Early onset coronary artery disease and aortic calcifications are characteristic features of patients with homozygous familial hypercholesterolemia. Standard medical therapy includes dietary modification, pharmacotherapy, and lipoprotein apheresis to lower serum low-density lipoprotein cholesterol (LDL-C). Liver transplant is a surgical option for the treatment of homozygous familial hypercholesterolemia and can lead to normal cholesterol levels. Vascular calcifications are known to progress despite standard medical therapy and have been reported after liver transplant in the setting of rejection. We present the first report of progressive severe aortic valve stenosis in a patient despite liver transplant with normalization of lipid levels and no history of graft rejection.
- HoFH —
- homozygous familial hypercholesterolemia
- LDL —
- low-density lipoprotein
- LDL-C —
- low-density lipoprotein cholesterol
- LDL-R —
- low-density lipoprotein receptor
- Lp (a) —
- lipoprotein (a)
Homozygous familial hypercholesterolemia (HoFH) is a rare disorder caused by a number of gene mutations associated with the low-density lipoprotein receptor (LDL-R) that results in defective or absent LDL receptor function leading to an inability of the liver to uptake LDL cholesterol (LDL-C).1 Extremely elevated blood levels of LDL-C are a hallmark of the disease that, if left untreated, can lead to premature coronary heart disease, vascular calcifications, and valvar and supravalvar aortic stenosis.1–7 Dietary modification in combination with a trial of medications (eg, statins, ezetimibe, bile resins) and lipid apheresis is the standard therapy for the disorder in an attempt to lower LDL-C.3,5,8 However, complete and sustained normalization of lipids is rarely successful, and despite aggressive lipid-lowering medical therapies, aortic calcifications are known to progress.2,4,5,9–12 Liver transplant is a surgical option that can be used in more severe cases and has been shown to prevent the development and progression of vascular disease.13,14 Progression of vascular disease has been reported after liver transplant, however only in the setting of rejection.15 We present a case of a patient with progressive severe valvar and supravalvar aortic stenosis despite liver transplant with normalization of cholesterol levels and without graft rejection. Informed consent was obtained from the parents of the patient for publication of this case report and accompanying images.
A 7-year old boy presented to his pediatrician at 3 years of age with xanthomas on his knees bilaterally. A serum lipid profile was obtained that showed total cholesterol of 1019 mg/dL, LDL of 946 mg/dL, high-density lipoprotein of 38 mg/dL, and triglycerides of 171 mg/dL. Genetic testing was obtained, which identified a homozygous mutation in LDLR: exon 8, nucleotide c.1090T>C, amino acid p.Cys364Arg (p.364R). In addition to being homozygous for the p.C364R mutation, the patient was also homozygous for multiple polymorphisms across the gene. Functional studies and additional testing on the parents were not performed. However, the parents are first cousins, which may explain the additional findings.
The patient was placed on a statin with dietary modification. A baseline echocardiogram showed mild supravalvar aortic stenosis with a peak velocity of 2.3 m/s (peak instantaneous gradient, 21 mm Hg; mean, 10 mm Hg) with normal left ventricular size and function. A computed tomographic angiography of the heart and coronary arteries was obtained, which showed no significant coronary artery stenosis and no gross atherosclerotic plaques. His cholesterol levels improved slightly but remained significantly elevated with a total cholesterol of 832 mg/dL and LDL-C of 735 mg/dL. The patient was referred for LDL apheresis with consideration for possible liver transplant.
Cardiac catheterization was performed at 5.75 years of age as part of the evaluation for possible liver transplant. Selective coronary angiography demonstrated a 60% discrete narrowing in the left main coronary artery, a 60% discrete narrowing in the left anterior descending artery, and severe stenosis of the proximal portion of the first large acute marginal branch of the right coronary artery (Fig 1). There was mild supravalvar aortic stenosis unchanged from baseline. The patient was started on aspirin and referred for coronary artery bypass grafting before liver transplant. Surgical inspection of the coronary arteries showed a plaque in the right coronary artery just beyond the acute marginal branch and a large xanthomatous plaque in the left main coronary artery. Two-vessel coronary artery bypass grafting was performed with the left internal mammary artery grafted to the left anterior descending artery and the right internal mammary artery grafted to the distal right coronary artery. The transesophageal echocardiogram at the time of the coronary bypass graft surgery under sedation showed a peak velocity across the aortic valve of 2.9 m/s (mean gradient, 15 mm Hg).
LDL apheresis was initiated shortly after surgery and performed at 2-week intervals with good results. However, after 3 treatments, the patient developed a catheter-related thrombus and apheresis was discontinued. Three weeks later, the patient underwent a liver transplant. The procedure was complicated by ventricular tachycardia and hemodynamic instability after hepatic clamping. A transesophageal echocardiogram under sedation was performed, which showed normal biventricular function, but with an increased gradient across the aortic valve of 4 to 4.5 m/s (peak instantaneous gradient, 64–80 mm Hg; mean, 35–40 mm Hg). The patient’s hemodynamic compromise was thought to be secondary to coronary ischemia in the setting of reduced preload and significant aortic stenosis. The decision was then made to perform the hepatectomy and liver implant on extracorporeal membrane oxygenation cardiopulmonary bypass support, which the patient tolerated well.
Cholesterol levels quickly normalized after liver transplant. The lipid panel remained normal 1 year posttransplant, and the xanthomas regressed (Fig 2). A liver biopsy obtained 5 months posttransplant showed chronic rejection versus ischemia, however, this improved with antiviral therapy, and the remainder of his liver biopsies remained negative for rejection. Aspirin therapy was continued, however statin therapy was not reinitiated post–liver transplant given the markedly normal lipids and risk of elevated liver function enzymes in the setting of liver transplant.
Despite normalization of lipid levels and the absence of rejection, the aortic stenosis continued to progress. Twenty months posttransplant, the transthoracic echocardiogram showed combined aortic valve hypoplasia, valvar and supravalvar stenosis with a peak velocity of 5.75 m/sec (peak instantaneous gradient, 132 mm Hg; mean, 76 mm Hg), and mild concentric left ventricular hypertrophy (Fig 3). Cardiac catheterization was performed, which confirmed valvar and supravalvar aortic stenosis with a peak systolic ejection gradient of 70 mm Hg. Balloon valvuloplasty of the aortic valve was attempted, however, there was no change in gradient despite technically successful balloon inflation. The patient was referred for surgery and subsequently underwent aortic root replacement with an 18 mm CryoLife aortic valve homograft. The operative findings were notable for a trileaflet aortic valve with extremely thickened leaflets and a supravalvar waist from a thickened aortic wall and apparent cholesterol plaque. The patient had an uncomplicated postoperative course and has remained clinically well. The most recent echocardiogram at 11 months postsurgery shows that the homograft valve has good leaflet mobility with trivial flow acceleration and regurgitation. A timeline of key events is shown in Fig 4.
HoFH is caused by a defect in the LDL-R gene or associated genes, which leads to extremely elevated serum levels of LDL-C. The frequency of clinical HoFH is estimated at ∼1 per 1 000 000, although higher frequencies have been reported in specific populations including French Canadians, Afrikaners in South Africa, and Christian Lebanese.1 In this case, the patient’s parents were first cousins. Patients typically present early in life with cutaneous xanthomas and arcus cornealis. Because of the elevated LDL-C levels, patients can develop premature coronary artery disease, aortic valve stenosis, and extensive vascular calcifications. The standard medical therapies include dietary modification in combination with pharmacotherapy (eg statins, ezetimibe, bile resins) and lipid apheresis to lower LDL-C. Liver transplant is often reserved for severe cases. Although lipid-lowering therapy is associated with delayed coronary events and prolonged survival in patients with HoFH, aortic calcifications continue to progress despite medical therapy and marked lowering of LDL-C.1–6 Xanthomas typically regress after therapy, however similar to vascular lesions, once calcified, they are less likely to regress.
Several factors have been shown to increase the risk of vascular calcifications and the rate of the progression of aortic stenosis. The formation of vascular calcifications may be related to osteoblast-like cells in the vascular smooth muscle, but the origin of the cells is controversial.5,16 Genetic studies have identified lipoprotein (a) [Lp (a)] as a risk factor for aortic calcification and progressive aortic stenosis.17 Lp (a) levels have been shown to be elevated in HoFH,18 however the Lp (a) level was not obtained in our patient before the initiation of lipid apheresis, so we are unable to comment on the role the protein may have played in this particular case. Late lipid apheresis initiated after the onset of aorta atheroma formation has also been associated with an increased rate of progression of aortic stenosis and has been shown to increase the likelihood of the need for surgical intervention,9 as was the case for our patient. Although statins are known to regress atherosclerosis and decrease the rate of cardiovascular events, they have been shown to increase coronary calcium formation, however the significance of this is not clearly understood.19
The progression of vascular calcifications has been reported after liver transplant, however this was in the setting of graft rejection.15 This is the first report of progressive aortic valve stenosis despite liver transplant in a patient with normalization of cholesterol levels and no history of graft rejection. Although immunosuppressive therapy may also play a role in vascular disease, this report suggests that even with a drastic reduction in LDL-C to normal by liver transplant, the rate of progression of aortic valve disease in HoFH may not be able to be slowed once vascular disease has been established. Aggressive early lowering of LDL-C before atheroma formation should be considered to prevent the development of aortic stenosis. More investigation is needed into the risk factors that affect the progression of vascular calcifications and prevention strategies.
We thank Neil Stone, MD, Professor F. J. Raal, FRCP, FRCPC, FCP(SA), Cert Endo, MMED, PhD, (Director, Carbohydrate and Lipid Metabolism Research Unit, Professor and Head, Division of Endocrinology & Metabolism, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg Hospital, Johannesburg, South Africa) and Lisa Cooper Hudgins, MD, (Associate Professor of Pediatrics in Medicine, The Rogosin Institute/Weill Cornell Medical College) for their input and insight into this case.
- Accepted June 28, 2016.
- Address correspondence to Joshua D. Robinson, MD, Department of Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Ave, Box 21, Chicago, IL 60611. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2016 by the American Academy of Pediatrics