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FH and Liver Transplantation

Dr. Mohammed Al DubayeeConsultant Pediatric Endocrinology

King Abdullah Specialized Children Hospital-Riyadh, Saudi Arabia

•Liver transplantation–is it a ‘cure?’A.Data on outcomes from clinics

B.Raised LDL-C post transplantation – why?

Liver Transplantation for HoFH Treatment

• The first patient undergoing liver transplantation for HoFH was reported by Starzl in 1984.

• The patient suffered repeated severe attacks of angina, requiring coronary artery bypass graft surgery.

• At age 6 years, she received combined heart and liver transplantation, resulting in her serum total cholesterol level decreasing from 1,225 to 300 mg/dL, or even lower.

• Unfortunately, the patient died 3 years after transplantation.

• There were eight patients with homozygous FH in the median age of 10 years (IQR 6–12).

• All patients were diagnosed based on the clinical presentation. None of them underwent genetic testing

• The echocardiography has shown normal findings in three patients, aortic stenosis in 4 pt. and left ventricle hypertrophy in one

• Two patients died two and 18 months after LT due to sudden cardiac arrest.

• 36 patients with FH, 20 (55%) were male and 16 were female with an age range of 2.5–28 yr.

• All the patients were diagnosed based on the clinical findings and cholesterol values.

• No genetic testing was performed.

• LDL apheresis was not available, so liver transplantation was considered as a treatment option instead

• Post-transplant surgical complications:

• Biliary stricture, internal bleeding , liver abscess

• Post-transplant medical complications:

• acute rejection, Septicemia, cytomegalovirus colitis,

• convulsions,

• Of 36 patients with FH who underwent liver transplantation, three (8%) died. All were younger than four yr of age.

• The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) was designed to improve insight into the prognostic factors, treatments, and mechanisms that influence the development of ASCVD and mortality in a well-defined FH population.

• It is a nationwide registry that includes FH patients living in Spain regardless of their original nationality.

• 5 patients underwent a liver transplant, • Two still require statin therapy. • 2 patients died, one as consequence of septicemia and the

other in the postoperative period after a liver transplant.

• Long- term cardiovascular benefits of liver transplant are not clear due to the few cases reported in the literature and the short- term follow-up.

Am J Cardiol 2016;118:504e510

• Cardiovascular complications:

❑ Two patients required transient antihypertensive therapy and a third with preexisting kidney disease continued on antihypertensive treatment

❑Patient 3 showed regression of CAD, but later, asymptomatic 30% to 49% stenosis of the minor ramus artery was detected.

❑2 patients showed progression in aortic stenosis after transplant.

❑ Lipid lowering does not slow the progression of aortic root and valve damage in patients with HoFH

❑ A 7-year old boy presented to his pediatrician at 3 years of age with xanthomas on his knees bilaterally.

❑ Homozygous mutation in LDLR

Metabolic syndrome post LT

• The prevalence of metabolic syndrome lies between 50–60% in the LT population

• Diabetes mellitus is diagnosed in 10–64% of LT patients, obesity (BMI >30 kg/m2) in 24–64%, dyslipidaemia in 40–66% and arterial hypertension in 40–85%

• LT is associated with increase in sdLDL-C, VLDL size and concentrations.

Mechanisms of pro-atherogenic lipoprotein profile of LTRs

❑Calcineurin inhibitors the backbone of vast majority of immunosuppressive regiments in LTR can promote dyslipidemia (Cyclosporine > Tacrolimus)

❑Hepatic denervation: alters lipid regulation post LT by altering lipid metabolism and VLDL secretion.

❑Hyperinsulinemia: which may increase apoB synthesis and results in the release of TG-enriched VLDL particles.

Metabolic syndrome post LT

• Immunosuppressive regimens cause both an exacerbation of pre-existing systemic and metabolic disorders and de novo post-LT arterial hypertension, hyperlipidaemia, diabetes and obesity through a number of mechanisms including:

❑Increased cholesterol synthesis,

❑Increased triglyceride secretion and ApoB a key component of VLDL,

❑Reduction in bile acid synthesis,

❑Reduced lipolysis in circulation and

❑Increased serum LDL-P and sdLDL-c.

Journal of Hepatology 2016 vol. 64 j 433–485

Critical Issues in Liver Transplantation for HoFH

1. Liver transplantation is a very high- risk procedure, necessitating extensive invasion and involving severe potential complications

2. Long-term immunosuppressant therapy carries risks of numerous adverse effects

3. Lack of organs

4. Liver transplantation for HoFH cannot be viewed in the same way as that for other fatal diseases, which have no treatment options other than transplantation.

The consensus panel on HoFH of the European Atherosclerosis Society

• Liver transplantation corrects the molecular defects of LDL clearance, resulting in a marked improvement in LDL-C levels; however, there are obvious disadvantages, including surgical complications and the necessity for lifelong immunosuppressive therapy.

• Therefore, they positioned liver transplantation as a limited management option applicable only to selected patients.

❖ Liver transplantation positioned as a cure for molecular defect

HOWEVER

❖ Acute and late morbidity due to risk of rejection and anti-rejection medication

❖ Significant early and late mortality

❖ Limited availability of livers for transplantation for HoFH

❖ Despite correcting the molecular defect the LDL-C levels do not achieve target levels

❖ Therefore is it really a CURE?

❖Are you going to recommend it to your patients?

Thank you