Metabolic Syndrome and Cardiovascular Risk Management After Liver Transplantation

Cardiovascular (CV) events are the second most common cause of nonhepatic death after liver transplantation, with an estimated prevalence of 11% of liver transplant recipients. Additionally, recipients with metabolic syndrome are up to 4 times more likely to suffer a CV event than recipients without metabolic syndrome. Furthermore, the rate of CV events after liver transplantation is projected to rise due to the growing prevalence of nonalcoholic fatty liver disease (NAFLD) and the increasing age of patients who receive liver transplants.

Unfortunately, metabolic comorbidities in liver transplantation are commonly overlooked by transplant physicians and primary care physicians. Transplant physicians tend to place stronger focus on liver function and immunosuppression issues than on metabolic comorbidities, while primary care physicians lack knowledge of drug interactions and have low confidence when it comes to managing and treating metabolic comorbidities in liver transplant recipients. Therefore, significant improvements to the management of metabolic syndrome after liver transplantation must be made to reduce the risk for CV events and mortality in this population.

Obesity

An estimated 37% of liver transplant recipients are obese at the time of transplantation.Additionally, between 30% and 70% of recipients are estimated to become overweight or obese following transplantation. On average, recipients gain about 5 kg within the first year and 10 kg within 3 years after transplantation. Recipients aged 50 and older and recipients who are obese before liver transplantation are at greater risk for obesity following transplantation than younger and nonobese counterparts.

Obesity after liver transplantation is multifactorial. The 2 main factors are reversal of the catabolic state of cirrhosis and increased appetite due to steroid use and the absence of chronic liver disease. However, weight gain and obesity are often overlooked by physicians after liver transplantation since greater focus is being placed on managing postoperative complications, sepsis, rejection, and renal dysfunction.

All liver transplant recipients should have discussions about diet and exercise with their physicians, but studies show the rate of long-term adherence to healthy lifestyle changes is poor. Bariatric surgery is typically not recommended following liver transplantation since the procedure is challenging and associated with high postoperative mortality of 5.3% and reoperation on 12.2% of patients. Rather, it is recommend using glucagon-like peptide-1 analogs for management of obesity after liver transplantation since these medications do not interact with immunosuppressive medications.

Type 2 Diabetes

Up to 30% of liver transplant recipients develop type 2 diabetes following their procedures. Risk factors for diabetes after liver transplantation include hepatitis C virus, cytomegalovirus infection, high-dose steroids, calcineurin inhibitors, and being more than 60 years of age. Other risk factors associated with diabetes after liver transplantation include central obesity before transplantation, hyperglycemia during the first month after transplantation, and staying in the intensive care unit for more than 15 days.

Glycemic control can be difficult following transplantation due to factors such as pain, surgical stress, steroid use, and the introduction of immunosuppression. Sliding scale intravenous insulin therapy is the standard of care for glycemic control until oral feeding is established, after which physicians can switch patients to subcutaneous insulin. Liver transplant recipients are formally diagnosed with diabetes if hyperglycemia persists 45 days following transplantation.

The International Liver Transplantation Society suggests that all liver transplant recipients undergo fasting glucose and HbA1c measurement at least 1 time at 3 to 6 months after transplantation, as well as at 12 months and every year thereafter. The treatment target for most patients is an HbA_1c of less than 7% (53 mmol/mol). Patients are also advised to undergo annual screening for retinopathy and proteinuria, make healthy lifestyle changes, and use oral antidiabetic medication, followed by insulin.

Metformin is considered a reasonable first-line treatment since it is shown to have a beneficial effect on CV events. Sulfonylureas, meglitinides, and thiazolidinediones may also be safe, though sodium-glucose cotransporter-2 inhibitors should be avoided since they may lead to volume depletion and increase the risk for genitourinary infections.

Dyslipidemia

Dyslipidemia is highly prevalent following liver transplantation and affects between 40% and 66% of recipients. Dyslipidemia in liver transplantation is associated with increased CV risk and associated morbidity, and mortality. Immunosuppression plays a key role in the development of hyperlipidemia after transplantation. Specifically, ciclosporin may inhibit hepatic bile acid-26 hydroxylase to result in decreased bile acid synthesis from cholesterol and reduced cholesterol transport into the bile and intestine.

The International Liver Transplantation Society suggests that a fasting lipid panel be obtained at 3 to 6 months, 1 year, and every year thereafter following liver transplantation. The recommended target level for low-density lipoprotein cholesterol is less than 100 mg/dL, and less than 250 mg/dL for triglyceride concentrations. Patients with hypercholesterolemia who have tried dietary and lifestyle measures without success should begin statin therapy using a low initial dose of lipophilic statins (20 mg per day of simvastatin or 10 mg per day of atorvastatin). For patients with persistent hypercholesterolemia, switching switch from ciclosporin to tacrolimus to reduce low-density lipoprotein concentration is recommended.

Hypertension

Hypertension is prevelant after liver transplantation and affects up to 70% of liver transplant recipients. Hypertension may occur due to systemic and renal vasoconstriction caused by calcineurin inhibitor immunosuppression, and from the mineralocorticoid effect of steroids.

Liver transplant recipients are recommended to undergo blood pressure monitoring daily for the first month after transplantation, again at 3 to 6 months, and annually thereafter. The blood pressure target for these patients is <130/80 mm Hg, which is the same target for those in the general population at high risk for CV events.

Hypertension management for liver transplant recipients should include low sodium intake, smoking cessation, abstinence from alcohol, and regular exercise. For pharmacotherapy, calcium channel blockers are the preferred first-line treatment due to their safety profile, minimal interaction with calcineurin inhibitor immunosuppression, and ability to reduce calcineurin inhibitor-induced renal vasoconstriction. However, diltiazem and verapamil should not be used due to potential drug interactions with calcineurin inhibitors. Up to 30% of liver transplant recipients with hypertension may require more than 1 drug to adequately manage blood pressure.

Nonalcoholic Fatty Liver Disease

Patients who receive liver transplants for NAFLD-related cirrhosis are at higher risk for NAFLD recurrence than those who receive transplants for other reasons. An estimated 30% to 60% of these patients will have recurring NAFLD within 1 to 5 years following transplantation. De-novo NAFLD after liver transplantation occurs in 20% to 35% of patients. Risk factors associated with de-novo NAFLD include obesity, type 2 diabetes, hyperlipidemia, tacrolimus-based immunosuppression, arterial hypertension, alcoholic cirrhosis as an indication for liver transplantation, and pretransplant graft steatosis.

At this time, there are no pharmacological treatments licensed for NAFLD, yet there are several ongoing randomized clinical trials, with expected results within the next 2 years. Liver transplant recipients who are overweight are recommended to lose 7% to 10% of their body weight through diet and healthy lifestyle changes to improve fibrosis and nonalcoholic steatohepatitis.

Conclusion

Data on the management of metabolic comorbidities in liver transplant recipients remain scarce, and it is unclear whether aggressive management of metabolic syndrome after liver transplantation can improve outcomes. Researchers suggest that fundamental changes be made to liver transplantation programs that incorporate 5- and 10-year survival data after transplantation, in addition to the usual 1-year survival data.

References

Fatourou EM and Tsochatzis EA. Management of metabolic syndrome and cardiovascular risk after liver transplantation. Lancet Gastroenterol Hepatol. 2019;4:731-741.