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Identification and management of heterozygous familial hypercholesterolemia: Summary and recommendations from an NHLBI workshop
Identification and Management of Heterozygous Familial Hypercholesterolemia: Summary and Recommendations from an NHLBI Workshop Diane E. Bild, MD, MPH, Roger R. Williams, MD, H. Bryan Brewer, MD, J. Alan Herd, MD, Thomas A. Pearson, MD, PhD, and Evan Stein, MD, PhD
Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswithserioushealthconsequences,affecting approximately 1 in BOO persons in the United states. Persons with hFH generally manifest elevatlons of low density lipoprotein (IDL) cholesterol throughout their lives and have a markedly increased risk of death from coronary artery disease. The hyperchulesterolemia of hFH is responsive to medication and diet, and, if detected early, aggredve LDL cholesterol control may prevent or substantially delay cardiovascular diiease. However, evidence suggests that many persons with hFH are undetected and inadequately treated. On July 20-25 1992, the National Heart, Lung, and Blood Instttute sponsored awwkshopto assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for kientificatiin and management that are known to be effective, and to identify opportunities and needs for intewention and research. (Am J Cardiol1993;72:1D-BD)
From the Clinical and Genetic Epidemiology Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland (D.E.B.); the Cardiovascular Genetics Research Clinic, University of Utah, Salt Lake City, Utah (R.R.W.); Molecular Disease Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland (H.B.B.); Department of Medicine, Baylor College of Medicine, Houston, Texas (J.A.H.); Mary Imogene Bassett Research Institute, Columbia University, Cooperstown, New York (T.A.P.); and Cardiovascular Research Center, The Christ Hospital, Cincinnati, Ohio (E.S.). Funding for publication has been provided by Merck Sharp and Dohme. Address for reprints: Diane E. Bild, MD, MPH, DECA/ NHLBI, 7550 Wisconsin Avenue, Room 300, Bethesda, Maryland 20892.
H
eterozygous familial hypercholesterolemia (hFH) is one of the most common monogenic disorders with serious health consequences, affecting approximately 1 in 500 persons in the United States.’ Persons with hFH generally have 2- to 3-fold elevations of low density lipoprotein (LDL) cholesterol. The risk of death from coronary artery disease among persons aged 20-74 years with hFH is increased almost 4-fold.2 The hypercholesterolemia of hFH is responsive to medication and diet, though usually 2 drugs in combination, and sometimes 3, are necessary to achieve desired levels of LDL cholesterol.3 If hFH is detected early, aggressive LDL cholesterol control may prevent or substantially delay cardiovascular disease. However, limited data suggest that many persons with hFH remain undetected. Frequently, among those who are found to have elevated cholesterol, the specific disorder, hFH, is not properly diagnosed, family members are not tested, affected persons are not informed of their diagnoses, and treatment is inadequate to control LDL cholesterol optimally. On July 20-21, 1992, the National Heart, Lung, and Blood Institute sponsored a workshop to assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for identification and management that are known to be effective, and to identify opportunities and needs for intervention and research. Four general areas were discussed at the workshop: pathophysiology and genetics of FH; diagnosis and case finding; medical management; and psychological, economic, and ethical issues. The following is a summary and a set of recommendations for intervention and research emanating from each of the 4 focus areas. PATHOPHYSIOLOGY AND GENETICS OF FAMILIAL HYPERCHOLESTEROLEMlA
In the early 1970s Brown and Goldstein4 determined that persons with homozygous FH had A SYMPOSIUM:
FAMILIAL
HYPERCHOLESTEROLEMIA
iD
defective LDL receptor activity that resulted in reduced LDL catabolism; to date, > 150 mutations have been identified at a single locus on chromosome 19. These mutations cause a variety of defects in LDL receptor function, including impaired synthesis, transport to the cell surface, binding and clustering at the cell surface, and degradation. Different defects resulting from the affected allele and function of the LDL receptors produced by the nonaffected allele probably account for much of the phenotypic heterogeneity in LDL levels observed in persons with hFH. In most geographic regions, receptor mutations among cases from different families bear no relation to each other. In certain populations, however, such as the French-Canadian, Lebanese, and South African Afrikaner populations, most of the cases can be accounted for by a few mutations because of the endogamy that occurred among the relatively isolated original settlers and their descendants who carried the mutations.5 Much can be learned about the phenotypic expression of different mutations from these populations. Concentrations of families with FH in a geographic area may also influence the efficiency of case-finding. Among persons with FH, LDL levels are heterogeneous and may be modified by the presence of other genes, such as those that determine LDL suppression and apolipoprotein E phenotype. Some LDL modulation may be caused by nonnuclear inheritance.6 High density lipoprotein and lipoprotein(a) levels may also modify the risk for atherosclerosis in persons with FH.7,8 Age, male gender, and smoking are associated with significantly increased risk of coronary artery disease in persons with FH,9 but the impact of other risk factors has not generally been well characterized. Recommendations: Important areas of research in the pathophysiology of hFH include the relation between specific mutations and phenotypes, how FH mutations interact with other modulating genes, the role of traditional cardiovascular disease risk factors in persons with hFH, and how some LDL receptor defects may cause only moderate hypercholesterolemia, not characterized as classic hFH. Better techniques need to be developed for diagnosis of hFH and determination of associated cardiovascular disease risk, by characterizing individual genotypes and determining biochemical and arterial effects of hFH. DIAGNOSIS AND CASE-FINDING The diagnosis of an isolated case of hFH is based on identification of high LDL levels and PD
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
72
evidence of an autosomal dominant mode of inheritance. The average total cholesterol in an adult with hFH is 360 mg/dL, with a range of approximately 250-550 mg/dL.9 Before making the diagnosis, secondary causes of hypercholesterolemia should be ruled out. Among the most common secondary causes are hypothyroidism and proteinuria. Xanthomas are present in approximately 70% of persons with hFH after age 20 years.lO Tendon xanthomas are virtually pathognomonic for FH.” Familial combined hyperlipoproteinemia is more common than hFH-from 1 in 100 to 1 in 50. However, the pattern of inheritance is not as distinct as hFH. There is limited information, particularly in the United States, on what proportion of persons with hFH are being appropriately identified. Data from review of medical records of persons with high cholesterol in primary care settings have shown that family screening rarely takes place.12 This suggests that testing of family members of persons with hypercholesterolemia, critical in the diagnosis of FH in families, is lacking. In a survey of close relatives of known hFH index cases, <33% of persons who reported cholesterol levels meeting criteria for hFH had been given the diagnosis of hFH by their physicians. l3 Of these adults, <50% were receiving medications, and <25% had received sufficient treatment to lower cholesterol below the 90th percentile for their age. Other surveys have found that only about half of adults have ever had their cholesterol checked.12J4 This suggests that case identification could be improved through increased testing of family members of suspected cases and, possibly, increased population screening. hFH meets the World Health Organization criteria for a worthwhile screening program, which include the ability to detect the condition in the preclinical phase, the existence of an accurate, acceptable test, and an accepted and effective treatment. Screening for hFH can be accomplished in the context of existing screening approaches for high cholesterol. The National Cholesterol Education Program (NCEP) has recommended that all persons over age 20 years have their cholesterol checked and that familial disorders be considered as a cause of hypercholesterolemia, including testing first degree relatives if a genetic etiology is suspected.15The NCEP Pediatric Panel has recommended testing children of adults who have evidence of premature coronary artery disease16 or total cholesterol >240 mg/dL, an approach that increases the probability of identifying persons
SEPTEMBER
30, 1993
with hypercholesterolemia that has a strong genetic basis. hFH is different from polygenic hypercholesterolemia in several respects that alter the usual approach to identification and management. First, it is less common than polygenic hyperlipidemia or familial combined hyperlipidemia. Thus, population-based screening for hFH, per se, is relatively inefficient. Second, it is an autosomal dominant disorder. This necessitates the testing of family members to establish the diagnosis and the provision of appropriate genetic counseling for affected individuals. Third, children are affected and should be treated as outlined by the Pediatric Panel of the NCEP.lh Fourth, the therapeutic approaches are usually different than for more common forms of hypercholesterolemia. For example, obesity is common in familial combined and polygenic hypercholesterolemia, and weight loss may achieve significant reductions in LDL. However, obesity is relatively uncommon in hFH, and weight reduction is less effective and should not be relied on as mainline treatment. The marked excess of coronary artery disease mortality among young adults with hFH (standardized mortality ratio, 9,686 among 20-39 year olds)* suggests that this form of hypercholesterolemia confers a higher risk for coronary disease than other forms. Whether this increased risk is due to the longer exposure to LDL, essentially since birth, or from other factors needs to be better evaluated. Experience from Utah suggests that tracing hFH through families is a highly efficient method of case ascertainment. The probability of hFH, given a high cholesterol value, increases dramatically once a family member with hFH is identified.13 For example, at a total cholesterol of 310 mg/dL, only 4% of adults from the general population will have hFH, whereas among first degree relatives of a person with hFH, 95% of persons with a level of 310 mg/dL will have hFH.r3 In British Columbia, a program has been developed to train physicians and support family screening for hFH.r’ This approach has been highly successful in identifying persons with hFH and may serve as a model for other communities. Recommendations: Screening and identification programs should integrate population-based screening of cholesterol, family screening and pedigree analysis, and investigation of patients and the families of patients with premature coronary heart disease. The medical care system needs to assure that appropriate family screening is conducted, that persons with hFH are provided with accurate
diagnoses and appropriate counseling, and that they are managed appropriately. Minimum cutpoints for pedigree analysis should be established and promoted as part of national screening recommendations. The main rationale for emphasizing this approach to the detection of hFH are the potential relative efficiency of pedigree analysis, to assure that persons with hFH are identified early in life, and to provide an opportunity for genetic counseling. MEDICAL MANAGEMENT OF hFH The primary care practitioner, by practical and economic necessity, is frequently the first clinician to encounter a new case of hFH, although he or she may fail to recognize it as such. There is currently no tested or accepted algorithm for determining who should assume clinical responsibility for persons with hFH. It is likely that health care providers with different areas of expertise may need to be involved, depending on the severity of the hyperlipidemia, the presence of atherosclerotic complications, and the need for genetic counseling.18According to 1989 NCEP guidelines, if routine drug treatment does not achieve optimal LDL levels, referral to or consultation with a lipid specialist should be considered. The physician with primary responsibility needs to be constantly aware of the potential for premature atherosclerosis. For early detection and management of cardiovascular disease complications, a cardiologist should be involved in the management. Because of high risk a priori for coronary atherosclerosis, some FH experts recommend periodic treadmill electrocardiograms and subsequent tests for asymptomatic middle-aged patients with hFH. Other physicians follow routine guidelines, relying mainly on angina to prompt the need for testing. Studies are needed in large numbers of hFH patients to determine which approach is best for hFH. Nutritionists play a very important role in dietary counseling of persons with hFH and even homozygous FH. Substantial LDL lowering is achievable with dietary manipulation. Other dietary factors may be important in hFH, including dietary antioxidants and monounsaturated fatty acid composition. l9 Dietary treatment of FH should be conducted in the context of the family in order to optimize success. Bile acid sequestrants, nicotinic acid, and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are all effective in lowering LDL cholesterol in persons with hFH; however, HMGCoA reductase inhibitors tend to achieve the A SYMPOSIUM: FAMILIAL HYPERCHOLESTEROLEMIA
3D
greatest lowering of LDL. Costs and side effects must be taken into account when prescribing a drug regimen. Combination therapy of 2 or 3 agents in low or moderate doses appears to offer the most cost-effective and side effect-free therapy.20 Combination therapy with 2 or 3 drugs at high or maximal doses is often required for those with severe FH and can achieve a 50-60% reduction in LDL cholesterol.2o A variety of more extreme nonpharmacologic approaches have been successful in lowering very high LDL cholesterol levels in conjunction with aggressive drug therapy, but these are generally reserved for persons with homozygous FH. These include LDL apheresis, portacaval shunts, intestinal bypass of the terminal ileum, liver transplant, and autologous transplantation of genetically altered hepatocytes.21 Recommendations: Primary care physicians, by practical necessity, are usually the first clinicians to encounter individuals or families with unsuspected hFH. These practitioners need appropriate education to enable them to suspect the possibility of a genetic disorder, to investigate the family, to make the diagnosis, and to institute appropriate dietary and pharmacologic therapy both in the patient and other affected family members. If appropriate reductions in LDL cholesterol are not achieved in a reasonable period of time, practitioners should be encouraged to consult with or refer patients to physicians with expertise in management of hFH. The establishment of a network of such specialists should be considered to assure a readily identifiable referral source. Biochemical and other parameters, such as age, gender, high density lipoprotein, lipoprotein(a), smoking status, and blood pressure status should be used to determine cardiovascular risk status. However, research is needed to help better determine risk, including quantification of atherosclerosis before it becomes clinically manifest. Similarly, methods should be identified to help monitor the effects of therapy to lower LDL and control other risk factors. More data are needed on the cost effectiveness of different drug regimens and on diet-drug interactions. More extreme methods such as LDL apheresis are generally reserved for homozygotes or the few heterozygotes with extremely high LDL levels. Long-term follow-up of persons who received portacaval shunting for FH would be worthwhile to evaluate better the effectiveness and complications of this treatment. The cost effectiveness of LDL apheresis and its role in specific FH subgroups, such as those with increased lipopro4D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
tein(a) or early aggressive coronary disease, should also be examined, although its uses will be more limited. Gene therapy research could offer lasting and effective therapy to homozygotes, but broader application of this approach requires much further development. PSYCHOLOGICAL, ECONOMIC, AND ETHICAL CONSIDERATIONS IN hFH MANAGEMENT Understanding the genetics of hFH and knowledge of its risks brings a special set of issues to the fore, which society may encounter increasingly as we discover the genetic basis for other disorders. hFH shares with other chronic conditions issues of adherence to complicated and life-style-altering regimens. However, little is understood about the psychologic impact of the diagnosis and treatment of hFH on the affected individual and on affected and unaffected family members. A particularly troublesome problem in the United States arises in the use of risk assessment as the basis for access to medical coverage or for assigning rates for health, life, and disability insurance. This raises questions about how screening tests might be applied, who should gain access to the information, and how the information is used.22 Paradoxically, some of the people insurance was originally designed to help are increasingly denied accessto coverage. Primary prevention of coronary artery disease in persons with hFH (based on single drug therapy) has been projected to have very favorable costeffectiveness ratios, including cost savings in certain subgroups. 23 It was found to be more cost effective than treatment of polygenic hypercholesterolemia. Cost effectiveness is less favorable (i.e., higher cost per year of life saved), both as the cost of intervention increases and in women than in men, and improves in the presence of other risk factors (because the risk of a subsequent event increases).23 Recommendations: Research is needed to understand better what factors determine adherence to lifelong regimens that significantly alter life-style and to develop approaches to improve adherence to treatment of hFH. Research is needed to understand the psychologic impacts of the knowledge of having hFH and how this affects family members and relations within the family. The high cost of lifelong therapy to prevent complications of hFH offers a substantial challenge to society in attempting to assure access to care for affected persons. Cost-effectiveness models of LDL lowering make important objective contributions to the debate
SEPTEMBER 30, 1993
over health care policy and should be considered in the formation of treatment recommendations. REFERENCES 1 Motulsky AG. Genetic aspects of familial hypercholesterolemia and its diagnosis. ArfeSosc&msis 1989;9(1 Suppl):l%‘l. 2. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolemia. BMI 1991;303:89?-896. 3. Illingworth DR, Bacon S. Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs. Alteriosclemis 1989;9( 1 Suppl):I121-134. 4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986,232:3ti7. 5. Davignon J, Roy M. Familial hypercholesterolemia in French Canadians: tak ing advantage of the presence of a “founder effect.” Am J Cardio11993;72:~10. 6. Hoeg JM. Homozygous familial hypercholesterolemia: a paradigm for phenotypic variation. Am J Cam?01 1993;72:11-14. 7. Streja D, Steiner G, Kwiterovich PO Jr. Plasma high-density lipoproteins and ischemic heart disease: studies in a large kindred with familial hypercholesterolemia. Am Intern Med 1978;89:871%30. 8. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson G, BoerwinkIe E. Utermann G. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypcrcholesterolemia. NE@ J Med 1990,322:1494-1499. 9. Stone NJ, Ley RI, Frederickson DS, Verter J. Coronary artery disease in 116 kindreds with familial type II hypxlipoproteinemia. Circularion 1974;49:476 488. 10. Kwiterotich PO, Frederickson DS, Lev RI. Familial hypercholesteremia (one form of familial type II hyperbetacholesterolaemia): a study of its biochemical, genetic, and clinical presentation in childhood. J Clin hat 1974;53:12371249.
ll. Goldstein JL Brown MS. Familial hypercholesterolemia.In: Sctiver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1989:1215-X250. 12. Pearson TA Diagnosis and case-finding in familial hypcrcholesterolemia: overview of issues. Am .I Car&l 1993;72:15-17. 13. Williams RR, Schumacher MC, Barlow GK, Hunt SC, Ware JL, Pratt M, Latham BD. Documented need for more effective diagnwis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah. Am J Cardiol 1993;72:&24. iA Census Bureau. Current Population Survey (unpublished data). 15. National Cholesterol Education Program. Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. US. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 8%2925, January 1989. 16. American Academy of Pediatrics. National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pedi&cs 1992;89:515-584. 17. Hayden MR, Josephson R. Development of a program for identification of patients with familial hypercholesterolemia in British Columbia: a model for prevention of coronary disease. Am J Cardiol1993;72:25-29. l.8. Schonfeld G. Who should treat familial hypercholesterolemia? Am J Cardial 1993;72:3Hl. 19. Connor WE, Connor SL. Importance of diet in the treatment of familial hypercholesterolemia. Am J Cardiol 19937242-53. 20. Illingworth DR. How effective is drug therapy in heterozygous familial hypercholesterolemia? Am J Cardi 1993;72:54-58. 21 Wilson JM, Grossman M. Therapeutic strategies for familial hypercholesterolemia based on somatic gene transfer. Am J Car&‘01 1993;72:59-63. 22. Murray TH. Ethics, genetic prediction, and heart disease. Am J Cardi 1993;72:80+%. 23. Goldman L, Goldman PA, Williams LW, Weinstein MC. Cost-effectiveness considerations in the treatment of heterozygous familial hypercholesterolemia with medications. Am J Cardiol1993;72:75-79.
A SYMPOSIUM:
FAMILIAL
HYPERCHOLESTEROLEMIA
5D
Heterozygous familial hyperchoiesterolemii (LFH) is one of the most common monogenic dii orderswithserioushealthconsequences,affecting approximately 1 in BOO persons in the United states. Persons with hFH generally manifest elevatlons of low density lipoprotein (IDL) cholesterol throughout their lives and have a markedly increased risk of death from coronary artery disease. The hyperchulesterolemia of hFH is responsive to medication and diet, and, if detected early, aggredve LDL cholesterol control may prevent or substantially delay cardiovascular diiease. However, evidence suggests that many persons with hFH are undetected and inadequately treated. On July 20-25 1992, the National Heart, Lung, and Blood Instttute sponsored awwkshopto assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for kientificatiin and management that are known to be effective, and to identify opportunities and needs for intewention and research. (Am J Cardiol1993;72:1D-BD)
From the Clinical and Genetic Epidemiology Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland (D.E.B.); the Cardiovascular Genetics Research Clinic, University of Utah, Salt Lake City, Utah (R.R.W.); Molecular Disease Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland (H.B.B.); Department of Medicine, Baylor College of Medicine, Houston, Texas (J.A.H.); Mary Imogene Bassett Research Institute, Columbia University, Cooperstown, New York (T.A.P.); and Cardiovascular Research Center, The Christ Hospital, Cincinnati, Ohio (E.S.). Funding for publication has been provided by Merck Sharp and Dohme. Address for reprints: Diane E. Bild, MD, MPH, DECA/ NHLBI, 7550 Wisconsin Avenue, Room 300, Bethesda, Maryland 20892.
H
eterozygous familial hypercholesterolemia (hFH) is one of the most common monogenic disorders with serious health consequences, affecting approximately 1 in 500 persons in the United States.’ Persons with hFH generally have 2- to 3-fold elevations of low density lipoprotein (LDL) cholesterol. The risk of death from coronary artery disease among persons aged 20-74 years with hFH is increased almost 4-fold.2 The hypercholesterolemia of hFH is responsive to medication and diet, though usually 2 drugs in combination, and sometimes 3, are necessary to achieve desired levels of LDL cholesterol.3 If hFH is detected early, aggressive LDL cholesterol control may prevent or substantially delay cardiovascular disease. However, limited data suggest that many persons with hFH remain undetected. Frequently, among those who are found to have elevated cholesterol, the specific disorder, hFH, is not properly diagnosed, family members are not tested, affected persons are not informed of their diagnoses, and treatment is inadequate to control LDL cholesterol optimally. On July 20-21, 1992, the National Heart, Lung, and Blood Institute sponsored a workshop to assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for identification and management that are known to be effective, and to identify opportunities and needs for intervention and research. Four general areas were discussed at the workshop: pathophysiology and genetics of FH; diagnosis and case finding; medical management; and psychological, economic, and ethical issues. The following is a summary and a set of recommendations for intervention and research emanating from each of the 4 focus areas. PATHOPHYSIOLOGY AND GENETICS OF FAMILIAL HYPERCHOLESTEROLEMlA
In the early 1970s Brown and Goldstein4 determined that persons with homozygous FH had A SYMPOSIUM:
FAMILIAL
HYPERCHOLESTEROLEMIA
iD
defective LDL receptor activity that resulted in reduced LDL catabolism; to date, > 150 mutations have been identified at a single locus on chromosome 19. These mutations cause a variety of defects in LDL receptor function, including impaired synthesis, transport to the cell surface, binding and clustering at the cell surface, and degradation. Different defects resulting from the affected allele and function of the LDL receptors produced by the nonaffected allele probably account for much of the phenotypic heterogeneity in LDL levels observed in persons with hFH. In most geographic regions, receptor mutations among cases from different families bear no relation to each other. In certain populations, however, such as the French-Canadian, Lebanese, and South African Afrikaner populations, most of the cases can be accounted for by a few mutations because of the endogamy that occurred among the relatively isolated original settlers and their descendants who carried the mutations.5 Much can be learned about the phenotypic expression of different mutations from these populations. Concentrations of families with FH in a geographic area may also influence the efficiency of case-finding. Among persons with FH, LDL levels are heterogeneous and may be modified by the presence of other genes, such as those that determine LDL suppression and apolipoprotein E phenotype. Some LDL modulation may be caused by nonnuclear inheritance.6 High density lipoprotein and lipoprotein(a) levels may also modify the risk for atherosclerosis in persons with FH.7,8 Age, male gender, and smoking are associated with significantly increased risk of coronary artery disease in persons with FH,9 but the impact of other risk factors has not generally been well characterized. Recommendations: Important areas of research in the pathophysiology of hFH include the relation between specific mutations and phenotypes, how FH mutations interact with other modulating genes, the role of traditional cardiovascular disease risk factors in persons with hFH, and how some LDL receptor defects may cause only moderate hypercholesterolemia, not characterized as classic hFH. Better techniques need to be developed for diagnosis of hFH and determination of associated cardiovascular disease risk, by characterizing individual genotypes and determining biochemical and arterial effects of hFH. DIAGNOSIS AND CASE-FINDING The diagnosis of an isolated case of hFH is based on identification of high LDL levels and PD
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
72
evidence of an autosomal dominant mode of inheritance. The average total cholesterol in an adult with hFH is 360 mg/dL, with a range of approximately 250-550 mg/dL.9 Before making the diagnosis, secondary causes of hypercholesterolemia should be ruled out. Among the most common secondary causes are hypothyroidism and proteinuria. Xanthomas are present in approximately 70% of persons with hFH after age 20 years.lO Tendon xanthomas are virtually pathognomonic for FH.” Familial combined hyperlipoproteinemia is more common than hFH-from 1 in 100 to 1 in 50. However, the pattern of inheritance is not as distinct as hFH. There is limited information, particularly in the United States, on what proportion of persons with hFH are being appropriately identified. Data from review of medical records of persons with high cholesterol in primary care settings have shown that family screening rarely takes place.12 This suggests that testing of family members of persons with hypercholesterolemia, critical in the diagnosis of FH in families, is lacking. In a survey of close relatives of known hFH index cases, <33% of persons who reported cholesterol levels meeting criteria for hFH had been given the diagnosis of hFH by their physicians. l3 Of these adults, <50% were receiving medications, and <25% had received sufficient treatment to lower cholesterol below the 90th percentile for their age. Other surveys have found that only about half of adults have ever had their cholesterol checked.12J4 This suggests that case identification could be improved through increased testing of family members of suspected cases and, possibly, increased population screening. hFH meets the World Health Organization criteria for a worthwhile screening program, which include the ability to detect the condition in the preclinical phase, the existence of an accurate, acceptable test, and an accepted and effective treatment. Screening for hFH can be accomplished in the context of existing screening approaches for high cholesterol. The National Cholesterol Education Program (NCEP) has recommended that all persons over age 20 years have their cholesterol checked and that familial disorders be considered as a cause of hypercholesterolemia, including testing first degree relatives if a genetic etiology is suspected.15The NCEP Pediatric Panel has recommended testing children of adults who have evidence of premature coronary artery disease16 or total cholesterol >240 mg/dL, an approach that increases the probability of identifying persons
SEPTEMBER
30, 1993
with hypercholesterolemia that has a strong genetic basis. hFH is different from polygenic hypercholesterolemia in several respects that alter the usual approach to identification and management. First, it is less common than polygenic hyperlipidemia or familial combined hyperlipidemia. Thus, population-based screening for hFH, per se, is relatively inefficient. Second, it is an autosomal dominant disorder. This necessitates the testing of family members to establish the diagnosis and the provision of appropriate genetic counseling for affected individuals. Third, children are affected and should be treated as outlined by the Pediatric Panel of the NCEP.lh Fourth, the therapeutic approaches are usually different than for more common forms of hypercholesterolemia. For example, obesity is common in familial combined and polygenic hypercholesterolemia, and weight loss may achieve significant reductions in LDL. However, obesity is relatively uncommon in hFH, and weight reduction is less effective and should not be relied on as mainline treatment. The marked excess of coronary artery disease mortality among young adults with hFH (standardized mortality ratio, 9,686 among 20-39 year olds)* suggests that this form of hypercholesterolemia confers a higher risk for coronary disease than other forms. Whether this increased risk is due to the longer exposure to LDL, essentially since birth, or from other factors needs to be better evaluated. Experience from Utah suggests that tracing hFH through families is a highly efficient method of case ascertainment. The probability of hFH, given a high cholesterol value, increases dramatically once a family member with hFH is identified.13 For example, at a total cholesterol of 310 mg/dL, only 4% of adults from the general population will have hFH, whereas among first degree relatives of a person with hFH, 95% of persons with a level of 310 mg/dL will have hFH.r3 In British Columbia, a program has been developed to train physicians and support family screening for hFH.r’ This approach has been highly successful in identifying persons with hFH and may serve as a model for other communities. Recommendations: Screening and identification programs should integrate population-based screening of cholesterol, family screening and pedigree analysis, and investigation of patients and the families of patients with premature coronary heart disease. The medical care system needs to assure that appropriate family screening is conducted, that persons with hFH are provided with accurate
diagnoses and appropriate counseling, and that they are managed appropriately. Minimum cutpoints for pedigree analysis should be established and promoted as part of national screening recommendations. The main rationale for emphasizing this approach to the detection of hFH are the potential relative efficiency of pedigree analysis, to assure that persons with hFH are identified early in life, and to provide an opportunity for genetic counseling. MEDICAL MANAGEMENT OF hFH The primary care practitioner, by practical and economic necessity, is frequently the first clinician to encounter a new case of hFH, although he or she may fail to recognize it as such. There is currently no tested or accepted algorithm for determining who should assume clinical responsibility for persons with hFH. It is likely that health care providers with different areas of expertise may need to be involved, depending on the severity of the hyperlipidemia, the presence of atherosclerotic complications, and the need for genetic counseling.18According to 1989 NCEP guidelines, if routine drug treatment does not achieve optimal LDL levels, referral to or consultation with a lipid specialist should be considered. The physician with primary responsibility needs to be constantly aware of the potential for premature atherosclerosis. For early detection and management of cardiovascular disease complications, a cardiologist should be involved in the management. Because of high risk a priori for coronary atherosclerosis, some FH experts recommend periodic treadmill electrocardiograms and subsequent tests for asymptomatic middle-aged patients with hFH. Other physicians follow routine guidelines, relying mainly on angina to prompt the need for testing. Studies are needed in large numbers of hFH patients to determine which approach is best for hFH. Nutritionists play a very important role in dietary counseling of persons with hFH and even homozygous FH. Substantial LDL lowering is achievable with dietary manipulation. Other dietary factors may be important in hFH, including dietary antioxidants and monounsaturated fatty acid composition. l9 Dietary treatment of FH should be conducted in the context of the family in order to optimize success. Bile acid sequestrants, nicotinic acid, and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are all effective in lowering LDL cholesterol in persons with hFH; however, HMGCoA reductase inhibitors tend to achieve the A SYMPOSIUM: FAMILIAL HYPERCHOLESTEROLEMIA
3D
greatest lowering of LDL. Costs and side effects must be taken into account when prescribing a drug regimen. Combination therapy of 2 or 3 agents in low or moderate doses appears to offer the most cost-effective and side effect-free therapy.20 Combination therapy with 2 or 3 drugs at high or maximal doses is often required for those with severe FH and can achieve a 50-60% reduction in LDL cholesterol.2o A variety of more extreme nonpharmacologic approaches have been successful in lowering very high LDL cholesterol levels in conjunction with aggressive drug therapy, but these are generally reserved for persons with homozygous FH. These include LDL apheresis, portacaval shunts, intestinal bypass of the terminal ileum, liver transplant, and autologous transplantation of genetically altered hepatocytes.21 Recommendations: Primary care physicians, by practical necessity, are usually the first clinicians to encounter individuals or families with unsuspected hFH. These practitioners need appropriate education to enable them to suspect the possibility of a genetic disorder, to investigate the family, to make the diagnosis, and to institute appropriate dietary and pharmacologic therapy both in the patient and other affected family members. If appropriate reductions in LDL cholesterol are not achieved in a reasonable period of time, practitioners should be encouraged to consult with or refer patients to physicians with expertise in management of hFH. The establishment of a network of such specialists should be considered to assure a readily identifiable referral source. Biochemical and other parameters, such as age, gender, high density lipoprotein, lipoprotein(a), smoking status, and blood pressure status should be used to determine cardiovascular risk status. However, research is needed to help better determine risk, including quantification of atherosclerosis before it becomes clinically manifest. Similarly, methods should be identified to help monitor the effects of therapy to lower LDL and control other risk factors. More data are needed on the cost effectiveness of different drug regimens and on diet-drug interactions. More extreme methods such as LDL apheresis are generally reserved for homozygotes or the few heterozygotes with extremely high LDL levels. Long-term follow-up of persons who received portacaval shunting for FH would be worthwhile to evaluate better the effectiveness and complications of this treatment. The cost effectiveness of LDL apheresis and its role in specific FH subgroups, such as those with increased lipopro4D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72
tein(a) or early aggressive coronary disease, should also be examined, although its uses will be more limited. Gene therapy research could offer lasting and effective therapy to homozygotes, but broader application of this approach requires much further development. PSYCHOLOGICAL, ECONOMIC, AND ETHICAL CONSIDERATIONS IN hFH MANAGEMENT Understanding the genetics of hFH and knowledge of its risks brings a special set of issues to the fore, which society may encounter increasingly as we discover the genetic basis for other disorders. hFH shares with other chronic conditions issues of adherence to complicated and life-style-altering regimens. However, little is understood about the psychologic impact of the diagnosis and treatment of hFH on the affected individual and on affected and unaffected family members. A particularly troublesome problem in the United States arises in the use of risk assessment as the basis for access to medical coverage or for assigning rates for health, life, and disability insurance. This raises questions about how screening tests might be applied, who should gain access to the information, and how the information is used.22 Paradoxically, some of the people insurance was originally designed to help are increasingly denied accessto coverage. Primary prevention of coronary artery disease in persons with hFH (based on single drug therapy) has been projected to have very favorable costeffectiveness ratios, including cost savings in certain subgroups. 23 It was found to be more cost effective than treatment of polygenic hypercholesterolemia. Cost effectiveness is less favorable (i.e., higher cost per year of life saved), both as the cost of intervention increases and in women than in men, and improves in the presence of other risk factors (because the risk of a subsequent event increases).23 Recommendations: Research is needed to understand better what factors determine adherence to lifelong regimens that significantly alter life-style and to develop approaches to improve adherence to treatment of hFH. Research is needed to understand the psychologic impacts of the knowledge of having hFH and how this affects family members and relations within the family. The high cost of lifelong therapy to prevent complications of hFH offers a substantial challenge to society in attempting to assure access to care for affected persons. Cost-effectiveness models of LDL lowering make important objective contributions to the debate
SEPTEMBER 30, 1993
over health care policy and should be considered in the formation of treatment recommendations. REFERENCES 1 Motulsky AG. Genetic aspects of familial hypercholesterolemia and its diagnosis. ArfeSosc&msis 1989;9(1 Suppl):l%‘l. 2. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolemia. BMI 1991;303:89?-896. 3. Illingworth DR, Bacon S. Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs. Alteriosclemis 1989;9( 1 Suppl):I121-134. 4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986,232:3ti7. 5. Davignon J, Roy M. Familial hypercholesterolemia in French Canadians: tak ing advantage of the presence of a “founder effect.” Am J Cardio11993;72:~10. 6. Hoeg JM. Homozygous familial hypercholesterolemia: a paradigm for phenotypic variation. Am J Cam?01 1993;72:11-14. 7. Streja D, Steiner G, Kwiterovich PO Jr. Plasma high-density lipoproteins and ischemic heart disease: studies in a large kindred with familial hypercholesterolemia. Am Intern Med 1978;89:871%30. 8. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson G, BoerwinkIe E. Utermann G. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypcrcholesterolemia. NE@ J Med 1990,322:1494-1499. 9. Stone NJ, Ley RI, Frederickson DS, Verter J. Coronary artery disease in 116 kindreds with familial type II hypxlipoproteinemia. Circularion 1974;49:476 488. 10. Kwiterotich PO, Frederickson DS, Lev RI. Familial hypercholesteremia (one form of familial type II hyperbetacholesterolaemia): a study of its biochemical, genetic, and clinical presentation in childhood. J Clin hat 1974;53:12371249.
ll. Goldstein JL Brown MS. Familial hypercholesterolemia.In: Sctiver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1989:1215-X250. 12. Pearson TA Diagnosis and case-finding in familial hypcrcholesterolemia: overview of issues. Am .I Car&l 1993;72:15-17. 13. Williams RR, Schumacher MC, Barlow GK, Hunt SC, Ware JL, Pratt M, Latham BD. Documented need for more effective diagnwis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah. Am J Cardiol 1993;72:&24. iA Census Bureau. Current Population Survey (unpublished data). 15. National Cholesterol Education Program. Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. US. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 8%2925, January 1989. 16. American Academy of Pediatrics. National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pedi&cs 1992;89:515-584. 17. Hayden MR, Josephson R. Development of a program for identification of patients with familial hypercholesterolemia in British Columbia: a model for prevention of coronary disease. Am J Cardiol1993;72:25-29. l.8. Schonfeld G. Who should treat familial hypercholesterolemia? Am J Cardial 1993;72:3Hl. 19. Connor WE, Connor SL. Importance of diet in the treatment of familial hypercholesterolemia. Am J Cardiol 19937242-53. 20. Illingworth DR. How effective is drug therapy in heterozygous familial hypercholesterolemia? Am J Cardi 1993;72:54-58. 21 Wilson JM, Grossman M. Therapeutic strategies for familial hypercholesterolemia based on somatic gene transfer. Am J Car&‘01 1993;72:59-63. 22. Murray TH. Ethics, genetic prediction, and heart disease. Am J Cardi 1993;72:80+%. 23. Goldman L, Goldman PA, Williams LW, Weinstein MC. Cost-effectiveness considerations in the treatment of heterozygous familial hypercholesterolemia with medications. Am J Cardiol1993;72:75-79.
A SYMPOSIUM:
FAMILIAL
HYPERCHOLESTEROLEMIA
5D