Correspondence

Familial Hypercholesterolemia

N Engl J Med 2007; 356:1779-1780April 26, 2007

Article

To the Editor:

Cuchel and colleagues (Jan. 11 issue)1 report that inhibition of the microsomal triglyceride transfer protein reduces plasma low-density lipoprotein (LDL) cholesterol in homozygous familial hypercholesterolemia — a finding that establishes the value of targeting this enzyme and provides hope for patients with this condition. Treatment-related hepatic steatosis was predictable from studies in animals,2 variable among study subjects, and reversible with discontinuation of the inhibitor. Although the long-term consequences of sustained hepatic steatosis are unclear, some clues might be found among genetic-deficiency states associated with the microsomal triglyceride transfer protein, in particular in patients with abetalipoproteinemia. For instance, cirrhosis has been reported in patients with abetalipoproteinemia.3 Furthermore, mice with liver-specific ablation of the microsomal triglyceride transfer protein have increased susceptibility to liver injury in addition to hepatic steatosis.4 Fat accumulation within enterocytes and steatorrhea are defining features of abetalipoproteinemia; ileal adenocarcinoma developed in one patient with abetalipoproteinemia who survived for a long period.5

Further evaluation is necessary to determine whether similar long-term complications will occur in patients with homozygous familial hypercholesterolemia who receive long-term treatment with inhibitors of microsomal triglyceride transfer protein. The potential complications of this treatment must of course be balanced against such likely benefits as cardiovascular protection and the reduced need for plasma exchange, LDL apheresis, or liver transplantation as methods to normalize plasma LDL cholesterol levels.

Robert A. Hegele, M.D., F.R.C.P.C.
University of Western Ontario, London, ON N6A 5K8, Canada
hegele@robarts.ca

5 References

1. 1

   Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007;356:148-156
   Full Text | Web of Science | Medline

2. 2

   Chandler CE, Wilder DE, Pettini JL, et al. CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. J Lipid Res 2003;44:1887-1901
   CrossRef | Web of Science | Medline

3. 3

   Partin JS, Partin JC, Schubert WK, McAdams AJ. Liver ultrastructure in abetalipoproteinemia: evolution of micronodular cirrhosis. Gastroenterology 1974;67:107-118
   Web of Science | Medline

4. 4

   Bjorkegren J, Beigneux A, Bergo MO, Maher JJ, Young SG. Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury. J Biol Chem 2002;277:5476-5483
   CrossRef | Web of Science | Medline

5. 5

   Al-Shali K, Wang J, Rosen F, Hegele RA. Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia. Clin Genet 2003;63:135-138
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Hegele that clues regarding the long-term consequences of inhibition of the microsomal triglyceride transfer protein might be found among patients with abetalipoproteinemia. To our knowledge, no systematic observational studies have been performed regarding liver disease or gastrointestinal tumors in patients with abetalipoproteinemia, although liver fibrosis has been reported in a small number of patients with this condition.1,2 In two of them, supplementation with medium-chain triglycerides has been implicated as a possible contributor to the liver disease. However, clinical liver disease does not develop in the majority of patients with abetalipoproteinemia despite the absence of the microsomal triglyceride transfer protein.1 The progression from simple steatosis to hepatic fibrosis may require the presence of some other precipitating factors. If this is the case, it may be important to perform careful monitoring for additional precipitating factors in patients who receive long-term treatment with an inhibitor of microsomal triglyceride transfer protein and to treat them accordingly. Only with longer-term studies will we be able to assess properly whether the benefits of inhibitors of microsomal triglyceride transfer protein in patients at high risk for premature cardiovascular disease outweigh the potential risks of hepatic and intestinal adverse events.

Marina Cuchel, M.D., Ph.D.
Daniel J. Rader, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104
rader@mail.upenn.edu

2 References

1. 1

   Kane J, Havel R. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In: Scriver CR, Beaudet A, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease. 8th ed. New York: McGraw-Hill, 2001:2717-52.
   

2. 2

   Braegger CP, Belli DC, Mentha G, Steinmann B. Persistence of the intestinal defect in abetalipoproteinaemia after liver transplantation. Eur J Pediatr 1998;157:576-578
   CrossRef | Web of Science | Medline