uniformly unsuccessful in receptor negative homozygotes (<2 residual LDL receptor activity, 
Ref. 62). More encouraging results have been achieved in receptor defective patients (>2% 
residual LDL receptor activity) treated with a combination of nicotinic acid, a bile binder and an 
HMG CoA reductase inhibitor (61). An alternative pharmacologic approach to treatment of 
homozygous FH involves the use of the drug probucol (78). This lipophilic drug is an 
antioxidant that has been associated with regression of xanthomas in some patients (79). Its 
mechanism of action is unknown, however, data in the WHHL rabbit suggests that it may inhibit 
the formation of oxidized LDL and promote regression of xanthomas (80). Unfortunately, its 
beneficial effect on LDL metabolism may be counterbalanced by an associated decrease in HDL. 
The most widely used form of therapy for homozygous FH involves repeated purging of 
LDL from the blood through the use of plasma exchange or LDL apheresis (4, 66-77). The 
longest clinical experience using this approach has been with plasma exchange. Patients treated 
every 1 to 2 weeks achieve substantial but variable decreases in serum cholesterol. Plasma 
exchange in combination with pharmacologic therapy can lead to a 50% reduction in serum 
cholesterol in some patients. A theoretical disadvantage of plasma exchange is that it causes a 
depletion of HDL. A protocol of plasma exchange every 1 to 2 weeks for periods greater than 3 
years is associated with diminished progression and occasional regression of atherosclerosis in 
the coronary arteries and proximal aorta. This, however, is not always the case as exemplified 
by a patient who experienced progression of cardiovascular disease during chronic plasma 
exchange therapy (81). 
Recent advances in this therapeutic concept, called LDL apheresis, have involved the 
development of extracorporial devices that selectively remove LDL (75-77). An advantage of 
this technique is that it does not perturb HDL levels. The long term consequences of LDL 
apheresis remains to be determined. Both plasma exchange and LDL apheresis are complicated 
by the necessity of weekly or bimonthly treatments for the life of the patient. No longitudinal 
studies have shown an improvement in the morbidity or morality of FH patients using these 
procedures. 
Several surgical procedures have been attempted to affect more permanent 
improvements in FH homozygotes. One approach is to perform an ileal bypass to promote 
intestinal losses of bile and cholesterol. FH homozygotes usually do not respond to this 
procedure (82). Another approach is to surgically create a portacaval shunt (3, 64, 65). A 
review of the experience with portacaval shunts in 45 FH homozygotes described a 25% decline 
in serum cholesterol in 38% of the patients (3). Metabolic studies indicate this effect is due 
primarily to a decrease in LDL synthesis. The long term consequences of portacaval shunts are 
unclear. 
The most dramatic and effective treatment of homozygous FH has been orthotopic liver 
transplantation with an organ that expresses normal levels of LDL receptor. To date, liver 
transplant has been attempted in 4 individuals, three of which were the recipients of a combined 
heart and liver transplant procedure (5-9). A summary of these patients are described below. 
S.J. was a FH homozygote who underwent a combined heart/liver transplant in 1983 at 
the age of 6 (5,6). Her total serum cholesterol fell from 1100 mg/dl to 200-300 mg/dl 
following the transplant, and finally to 150-200 mg/dl with the addition of an HMG Co-A 
reductase inhibitor. She did well after the operation but eventually developed complications of 
immunosuppressive therapy and died in 1991. A combined liver/heart transplant was 
unsuccessfully attempted on a 17 year old girl with FH and end-stage cardiomyopathy (7). The 
patient died of multiple complications that occurred in the perioperative period. A third 
liver/heart transplant was attempted in a FH homozygote by a group in Spain (9). The patient 
survived the procedure and realized a 71% decline in total serum cholesterol postoperatively. 
The final case was a 12 year old boy with homozygous FH who underwent a liver transplant in 
Recombinant DNA Research, Volume 15 
[159] 
