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Systemic lupus erythematosus: a combined deficiency disease
Medical Hypotheses (2004) 62, 922–924
http://intl.elsevierhealth.com/journals/mehy
Systemic lupus erythematosus: a combined deficiency disease Lit-Hung Leung1 Department of General Surgery, Hong Kong Central Hospital, Hong Kong Received 12 July 2003; accepted 23 January 2004
Summary To date, the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. By critically analyzing clinical facts and laboratory data, a hypothesis is proposed: drug-induced lupus erythematosus (DILE) is linked to a deficiency in Coenzyme A (CoA) that is secondary to a deficiency in pantothenic acid. This hypothesis is used to explain the high incidence of SLE in females, the role of sex hormones in this disease and the mechanism underlying a flare. The actions of anti-malarials and steroids are also discussed. The protean clinical presentation of SLE is attributed to co-existing deficiencies of dietary factors in addition to pantothenic acid. Contributing factors to these deficiencies may include increased nutritional requirements resulting from gene mutations. Treatment is replacement therapy with doses of pantothenic acid that is hundreds of times higher than that of the Dietary Reference Intake (DRI) and other vitamins. Using this method, 12 SLE females were studied with promising results. c 2004 Elsevier Ltd. All rights reserved.
The pathogenesis of SLE has baffled physicians for more than 150 years. More intriguing is its closely related disease, DILE, a condition in which drugs with different chemical structures and pharmaceutical activities give rise to similar symptoms in susceptible individuals [1]. However, it is an analysis of this apparent enigma that forms the basis of the author’s hypothesis regarding the pathogenesis not only of DILE, but also of SLE. When drugs produce comparable symptoms, they most likely share a common property. Here, I would like to use three drugs, namely, procainamide, hydralazine and isoniazid, that cause the Abbreviations: SLE, systemic lupus erythematosus; DILE, drug-induced lupus erythematosus; CoA, Coenzyme A; DRI, dietary reference intake DHEA, dehydroepiandrosterone. 1 Present address: P.O. Box 422, Bryn Mawr, PA 19010, USA. E-mail address: [email protected].
majority of cases of DILE to illustrate my point. Once ingested, these drugs are all metabolized via acetylation, a process requiring the participation of CoA, of which pantothenic acid, a vitamin, is a component. Vitamins, as coenzymes in metabolism, are prone to losses and require replenishment. This loss is in some ways tied to the amount of work they do. If the replenishment of a vitamin does not match that of its loss, deficiency of the vitamin would slowly become evident, giving rise to clinical symptoms. Therefore, in such drug-induced acetylation, the increased demand for CoA, and hence pantothenic acid, might entail a deficiency of the vitamin. This explains the delayed onset of clinical DILE. Stop the drug, the increased demand ends and the symptoms gradually subside, as seen in clinical practice. While the metabolism of other DILE drugs might not directly involve CoA, reactions along their
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.01.017
Systemic lupus erythematosus metabolic pathways may require the coenzyme, leading to its eventual deficiency. Admittedly, this is uncommon, but so are the incidences of DILE of these drugs [2]. If DILE is associated with a deficiency in pantothenic acid, is SLE similarly so? Evidence is to suggest that it is. One of the most puzzling aspects of SLE is its sex incidence. During the reproductive period, the female incidence gradually outnumbers that of the male [3]. This phenomenon can be explained by this deficiency theory. Data in the literature show that in the interval of one menstrual cycle, a female secretes more sex hormones in her preparation for the fertilized ovum’s implantation than her male counterpart [4]. A larger amount of sex hormones produced means a bigger demand/loss of CoA, which is also required in the synthesis of cholesterol, the backbone on which all sex hormones are built. Thus, females are more prone to pantothenic acid deficiency. As a woman matures from puberty to menopause, the tendency for such a deficiency increases with every menstrual cycle that passes. Clinically, more females succumb to the disease process, widening the sex incidence as they advance into middle age. The human body responds to this mounting deficiency by cutting back on any work that CoA does. This is borne out by SLE patients’ low sex hormones levels, even at the prompting of an increased amount of follicle-stimulating hormone and luteinizing hormone [5,6]. The female SLE patients also tend to have late menarche, irregular menses, amenorrhea, and early menopause, all of which effectively trim down sex hormone production [7]. Serum cortisol and dehydroepiandrosterone (DHEA) levels are also low. These findings also provide insight into the empirical use of steroids and the antimalarials in SLE. Both drugs provide a CoA-sparing effect. Steroids relieve the continuous glucocorticoid production effort whereas anti-malarials share with CoA’s lipid lowering effect. It seems only too probable that part of DHEA’s effect is also based on this. Its prefabricated steroidal structure bypasses the intermediate steps in steroid synthesis. Increased demand for CoA during premenstrual periods and times of stress causes more frequent relapses in SLE patients, an observation that also supports this deficiency theory [8]. Interestingly, the connective tissues and non-vital organs are often first affected in the SLE disease process while the vital organs later. This further lends credence to the deficiency theory. If SLE patients are deficient in pantothenic acid, are they not likely to have deficiencies of other essential nutrients? A deficiency in a single vitamin
923 should give rise to more consistent symptoms. Protean symptoms could arise if there were multiple deficiencies. Deficiencies in different combinations of nutrients in varying degrees would give a clinical picture that is as unpredictable as in SLE. It is reasonable to suggest that SLE is a combined deficiency disease whose main deficiency is pantothenic acid. This theory becomes more convincing if deficiency is not seen solely as an insufficient intake, but rather nutritional requirements, altered by factors that include genetic variation and mutation, that are many times more than what are recognized as normal [9]. It was estimated that the requirement of vitamin C might vary through a range of 80-folds in humans, a viewpoint that goes well with the concept of biochemical individuality [10,11]. It has been reported that the Michaelis constants of enzymes increase with a decreased binding affinity for their respective coenzymes as a result of mutation of genes, commonly occurred as a singlenucleotide polymorphism [12]. Such reduced coenzyme binding can decrease the enzymatic activity by as much as 150-folds. This can be remedied by raising the concentration of cellular coenzyme level by administering high dose of the corresponding vitamin. This is best summed up by Pauling [12]: “This mechanism of action of gene mutation is only one of several that leads to disadvantageous manifestations that could be overcome by an increase, perhaps greatly increase, in the concentration of a vital substance in the body. These conclusions obviously suggest a rationale for megavitamin therapy.” In SLE, whether such single-nucleotide polymorphism exists, or indeed is the main cause for the clinically expressed coenzyme deficiency, remains to be seen. Such rationale was applied to the treatment of SLE patients in a study in which vitamin supplements that were hundreds of times higher than that of the DRI were administered. Pantothenic acid was given at 10 g a day, a dosage also used in the treatment of acne patients [13]. Included in the regimen were 2 g of vitamin C, 500 mg of B1, 200 mg of B6, 2 mg of B12 and two tablets of Super B and two tablets of multivitamins with minerals per day. These additional supplements, as more research is done on the subject, will certainly need to be revised. There were 12 patients, all females aged between 18 and 43. They were followed up for up to 2 years. The results were encouraging. Within four weeks, they all showed a varying degree of improvement, particularly the symptom of fatigue. Later follow-up showed that the incidence of fever was decreased and no major flares were noted. In many cases, the original SLE medications could gradually be reduced.
924 It is true that SLE is a disease whose clinical facts are well established. Unfortunately, these are data that cannot be strung together for want of any identifiable pathological agent. The combined deficiency hypothesis could explain most of the facts and controversies that revolve around the subject, suggesting that this might well be the cause of the disease process. The issue of megavitamin therapy is again raised. Will this hypothesis help to change the viewpoint of conventional medicine? For a full text, please go to www.deficiencydiseases.com.
References [1] Rich MW. Drug-induced lupus. The list of culprits grows. Postgrad Med 1996;100:299–302 [review, 307–308]. [2] Carter JD, Valeriano-Marcet J, Kanik KS, Vasey FB. Antinuclear anti-body-negative, drug induced lupus caused by lisinopril. South Med J 2001;94:1122–3. [3] Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum 1973;3:1–54. [4] Fauci AS, Braunwald E, editors. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 1998. p. 2103.
Leung [5] Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, Giusti M, Piccoli A, Grella P, Gambari PF. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum 2002;47:202–9. [6] Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–8. [7] Pasoto SG, Mendonca BB, Bonfa E. Menstrual disturbances in patients with systemic lupus erythematosus without alkylating therapy: clinical, hormonal and therapeutic associations. Lupus 2002;11:175–80. [8] Ruiz-Irastorza G, Lima F, Alves J, Khamashta MA, Simpson J, Hughes GR, Buchanan NM. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996;35:133–8. [9] Eckhardt RB. Genetic research and nutritional individuality. J Nutr 2001;131:336–9. [10] Linus Pauling. How to live longer and feel better. Avon Books; 1987. p. 106. [11] Williams RJ. Biochemical Individuality. New Canaan, Connecticut: Keats Publishing; 1998. p. 153–184. [12] Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr 2002;75:616–58 [review]. [13] Leung LH. Pantothenic acid deficiency as the pathogenesis of acne vulgaris. Med Hypotheses 1995;44:490–2.
http://intl.elsevierhealth.com/journals/mehy
Systemic lupus erythematosus: a combined deficiency disease Lit-Hung Leung1 Department of General Surgery, Hong Kong Central Hospital, Hong Kong Received 12 July 2003; accepted 23 January 2004
Summary To date, the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. By critically analyzing clinical facts and laboratory data, a hypothesis is proposed: drug-induced lupus erythematosus (DILE) is linked to a deficiency in Coenzyme A (CoA) that is secondary to a deficiency in pantothenic acid. This hypothesis is used to explain the high incidence of SLE in females, the role of sex hormones in this disease and the mechanism underlying a flare. The actions of anti-malarials and steroids are also discussed. The protean clinical presentation of SLE is attributed to co-existing deficiencies of dietary factors in addition to pantothenic acid. Contributing factors to these deficiencies may include increased nutritional requirements resulting from gene mutations. Treatment is replacement therapy with doses of pantothenic acid that is hundreds of times higher than that of the Dietary Reference Intake (DRI) and other vitamins. Using this method, 12 SLE females were studied with promising results. c 2004 Elsevier Ltd. All rights reserved.
The pathogenesis of SLE has baffled physicians for more than 150 years. More intriguing is its closely related disease, DILE, a condition in which drugs with different chemical structures and pharmaceutical activities give rise to similar symptoms in susceptible individuals [1]. However, it is an analysis of this apparent enigma that forms the basis of the author’s hypothesis regarding the pathogenesis not only of DILE, but also of SLE. When drugs produce comparable symptoms, they most likely share a common property. Here, I would like to use three drugs, namely, procainamide, hydralazine and isoniazid, that cause the Abbreviations: SLE, systemic lupus erythematosus; DILE, drug-induced lupus erythematosus; CoA, Coenzyme A; DRI, dietary reference intake DHEA, dehydroepiandrosterone. 1 Present address: P.O. Box 422, Bryn Mawr, PA 19010, USA. E-mail address: [email protected].
majority of cases of DILE to illustrate my point. Once ingested, these drugs are all metabolized via acetylation, a process requiring the participation of CoA, of which pantothenic acid, a vitamin, is a component. Vitamins, as coenzymes in metabolism, are prone to losses and require replenishment. This loss is in some ways tied to the amount of work they do. If the replenishment of a vitamin does not match that of its loss, deficiency of the vitamin would slowly become evident, giving rise to clinical symptoms. Therefore, in such drug-induced acetylation, the increased demand for CoA, and hence pantothenic acid, might entail a deficiency of the vitamin. This explains the delayed onset of clinical DILE. Stop the drug, the increased demand ends and the symptoms gradually subside, as seen in clinical practice. While the metabolism of other DILE drugs might not directly involve CoA, reactions along their
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.01.017
Systemic lupus erythematosus metabolic pathways may require the coenzyme, leading to its eventual deficiency. Admittedly, this is uncommon, but so are the incidences of DILE of these drugs [2]. If DILE is associated with a deficiency in pantothenic acid, is SLE similarly so? Evidence is to suggest that it is. One of the most puzzling aspects of SLE is its sex incidence. During the reproductive period, the female incidence gradually outnumbers that of the male [3]. This phenomenon can be explained by this deficiency theory. Data in the literature show that in the interval of one menstrual cycle, a female secretes more sex hormones in her preparation for the fertilized ovum’s implantation than her male counterpart [4]. A larger amount of sex hormones produced means a bigger demand/loss of CoA, which is also required in the synthesis of cholesterol, the backbone on which all sex hormones are built. Thus, females are more prone to pantothenic acid deficiency. As a woman matures from puberty to menopause, the tendency for such a deficiency increases with every menstrual cycle that passes. Clinically, more females succumb to the disease process, widening the sex incidence as they advance into middle age. The human body responds to this mounting deficiency by cutting back on any work that CoA does. This is borne out by SLE patients’ low sex hormones levels, even at the prompting of an increased amount of follicle-stimulating hormone and luteinizing hormone [5,6]. The female SLE patients also tend to have late menarche, irregular menses, amenorrhea, and early menopause, all of which effectively trim down sex hormone production [7]. Serum cortisol and dehydroepiandrosterone (DHEA) levels are also low. These findings also provide insight into the empirical use of steroids and the antimalarials in SLE. Both drugs provide a CoA-sparing effect. Steroids relieve the continuous glucocorticoid production effort whereas anti-malarials share with CoA’s lipid lowering effect. It seems only too probable that part of DHEA’s effect is also based on this. Its prefabricated steroidal structure bypasses the intermediate steps in steroid synthesis. Increased demand for CoA during premenstrual periods and times of stress causes more frequent relapses in SLE patients, an observation that also supports this deficiency theory [8]. Interestingly, the connective tissues and non-vital organs are often first affected in the SLE disease process while the vital organs later. This further lends credence to the deficiency theory. If SLE patients are deficient in pantothenic acid, are they not likely to have deficiencies of other essential nutrients? A deficiency in a single vitamin
923 should give rise to more consistent symptoms. Protean symptoms could arise if there were multiple deficiencies. Deficiencies in different combinations of nutrients in varying degrees would give a clinical picture that is as unpredictable as in SLE. It is reasonable to suggest that SLE is a combined deficiency disease whose main deficiency is pantothenic acid. This theory becomes more convincing if deficiency is not seen solely as an insufficient intake, but rather nutritional requirements, altered by factors that include genetic variation and mutation, that are many times more than what are recognized as normal [9]. It was estimated that the requirement of vitamin C might vary through a range of 80-folds in humans, a viewpoint that goes well with the concept of biochemical individuality [10,11]. It has been reported that the Michaelis constants of enzymes increase with a decreased binding affinity for their respective coenzymes as a result of mutation of genes, commonly occurred as a singlenucleotide polymorphism [12]. Such reduced coenzyme binding can decrease the enzymatic activity by as much as 150-folds. This can be remedied by raising the concentration of cellular coenzyme level by administering high dose of the corresponding vitamin. This is best summed up by Pauling [12]: “This mechanism of action of gene mutation is only one of several that leads to disadvantageous manifestations that could be overcome by an increase, perhaps greatly increase, in the concentration of a vital substance in the body. These conclusions obviously suggest a rationale for megavitamin therapy.” In SLE, whether such single-nucleotide polymorphism exists, or indeed is the main cause for the clinically expressed coenzyme deficiency, remains to be seen. Such rationale was applied to the treatment of SLE patients in a study in which vitamin supplements that were hundreds of times higher than that of the DRI were administered. Pantothenic acid was given at 10 g a day, a dosage also used in the treatment of acne patients [13]. Included in the regimen were 2 g of vitamin C, 500 mg of B1, 200 mg of B6, 2 mg of B12 and two tablets of Super B and two tablets of multivitamins with minerals per day. These additional supplements, as more research is done on the subject, will certainly need to be revised. There were 12 patients, all females aged between 18 and 43. They were followed up for up to 2 years. The results were encouraging. Within four weeks, they all showed a varying degree of improvement, particularly the symptom of fatigue. Later follow-up showed that the incidence of fever was decreased and no major flares were noted. In many cases, the original SLE medications could gradually be reduced.
924 It is true that SLE is a disease whose clinical facts are well established. Unfortunately, these are data that cannot be strung together for want of any identifiable pathological agent. The combined deficiency hypothesis could explain most of the facts and controversies that revolve around the subject, suggesting that this might well be the cause of the disease process. The issue of megavitamin therapy is again raised. Will this hypothesis help to change the viewpoint of conventional medicine? For a full text, please go to www.deficiencydiseases.com.
References [1] Rich MW. Drug-induced lupus. The list of culprits grows. Postgrad Med 1996;100:299–302 [review, 307–308]. [2] Carter JD, Valeriano-Marcet J, Kanik KS, Vasey FB. Antinuclear anti-body-negative, drug induced lupus caused by lisinopril. South Med J 2001;94:1122–3. [3] Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum 1973;3:1–54. [4] Fauci AS, Braunwald E, editors. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 1998. p. 2103.
Leung [5] Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, Giusti M, Piccoli A, Grella P, Gambari PF. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum 2002;47:202–9. [6] Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–8. [7] Pasoto SG, Mendonca BB, Bonfa E. Menstrual disturbances in patients with systemic lupus erythematosus without alkylating therapy: clinical, hormonal and therapeutic associations. Lupus 2002;11:175–80. [8] Ruiz-Irastorza G, Lima F, Alves J, Khamashta MA, Simpson J, Hughes GR, Buchanan NM. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996;35:133–8. [9] Eckhardt RB. Genetic research and nutritional individuality. J Nutr 2001;131:336–9. [10] Linus Pauling. How to live longer and feel better. Avon Books; 1987. p. 106. [11] Williams RJ. Biochemical Individuality. New Canaan, Connecticut: Keats Publishing; 1998. p. 153–184. [12] Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr 2002;75:616–58 [review]. [13] Leung LH. Pantothenic acid deficiency as the pathogenesis of acne vulgaris. Med Hypotheses 1995;44:490–2.