The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III) identified metabolic syndrome (MS) as a multiplex risk factor for cardiovascular disease (CVD). Clustering of metabolic abnormalities such as hypertension, dyslipidemia, elevated fasting blood glucose, and obesity is known as the metabolic syndrome (MS). Criteria of ATP III are shown in Table 5.1; diagnosis of MS can be made when at least three of five of the listed components are present. Abdominal obesity, recognized by increased waist circumference, is the first criterion listed. Also listed are raised triglycerides, reduced HDL cholesterol, elevated blood pressure, and raised plasma glucose. Explicit demonstration of insulin resistance is not required for diagnosis; however, most persons meeting ATP III criteria will be insulin resistant [5].

MS is common among liver transplant recipients before and after transplantation. In the pre-transplant phase, the prevalence of MS can vary from 29 % in patients with cryptogenetic cirrhosis to 8 % in patients with end-stage liver disease caused by other etiologies [6]. Furthermore, the frequency of non-alcoholic fatty liver disease (NAFLD) as the indication for liver transplantation has been steadily increasing in recent years in all countries, and, in this population, obesity and diabetes are common features in patients awaiting liver transplant. In the kidney transplant setting, MS is a common condition after transplantation; the ALERT core study including 1,706 patients found that over 30 % of the recipients had MS criteria at entry [7]. After transplant many factors, primarily immunosuppression, contribute as a strong promoter of metabolic syndrome that develops in up to two-thirds of patients within the first five postoperative years. The most common metabolic side effects of immunosuppressive drugs are shown in Table 5.2. Other factors contribute to maintaining and raising the prevalence of metabolic syndrome after transplant, principally physical inactivity. Solid organ recipients are mostly sedentary, and most of them do not engage in work activity. Many studies revealed that transplant survivors had lower physical scores than the general population of the same age [8]. Calorie consumption, principally consisting of fat and carbohydrates, rises over the years after liver transplantation. Rising calorie intake combined with low physical activity contributes to the high prevalence of metabolic syndrome. Cirrhotic liver recipients lose lean mass in the pre-transplant period; the low levels of physical activity thereafter contribute to the reduction of lean mass and body water composition observed over the years. Other factors such as hepatitis C infection or methylprednisolone boluses are independent risk factors for the development of diabetes. As regards the function of the kidney graft, a recent study revealed that metabolic syndrome was associated with increased risk of graft failure [7].

The WHO categorizes obesity according to BMI (overweight = BMI 25–29.9 kg/m², class I = BMI 30–34.9 kg/m², class II = BMI 35–39.9 kg/m², class III = BMI >40 kg/m²). Abdominal obesity, typically manifesting as increased abdominal girth, is more metabolically active than peripheral adipose tissue; this feature has been associated with a higher risk of cardiovascular disease than peripheral obesity [9]. Recent studies described that over one-third of patients with decompensated cirrhosis are obese. In addition, NAFLD-related cirrhosis as an indication for liver transplant has been shown to continue to increase over time. In a large study published in 2005, the 5-year mortality was significantly higher both in the severely and morbidly obese subjects (P < 0.05), mostly as a result of adverse cardiovascular events concluding that morbid obesity should be considered a relative contraindication for liver transplantation [10]. Subsequent studies analyzed the confounding effect of ascites showing that correcting for ascites volume, 20 % of patients move into a lower BMI classification; these studies concluded that corrected BMI is not independently predictive of patient or graft survival and obesity “per se” should not be considered a contraindication for liver transplantation [11]. In the kidney transplant setting, almost 60 % of recipients are overweight at the time of transplantation, representing a 116 % increase from 1987. Indeed, in many transplant centers, a BMI of 35 kg/m² or greater is a common reason to exclude patients from transplantation. Despite this, the impact of obesity on patient and graft survival remains controversial [12].

The prevalence of hypercholesterolemia after solid organ transplantation rises to 43 % and hypertriglyceridemia to 40 %, while in 10–12 % dyslipidemia is characterized by an increase of cholesterol and triglycerides. The etiology of posttransplant hyperlipidemia is multifactorial; the main causes are increased appetite, obesity, and high prevalence of de novo diabetes and chronic renal failure; these factors are associated with the lipid-increasing effect of immunosuppressive therapy. CsA, tacrolimus, and rapamycin enhance lipolysis and inhibit lipid storage and expression of lypogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy. Steroids increase the excretion and hepatic VLDL conversion to LDL. Dyslipidemia is a well-known risk factor for cardiovascular diseases and is associated with reduced graft and patient survival in transplant recipients [13].

Hypertension is defined as the development of arterial pressure values ≥140/90 in a previously normotensive patient. Systemic arterial hypertension is a major complication in organ transplantation, reaching a prevalence of between 60 and 90 % during treatment with calcineurin inhibitors 10 years after transplantation; 20 % of patients require treatment with more than one drug [14]. Therapy with calcineurin inhibitors and steroids is the main cause of hypertension; cyclosporine is associated with increased production of renin and angiotensin; both calcineurin inhibitors cause increased synthesis of vasoconstrictor factors such as endothelin and reduced secretion of vasodilators prostacyclin and nitric oxide. Steroids increase the activity of the renin-angiotensin system and the vasoconstrictor response to norepinephrine and angiotensin II. In view of the risk of cardiovascular events in organ transplant patients, the blood pressure values recommended for the treatment of arterial hypertension are ≥130/80 mmHg and ≥125/75 mmHg in diabetic patients with proteinuria or renal insufficiency.

Cirrhotic patients frequently develop glucose intolerance and diabetes caused by insulin peripheral resistance, with reduced glycogen synthesis and impaired glucose oxidation [15]. Many patients will either remain diabetic or develop new-onset diabetes (NOD) after liver transplant.

Immunosuppressive therapy and HCV infection are the main risk factors related to post-liver transplant new-onset diabetes. Denervation of transplanted liver may contribute to the increase in insulin resistance. The incidence of preexisting diabetes as well as new-onset diabetes after renal transplantation (NODAT) varies from study to study and ranges from approximately 2–25 % with current immunosuppression, but with more diabetogenic immunosuppressive therapy, the incidence of diabetes may appear earlier after transplantation and can even rise to 46 % [16].

Corticosteroids decrease pancreatic beta-cell insulin production, increase gluconeogenesis, and decrease peripheral glucose utilization. In general, immunosuppression with calcineurin inhibitors leads to impaired glucose tolerance, and treatment with tacrolimus is associated with a higher risk of developing NODAT than treatment with cyclosporine [16]. Fasting glucose has a low sensitivity for diagnosing posttransplant diabetes mellitus (PTDM); therefore, the cutoff at 100 mg/dl for impaired fasting glucose seems more appropriate than 110 mg/dl. At present, the oral glucose tolerance test (OGTT) is considered the gold standard for diagnosing PTDM [17]. Regular monitoring of fasting blood glucose and OGTT, at least every 3 months, is strongly advised. Glycosylated hemoglobin assay (HbA1c) should be performed periodically after the third posttransplant month; HbA1c 5.7–6.4 % or higher indicates the need to follow up with a recognized diagnostic test.

Although renal transplantation substantially reduces cardiovascular risk, CVD remains the most important cause of morbidity and mortality. CVDs are the third most common late cause of death also in liver transplantation, accounting for 12–21 % of deaths; this may be an underestimation since some deaths characterized as “unknown” include sudden cardiac deaths. Detection and early treatment of risk factors of cardiovascular disease may impact long-term posttransplant survival. A recent meta-analysis showed that the 10-year risk of developing CV events among the post-OLT recipients was 13.6 % with a 64 % greater risk of experiencing CV events than controls. Liver recipients with metabolic syndrome were approximately four times more likely to have a CV event [18].