Components of Post-Liver Transplantation Metabolic Syndrome

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1		Adnan Khan	--	1806	2022-06-02 17:23:01	\|
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This entry is adapted from the peer-reviewed paper 10.3390/livers2020006

Survival rates after liver transplantation have increased dramatically over the past 20 years. Cardiovascular disease is the most common extra-hepatic cause of mortality in the long-term post liver transplant. This is intimately linked with both the higher pre-existing rates of metabolic syndrome in these patients as well as increased propensity to develop de novo metabolic syndrome post-transplant. This unfavorable metabolic profile that contributes to cardiovascular disease is multifactorial and largely preventable.

liver transplant metabolic syndrome chronic liver disease

1. Hypertension

Although most patients with cirrhosis tend to have very low blood pressure, post-LT HTN is prevalent. A retrospective study in Spain assessed the prevalence of HTN in post-LT patients; 49.1% of those surviving 5 years or more were found to have HTN, while other studies found that up to 70.6% of patients developed HTN within the first year post-LT ^[1]^[2].

Steroids are sometimes used after LT to reduce transplant rejection, although their use is falling out of favor for steroid-sparing immunosuppressive regimens. They are sometimes necessary as adjuncts to steroid-sparing agents to prevent rejection, and patients can be on these for long periods of time. With prolonged use, steroids have been shown to cause HTN. Steroid-induced HTN results from the overstimulation of the mineralocorticoid receptor, leading to sodium and water retention in the kidney and increased pressure. Steroid withdrawal after LT decreases the prevalence of HTN, diabetes, and hypercholesterolemia ^[3].

While steroid use is variable among transplant programs, all patients’ post-LT immunosuppressive regimen will include lifelong use of one of three medication classes: Calcineurin inhibitors (CNI), mTOR inhibitors, or inhibitors of purine and pyrimidine synthesis ^[4]. CNI and mTOR inhibitors increase blood pressure to a larger extent than mycophenolate mofetil (an inhibitor of purine and pyrimidine synthesis) ^[5]. A European trial comparing CNI and tacrolimus use observed HTN in 25.7% of CNI-treated patients and 17.2% of tacrolimus-treated patients after 6 months and 82% of CNI-treated patients and 64% of tacrolimus-treated patients after 24 months (about 2 years) post-transplant ^[6]. HTN was associated with more severe renal dysfunction in tacrolimus-treated patients and increased body weight in cyclosporine-treated patients ^[6].

As a result of the known side effects of the above immunosuppressive agents, the international LT society’s consensus statement suggests minimizing the use of corticosteroids and CNIs post LT when possible. This, in addition to lifestyle changes and medical therapy for HTN if necessary, is a “strong recommendation” with a “moderate quality/certainty of evidence” ^[7]. Specific management of HTN post-LT is discussed later.

2. Diabetes Mellitus

The prevalence of post-transplant diabetes mellitus (PTDM) among LT recipients is greater than that of the general population at 20–40% ^[8]. Both NASH and Hepatitis C are associated with predisposition to develop PTDM, and combined these indications for LT are almost greater than patients undergoing transplantation for any other reason put together ^[9].

Corticosteroids used post-LT increase the hepatic output of glucose and decrease insulin production and insulin sensitivity. Reduction in steroid therapy has had efficacious results, but avoiding steroids entirely is not recommended ^[10]. CNIs induce insulin secretory dysfunction, with a greater degree of glucose impairment noted with tacrolimus over cyclosporine ^[9]. Studies have also shown that tacrolimus use lessens the need for concomitant steroid therapy and lessens graft loss and rejection ^[11]. The use of sirolimus remains conflicting in the literature. While some studies associated mTORs with a higher risk of developing PTDM than other immunosuppressants, others found them to have a less pronounced impact on glucose regulation than CNIs ^[12]^[13].

Ultimately, regardless of the chosen immunosuppression regimen, screening regularly for diabetes and ensuring strict control remain important. Both pre-LT diabetes as well as PTDM are associated with increased liver-related mortality in the long-term post-LT phase, independent of other factors ^[8]. In the study reviewing post-LT causes of mortality of 798 transplant recipients from the NIDDK Liver Transplantation Database, when pre-LT diabetics are excluded, new onset diabetes is associated with increased long-term mortality (HR 1.61, CI 1.05–2.48, p = 0.039) ^[14]. When pre-LT diabetics are included, sustained diabetes without adequate control is also independently associated with death in a time-dependent fashion (HR 1.87, CI 1.41–2.48, p < 0.001) ^[14].

Management of PTDM remains similar to that of non-transplant patients and involves lifestyle modifications, pharmacotherapy, and the monitoring of immunosuppressive agents. These patients, however, are more complicated because they are more frequently exposed to steroids and other immunosuppressants with frequently changing doses, making their diabetes more difficult to control. While steroid and CNI withdrawal would be beneficial to manage PTDM, this decision should be made with priority given to maintaining allograft viability ^[15].

3. Obesity

One component of metabolic syndrome is elevated waist circumference, measured as greater than 102 cm in males (40 inches) or greater than 88 cm in females (35 inches). Weight gain is a common manifestation after LT; nearly two thirds of patients become obese after transplantation ^[15]^[16]. The weight gain associated with LT is multifactorial in nature. Cirrhosis presents as a hypermetabolic and malabsorptive state. Thus, prior to LT, patients may be malnourished; this is especially common with alcoholic liver disease. With the reversal of cirrhosis and chronic disease, there is also a reversal of patients’ appetites ^[17].

Another challenge of managing post-transplant obesity is related to the role that immunosuppressives play in inducing obesity. LT has an 83% and 75% 1- and 5-year survival rate, respectively, with developments in immunosuppression playing a significant role in this improvement ^[18]^[19]. The mainstay of immunosuppression post-LT includes corticosteroids, which are used initially at high intravenous doses and tapered to maintenance doses within the first 6 months of transplant ^[18]. The other mainstays of immunosuppression include CNIs such as tacrolimusa and cyclosporine, and mTOR inhibitors such as Sirolimus and Everolimus. Glucocorticoids activate gluconeogenesis in the liver promote insulin resistance in adipose tissue, and modulate insulin and glucagon secretion to increase blood glucose levels ^[20]. In acute situations, these changes help to increase glucose levels in response to stress; however, chronically they can cause long-term effects in the hypothalamus-pituitary axis and influence eating behavior that may promote the consumption of higher calories and sweeter food ^[21].

Further, the challenges of post-transplant obesity are complicated by the overall obesity epidemic in the United States (US). Obesity, defined by the World Health Organization as a BMI above 25, is seen in up to 42% of the US population according to the CDC (Centers for Disease Control). NAFLD is a spectrum of disease that includes progression to NASH and eventually cirrhosis. In 2013, NASH became the second leading indication of LT and is projected to become the leading indication for LT in the future ^[22]. These trends have also been reflected in the increased prevalence of obesity in LT candidates. Data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients 2017 report revealed that 38.5% of LT candidates were obese ^[23]. This trend has had implications in LT; one medium-sized retrospective study at a European center showed increased mortality in obese patients compared to non-obese patients ^[24]. Another study based at a university hospital in the United States showed more postoperative complications in obese patients undergoing LT ^[25]. While in the previously mentioned study, the long-term patient survival was comparable, a larger database study conducted using the United Network for Organ Sharing database concluded that obesity is associated with increased mortality in patients undergoing LT ^[26].

Management of obesity after LT has become an important consideration. Bariatric surgery has been proposed as a management option and is indicated for patients with a BMI > 35 and comorbidities or BMI > 40. Lasailly et al. demonstrated that bariatric surgery caused histologic improvements in NAFLD, including the resolution of NASH in 84% of patients and the regression of fibrosis in 70% of patients, which was maintained through 5 years of follow-up ^[27]. Unfortunately, bariatric surgery in the LT patient is vastly more complicated than it is for other patients. Changes in anatomy post-LT must be considered, as must several risks unique to this population, including: causing variceal bleeding when accessing the gastric fundus, risk of injury to the allograft, or causing issues related to impaired gastrointestinal absorption that affect immunosuppression ^[28]. In their large review of bariatric surgery and LT, Diwan et al. recommended Sleeve Gastrectomy as their procedure of choice due to minimal operative risk, lack of prosthetic device insertion, and minimal changes to immunosuppression absorption, although they did note that the body of evidence was small ^[28]. Timing of the surgery has not been directly compared, including pre-LT, simultaneous with LT, and post-LT. Further prospective studies may elucidate more on this topic.

4. Dyslipidemia

The liver is known to play a crucial role in lipid and lipoprotein metabolism. Dyslipidemia, specifically an increased ratio of low-density lipoprotein compared to high-density lipoprotein, predisposes patients to atherosclerosis, which is in turn linked to the increased morbidity and mortality of CVD seen in post-LT patients ^[29]. Hyperlipidemia has been reported in up to 66% of patients, with dyslipidemia reported in 46% of patients in one smaller study ^[30]^[31]. Contributions to the dyslipidemia seen in post-transplant liver patients include the rising prevalence of NAFLD as an indication for LT obesity and the metabolic effects of immunosuppressives. Glucocorticoids and CNIs are known to induce insulin resistance, leading to dyslipidemia, which favors the production of atherogenic lipoproteins ^[20]^[29]^[32]. Studies investigating different CNIs, specifically tacrolimus compared to cyclosporine, have shown that tacrolimus-based immunosuppression reduces the incidence of dyslipidemia compared to cyclosporine ^[32]^[33]. While the exact mechanisms by which cyclosporine affects lipoprotein metabolism are unclear, one proposed mechanism of dyslipidemia is through altering bile-acid synthesis, a way in which the body lowers serum cholesterol ^[29]. Cyclosporine inhibits 7-alpha hydroxylase, the rate-limiting enzyme of bile-acid synthesis ^[34]. Studies that evaluated switching from cyclosporine to tacrolimus in renal and LT patients showed significant reductions in lipid levels ^[35]^[36]. Sirolimus, an mTOR inhibitor, is also associated with significant dyslipidemia, including hypertriglyceridemia and hypercholesterolemia; interestingly, sirolimus has been shown in some studies to not increase CVD due to a postulated protective affect against atherosclerosis ^[37]. In a large, randomized clinical trial of LT patients, immunosuppressive regimens with conversion to sirolimus had higher incidence of hyperlipidemia compared to patients who continued tacrolimus therapy ^[38].

In terms of the management of dyslipidemia associated with LT, lifestyle and dietary interventions should be employed early. Patients should be followed with a fasting lipid panel annually ^[39]. For patients with persistent dyslipidemia, HMG CoA reductase inhibitors should be considered, especially in patients with an LDL > 100 mg/dL ^[17]. Consideration should be given to the fact that many statins and immunosuppressives including calcineurin and mTOR inhibitors are metabolized by cytochrome P450-3A4. It has been noted that interactions occur more frequently with cyclosporine compared to tacrolimus. LeMahieu et al. demonstrated that tacrolimus does not interact with atorvastatin in the same way that cyclosporine does, and hence does not require dose reduction ^[40]. Pravastatin is not metabolized by the P450 system, and Rosuvastatin is metabolized through the 2C9 pathway, both of which may be reasonable options ^[41]. Fluvastatin has been shown to be safe and well tolerated in renal transplant patients on cyclosporine ^[42]. Hypertriglyceridemia can be treated effectively with fish oils, with previous studies showing no significant effects on cyclosporine metabolism ^[43]. PSK-9 inhibitors have shown promise in treating dyslipidemia; however, further prospective studies are necessary to assess their efficacy and safety in LT patients.

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