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Liver Transplantation for Homozygous Familial Hypercholesterolemia: Two Case Reports
Liver Transplantation for Homozygous Familial Hypercholesterolemia: Two Case Reports F. Kakaei, S. Nikeghbalian, K. Kazemi, H. Salahi, A. Bahador, S.M. Dehghani, M. Dehghani, S.M. Nejatollahi, A. Shamsaeefar, M.B. Khosravi, and S.A. Malek-Hosseini ABSTRACT Homozygous familial hypercholesterolemia (HFHC) is a rare inherited condition with an incidence of one in one million. It is associated with severe premature atherosclerosis and early death from cardiovascular complications. Mutation in the gene that encodes the synthesis of the cellular receptor for low-density lipoprotein (LDL) is responsible for this metabolic disorder. Currently, the only effective treatment for this disease is liver transplantation, which alone or in association with medications, normalizes plasma cholesterol level. The authors report the results of liver transplantation for two cases of HFHC. The first case, a 15-year-old boy received a whole liver from a deceased donor, and the second, an 11-year-old boy, received a left liver lobe transplant from his mother’s sister. Their preoperative fasting lipid concentrations were grossly raised. The older boy had severe atherosclerotic heart disease and had undergone coronary artery bypass grafting 5 months before transplantation. Both had preoperative plasma cholesterol levels higher than 750 mg/dL with normal thyroid and liver function tests. After the operation, the patients received methylprednisolone as pulse therapy followed by oral prednisolone, mycophenolate mofetil, and tacrolimus for immunosuppression. Their hospital stays were 24 and 13 days, respectively. The first case needed reexploration because of bleeding on the second day after the operation. The lipid concentrations rapidly returned to the normal range in the first week after the operation, remaining in this range over the first 6 months of follow-up. Liver transplantation offers an highly effective treatment for HFHC. It is better to operate on patients before severe atherosclerotic changes in the coronary arteries. All patients must undergo a complete cardiac evaluation before surgery. OMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HFHC) is a rare inherited condition with an incidence of one in a million. It is associated with severe premature atherosclerosis and early death from cardiovascular complications. A mutation in the gene that encodes the synthesis of the cellular receptor for low-density lipoprotein is responsible for this metabolic disorder. Having two abnormal copies (homozygous) may cause severe cardiovascular disease in childhood.1 This subtype has a low response to all lipidlowering protocols except Low-density lipoprotein (LDL) apheresis, a treatment that is time-consuming and expensive and must be performed every 1 to 2 weeks. Although it retards the development of atherosclerosis, it does not prevent it, because of the recurrent hypercholesterolemia between procedures2 Currently, this treatment option is not available in Iran. Treatment, which should be initiated as soon as possible,1 is only liver transplantation, which alone or together with
H
medications normalizes plasma cholesterol level. Herein we have reported two cases of HFHC who underwent liver transplantation. CASE REPORTS Case 1 The first case was a 15-year-old boy who presented with cutaneous xanthoma at 5 years prior to transplantation (Fig 1). He displayed signs and symptoms of ischemic heart disease, namely, chest pain and dyspnea on exertion, leading to classification as New York From the Shiraz Transplant Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Address reprint requests to Kourosh Kazemi, Fellow of Transplantation Surgery, Shiraz University of Medical Sciences, Shiraz Transplant Center, Namazi Hospital, Namazi Square, Shiraz, Iran 71937-11351. E-mail: [email protected]
© 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.07.028
Transplantation Proceedings, 41, 2939 –2941 (2009)
2939
2940
KAKAEI, NIKEGHBALIAN, KAZEMI ET AL Table 1. Laboratory Data of Case 1 in Chronological Order Day Enlistment
⫺6
459 140 115 0.8 9.2 38 34 203 2.5 49
549 140 95 0.8 8.8 38 34 203 2.8 50
Total cholesterol TG FBS Creatinine HGB AST ALT Alkaline phosph GGT Weight
Operation
1
2
5
12
13
100 07 a 9.2 ¡ 6.5 1120 1000 309 2.8 50
120 131 143 0.5 b 9.3 ¡ 6 1140 1020 246 2.1 50
100 145 110 0.6 9.9 1010 1080 223 2.7 50
116 148 94 1 9.9 186 498 613 1.5 46
108 153 91 1.9 8.9 76 70 327 2.6 44
92 160 90 1.6 8 21 53 310 2.5 44
15
148 152 95 1.5 88 220 720 1134 2.5 42
17
22
153 150 94 1.2 9.3 16 26 294 2.2 42
160 145 88 1.2 9.1 18 23 283 2.1 42
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FBS, fasting blood sugar; GGT, gamma-glutamyltransferase; HGB, hemoglobin; TG, triglycerides. a The patient received two bags of packed cells during transplant. b The patient was taken to the operating room due to internal bleeding and received two bags of packed cells.
Heart Association class III at 1.5 years prior to transplantation. His lipid profile showed a total cholesterol level between 450 and 550 mg/dL when being listed for liver transplantation; it was unresponsive to conservative lipid-lowering medications. His Child-TurrcottPugh (CTP) class was A and his score, 5. He waited a little over 4 months before transplantation. Three-vessel coronary artery bypass grafting had been performed due to his coronary artery disease at 5 months before the transplant. He received a whole liver from a deceased donor. On the second postoperative day, he needed reexploration because of internal bleeding. Following his second operation, he had a smooth postoperative course except for a transient rise in serum creatinine and liver enzymes. On the first postoperative day, his lipid profile began to normalize rapidly (Table 1), initially dropping to 116 and fluctuating around 150 mg/dL before discharge at 24 days postoperatively. After the operation, the patient received methylprednisolone as pulse therapy followed by oral prednisolone, mycophenolate mofetil, and tacrolimus for immunosuppression.
Case 2 The second case was an 11-year-old boy who received a left liver lobe transplant from his mother’s sister. His parents had been evaluated as possible candidates for the partial transplant but were excluded on the suspicion that they were heterozygous for familial hypercholesterolemia due to a high lipid profile. He showed no
signs of coronary artery disease according to an echocardiography and coronary vessel angiography. Like the first case, he initially had a high lipid profile (956 mg/dL on listing), which was unresponsive to medical therapy, but he had a fewer cutaneous xanthomas. He was listed with a CTP score of 5 and class A. His postoperative course was uneventful; the lipid profile normalized promptly (Table 2). His immunosuppressive protocol was the same as case 1.
DISCUSSION
The management of patients with homozygous HFHC still represents a major medical challenge. The first patient exhibited progression of atherosclerosis because of extensively elevated LDL cholesterol levels. This might have resulted in the development of severe, lethal cardiovascular events even in early childhood. The early initiation of effective therapy is therefore mandatory. But even with novel lipid-lowering therapeutic regimens, the progression of atherosclerosis can only be slowed, but not stopped. Close monitoring is therefore required for signs of ischemic heart disease ideally with noninvasive methodology. However with respect HFHC special emphasis has to be made for good timing of the liver transplantation procedure. Although it is possible to treat HFHC patients with ad-
Table 2. Laboratory Data of Case 2 in Chronological Order Day
Total cholesterol TG FBS Creatinine HGB AST ALT Alkaline phosphatase GGT Weight
Enlistment
⫺6
956 200 89 0.5 12.6 36 27 840 2.7 35
895 195 105 1.6 27 20 960 2.8 36
Operation
1
2
4
5
185 0.8 12.2 3925 5395 786 2.9 36
436 43 174 0.8 13.2 2265 4205 704 1.6 38
138 41 159 0.8 11.5 810 2585 587 2.5 37
165 62 102 1 10.4 263 1074 533 1.6 37
145 77 164 1.6 9.7 182 170 866 37
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FBS, fasting blood sugar; GGT, gamma-glutamyltransferase; HGB, hemoglobin; TG, triglycerides.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
vanced heart disease by combined heart/liver transplantation, we strongly recommend considering orthotopic liver transplantation before the development of severe coronary artery disease that might result in major complications and limit the success of the surgical procedure.3,4 The two cases presented herein were our first experience with liver transplantation for HFHC. We originally had another case of HFHC and aortic stenosis who was on the transplant waiting list and underwent living donor liver transplantation from his mother, but in the immediate postoperative course suffered a sudden cardiac arrest and expired. He had a mild aortic stenosis, but normal coronary angiography in preoperative cardiac evaluation 3 months before the operation. In summary, orthotopic liver transplantation is a safe and feasible therapeutic option to treat patients with HFHC with progression of atherosclerotic disease that cannot be controlled by conservative therapy. Good timing of the procedure is mandatory to avoid atherosclerotic damage to the cardiovascular system resulting in complications that limit the success of transplantation or put the patient at additional risk. REFERENCES 1. Kavey RE, Allada V, Daniels SR, et al: American Heart Association Expert Panel on Population and Prevention Sci-
2941 ence; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 114:2710, 2006 2. Rader DJ, Cohen J, Hobbs HH: Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 111:1795, 2003 3. Offstad J, Schrumpf E, Geiran O, et al: Plasma exchange and heart-liver transplantation in a patient with homozygous familial hypercholesterolemia. Clin Transplant 15:432, 2001 4. Schmidt HH, Tietge UJ, Buettner J, et al: Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation. Clin Transplant 22:180, 2008
H
medications normalizes plasma cholesterol level. Herein we have reported two cases of HFHC who underwent liver transplantation. CASE REPORTS Case 1 The first case was a 15-year-old boy who presented with cutaneous xanthoma at 5 years prior to transplantation (Fig 1). He displayed signs and symptoms of ischemic heart disease, namely, chest pain and dyspnea on exertion, leading to classification as New York From the Shiraz Transplant Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Address reprint requests to Kourosh Kazemi, Fellow of Transplantation Surgery, Shiraz University of Medical Sciences, Shiraz Transplant Center, Namazi Hospital, Namazi Square, Shiraz, Iran 71937-11351. E-mail: [email protected]
© 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.07.028
Transplantation Proceedings, 41, 2939 –2941 (2009)
2939
2940
KAKAEI, NIKEGHBALIAN, KAZEMI ET AL Table 1. Laboratory Data of Case 1 in Chronological Order Day Enlistment
⫺6
459 140 115 0.8 9.2 38 34 203 2.5 49
549 140 95 0.8 8.8 38 34 203 2.8 50
Total cholesterol TG FBS Creatinine HGB AST ALT Alkaline phosph GGT Weight
Operation
1
2
5
12
13
100 07 a 9.2 ¡ 6.5 1120 1000 309 2.8 50
120 131 143 0.5 b 9.3 ¡ 6 1140 1020 246 2.1 50
100 145 110 0.6 9.9 1010 1080 223 2.7 50
116 148 94 1 9.9 186 498 613 1.5 46
108 153 91 1.9 8.9 76 70 327 2.6 44
92 160 90 1.6 8 21 53 310 2.5 44
15
148 152 95 1.5 88 220 720 1134 2.5 42
17
22
153 150 94 1.2 9.3 16 26 294 2.2 42
160 145 88 1.2 9.1 18 23 283 2.1 42
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FBS, fasting blood sugar; GGT, gamma-glutamyltransferase; HGB, hemoglobin; TG, triglycerides. a The patient received two bags of packed cells during transplant. b The patient was taken to the operating room due to internal bleeding and received two bags of packed cells.
Heart Association class III at 1.5 years prior to transplantation. His lipid profile showed a total cholesterol level between 450 and 550 mg/dL when being listed for liver transplantation; it was unresponsive to conservative lipid-lowering medications. His Child-TurrcottPugh (CTP) class was A and his score, 5. He waited a little over 4 months before transplantation. Three-vessel coronary artery bypass grafting had been performed due to his coronary artery disease at 5 months before the transplant. He received a whole liver from a deceased donor. On the second postoperative day, he needed reexploration because of internal bleeding. Following his second operation, he had a smooth postoperative course except for a transient rise in serum creatinine and liver enzymes. On the first postoperative day, his lipid profile began to normalize rapidly (Table 1), initially dropping to 116 and fluctuating around 150 mg/dL before discharge at 24 days postoperatively. After the operation, the patient received methylprednisolone as pulse therapy followed by oral prednisolone, mycophenolate mofetil, and tacrolimus for immunosuppression.
Case 2 The second case was an 11-year-old boy who received a left liver lobe transplant from his mother’s sister. His parents had been evaluated as possible candidates for the partial transplant but were excluded on the suspicion that they were heterozygous for familial hypercholesterolemia due to a high lipid profile. He showed no
signs of coronary artery disease according to an echocardiography and coronary vessel angiography. Like the first case, he initially had a high lipid profile (956 mg/dL on listing), which was unresponsive to medical therapy, but he had a fewer cutaneous xanthomas. He was listed with a CTP score of 5 and class A. His postoperative course was uneventful; the lipid profile normalized promptly (Table 2). His immunosuppressive protocol was the same as case 1.
DISCUSSION
The management of patients with homozygous HFHC still represents a major medical challenge. The first patient exhibited progression of atherosclerosis because of extensively elevated LDL cholesterol levels. This might have resulted in the development of severe, lethal cardiovascular events even in early childhood. The early initiation of effective therapy is therefore mandatory. But even with novel lipid-lowering therapeutic regimens, the progression of atherosclerosis can only be slowed, but not stopped. Close monitoring is therefore required for signs of ischemic heart disease ideally with noninvasive methodology. However with respect HFHC special emphasis has to be made for good timing of the liver transplantation procedure. Although it is possible to treat HFHC patients with ad-
Table 2. Laboratory Data of Case 2 in Chronological Order Day
Total cholesterol TG FBS Creatinine HGB AST ALT Alkaline phosphatase GGT Weight
Enlistment
⫺6
956 200 89 0.5 12.6 36 27 840 2.7 35
895 195 105 1.6 27 20 960 2.8 36
Operation
1
2
4
5
185 0.8 12.2 3925 5395 786 2.9 36
436 43 174 0.8 13.2 2265 4205 704 1.6 38
138 41 159 0.8 11.5 810 2585 587 2.5 37
165 62 102 1 10.4 263 1074 533 1.6 37
145 77 164 1.6 9.7 182 170 866 37
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FBS, fasting blood sugar; GGT, gamma-glutamyltransferase; HGB, hemoglobin; TG, triglycerides.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
vanced heart disease by combined heart/liver transplantation, we strongly recommend considering orthotopic liver transplantation before the development of severe coronary artery disease that might result in major complications and limit the success of the surgical procedure.3,4 The two cases presented herein were our first experience with liver transplantation for HFHC. We originally had another case of HFHC and aortic stenosis who was on the transplant waiting list and underwent living donor liver transplantation from his mother, but in the immediate postoperative course suffered a sudden cardiac arrest and expired. He had a mild aortic stenosis, but normal coronary angiography in preoperative cardiac evaluation 3 months before the operation. In summary, orthotopic liver transplantation is a safe and feasible therapeutic option to treat patients with HFHC with progression of atherosclerotic disease that cannot be controlled by conservative therapy. Good timing of the procedure is mandatory to avoid atherosclerotic damage to the cardiovascular system resulting in complications that limit the success of transplantation or put the patient at additional risk. REFERENCES 1. Kavey RE, Allada V, Daniels SR, et al: American Heart Association Expert Panel on Population and Prevention Sci-
2941 ence; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 114:2710, 2006 2. Rader DJ, Cohen J, Hobbs HH: Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 111:1795, 2003 3. Offstad J, Schrumpf E, Geiran O, et al: Plasma exchange and heart-liver transplantation in a patient with homozygous familial hypercholesterolemia. Clin Transplant 15:432, 2001 4. Schmidt HH, Tietge UJ, Buettner J, et al: Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation. Clin Transplant 22:180, 2008