- Email: [email protected]
Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: The reply
Letters to the Editor
mains unclear (1). Organisms with unusual virulence characteristics, such as transparent colony type, agglutinability with wheat germ lectin, and proline auxotype, are associated with an increased risk of dissemination (1–3). These characteristics, however, are not good distinguishing markers of virulence in gonococcal meningitis (2,3). All studied isolates from gonococcal meningitis have been sensitive to penicillin (3), and no relapses or major neurological sequelae have been reported after adequate treatment. Ali Mofredj, MD Jacques Robin Rakotondrantoanina, MD Daoud Baraka, MD Yves Madec, MD Service de Re´animation Patrice Lemaitre, MD Laboratoire de Microbiologie Hoˆpital Laennec Creil, France 1. Ross JDC. Systemic gonococcal infection. Genitourin Med. 1996;72:404 – 407. 2. Del Rio C, Stephens DS, Knapp JS, et al. Comparison of isolates of Neisseria gonorrhoeae causing meningitis and report of gonococcal meningitis in a patient with C8 deficiency. J Clin Microbiol. 1989;27:1045– 1049. 3. Rice RJ, Schalla WO, Whittington WL, et al. Phenotypic characterization of Neisseria gonorrhoeae isolated from three cases of meningitis. J Infect Dis. 1986;153:362–365. 4. Holmes KK, Counts GW, Beaty HN. Disseminated gonococcal infection. Ann Intern Med. 1971;74:979 –993. 5. Leads from the MMWR. Disseminated gonococcal infections and meningitis— Pennsylvania. JAMA. 1984;251:1943–1944. 6. Sayeed ZA, Bhaduri U, Howell E, Meyers HL. Gonococcal meningitis. A review. JAMA. 1972;219:1730 –1731. 7. Henderson G, Ritchie WT. Gonococcal meningitis. Rev Neurol Psychiatr. 1909;7: 75– 87. 8. Smith D. Gonococcal meningitis. Lancet. 1922;1:1217. 9. Branham SE, Mitchell RH, Brainin W. Gonococcic meningitis. JAMA. 1938;110: 1804 –1806. 10. Peterson BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med. 1979;90:917–920.
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July 2000
EFFECTS OF DIETARY PHYTOSTEROLS ON CHOLESTEROL METABOLISM AND ATHEROSCLEROSIS To the Editor: I read the interesting review about the effects of dietary plant sterols on cholesterol metabolism and atherosclerosis (1). Another adverse effect of these compounds that has implications for public health should be mentioned. Plant-sterol– enriched margarines are now widely available, and it has been suggested that these spreads be consumed regularly for their cholesterol-lowering effects (2). Although these margarines, in doses recommended for consumption, decrease low-density-lipoprotein (LDL) cholesterol levels by about 10%, they also decrease serum lycopene and alphaand beta-carotene levels by 20% (3,4). This occurs because plant sterols interfere with the intestinal absorption of dietary carotenoids. Serum lycopene levels are inversely associated with atherosclerosis (5) and many cancers (6). Therefore, from a public-health perspective, long-term intake of plant-sterol– enriched margarines may increase the risk of atherosclerosis and some cancers. Is the benefit of lowering LDLcholesterol levels by 10% worth the risk of lowering carotenoid levels by 20%? These uncertainties will be best resolved by properly designed trials. Until then, perhaps we should use these spreads in moderation. Mark R. Goldstein, MD West Chester, Pennsylvania 1. Moghadasian MH, Frohlich JJ. Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence. Am J Med. 1999;107:588 – 594. 2. Cholesterol cutters. Consumer Reports. 1999:9. 3. Weststrate JA, Meijer GW. Plant sterol-en-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109
1 LINE SHORT
riched margarines and reduction of plasma total and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1998;58:334 –343. 4. Hendriks HFJ, Westetrate JA, van Vliet T, Meijer GW. Spreads enriched with these different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53:319 –327. 5. Klipstein-Grobusch K, Launer U, Geleijnse JM, et al. Serum carotenoids and atherosclerosis: the Rotterdam Study. Atherosclerosis. 2000;148:49 –56. 6. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–331.
The Reply: We thank Dr. Goldstein for his letter stressing the importance of the public health perspective and possible risks associated with plant-sterol– enriched food products. We agree that there are many remaining questions, and some of them concern the possible interference of plant sterols with the absorption of antioxidant vitamins. However, the associations of serum levels of carotenoids with atherosclerosis and cancer are not clear (1–5). Similarly, only a nonsignificant (P ⫽ 0.13) inverse correlation between serum lycopene levels and the risk of aortic atherosclerosis was observed by Klipstein-Grobusch et al (6); this was assessed in only a subgroup of patients. As the serum levels of carotenoids, including lycopene, depend upon several factors, including dietary habits (7), smoking (1), and alcohol consumption (8), it is hard to evaluate observational data that have not been adjusted for these variables (9,10). Furthermore, in a study by Hendriks et al (9), consumption of phytosterol was not associated with a significant decrease in lipidstandardized serum lycopene levels. Nevertheless, as we suggested in our review (11) and Dr. Goldstein reemphasized, properly designed clinical
Letters to the Editor
trials should be carried out to resolve these issues. Jiri J. Frohlich, MD Mohammed H. Moghadasian, DVM, MSc, PhD University of British Columbia St. Paul’s Hospital Vancouver, British Columbia, Canada 1. Street DA, Comstock GW, Salkeld RM, et al. Serum antioxidant and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation. 1994;90: 1154 –1161. 2. Slattery ML, Benson J, Curtin K, et al. Carotenoids and colon cancer (1). Am J Clin Nutr. 2000;71:575–582. 3. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–331. 4. Kritchevsky SB. Beta-carotene, carotenoids and the prevention of coronary heart disease. J Nutr. 2000;130 (suppl 1S): 5– 8. 5. Albanes D. Beta-carotene and lung cancer: a case tudy. Am J Clin Nutr. 1999;69: 1345S–1350S. 6. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, et al. Serum carotenoids and atherosclerosis. The Rotterdam study. Atherosclerosis. 2000;148:49 –56. 7. Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997; 66:116 –122. 8. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69:1071–1085. 9. Hendiks HFJ, Weststrate JA, van Vliet T, Meijer GW. Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53:319 –327. 10. Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1998;52:334 –343. 11. Moghadasian MH, Frohlich JJ. Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence. Am J Med. 1999;107: 588 –594.
SWEET’S SYNDROME AS A LIFE-THREATENING DERMATOSIS Letter to the Editor: A 38-year-old man presented to the emergency department with a fever and a painful skin lesion on his left shoulder. On physical examination, he appeared seriously ill, with a temperature of 39⬚C, a pulse rate of 120 beats per minute, and blood pressure of 100/60 mm Hg. The plaque on his shoulder was edematous and erythematous, and measured 10 cm in maximum diameter. Laboratory studies revealed a hemoglobin level of 8.6 g/dL, a leukocyte count of 22 ⫻ 109/L, a platelet count of 60 ⫻ 109/L, and a serum creatinine level of 4.2 mg/dL. The patient was admitted to the intensive care unit because of presumed sepsis, and the lesion was surgically debrided (Figure 1). Histologic examination showed dermal necrosis, thought to be consistent with necrotizing cellulitis, although skin and blood cultures were negative. His renal function improved during the next 72 hours, but his leukocyte count remained elevated. A bonemarrow examination showed myeloid hyperplasia with dysplasia. Seven days after admission, the patient began to develop painful, purple-red plaques on the face, right shoulder, arms, and trunk (Figure 2). His leukocyte count was 40 ⫻ 109/L without neutrophilia. A skin biopsy specimen showed a neutrophilic dermal infiltrate without vasculitis. A diagnosis of Sweet’s syndrome was made. The skin lesions resolved spontaneously, but 2 weeks later the patient developed new lesions in both retroauricular folds, showing Ko¨bner’s phenomenon. Treatment with prednisone was initiated, to which the patient responded. Three months after admission, a new bone-marrow evaluation was consistent with acute myeloid leukemia (FAB M5b). Che-
July 2000
1 LINE SHORT
Figure 1. Granulomatous tissue on the left shoulder 1 week after surgical debridement.
motherapy was started, but the patient died of fulminant sepsis during treatment. Sweet’s syndrome is a neutrophilic dermatosis characterized by fever, neutrophilia, acute onset of erythematous and edematous plaques, and a neutrophilic dermal infiltrate without vasculitis (1). Extracutaneous manifestations involving the lungs, liver, and kidneys have also been described (2,3). The differential diagnosis includes erythema multiforme, cellulitis, and disseminated vesiculopustular forms of pyoderma gangrenosum (4). Associated malignancies, the majority of which are hematologic (5), are found in approximately 15% of patients. In contrast to the classic form of Sweet’s syndrome, patients with malignancies are predominantly men with otherwise unexplained anemia, no neutrophilia, more severe cutaneous lesions, more frequent extracutaneous involvement, and a high rate of disease recurrence (2,3). Because of the abrupt onset and severity of our patient’s symptoms, we initially treated him for sepsis second-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 73
mains unclear (1). Organisms with unusual virulence characteristics, such as transparent colony type, agglutinability with wheat germ lectin, and proline auxotype, are associated with an increased risk of dissemination (1–3). These characteristics, however, are not good distinguishing markers of virulence in gonococcal meningitis (2,3). All studied isolates from gonococcal meningitis have been sensitive to penicillin (3), and no relapses or major neurological sequelae have been reported after adequate treatment. Ali Mofredj, MD Jacques Robin Rakotondrantoanina, MD Daoud Baraka, MD Yves Madec, MD Service de Re´animation Patrice Lemaitre, MD Laboratoire de Microbiologie Hoˆpital Laennec Creil, France 1. Ross JDC. Systemic gonococcal infection. Genitourin Med. 1996;72:404 – 407. 2. Del Rio C, Stephens DS, Knapp JS, et al. Comparison of isolates of Neisseria gonorrhoeae causing meningitis and report of gonococcal meningitis in a patient with C8 deficiency. J Clin Microbiol. 1989;27:1045– 1049. 3. Rice RJ, Schalla WO, Whittington WL, et al. Phenotypic characterization of Neisseria gonorrhoeae isolated from three cases of meningitis. J Infect Dis. 1986;153:362–365. 4. Holmes KK, Counts GW, Beaty HN. Disseminated gonococcal infection. Ann Intern Med. 1971;74:979 –993. 5. Leads from the MMWR. Disseminated gonococcal infections and meningitis— Pennsylvania. JAMA. 1984;251:1943–1944. 6. Sayeed ZA, Bhaduri U, Howell E, Meyers HL. Gonococcal meningitis. A review. JAMA. 1972;219:1730 –1731. 7. Henderson G, Ritchie WT. Gonococcal meningitis. Rev Neurol Psychiatr. 1909;7: 75– 87. 8. Smith D. Gonococcal meningitis. Lancet. 1922;1:1217. 9. Branham SE, Mitchell RH, Brainin W. Gonococcic meningitis. JAMA. 1938;110: 1804 –1806. 10. Peterson BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med. 1979;90:917–920.
72
July 2000
EFFECTS OF DIETARY PHYTOSTEROLS ON CHOLESTEROL METABOLISM AND ATHEROSCLEROSIS To the Editor: I read the interesting review about the effects of dietary plant sterols on cholesterol metabolism and atherosclerosis (1). Another adverse effect of these compounds that has implications for public health should be mentioned. Plant-sterol– enriched margarines are now widely available, and it has been suggested that these spreads be consumed regularly for their cholesterol-lowering effects (2). Although these margarines, in doses recommended for consumption, decrease low-density-lipoprotein (LDL) cholesterol levels by about 10%, they also decrease serum lycopene and alphaand beta-carotene levels by 20% (3,4). This occurs because plant sterols interfere with the intestinal absorption of dietary carotenoids. Serum lycopene levels are inversely associated with atherosclerosis (5) and many cancers (6). Therefore, from a public-health perspective, long-term intake of plant-sterol– enriched margarines may increase the risk of atherosclerosis and some cancers. Is the benefit of lowering LDLcholesterol levels by 10% worth the risk of lowering carotenoid levels by 20%? These uncertainties will be best resolved by properly designed trials. Until then, perhaps we should use these spreads in moderation. Mark R. Goldstein, MD West Chester, Pennsylvania 1. Moghadasian MH, Frohlich JJ. Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence. Am J Med. 1999;107:588 – 594. 2. Cholesterol cutters. Consumer Reports. 1999:9. 3. Weststrate JA, Meijer GW. Plant sterol-en-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109
1 LINE SHORT
riched margarines and reduction of plasma total and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1998;58:334 –343. 4. Hendriks HFJ, Westetrate JA, van Vliet T, Meijer GW. Spreads enriched with these different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53:319 –327. 5. Klipstein-Grobusch K, Launer U, Geleijnse JM, et al. Serum carotenoids and atherosclerosis: the Rotterdam Study. Atherosclerosis. 2000;148:49 –56. 6. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–331.
The Reply: We thank Dr. Goldstein for his letter stressing the importance of the public health perspective and possible risks associated with plant-sterol– enriched food products. We agree that there are many remaining questions, and some of them concern the possible interference of plant sterols with the absorption of antioxidant vitamins. However, the associations of serum levels of carotenoids with atherosclerosis and cancer are not clear (1–5). Similarly, only a nonsignificant (P ⫽ 0.13) inverse correlation between serum lycopene levels and the risk of aortic atherosclerosis was observed by Klipstein-Grobusch et al (6); this was assessed in only a subgroup of patients. As the serum levels of carotenoids, including lycopene, depend upon several factors, including dietary habits (7), smoking (1), and alcohol consumption (8), it is hard to evaluate observational data that have not been adjusted for these variables (9,10). Furthermore, in a study by Hendriks et al (9), consumption of phytosterol was not associated with a significant decrease in lipidstandardized serum lycopene levels. Nevertheless, as we suggested in our review (11) and Dr. Goldstein reemphasized, properly designed clinical
Letters to the Editor
trials should be carried out to resolve these issues. Jiri J. Frohlich, MD Mohammed H. Moghadasian, DVM, MSc, PhD University of British Columbia St. Paul’s Hospital Vancouver, British Columbia, Canada 1. Street DA, Comstock GW, Salkeld RM, et al. Serum antioxidant and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation. 1994;90: 1154 –1161. 2. Slattery ML, Benson J, Curtin K, et al. Carotenoids and colon cancer (1). Am J Clin Nutr. 2000;71:575–582. 3. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–331. 4. Kritchevsky SB. Beta-carotene, carotenoids and the prevention of coronary heart disease. J Nutr. 2000;130 (suppl 1S): 5– 8. 5. Albanes D. Beta-carotene and lung cancer: a case tudy. Am J Clin Nutr. 1999;69: 1345S–1350S. 6. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, et al. Serum carotenoids and atherosclerosis. The Rotterdam study. Atherosclerosis. 2000;148:49 –56. 7. Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997; 66:116 –122. 8. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69:1071–1085. 9. Hendiks HFJ, Weststrate JA, van Vliet T, Meijer GW. Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53:319 –327. 10. Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1998;52:334 –343. 11. Moghadasian MH, Frohlich JJ. Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence. Am J Med. 1999;107: 588 –594.
SWEET’S SYNDROME AS A LIFE-THREATENING DERMATOSIS Letter to the Editor: A 38-year-old man presented to the emergency department with a fever and a painful skin lesion on his left shoulder. On physical examination, he appeared seriously ill, with a temperature of 39⬚C, a pulse rate of 120 beats per minute, and blood pressure of 100/60 mm Hg. The plaque on his shoulder was edematous and erythematous, and measured 10 cm in maximum diameter. Laboratory studies revealed a hemoglobin level of 8.6 g/dL, a leukocyte count of 22 ⫻ 109/L, a platelet count of 60 ⫻ 109/L, and a serum creatinine level of 4.2 mg/dL. The patient was admitted to the intensive care unit because of presumed sepsis, and the lesion was surgically debrided (Figure 1). Histologic examination showed dermal necrosis, thought to be consistent with necrotizing cellulitis, although skin and blood cultures were negative. His renal function improved during the next 72 hours, but his leukocyte count remained elevated. A bonemarrow examination showed myeloid hyperplasia with dysplasia. Seven days after admission, the patient began to develop painful, purple-red plaques on the face, right shoulder, arms, and trunk (Figure 2). His leukocyte count was 40 ⫻ 109/L without neutrophilia. A skin biopsy specimen showed a neutrophilic dermal infiltrate without vasculitis. A diagnosis of Sweet’s syndrome was made. The skin lesions resolved spontaneously, but 2 weeks later the patient developed new lesions in both retroauricular folds, showing Ko¨bner’s phenomenon. Treatment with prednisone was initiated, to which the patient responded. Three months after admission, a new bone-marrow evaluation was consistent with acute myeloid leukemia (FAB M5b). Che-
July 2000
1 LINE SHORT
Figure 1. Granulomatous tissue on the left shoulder 1 week after surgical debridement.
motherapy was started, but the patient died of fulminant sepsis during treatment. Sweet’s syndrome is a neutrophilic dermatosis characterized by fever, neutrophilia, acute onset of erythematous and edematous plaques, and a neutrophilic dermal infiltrate without vasculitis (1). Extracutaneous manifestations involving the lungs, liver, and kidneys have also been described (2,3). The differential diagnosis includes erythema multiforme, cellulitis, and disseminated vesiculopustular forms of pyoderma gangrenosum (4). Associated malignancies, the majority of which are hematologic (5), are found in approximately 15% of patients. In contrast to the classic form of Sweet’s syndrome, patients with malignancies are predominantly men with otherwise unexplained anemia, no neutrophilia, more severe cutaneous lesions, more frequent extracutaneous involvement, and a high rate of disease recurrence (2,3). Because of the abrupt onset and severity of our patient’s symptoms, we initially treated him for sepsis second-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 73