Received: 10 December 2022 | Accepted: 9 March 2023
DOI: 10.1097/CLD.0000000000000040
REVIEW
Management of metabolic syndrome after liver transplant
Apaar Dadlani1 | Tzu-Hao Lee1,2
1
Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
2
Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
Correspondence
Tzu-Hao Lee, MD, Assistant Professor of Medicine and Surgery, Baylor College of Medicine, Houston TX.
Email:
INTRODUCTION (AASLD) and American Society of Transplant (AST)
recommend screening all LT recipients annually with a
Metabolic syndrome (MetS), defined by a constellation of fasting lipid panel and starting intervention if LDL
obesity, dyslipidemia, insulin resistance/diabetes melli- cholesterol level is > 100 mg/dL (Figure 2).[4] Statin
tus (DM), and hypertension, is observed in over half of therapy should be introduced if lifestyle changes are not
the liver transplant (LT) recipients within 3 years after enough. In patients with refractory hyperlipidemia,
LT.[1] Post-LT MetS is associated with multiple compli- adjustment of immunosuppressive medication might
cations, including NASH in the graft and, even more be needed. Although statins are a key medication in
importantly, cardiovascular and renal complications, treating hyperlipidemia in post-LT recipients, it is
which are the major leading causes of death after LT.[2] important to recognize possible drug-drug interactions
Several factors, including pre-LT weight, age, diabetes, between statins and CNI (Table 2). For example,
and triglyceride levels, are known to be associated with concomitant use of cyclosporine and most statin
post-LT MetS (Figure 1). Post-LT immunosuppressive drugs, except for pravastatin and fluvastatin, can
medications can not only exacerbate pre-existing MetS increase the risk of myopathy.
but also cause de novo post-LT MetS (Table 1). Given
the longer survival of LT recipients and the increasing
numbers of patients with NASH undergoing LT, DIABETES
monitoring and managing post-LT MetS has become
even more critical in the current era. Approximately 15% of patients develop new-onset
diabetes mellitus (NODM) after LT, and around one-
third of the overall LT recipients have diabetes at the
Dyslipidemia time of LT.[5] Both poorly controlled pre-existing DM and
NODM have been shown to increase long-term mortal-
Dyslipidemia is a major risk factor for cardiovascular ity in post-LT patients.[2] Risk factors for developing DM
morbidity and mortality and was found in up to 60% of include longer-term steroid use, obesity, HCV, alcohol,
LT recipients.[3] In addition to pre-existing risk factors and CNIs, which can decrease insulin synthesis/
before LT, this can be attributed to immunosuppressive secretion and induce insulin resistance. Compared with
medications, especially calcineurin inhibitors (CNIs), those who used cyclosporine, patients on tacrolimus
mammalian target of rapamycin (mTOR) inhibitors, and have a higher risk of developing diabetes (Table 1).[6]
glucocorticoids (Table 1). Current guidelines from the Current guidelines recommend monitoring fasting
American Association for the Study of Liver Disease plasma blood glucose every 3 months in the first year
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; AASLD, American Association for the Study of Liver Disease; ARB, angiotensin receptor blockers;
AST, American Society of Transplant; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CNIs, calcineurin inhibitors; DM, diabetes mellitus;
DPP-4, dipeptidyl peptidase-4 inhibitors; GLP-1, Glucagon-like peptide-1; LT, liver transplant; mTOR, mammalian target of rapamycin; MetS, metabolic syndrome;
NODM, new-onset diabetes mellitus; TZD, thiazolidinediones.
-------------------------------------------------------------------------------------------------------
Copyright © 2023 American Association for the Study of Liver Diseases.
Clinical Liver Disease. 2023;21:155–159. www.cldlearning.com | 155
Copyright © 2023 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited.
, 156
| CLINICAL LIVER DISEASE
FIGURE 1 Factors associated with post-liver transplant metabolic syndrome. Abbreviation: mTOR, mammalian target of rapamycin.
after OLT and then annually (Table 2).[4,7] If the diagnosis includes lifestyle modification. Dihydropyridine calcium
of diabetes is confirmed, lifestyle modification and channel blockers such as amlodipine and nifedipine
pharmacologic therapy should target a long-term goal are commonly used, given they can counteract the
of HbA1c <7.0.[4] Insulin is likely the safest and most vasoconstrictive effect of CNIs with few adverse
effective treatment option during the immediate effects and drug-drug interaction with immunosup-
postoperative phase when blood sugar is elevated due pression medications. Current AASLD/AST guidelines
to high-dose corticosteroids.[7] As the steroid dose tapers also recommend using angiotensin-converting enzyme
down, patients with NODM may experience improvement inhibitors, angiotensin receptor blockers, or direct
in their hyperglycemia, and oral hypoglycemic agents renin inhibitors as first-line antihypertensive therapy
may be appropriate. However, it is important to consider in LT recipients with DM, chronic kidney disease, and/
the patient’s renal function, given the restriction of some or significant proteinuria.[4] However, the use of these
commonly used medications such as metformin agents is often limited due to hyperkalemia from CNIs.
(Table 3).[4,7] Beta-blockers such as carvedilol serve as good
second-line antihypertensives. Hypertension in LT
recipients can be quite severe. Up to 30% of patients
HYPERTENSION require more than 1 medication to control their blood
pressure.[3]
Hypertension can be found in up to three-quarters of
patients after LT.[3] Hypertension in LT recipients
increases the risk of cardiovascular and renal compli- OBESITY
cations. Immunosuppressive medication plays a vital
role in the pathophysiology of hypertension in post-LT Weight gain is common after LT due to improved overall
patients. CNIs can cause increased renal arteriolar health, reverse catabolic state, and adverse effects from
vasoconstriction and sodium retention, leading to immunosuppressive medicine such as corticosteroids
significantly increased blood pressure. Steroids and and cyclosporine. About one-third of patients who are
mTOR inhibitors can also cause hypertension with a normal weight at the time of LT become obese after
smaller degree of impact. Blood pressure should be LT.[8] Initial treatment includes diet modification and
measured at every post-LT clinic visit. Home measure- exercise. Tapering steroid dose and switching from
ment of blood pressure is also strongly encouraged. cyclosporine to tacrolimus may also need to be
The blood pressure target in post-LT patients is considered. In patients with severe obesity despite
< 130/80 mm Hg.[4] The first line of management lifestyle modification, bariatric surgery is a reasonable
TABLE 1 Immunosuppressive therapy and association with metabolic syndrome
Steroids Tacrolimus Cyclosporine mTOR inhibitor
Dyslipidemia + + ++ +++
Diabetes +++ ++ + —
Hypertension + ++ ++ +
Weight gain/obesity ++ −/+ + —
Abbreviations: mTOR, Mammalian target of rapamycin.
Copyright © 2023 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited.
DOI: 10.1097/CLD.0000000000000040
REVIEW
Management of metabolic syndrome after liver transplant
Apaar Dadlani1 | Tzu-Hao Lee1,2
1
Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
2
Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
Correspondence
Tzu-Hao Lee, MD, Assistant Professor of Medicine and Surgery, Baylor College of Medicine, Houston TX.
Email:
INTRODUCTION (AASLD) and American Society of Transplant (AST)
recommend screening all LT recipients annually with a
Metabolic syndrome (MetS), defined by a constellation of fasting lipid panel and starting intervention if LDL
obesity, dyslipidemia, insulin resistance/diabetes melli- cholesterol level is > 100 mg/dL (Figure 2).[4] Statin
tus (DM), and hypertension, is observed in over half of therapy should be introduced if lifestyle changes are not
the liver transplant (LT) recipients within 3 years after enough. In patients with refractory hyperlipidemia,
LT.[1] Post-LT MetS is associated with multiple compli- adjustment of immunosuppressive medication might
cations, including NASH in the graft and, even more be needed. Although statins are a key medication in
importantly, cardiovascular and renal complications, treating hyperlipidemia in post-LT recipients, it is
which are the major leading causes of death after LT.[2] important to recognize possible drug-drug interactions
Several factors, including pre-LT weight, age, diabetes, between statins and CNI (Table 2). For example,
and triglyceride levels, are known to be associated with concomitant use of cyclosporine and most statin
post-LT MetS (Figure 1). Post-LT immunosuppressive drugs, except for pravastatin and fluvastatin, can
medications can not only exacerbate pre-existing MetS increase the risk of myopathy.
but also cause de novo post-LT MetS (Table 1). Given
the longer survival of LT recipients and the increasing
numbers of patients with NASH undergoing LT, DIABETES
monitoring and managing post-LT MetS has become
even more critical in the current era. Approximately 15% of patients develop new-onset
diabetes mellitus (NODM) after LT, and around one-
third of the overall LT recipients have diabetes at the
Dyslipidemia time of LT.[5] Both poorly controlled pre-existing DM and
NODM have been shown to increase long-term mortal-
Dyslipidemia is a major risk factor for cardiovascular ity in post-LT patients.[2] Risk factors for developing DM
morbidity and mortality and was found in up to 60% of include longer-term steroid use, obesity, HCV, alcohol,
LT recipients.[3] In addition to pre-existing risk factors and CNIs, which can decrease insulin synthesis/
before LT, this can be attributed to immunosuppressive secretion and induce insulin resistance. Compared with
medications, especially calcineurin inhibitors (CNIs), those who used cyclosporine, patients on tacrolimus
mammalian target of rapamycin (mTOR) inhibitors, and have a higher risk of developing diabetes (Table 1).[6]
glucocorticoids (Table 1). Current guidelines from the Current guidelines recommend monitoring fasting
American Association for the Study of Liver Disease plasma blood glucose every 3 months in the first year
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; AASLD, American Association for the Study of Liver Disease; ARB, angiotensin receptor blockers;
AST, American Society of Transplant; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CNIs, calcineurin inhibitors; DM, diabetes mellitus;
DPP-4, dipeptidyl peptidase-4 inhibitors; GLP-1, Glucagon-like peptide-1; LT, liver transplant; mTOR, mammalian target of rapamycin; MetS, metabolic syndrome;
NODM, new-onset diabetes mellitus; TZD, thiazolidinediones.
-------------------------------------------------------------------------------------------------------
Copyright © 2023 American Association for the Study of Liver Diseases.
Clinical Liver Disease. 2023;21:155–159. www.cldlearning.com | 155
Copyright © 2023 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited.
, 156
| CLINICAL LIVER DISEASE
FIGURE 1 Factors associated with post-liver transplant metabolic syndrome. Abbreviation: mTOR, mammalian target of rapamycin.
after OLT and then annually (Table 2).[4,7] If the diagnosis includes lifestyle modification. Dihydropyridine calcium
of diabetes is confirmed, lifestyle modification and channel blockers such as amlodipine and nifedipine
pharmacologic therapy should target a long-term goal are commonly used, given they can counteract the
of HbA1c <7.0.[4] Insulin is likely the safest and most vasoconstrictive effect of CNIs with few adverse
effective treatment option during the immediate effects and drug-drug interaction with immunosup-
postoperative phase when blood sugar is elevated due pression medications. Current AASLD/AST guidelines
to high-dose corticosteroids.[7] As the steroid dose tapers also recommend using angiotensin-converting enzyme
down, patients with NODM may experience improvement inhibitors, angiotensin receptor blockers, or direct
in their hyperglycemia, and oral hypoglycemic agents renin inhibitors as first-line antihypertensive therapy
may be appropriate. However, it is important to consider in LT recipients with DM, chronic kidney disease, and/
the patient’s renal function, given the restriction of some or significant proteinuria.[4] However, the use of these
commonly used medications such as metformin agents is often limited due to hyperkalemia from CNIs.
(Table 3).[4,7] Beta-blockers such as carvedilol serve as good
second-line antihypertensives. Hypertension in LT
recipients can be quite severe. Up to 30% of patients
HYPERTENSION require more than 1 medication to control their blood
pressure.[3]
Hypertension can be found in up to three-quarters of
patients after LT.[3] Hypertension in LT recipients
increases the risk of cardiovascular and renal compli- OBESITY
cations. Immunosuppressive medication plays a vital
role in the pathophysiology of hypertension in post-LT Weight gain is common after LT due to improved overall
patients. CNIs can cause increased renal arteriolar health, reverse catabolic state, and adverse effects from
vasoconstriction and sodium retention, leading to immunosuppressive medicine such as corticosteroids
significantly increased blood pressure. Steroids and and cyclosporine. About one-third of patients who are
mTOR inhibitors can also cause hypertension with a normal weight at the time of LT become obese after
smaller degree of impact. Blood pressure should be LT.[8] Initial treatment includes diet modification and
measured at every post-LT clinic visit. Home measure- exercise. Tapering steroid dose and switching from
ment of blood pressure is also strongly encouraged. cyclosporine to tacrolimus may also need to be
The blood pressure target in post-LT patients is considered. In patients with severe obesity despite
< 130/80 mm Hg.[4] The first line of management lifestyle modification, bariatric surgery is a reasonable
TABLE 1 Immunosuppressive therapy and association with metabolic syndrome
Steroids Tacrolimus Cyclosporine mTOR inhibitor
Dyslipidemia + + ++ +++
Diabetes +++ ++ + —
Hypertension + ++ ++ +
Weight gain/obesity ++ −/+ + —
Abbreviations: mTOR, Mammalian target of rapamycin.
Copyright © 2023 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article prohibited.
