Author Affiliations: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine (Zheng J and Wang WL); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Wang WL), Hangzhou 310003, China; Department of Surgery, The University of Hong Kong, Hong Kong, China (Zheng J)

Corresponding Author: Wei-Lin Wang, MD, PhD, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, No. 79 Qingchun Road, Hangzhou 310003, China (Tel/Fax: +86-571-87236570; Email: wam@zju.edu.cn)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60037-6

Published online November 18, 2015.

 

 

Contributors: WWL proposed the study. ZJ wrote the first draft. Both authors contributed to the design and interpretation of the study and to further drafts. WWL is the guarantor.

Funding: This study was supported by a grant from the Public Welfare Technology Application Research Plan of Zhejiang (2015C33117).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Liver transplantation is a treatment of choice for both acute and chronic liver failure. Accompanied with the increase of long-term survival rates of recipients, metabolic syndrome and its individual components, including obesity, hyperglycemia, hypertension and hyperlipidemia, have become more frequent post liver transplantation. Here we reviewed the literature concerning the risk factors for the development of metabolic complications in liver recipients.

 

DATA SOURCES: PubMed was searched for English-language articles published from January 2000 to June 2015. The search criteria focused on risk factors for metabolic syndrome after liver transplantation.

 

RESULT: The risk factors of metabolic syndrome in liver recipients include older age, obesity, pre-transplantation diabetes mellitus, hepatitis C virus infection, certain genetic polymorphisms and the use of immunosuppressive drugs.

 

CONCLUSION: Active intervention of the risk factors will reduce the occurrence rate of metabolic syndrome after liver transplantation and improve the recipients' quality of life.

 

(Hepatobiliary Pancreat Dis Int 2015;14:582-587)

 

KEY WORDS: liver transplantation; risk factors; hypertension; hyperlipidemia; diabetes mellitus

Liver transplantation (LT) has been accepted as the most effective treatment for end-stage liver disease for more than two decades.^[1] There are now more than 250 LT centers worldwide. Pooled research data suggest that the 1-, 5- and 10-year survival rates after LT are 90%, 80% and 60%, respectively.^[2-4] A total of 63% mortalities are liver function unrelated.^[5] Complications following LT significantly affect the quality of life in long-term survivors. Metabolic syndrome (MS) is the most common complication after LT, with an incidence of 50%-60%. The incidences of diabetes mellitus (DM), hypertension and hyperlipidemia are 10%-64%, 40%-85% and 40%-66%, respectively. MS is an established risk factor for atherosclerosis and cardiovascular disease which result in high mortality and poor quality of life.

 

The National Cholesterol Education Program Adult Treatment Panel III criteria are widely accepted for the diagnosis of MS.^{[6, 7]} Components of MS include obesity, hyperglycemia, hypertension and hyperlipidemia (Table 1).^[8] Other organizations that have published diagnostic criteria are the International Diabetes Federation and the Japan Society for the Study of Obesity. There have been a number of studies on the prevalence of and risk factors for the individual components of MS in living donor liver transplant recipients.^[9-11] It appears that the presence of underlying disease states, obesity, older age and certain genetic polymorphisms in the living donor are risk factors for the development of MS in recipients.^[12] In addition, treatments given to the recipient, including immunosuppressive drugs, corticosteroids, calcineurin inhibitors (CNIs) and the mammalian target of rapamycin inhibitor (mTORi), are implicated in the development of hyperglycemia, hypertension and hyperlipidemia (Table 2).^{[8, 12-16]}

 

The present review was to categorize the MS, the risk factors and the aspects that the physicians need to pay attention in practice.

 

 

Fifteen percent of LT patients develop DM. Patients with PTDM have higher morbidity rates than those with DM in the non-liver transplant population.^{[17, 18]} PTDM is a risk factor for other diseases, including cardiovascular disease and postoperative infection.

 

PTDM was categorized as transient and persistent PTDM.^[19] Among the 74 patients with PTDM in Ahn and colleagues' analysis,^[19] 42 (56.8%) showed transient PTDM, while 32 (43.2%) showed persistent one. The mechanism underlying PTDM is not clear; the disturbed carbohydrate metabolism is common immediately after LT. Other risk factors include: male gender; high body mass index; positive family history; hepatitis C virus (HCV) infection; age; drugs including corticosteroids, immunosuppressive agents, CNIs and rapamycin;^[17] and gene polymorphisms.

 

Many publications have demonstrated that age is an independent risk factor for metabolic derangements after transplantation.^[20-22] Age >45 years is a risk factor for abnormal glucose metabolism [odds ratio (OR) 1.164; 95% confidence intervals (CI): 1.164-3.112], and the effect can persist for up to 3 years post LT. Obesity is closely related to glucose metabolism; research has shown that obesity is a factor associated with disturbed carbohydrate metabolism after transplantation.^[21] A meta-analysis of 4580 patients showed that the average pre-transplant body mass index was higher in patients with PTDM than in those without PTDM.^[22] The same meta-analysis also showed that male gender was an independent risk factor. Family history of DM significantly increases the risk of PTDM.

 

There is a relationship between HCV infection and DM in patients with liver disease.^[23] Shintani et al^[24] proposed that this may be a consequence of a direct effect of the virus on insulin signaling, whereas Petitet al^[25] did not verify this notion because there was no correlation between HCV viral load and homeostasis model assessment of insulin resistance (HOMA-IR) of β-cell function. Patients with the combination of post transplantation MS (PTMS) and non-alcoholic fatty liver disease caused by HCV infection are at high risk of progressive liver fibrosis, which itself can alter glucose metabolism.

 

Immunosuppressive medication is a major risk factor of PTDM. The pro-diabetic effect of corticosteroids is well-known. Corticosteroids cause insulin resistance and enhance gluconeogenesis.^[26] High doses of corticosteroids are used in the early phase post transplantation, but whenever possible they should be rapidly tapered. CNIs are also associated with PTDM. The pooled results of 10 studies showed that tacrolimus (TAC) based immunosuppressant therapy is, when compared to that based upon cyclosporine A (CSA), an independent risk factor for the development of PTDM (OR=1.34; 95% CI: 1.03-1.76).^[22] It is important to consider this when planning the postoperative immunosuppressive regimen. There is also considerable evidence that appropriately minimizing the use of CNIs improves long-term outcomes without compromizing graft survival.^[27-29] Plasma concentration of TAC in excess of 10 ng/mL is an independent risk factor of PTDM.^[30]

 

Within the last five years, scientists found that polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene in liver transplant donors are an independent risk factor of PTDM.^[30] The TCF7L2 protein is important in the regulation of cell proliferation and differentiation, including comprising the islets of Langerhans and beta cells,^[31] with consequent effects on insulin secretion.

 

Although the mechanisms and risk factors of PTDM are still not clear, careful use of TAC and corticosteroids reduce the likelihood of PTDM. Paying attention to the risk factors in individual patient helps identifying the potential patients of PTDM and these patients can be benefited from early interventions.

 

 

Hypertension is an important factor affecting recipient survival. Hypertension is very common (50%-100%) in liver recipients.^[32-36] The diagnostic criteria are the same as those universally recognized.

 

Hypertension develops in the first 6 months after LT as a consequence of systemic vasoconstriction, elevation in plasma endothelin-1 concentrations, and increases in arterial stiffness.^[37] There is also a report of hypertension manifested as an increase in blood pressure from 98/60 mmHg to 170/108 mmHg after LT. The pathogenesis of LT-related hypertension is vasoconstriction leading to elevated systemic and renal vascular resistances.^[38]

 

Immunosuppressive medication, particularly CNIs and corticosteroids, plays an important part in the development of hypertension post LT. The primary mechanism of CNI induced hypertension is arterial vasoconstriction with magnification of hemodynamic changes, leading to increased systemic vascular resistance. The effect of vasoconstriction in the kidney is sodium retention and thus, both plasma volume expansion and increased peripheral resistance coexist. It has been reported that the rate of hypertension in patients on TAC may be lower than that in those on CSA during the first year after LT.^[34] However, the evidence is conflicting.^{[39, 40]} One possible explanation for this is that the dose of steroids was higher in patients treated with CSA than in those treated with TAC. Corticosteroids are considered an essential element of the early post LT immunosuppressive regimen. However, they affect mineralocorticoid metabolism, and cause sodium retention through the renin-angiotensin-aldosterone system.

 

The etiology of hypertension after LT is complicated. It is influenced by body mass index, the occurrence of hyperglycemia following LT, and age. Several studies^[35-37] have shown that a body mass index >30 kg/m² significantly increases the risk of hypertension pre and post LT. MS has statistical significance in affecting blood pressure before and after LT.^[16] Those with high fasting blood glucose levels have a higher prevalence of hypertension 12 months later. Multivariate analysis showed that older age is a risk factor for hypertension after LT. In one study, chronic sympathetic over activity with vasoconstriction and increased sodium sensitivity was found, whether or not patients were on CNIs.^[41]

 

It is relatively straightforward to reduce the risk of hypertension post LT by careful consideration of the known risk factors. Attention should be paid to ensure that the patient eats a low salt diet, controls weight if appropriate, and appropriately adjusts the immunosuppressive drugs.

 

 

Hyperlipidemia post LT is not unusual. Its incidence is estimated to be 45%-69%.^{[42, 43]} Known risk factors for its development are increased nutrient intake; age; body weight; DM; renal dysfunction; and the use of immunosuppressive drugs, including steroids, CSA and TAC.^[44] Hyperlipidemia has a significant impact on the risk of cardiovascular disease post LT and therefore, early recognition is important.

 

Post-transplant studies have shown that the immunosuppressant regimen is an important determinant for the development of dyslipidemia. The incidence of both hyperlipidemia and hypertriglyceridemia is higher in patients treated with CSA than those with TAC; 14% vs 5% and 49% vs 17%, respectively.^[45-49] This may be a consequence of the inhibition of 27-oxycholesterol, with activation of a number of key enzymes involved in cholesterol synthesis leading to hypercholesterolemia.^[50] Long-term use of corticosteroids is also associated with the development of hyperlipidemia.^{[51, 52]} Steroid-free or sparing immunosuppressant regimens reduce hypertriglyceridemia.^[53] However, Neff et al^[54] did not get the same results. Another immunosuppressant, sirolimus, is also implicated in the development of dyslipidemia, with a reported incidence as high as 55%.^[55] The risk of hyperlipidemia in patients treated with sirolimus was higher than in those with corticosteroids.^[34] The mechanism appears to involve changes in the insulin signaling pathway leading to increased triglyceride production and secretion.^[56]

 

Recent research linked polymorphisms of the low density lipoprotein receptor (LDLR) gene in the donor to hyperlipidemia in the recipient.^[57] This demonstrates the possibility of transmitting pathogenic mutations of the LDLR gene from donor to recipient.^{[58, 59]}

 

Diet plays an important part in the management of post-transplant hyperlipidemia; this has been appreciated for decades.^[60] A study involving 85 LT patients treated with standard triple immunosuppression found that the following factors were predictive of hypercholesterolemia in univariate analysis: female gender, pre-transplantation cholesterol levels >141 mg/dL, the need for more than three 'boluses' of methylprednisolone, and pre-transplantation cholestatic liver disease. Multivariate analysis revealed that only the pre-transplantation cholesterol level remained significant (OR=5.5; 95% CI: 1.4-21.0). In a different study,^[61] multivariate analysis found that the risk of hypertriglyceridemia was associated with pre-transplantation liver disease (OR=6.8; 95% CI: 1.2-40.0) and post-transplantation renal dysfunction (OR=5.4; 95% CI: 1.9-15.4).

 

 

Currently, MS after LT is an established risk factor for atherosclerosis and cardiovascular disease, which are important causes of morbidity and mortality in the liver recipients. Taken together, the available evidence suggests that the following are risk factors for PTMS: older age, obesity, pre-transplantation DM, and pre-transplantation liver disease. Certain genetic polymorphisms and the use of immunosuppressive drugs are also important. Active intervention to reduce the impact of risk factors will improve the quality of life in liver recipients. However, there are others that have not been considered, such as the possible contribution made to PTMS by changes in the intestinal microecology after LT.^[62] More in depth research aimed to minimize PTMS is required. 

 

 

1 National Institutes of Health Consensus Development Conference Statement: liver transplantation--June 20-23, 1983. Hepatology 1984;4:107S-110S. PMID: 6363254

2 Belle SH, Porayko MK, Hoofnagle JH, Lake JR, Zetterman RK. Changes in quality of life after liver transplantation among adults. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database (LTD). Liver Transpl Surg 1997;3:93-104. PMID: 9346722

3 Germani G, Theocharidou E, Adam R, Karam V, Wendon J, O'Grady J, et al. Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database. J Hepatol 2012;57:288-296. PMID: 22521347

4 Wang H, Jiang W, Zhou Z, Long J, Li W, Fan ST. Liver transplantation in mainland China: the overview of CLTR 2011 annual scientific report. Hepatobiliary Surg Nutr 2013;2:188-197. PMID: 24570944

5 Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant 2010;10:1420-1427. PMID: 20486907

6 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421. PMID: 12485966

7 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-2752. PMID: 16157765

8 Charco R, Cantarell C, Vargas V, Capdevila L, Lázaro JL, Hidalgo E, et al. Serum cholesterol changes in long-term survivors of liver transplantation: a comparison between cyclosporine and tacrolimus therapy. Liver Transpl Surg 1999;5:204-208. PMID: 10226111

9 Honda M, Asonuma K, Hayashida S, Suda H, Ohya Y, Lee KJ, et al. Incidence and risk factors for new-onset diabetes in living-donor liver transplant recipients. Clin Transplant 2013;27: 426-435. PMID: 23464510

10 Yadav AD, Chang YH, Aqel BA, Byrne TJ, Chakkera HA, Douglas DD, et al. New onset diabetes mellitus in living donor versus deceased donor liver transplant recipients: analysis of the UNOS/OPTN Database. J Transplant 2013;2013:269096. PMID: 24205434

11 Ling Q, Wang K, Lu D, Guo HJ, Jiang WS, He XX, et al. Major influence of renal function on hyperlipidemia after living donor liver transplantation. World J Gastroenterol 2012;18:7033-7039. PMID: 23323005

12 Parekh J, Corley DA, Feng S. Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation. Am J Transplant 2012;12:2181-2187. PMID: 22548965

13 Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, Blumberg E, 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. Liver Transpl 2013;19:3-26. PMID: 23281277

14 Kim WR, Smith JM, Skeans MA, Schladt DP, Schnitzler MA, Edwards EB, et al. OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant 2014;14:69-96. PMID: 24373168

15 Watt KD, Charlton MR. Metabolic syndrome and liver transplantation: a review and guide to management. J Hepatol 2010;53:199-206. PMID: 20451282

16 Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl 2011;17:15-22. PMID: 21254340

17 Lane JT, Dagogo-Jack S. Approach to the patient with new-onset diabetes after transplant (NODAT). J Clin Endocrinol Metab 2011;96:3289-3297. PMID: 22058376

18 Wilkinson A, Davidson J, Dotta F, Home PD, Keown P, Kiberd B, et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005;19:291-298. PMID: 15877787

19 Ahn HY, Cho YM, Yi NJ, Suh KS, Lee KU, Park KS, et al. Predictive factors associated with the reversibility of post-transplantation diabetes mellitus following liver transplantation. J Korean Med Sci 2009;24:567-570. PMID: 19654934

20 Ali IH, Adberrahim E, Ben Abdelghani K, Barbouch S, Mchirgui N, Khiari K, et al. Incidence and risk factors for post-renal transplant diabetes mellitus. Transplant Proc 2011;43:568-571. PMID: 21440763

21 Bonet J, Martinez-Castelao A, Bayés B. Metabolic syndrome in hemodialysis patients as a risk factor for new-onset diabetes mellitus after renal transplant: a prospective observational study. Diabetes Metab Syndr Obes 2013;6:339-346. PMID: 24082792

22 Li DW, Lu TF, Hua XW, Dai HJ, Cui XL, Zhang JJ, et al. Risk factors for new onset diabetes mellitus after liver transplantation: A meta-analysis. World J Gastroenterol 2015;21:6329-6340. PMID: 26034369

23 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133:592-599. PMID: 11033586

24 Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004;126:840-848. PMID: 14988838

25 Petit JM, Bour JB, Galland-Jos C, Minello A, Verges B, Guiguet M, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol 2001;35:279-283. PMID: 11580152

26 Rodríguez-Perálvarez M, Germani G, Darius T, Lerut J, Tsochatzis E, Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2012;12:2797-2814. PMID: 22703529

27 Rodríguez-Perálvarez M, Germani G, Papastergiou V, Tsochatzis E, Thalassinos E, Luong TV, et al. Early tacrolimus exposure after liver transplantation: relationship with moderate/severe acute rejection and long-term outcome. J Hepatol 2013;58:262-270. PMID: 23023010

28 Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, Pieri G, García-Caparrós C, O'Beirne J, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol 2013;59:1193-1199. PMID: 23867318

29 Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004;4:583-595. PMID: 15023151

30 Ling Q, Xie H, Lu D, Wei X, Gao F, Zhou L, et al. Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population. J Hepatol 2013;58:271-277. PMID: 23041303

31 Musavi Z, Azarpira N, Sangtarash MH, Kordi M, Kazemi K, Geramizadeh B, et al. Polymorphism of transcription factor-7-Like 2 (TCF7L2) gene and new-onset diabetes after liver transplantation. Int J Organ Transplant Med 2015;6:14-22. PMID: 25737773

32 Gonwa TA. Hypertension and renal dysfunction in long-term liver transplant recipients. Liver Transpl 2001;7:S22-26. PMID: 11689773

33 Jain A, Reyes J, Kashyap R, Rohal S, Abu-Elmagd K, Starzl T, et al. What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg 1999;230:441-448. PMID: 10493490

34 Canzanello VJ, Textor SC, Taler SJ, Schwartz LL, Porayko MK, Wiesner RH, et al. Late hypertension after liver transplantation: a comparison of cyclosporine and tacrolimus (FK 506). Liver Transpl Surg 1998;4:328-334. PMID: 9649648

35 Hryniewiecka E, Zegarska J, Paczek L. Arterial hypertension in liver transplant recipients. Transplant Proc 2011;43:3029-3034. PMID: 21996217

36 Fernández-Miranda C, Sanz M, dela Calle A, Loinaz C, Gómez R, Jiménez C, et al. Cardiovascular risk factors in 116 patients 5 years or more after liver transplantation. Transpl Int 2002;15:556-562. PMID: 12461660

37 Neal DA, Brown MJ, Wilkinson IB, Alexander GJ. Mechanisms of hypertension after liver transplantation. Transplantation 2005;79:935-940. PMID: 15849546

38 Textor SC. De novo hypertension after liver transplantation. Hypertension 1993;22:257-267. PMID: 8340162

39 Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-940. PMID: 12954741

40 Rossetto A, Bitetto D, Bresadola V, Lorenzin D, Baccarani U, De Anna D, et al. Cardiovascular risk factors and immunosuppressive regimen after liver transplantation. Transplant Proc 2010;42:2576-2578. PMID: 20832547

41 Zbroch E, Ma?yszko J, My?liwiec M, Przyby?owski P, Durlik M. Hypertension in solid organ transplant recipients. Ann Transplant 2012;17:100-107. PMID: 22466914

42 Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation 1997;63:331-338. PMID: 9039919

43 Imagawa DK, Dawson S 3rd, Holt CD, Kirk PS, Kaldas FM, Shackleton CR, et al. Hyperlipidemia after liver transplantation: natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin. Transplantation 1996;62:934-942. PMID: 8878387

44 Kanbay M, Yildirir A, Akcay A, Colak T, Ozdemir FN, Muderrisoglu H, et al. Effects of immunosuppressive drugs on serum lipid levels in renal transplant recipients. Transplant Proc 2006;38:502-505. PMID: 16549160

45 Clark W. Tacrolimus: immunosuppression following liver and kidney transplant. J Clin Pharm Ther 1996;21:135-1341. PMID: 8873845

46 Guckelberger O, Bechstein WO, Neuhaus R, Luesebrink R, Lemmens HP, Kratschmer B, et al. Cardiovascular risk factors in long-term follow-up after orthotopic liver transplantation. Clin Transplant 1997;11:60-65. PMID: 9067697

47 Rabkin JM, Corless CL, Rosen HR, Olyaei AJ. Immunosuppression impact on long-term cardiovascular complications after liver transplantation. Am J Surg 2002;183:595-599. PMID: 12034401

48 Stegall MD, Wachs ME, Everson G, Steinberg T, Bilir B, Shrestha R, et al. Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus. Transplantation 1997;64:1755-1760. PMID: 9422416

49 Manzarbeitia C, Reich DJ, Rothstein KD, Braitman LE, Levin S, Munoz SJ. Tacrolimus conversion improves hyperlipidemic states in stable liver transplant recipients. Liver Transpl 2001;7:93-99. PMID: 11172391

50 Gueguen Y, Ferrari L, Souidi M, Batt AM, Lutton C, Siest G, et al. Compared effect of immunosuppressive drugs cyclosporine A and rapamycin on cholesterol homeostasis key enzymes CYP27A1 and HMG-CoA reductase. Basic Clin Pharmacol Toxicol 2007;100:392-397. PMID: 17516993

51 Stegall MD, Everson GT, Schroter G, Karrer F, Bilir B, Sternberg T, et al. Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension, and hypercholesterolemia without causing graft loss. Hepatology 1997;25:173-177. PMID: 8985286

52 Boillot O, Mayer DA, Boudjema K, Salizzoni M, Gridelli B, Filipponi F, et al. Corticosteroid-free immunosuppression with tacrolimus following induction with daclizumab: a large randomized clinical study. Liver Transpl 2005;11:61-67. PMID: 15690537

53 Klintmalm GB, Washburn WK, Rudich SM, Heffron TG, Teperman LW, Fasola C, et al. Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl 2007;13:1521-1531. PMID: 17969201

54 Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003;35:209S-216S. PMID: 12742498

55 Morrisett JD, Abdel-Fattah G, Hoogeveen R, Mitchell E, Ballantyne CM, Pownall HJ, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 2002;43:1170-1180. PMID: 12177161

56 Trotter JF, Wachs ME, Trouillot TE, Bak T, Kugelmas M, Kam I, et al. Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transpl 2001;7:401-408. PMID: 11349259

57 Nikkilä K1, Åberg F, Isoniemi H. Transmission of LDLR mutation from donor through liver transplantation resulting in hypercholesterolemia in the recipient. Am J Transplant 2014;14:2898-2902. PMID: 25231171

58 Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm 2013;19:139-149. PMID: 23461430

59 Van Craeyveld E, Jacobs F, Gordts SC, De Geest B. Gene therapy for familial hypercholesterolemia. Curr Pharm Des 2011;17:2575-2591. PMID: 21774774

60 Fellström B. Impact and management of hyperlipidemia posttransplantation. Transplantation 2000;70:SS51-57. PMID: 11152232

61 Gisbert C, Prieto M, Berenguer M, Bretó M, Carrasco D, de Juan M, et al. Hyperlipidemia in liver transplant recipients: prevalence and risk factors. Liver Transpl Surg 1997;3:416-422. PMID: 9346772

62 Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59-64. PMID: 25079328