol) was superior to both pioglitazone and placebo in improving histologic features of NASH in patients with type 2 diabetes mellitus in a large, multicenter study.71 Longer term vitamin E use is associated with an increased risk of tumors (eg, prostate cancer) and cardiovascular disease and should therefore not be used in the long periods, for example, for longer than 1 year. Pioglitazone use is associated with weight gain71 and has a signal for potential hepatotoxicity.72 The weight gain associated with thiazolidinediones may, in the medium and long term, negate their modest reported histologic benefits. For these reasons, we suggest that vitamin E (800 IU/d of a-tocopherol) be considered in all patients with histologically proven recurrence of NASH. Pioglitazone should only be considered in patients with recurrence of NASH and who have type 2 diabetes mellitus. Growth hormone therapy should be considered for patients with NASH secondary to hypopituitarism after liver transplantation.62
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Liver Transplantation for NASH or CC: •Annual screen for features of metabolic syndrome •Mediterranean diet (including 60 mL/d extra virgin olive oil) • ≥2 cups/d filtered coffee •Nutrition consultation
Any of: •Elevated transaminase(s) •Steatosis on U/S •Hypopituitarism •Abnormal liver stiffness on MR elastography
Consider Liver Biopsy
Reevaluate in 1 y
NASH No NASH Nutrition consultation Vitamin E (800 IU/d) Metformin or TZD if T2DM Growth hormone if hypopituitarism
Fig. 3. An algorithm for the general management of patients who undergo liver transplantation for nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis (CC) is shown. Features of the metabolic syndrome are common and are a common source of morbidity and mortality. The low frequency of progressive recurrence of NASH mandates a selective approach to obtaining liver biopsies. T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione; U/S, ultrasonography.
Key considerations in prescribing immunosuppression and pharmacotherapy of the metabolic syndrome are presented in Table 1. For further information see, Hameed B, Terrault N: Emerging Therapies for Nonalcoholic Fatty Liver Disease, in this issue. Dietary Considerations Cholesterol
There is overwhelming evidence that cholesterol is a key lipotoxic trigger for NASH. Mechanisms of cholesterol lipotoxicity include sensitization of hepatocytes to tumor necrosis factor-a and Fas,73 depletion of mitochondrial glutathione with subsequent loss of mitochondrial membrane function, ultimately leading to cytochrome C translocation to the cytosol.74,75 The importance of cholesterol-induced glutathione depletion is further implied by the observation that supplementation of mitochondrial glutathione restores mitochondrial function and attenuates the histologic features of NASH.74 Increases in hepatic and hepatocyte mitochondrial cholesterol have been a highly reproducible finding in animal models of NASH.73,76–78 In the absence of an approved pharmacotherapy and based on the substantial evidence implicating dietary cholesterol as a lipotoxic trigger for NASH, dietary cholesterol intake should be minimized routinely in patients with fatty liver disease, including liver transplant recipients.
Table 1 Immunosuppression and pharmacotherapy of the metabolic syndrome
Drug
HMG-CoA Reductase Inhibitors (Statins)
Metformin
Thiazolidinediones ACEi
No drug–drug No drug–drug Increase interactions interactions in HMG-CoA reductase inhibitor concentrations Antiproliferative Mycophenolate No drug–drug Case report interaction of increased anemia with rosiglitazone No drug–drug mTORi Everolimus No clinically Sirolimus interactions significant interactions
CNI
Tacrolimus Cyclosporine
ARB
Increased risk of elevated serum creatinine and serum potassium
No drug–drug interactions
Increased risk of angioedema
CCB
PPI
Increase in CNI CNI exposure concentrations can increase
No drug–drug No drug–drug interactions interactions
Decreased mycophenolate concentrations
No drug–drug Increase interactions in mTORi concentrations
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CNI can inhibit the metabolism of most statins. The safest combination with CNI is pravastatin owing to its metabolism being less dependent upon CYP3A4. Reduction of other statin doses may be necessary and monitoring of myotoxicity is important. mTORi can cause angioedema and risk is increased with concomitant administration of ACEi. There is no metabolic drug–drug interaction described in the literature. CNI vasoconstrict the afferent arteriole and both ACEi and ARBs vasodilate the efferent renal arteriole. Concomitant administration may result in decreased renal perfusion causing an elevated serum creatinine. Both agents can lead to hyperkalemia owing to this mechanism and the CNI’s ability to induce distal renal tubular acidosis. Combination therapy has been used safely, but judicious monitoring of renal function is imperative. Both dihydropyridine and nondihydropyridine CCB inhibit CYP3A metabolism of CNI and increase CNI whole blood concentrations. Dihydropyridine CCB in combination with CNI are not routinely clinically significant. Nondihydropyridine CCB, both verapamil and diltiazem, are potent inhibitors and usually require dose adjustments of CNI when initiating, titrating, or discontinuing these agents. Nondihydropyridine CCB, both verapamil and diltiazem, potently inhibit the metabolism of both mTORi. Empiric dose adjustments of the mTORi are warranted when initiating, titrating, or discontinuing these agents. Dihydropyridine CCB can inhibit metabolism of mTORi but are generally not clinically significant. PPI, particularly omeprazole and lansoprazole, can increase concentrations of CNI by potentially inhibiting CYP3A4 metabolism of tacrolimus, particularly in those that are poor or intermediate metabolizers at CYP2C19. Coadministration of mycophenolate mofetil with PPI, particularly lansoprazole and pantoprazole, can reduce exposure of mycophenolate. Increased gastric pH may contribute to decreased mycophenolate solubility. Pantoprazole administered with mycophenolic acid in healthy volunteers did not alter pharmacokinetics of a single dose of mycophenolic acid. Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor antagonists; CCB, calcium channel blockers; CNI, calcineurin inhibitor; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; mTORi, mammalian target of rapamycin inhibitors; PPI, proton pump inhibitors.
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Coffee
Empiric pharmacotherapy of NAFLD with insulin-sensitizing agents or vitamin E is of marginal benefit (at best) and confers substantial risk (eg, weight gain). Several nonpharmacologic interventions have, however, emerged as beneficial for obesity and for reducing histologic severity and impact in NAFLD. The most compelling evidence is for coffee consumption; 2 to 4 cups of coffee consumed daily has been associated with improved histologic features of NAFLD and a reduction in the severity of components of the metabolic syndrome. Regardless of mechanism, coffee consumption is associated independently with a 12% decrease in mortality when compared with no coffee consumption.79 The benefit seems to be greatest with filtered coffee rather than consumption of espresso or tea.80 Consumption of 2 or more cups of coffee per day is also associated with decreased rates of hepatic fibrosis for patients with chronic liver diseases,81 including NASH.82 Although cause and effect is not established, a systematic review reported improved serum transaminases, decreased frequency of progression to cirrhosis and HCC, and lowered overall mortality in association with regular coffee consumption.83 Although multiple components of coffee may contribute to the beneficial effects, coffee polyphenols and caffeine have been demonstrated to have antioxidant effects,84 downregulate transforming growth factor-beta1 and SMAD2/3, increase peroxisome proliferator activated receptorgamma receptor expression,85 and to decrease activation of hepatic stellate cells.86,87 Based on the substantial sum of these observations, recipients with obesity and/or NAFLD should be encouraged to consume 2 or more cups of coffee per day. Mediterranean diet and olive oil
A Mediterranean diet is defined by a diet composed of primarily fruits, vegetables, whole grains, legumes, and nuts and replacement of butter with extra virgin olive oil. Herbs and spices replace salt to flavor foods. Red meat is largely replaced by fish and poultry, which are eaten at least twice a week. A large (n 5 7447), prospective study in which diets were supplemented with extra virgin olive oil (w60 mL/d) versus no supplementation of olive oil, observed that olive oil supplementation reduced the incidence of major cardiovascular events by 30%.80 The hazard ratio for all-cause mortality was 0.70 (95% CI, 0.54–0.92) for the group assigned to a Mediterranean diet with extra virgin olive oil when compared with the control group in multivariate analysis. Olive oil also has specific benefits in patients with NAFLD, reducing hepatic steatosis and improving inflammatory markers.88–90 On the basis of these observations and in the absence of any risk associated with consumption of extra virgin olive oil, we recommend a Mediterranean diet, including approximately 60 mL/d of olive oil for liver transplant recipients. REFERENCES
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