Progressive Aortic Stenosis in Homozygous Familial Hypercholesterolemia After Liver TransplantMargaret Greco, MD, a, b Joshua D. Robinson, MD, a, b, c Osama Eltayeb, MD, d, e Irwin Benuck, MD, PhDa, b

Divisions of aCardiology and dCardiothoracic Surgery, Ann

and Robert H. Lurie Children’s Hospital of Chicago, Chicago,

Illinois; and Departments of bPediatrics, cRadiology, and eSurgery, Northwestern University Feinberg School of

Medicine, Chicago Illinois

Dr Greco drafted the initial manuscript;

Drs Robinson, Eltayeb, and Benuck reviewed and

revised the manuscript; and all authors approved

the fi nal manuscript as submitted and agree to be

accountable for all aspects of the work.

DOI: 10.1542/peds.2016-0740

Accepted for publication Jun 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: jdrobinson@

luriechildrens.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,

1098-4275).

Copyright © 2016 by the American Academy of

Pediatrics

FINANCIAL DISCLOSURE: The authors have

indicated they have no fi nancial relationships

relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors

have indicated they have no potential confl icts of

interest to disclose.

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.

CASE REPORT

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,

abstractEarly 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.

CASE REPORTPEDIATRICS Volume 138 , number 5 , November 2016 :e 20160740

To cite: Greco M, Robinson JD, Eltayeb O, et al.

Progressive Aortic Stenosis in Homozygous Familial

Hypercholesterolemia After Liver Transplant.

Pediatrics. 2016;138(5):e20160740

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GRECO et al

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

e2

FIGURE 1Coronary angiography showing 60% discrete narrowing in the left main coronary artery and 60% discrete narrowing in the left anterior descending artery.

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PEDIATRICS Volume 138 , number 5 , November 2016

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.

DISCUSSION

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

e3

FIGURE 2Xanthomas before and after liver transplant.

FIGURE 3Transthoracic echocardiogram showing parasternal long axis view of the aorta with calcifi cations and left ventricular hypertrophy.

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GRECO et al

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.

ACKNOWLEDGMENTS

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.

ABBREVIATIONS

HoFH:  homozygous familial

hypercholesterolemia

LDL:  low-density lipoprotein

LDL-C:  low-density lipoprotein

cholesterol

LDL-R:  low-density lipoprotein

receptor

Lp (a):  lipoprotein (a)

e4

FIGURE 4Timeline of key events, progression of aortic stenosis, and cholesterol levels. AS, aortic stenosis; CTA, computed tomography angiography; ECHO, echocardiogram; HDL, high-density lipoprotein (normal >45 mg/dL); LDL, low-density lipoprotein (normal 55–109 mg/dL); TC, total cholesterol (normal 100–160 mg/dL; TEE, transesophageal; TG, triglycerides; TTE, transthoracic.

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PEDIATRICS Volume 138 , number 5 , November 2016

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originally published online October 11, 2016; Pediatrics Margaret Greco, Joshua D. Robinson, Osama Eltayeb and Irwin Benuck

Liver TransplantProgressive Aortic Stenosis in Homozygous Familial Hypercholesterolemia After

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