Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study

Table 1 Incidence or prevalence of risk factors of the different manifestations of the metabolic syndrome after orthotopic liver transplantation

Disease	Incidence/prevalence	Risk factors	Ref.
Diabetes mellitus	9%-21% (incidence)	Male gender	[65,105-107]
		High pre-LT BMI
		Family history
		Hepatitis C
		Older age immunosuppressants rapamycin gene polymorphisms
		TCF7L2 gene polymorphisms (donor)
Hyperlipidemia	45%-69% (prevalence)	Diet	[38,108-110]
		Older age
		High BMI
		DM
		Renal impairment, immunosuppressants
		low-density lipoprotein receptor gene polymorphism (donor)
Arterial hypertension	60%-70% (prevalence)	Obesity	[106,111,112]
		Older age
		Impaired glycemia
		Immunosuppressants
Overweight-obesity	24%-31% (prevalence)	High BMI before LT	[113-116]
		Diet
		Immunosuppressants
Metabolic syndrome	40%-60% (prevalence)	Older age	[33,106,117,118]
		Obesity and increased BMI
		pre-LT DM
		Genetic polymorphisms in the living donor
		High-dosage immunosuppressive drugs
		Changes in intestinal microbiota
NAFLD/NASH	18%-100% (incidence of NAFLD in NASH and cryptogenic recipients)	DM	[18,33,80,119-124]
	0%-14% (incidence of NASH in NASH and cryptogenic recipients)	Obesity and weight gain, dyslipidemia
	10%-40% (incidence of NAFLD in non-NASH or cyptogenic recipients)	Genetic predisposition (presence of the rs738409-G allele of the Patatin-like phospholipase)
		Arterial hypertension
		Immunosuppressant
		pre-LT alcoholic cirrhosis
		Liver graft steatosis

NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.

Table 2 Most used immunosuppressive drugs and main metabolic side effects

Factor	Metabolic consequences	Ref.
Steroid	Increased fat deposition with truncal fat distribution	[36,53-55]
	Decreased fat oxidation
	Increased gluconeogenesis
	Obesity
	Decreased glucose utilization
	Decreased b-cell insulin production
	Increased proteolysis,
	Reduced protein synthesis
	Insulin resistance
	Diabetes, NAFLD
	Mineralocorticoids effects
	Sodium retention
	Hypertension
	Hyperlipemia
Calcineurin inhibitor	Tacrolimus:	[58-65]
	b-cell toxicity
	Decreased insulin secretion
	Insulin resistance,
	Diabetes (more than cyclosporine)
	Cyclosporine:
	Decreased energy metabolism and muscle mass obesity
	Weight gain
	Decreased cholesterol transport into bile hyperlipidemia
	Occupy LDL receptor
	(more than tacrolimus)
	Renal vasoconstriction
	Hypertension
	(more than tacrolimus)
mTOR inhibitor	Increase insulin response	[68,125-129]
	Block b-cell proliferation
	Alter insulin signaling
	Decreased diabetes
	Increased diabetes
	Increased triglyceride production pathways
	And secretion
	Increased adipose tissue lipase activity
	Hyperlipidemia
	Decreased Lipoprotein lipase activity
Anti-metabolites	Mycophenolate mofetil:	[145-149]
	No nephrotoxity
	No effect on lipid profile, hypertention or diabetes mellitus
	Azatioprine:
	Vascular calcification
	Arteriosclerosis
Monoclonal antibodies	Basiliximab	[150]
	No nephrotoxity
	Rare effect on lipid profile, hypertension and diabetes mellitus

Table 3 Post transplant metabolic syndrome manifestations and their possible therapy

Disease	Suggested therapy	Contraindicated therapy	Ref.
Diabetes mellitus	Insuline: in the early post-operative setting	Metformin: not usable with renal failure (lactic acidosis)	[130-133,151-157]
	Life-style modification (diet, physical activity)	Thiazolidinediones: may be associated to hepato and cardiotoxicity and are adipogenic
	Oral hypoglicemic agent (after steroids tapering):	Second generation sulfonylureas: determine weight gain, hypoglycaemia, may increase CNI level
	Metformin: less weight gain and hypoglicemia	Meglitinides: determine weight gain, hypoglycemia (only with renal insuff), CNI may increase repaglinide level, are expensive
	Thiazolidinediones: well tolerated, may improve post-LT NAFLD	Alpha-glucosidase inhibitors: determine gastrointestinal side effects,are less effective, are expensive
	Dypeptyl peptidase-4 (DPP4) inhibitors, well tolerate, no weight gain, no hypoglicemia, potential anti-inflammation, antihypertension, antiapoptosis effects and immunomodulation on the heart, vessels, and kidney, independent of their hypoglicemic effect	Selective renal sodium glucose co-transporter 2 (SGLT 2): dapagliflozin, canagliflozin, empagliflozin, well tolerated but reported hepato-toxicity, contraindicated in patients with renal impairment
Hyperlipidemia	Hypercholesterolemia responds to:	Statins (except pravastatin and flestatin) are metabolized by cytochrome P-450 3A4, the same that metabolize CNIs and sirolimus so they must be used with caution because of myotoxicity	[134-138]
	HMGCoA inibitors (statins): pravastatine is the most studied and used but also atorvastatin, simvastatin, lovastatin, cerivastatin and fluvastatin are used	If used with statins fibrates may increase calcineurin inibitors levels
	Diet rich in omega 3 fatty acids, fruits, vegetables and dietary fiber
	Hypertrigliceridemia responds to:
	Fish oil (omega 3)
	Fibric acid derivates (gemfibrosil, clofibrate, fenofibrate)
Arterial hypertension	First line agents: calcium channels blockers (amlodipine, isradipine, felodipine)	Nifedipine may increase CNI levels and may cause leg edema	[139-141]
	Second line agents: specific β-blockers, ACE inibitors, angiotensin receptors blockers and loop diuretics	ACE inibitors and angiotensin receptors blockers may exacerbate CNI-induced hyperkalemia, but may provide anti-fibrotic properties and possibly protect against calcineurin induced renal injury
		Thiazides and other diuretics must be used with close follow-up because of potentiation of electrolyte abnormalities, hyperuricemia and renal dysfunction
Obesity	Bariatric surgery: well tolerated and successful but require a complex reoperation	Orlistat (tetrahydrolipstatin), inhibitor of pancreatic lipase has limited efficacy and possibly interferes with immunosuppressive therapy	[141-144]
	Gastric banding at the time of liver transplant procedure seems successful and well tolerate	Gastric bypass surgery can affect intestinal drug absorption