Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited, life-threatening, metabolic disorder of low-density lipoprotein (LDL) receptor function characterized by elevated serum LDL cholesterol (LDL-C) and rapidly progressive atherosclerotic cardiovascular disease (ACVD). Since LDL receptors are predominantly found on hepatocytes, orthotopic liver transplantation (OLT) has emerged as a viable intervention for HoFH because LDL receptor activity is restored. This study assessed the effects of OLT on ACVD and ACVD risk factors in pediatric patients with HoFH. We analyzed lipids, lipoproteins, body mass index, glucose, blood pressure, and cardiovascular imaging in 8 pediatric patients who underwent OLT for HoFH. Total serum cholesterol, LDL-C, lipoprotein (a), and apolipoprotein B/apolipoprotein A1 ratio decreased to normal values in all subjects (p values <0.001) at 1 month after OLT and were maintained for the length of follow-up (2 to 6 years). There were few complications related to surgery or immunosuppressive therapy. Two patients developed mild hypertension. In the first 4 subjects monitored for 4 to 6 years after OLT, coronary artery disease did not develop or progress except in 1 minor artery in 1 subject and actually regressed in 2 subjects with >50% stenosis. However, aortic valve stenosis progressed in 2 of 4 subjects. In conclusion, OLT is an effective therapeutic option for patients with HoFH with coronary artery disease and persistently elevated serum LDL-C despite maximum medical therapy. Aortic valvular disease may progress. Long-term data are needed to evaluate the true risk-benefit ratio of this surgical approach.
Homozygous familial hypercholesterolemia (HoFH) is a life-threatening inborn error characterized by severely elevated serum low-density lipoprotein cholesterol (LDL-C) levels (12.9 to 25.9 mmol/L) due to impaired LDL clearance. Clinical manifestations include xanthomas, arcus cornea and progressive, early atherosclerotic cardiovascular disease (ACVD). Over 1,600 mutations in both alleles that code for the LDL receptor have been reported to affect 1 in 320,000 subjects. Mutations in genes for apolipoprotein (apo) B, proprotein convertase subtilisin kexin 9, and LDL receptor adaptor protein 1 that reduce LDL receptor activity are less frequent causes of HoFH. Untreated subjects develop progressive coronary artery disease (CAD) and aortic valve disease leading to myocardial infarction or sudden death, even in early childhood. Optimal medical therapy includes dietary restrictions, lipid-lowering agents, and plasma/LDL-C apheresis. These interventions often only delay cardiovascular consequences as LDL-C levels usually remain far above acceptable goals. Transfection of normal genes for the LDL receptor using retrovirus vectors into humans was not successful. Other approaches for gene therapy are currently being explored. LDL receptors and other proteins that may be abnormal in HoFH are predominantly found on hepatocytes. Therefore, orthotopic liver transplantation (OLT) offers an alternative treatment for HoFH regardless of the mutation. Since the first report of combined heart-liver transplant in a 6-year-old child with HoFH, there have been case reports worldwide of liver transplantation that demonstrate a dramatic and rapid reduction of LDL-C into the normal range. However, few centers have studied in detail the changes in ACVD and the effects of immunosuppressive agents (ISPs) on cardiovascular risk factors such as hypertension and glucose intolerance. This case series describes the changes in lipids, other cardiovascular risk factors, and cardiac vascular/valvular anatomy in 8 pediatric patients with HoFH after OLT.
Methods
We reviewed data collected prospectively from 4 pediatric patients enrolled in the Rogosin HoFH Repository (patients 1 to 4) and retrospectively from 4 other pediatric patients with the condition. All patients were evaluated and transplanted at a single center. Participants gave informed written consent/assent to participate in prospective data collection. The Weill Cornell Medical College and Columbia University Medical Center Institutional Review Boards approved the data collection.
Living-related liver donation was not offered to these children since the parents and many of their relatives were heterozygous for the disease. Organs from deceased donors with hyperlipidemia were also excluded. Patients with HoFH merit special case appeals for the assignment of allocated points that better represent their actual mortality risk on the United Network for Organ Sharing wait list. Justification for the appeal is driven by the degree of existing cardiovascular disease and the inability to control blood cholesterol levels with medical management. With current prioritization algorithms, listing before the age of 12 will increase priority in the pool of pediatric deceased donor grafts; listing before age 18 will still provide some benefit as pediatric priority is carried into adulthood.
All recipients were evaluated with echocardiogram (echo), 64-slice coronary computed tomography angiography (CCTA), or coronary catheterization and, in some cases, intravascular ultrasound (IVUS) to stratify cardiovascular risk and to guide appropriate preoperative, perioperative, and postoperative monitoring and intervention. These results provided a baseline to evaluate progression, stabilization, or regression of ACVD after OLT. Intraoperative transesophageal echo and serial troponin levels were monitored in the 3 patients with significant ACVD. Standard ISP was administered after OLT, as per center protocol, regardless of baseline CAD, including tacrolimus, mycophenolate mofetil, and glucocorticosteroids without induction. Liver function tests, creatinine and tacrolimus levels were monitored according to center protocol.
Fasting lipid panels, lipoprotein (a) [Lp(a)], apo A1, apo B, glucose, blood pressure, and body mass index (BMI) were monitored initially weekly, then biweekly, then monthly during the first year and every 3 months thereafter. A statistically significant change was defined as a p value <0.05 by paired t test. An examination by a cardiologist, electrocardiogram (ECG), and echo were performed annually. Coronary artery imaging was repeated within 3 years of OLT in 4 of 8 recipients and at varying intervals thereafter, depending on valvular and vascular status; the remaining 4 patients are still within this time frame.
CCTA images were reviewed on a dedicated 3-dimensional workstation at the Dalio Institute of Cardiovascular Imaging by a single, certified level III reader of the Board of Cardiovascular Computed Tomography. Reads were initially blinded but later unblinded to ensure consistency and to exclude artifacts. The unblinded reads were still blinded to each subject’s study date and therapy. Segmental scores from blinded and unblinded reads were similar. Multiplanar reformats and cross-sectional images were used to evaluate abnormal areas of minimal luminal diameter. The degree of stenosis and severity in each coronary artery segment was graded in accordance with the Society of Cardiovascular Computed Tomography guidelines. The results are presented as percent of stenosis for the most severely affected segment of any epicardial artery >2 mm: normal (0%), minimal (1% to 24%), mild (25% to 49%), moderate (50% to 69%), severe (70% to 99%), and complete occlusion (100%).
Results
The patient characteristics and clinical course are summarized in Table 1 . LDL receptor mutations were defined as true homozygotes in 5 and compound heterozygotes in 1 (Progenika Inc, for patients 1 to 4 and by Affymetrix Cytoscan HD platform for 7 and 8). Large subcutaneous and/or tendon xanthomas were present in 7 subjects. Five patients never had LDL apheresis because of inadequate venous access or lack of local availability for the procedure. Prepheresis LDL-C levels remained >9.8 mmol/L in the remainder. Patient 4 required stenting of the left main coronary artery. Patient 3 had a portacaval shunt at age 5 and LDL-C apheresis since age 10, but developed obstructive ACVD at age 14. He also developed idiopathic nephrotic syndrome, poorly controlled hypertension, and renal failure due to membranoproliferative glomerulonephritis and received a combined liver-kidney transplant.
| ID | Country of Origin | Age (y) at Dx | Age (y) at OLT | Current Age (y) | Sex | Genetic Mutation | Tx Organ | Medical Rx before OLT | Current Medical Rx |
|---|---|---|---|---|---|---|---|---|---|
| 1 | China | 2 | 3 | 9 | M | 302A>G, 1216C>A | Liver-LLS | statins, ez | Tac, ASA |
| 2 | Dominican Republic | 1 | 8 | 13 | F | 590G>A | Liver-whole | statins, ez, LDL-C apheresis | Tac, ASA |
| 3 | Syria | 1 | 17 | 23 | M | 2043C>A | Liver-Right lobe, Kidney | statins, ez, portacaval shunt, 5 anti-hypertensives, levothyroxine, heparin, LDL-C apheresis | Tac, MMF statins losartan, ASA |
| 4 | Dominican Republic | 5 | 15 | 19 | F | 590G>A | Liver- LLS | statins, ez, clopidogrel, metoprolol, ASA, LDL-C apheresis | Tac sirolimus clopidogrel, Statins, ASA |
| 5 | Saudi Arabia | 2 | 11 | 12 | F | – | Liver-whole | statins | Tac, statins, ASA |
| 6 | Saudi Arabia | 2 | 3 | 4 | F | – | Liver-whole | statins | Tac, ASA |
| 7 | Saudi Arabia | 3 | 4 | 4 | F | 2027delG | Liver- LLS | statins | Tac ASA |
| 8 | Saudi Arabia | 1 | 2 | 2 | M | 2027delG | Liver-whole | none | Tac, ASA |
The wait time for OLT ranged from 4 to 36 weeks (mean 10), with 7 subjects waiting <6 months. The postoperative length of stay was 5 to 9 days (mean 7). No significant adverse events occurred during surgery. Two patients had transient elevations in troponin (0.16 and 0.26 ng/ml, respectively) without ECG or transesophageal echo signs of cardiac ischemia. In the 3 older patients with advanced disease, atherosclerotic plaques were noted during hepatic artery anastomosis, and patient 3, who underwent liver-kidney transplantation, required extensive endarterectomy to remove heavy calcifications from the renal artery. Patient 2 underwent therapeutic endoscopic retrograde cholangiopancreatogram for biliary obstruction and experienced self-limited pancreatitis 6 weeks after her OLT. Patient 8 required biliary reconstruction for a bile leak 5 months after OLT.
Prednisone was tapered off by 3 to 6 months in 7 patients, and mycophenolate mofetil was discontinued 2 to 3 months after steroids were stopped, as per center protocol. Patient 3, the combined liver/kidney recipient, continues on tacrolimus and mycophenolate mofetil. Patient 4 required repeated steroid pulses and eventually rapamycin to control 3 episodes of acute hepatocellular rejection (ACR). Patient 8 also had ACR 6 months after OLT that was easily controlled.
There were few infectious complications. Patient 7 developed viremia early after transplant from a cytomegalovirus positive donor. She responded well to antiviral therapy and ISP reduction. Patient 4 was hospitalized for acute pyelonephritis with septic shock at 42 months after transplant but quickly responded to antibiotic therapy. ISP may have exacerbated the severity of this infection.
In all patients LDL-C and Lp (a) levels rapidly decreased by 80% and 60%, respectively, at 1 month after OLT and persisted at normal levels ( Figure 1 , Table 2 ). Low-dose statin therapy was continued in 3 patients with obstructive CAD to achieve LDL-C levels <2.6 mmol/L but was discontinued in 2 because of elevated liver enzymes. All patients are receiving low-dose aspirin that began 24 hours after OLT since it represents low risk and potential benefit in reducing ACVD events and hepatic artery thrombosis. Skin xanthomas flattened in all recipients ( Figure 2 ). Other cardiovascular risk factors were monitored. Two patients required transient antihypertensive therapy and a third with preexisting kidney disease continued on antihypertensive therapy, albeit at a significantly reduced dose. Two patients were overweight before and after OLT (BMI 85th to 90th percentile for age). No patient smoked cigarettes.
| Time | AT Dx | Pre OLT | 1 m | 6 m | 12 m | 24 m | 36 m | 48 m | 60 m |
|---|---|---|---|---|---|---|---|---|---|
| N | 8 | 8 | 8 | 8 | 6 | 4 | 4 | 4 | 3 |
| TC (mmol/L) (mg/dl) | 22.8±1.9 881.7±73.5 | 17.3±7.2 6691±278.4 | 5.1±0.7* 197.2±27.1 | 4.2±0.6* 162.4±23.2 | 4.6±0.8* 177.9±31 | 4.6±0.9* 177.9±34.8 | 4.2±0.8* 162.4±31 | 4.5±0.9* 174±34.8 | 4.3±0.8* 166.3±31 |
| LDL-C (mmol/L) (mg/dl) | 21.2±2.2 819.8±85.1 | 15.6±6.7* 603.2±259.1 | 2.8±0.5* 108.3±19.3 | 2.7±0.6* 104.4±23.2 | 3±0.9* 116±34.8 | 2.8±0.9* 108.3±34.8 | 2.7±0.8* 104.4±30.9 | 2.8±0.6* 108.3±23.2 | 2.7±0.6* 104.4±23.2 |
| Lp(a) (μmol/L) (mg/dl) | N/A | 2.2±1.2 61.6±33.6 | 0.8±0.7** 22.4±19.6 | 0.5±0.3** 14±8.4 | 0.7±0.4** 19.6±8.4 | 0.9±0.4** 25.2±8.4 | 0.8±0.1** 22.4±2.8 | 1±0.6** 28±16.8 | 1.2±0.5** 33.6±14 |
| HDL-C (mmol/L) (mg/dl) | 1.1±0.5 42.5±19.3 | 0.8±0.9 30.9±34.8 | 1.4±0.3 54.1±11.6 | 1.1±0.2 42.5±7.7 | 1.2±0.2 46.4±7.7 | 1.2±0.3 46.4±11.6 | 1.2±0.3 46.4±11.6 | 1±0.1 38.7±3.9 | 1.2±0.2 46.4±7.7 |
| TG (mmol/L) (mg/dl) | 1.7±1 150.6±88.6 | 1.5±0.9 132.7±79.7 | 1.7±1.1 150.6±97.4 | 1±0.3 88.6±26.6 | 0.8±0.4 70.9±35.4 | 1.1±0.4 97.4±35.4 | 0.9±0.2 79.7±17.7 | 0.8±0.3 70.9±26.6 | 0.9±0.5 79.7±44.3 |
| ApoB/A1 ratio | N/A | 4.6±2 | 0.7±0.3* | 0.7±0.2* | 0.7±0.2* | 0.7±0.2* | 0.7±0.3* | 0.6±0.2* | 0.6±0.2* |
Table 3 details the anatomy of the coronary arteries, aorta, and aortic valve in the 4 subjects evaluated before and after OLT. Patient 3 showed regression of disease in the main coronaries at 1 year until 5 years after transplant, but at 5 years, a new asymptomatic 30% to 49% stenosis of the minor ramus artery was detected. Patient 4 showed less plaque after 4 years. Of the 4 patients still awaiting repeat coronary evaluation, patient 5 had baseline 80% and 30% stenosis of the proximal right and left anterior descending coronary artery, respectively. The other 3 had no CAD. Of all 8 baseline studies, only 1 coronary artery was calcified (patient 4). The aorta/aortic root was calcified (“echo bright”) in 4 patients, and the aortic valve was mildly diseased in 3 patients. It is important to note that 2 of 4 patients showed progression in aortic stenosis after transplant.
| Subject | Age (y) | Exam Type | Exam Time Pre or Post OLT | Exam Time (m) | Coronary arterial narrowing (% stenosis) | Aorta | Aortic Valve | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LM | LAD | LCX | RC | Other | |||||||
| 3 | 17.5 | Angio IVUS | Pre | 3 | 0% | 50% | 1-25% | 90% | 50% 1 st septal | normal aortic root | normal |
| 20 | Angio IVUS | Post 1 | 26 | 0% | 20% | no change | 25-49% | no change | no change | normal | |
| 23.5 | Angio IVUS | Post 2 | 64 | 0% | mildly ectatic | mildly ectatic | no change | mild stenosis 1 st septal, 25-49% ramus | no change | normal | |
| 4 | 15 | CCTA | Pre | 2 | patent stent | 0% | 1-25% | 25-49% | 1-25% OM1, 2;RPLB | calcified aortic root and ascending aorta, small plaque thoracic aorta | mild stenosis and insufficiency |
| 16.5 | CCTA | Post 1 | 14 | no change | 0% | 0% | no change | no change OM1, 2; NE-RPLB | no change | no change | |
| 19.5 | CCTA | Post 2 | 51 | no change | 0% | 1-25% | 1-25% | no change OM1, 2; 0%-RPLB | no change | moderate stenosis, mild insufficiency | |
| 2 | 7.5 | CCTA | Pre | 9 | 0% | 0% | 0% | 1-25% | 1-25% D1, RPLB | moderate plaque near origin of LM and RC; mild plaque in thoracic aorta | mild insufficiency |
| 9.5 | CCTA | Post 1 | 15 | 1-25% | 1-25% | 0% | no change | no change D1, NE RPLB | no change | no change | |
| 12.5 | CCTA | Post 2 | 49 | 0% | 0% | 0% | no change | no change D1, 1-25% RPLB | more calcium in plaque | no change | |
| 1 | 3 | CCTA | Pre ∗ | 7 | 0% | 1-25% | NE | 0% | 1-25% D1 | mild non-calcified plaque in thoracic aorta | normal |
| 7 | CCTA | Post 1 ∗ | 41 | 0% | 0% | NE | 0% | NE D1 | some plaque calcified | mild plus insufficiency | |
| 10 | CCTA | Post 2 | 77 | 0% | 1-25% | NE | 0% | 1-25% D1 | no change | no change | |
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