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Vol.47, No.9 September 2004

CONTENTS

Autoimmune Diseases

Mechanisms of Autoimmunity—Recent concept—

Kazuhiko YAMAMOTO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

Fundamentals of Treatment for Autoimmune Diseases

Seiji MINOTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Autoimmune Hematological Diseases

Kenji YOKOYAMA and Yasuo IKEDA . . . . . . . . . . . . . . . . . . . . . . . . . 412

Autoimmune Endocrine Diseases

Hiroki SHIMURA and Tetsuro KOBAYASHI . . . . . . . . . . . . . . . . . . . 419

Autoimmune Neurological Diseases

Fumihito YOSHII and Yukito SHINOHARA . . . . . . . . . . . . . . . . . . . . 425

Autoimmune Diseases in Dermatology

Hiroo YOKOZEKI and Kiyoshi NISHIOKA . . . . . . . . . . . . . . . . . . . . 431

Health Foods

Current System for Regulation of Health Foods in Japan

Heizo TANAKA et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

JMAJ, September 2004—Vol. 47, No. 9 403

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 129, No. 7, 2003, pages 895–898).

Introduction

Autoimmunity is generally defined as a phe-nomenon in which antibodies or T cells reactwith autoantigens. Autoimmunity induces auto-immune diseases. Recent studies have revealedthat such autoantibodies or autoreactive T cellsexist even in healthy individuals. The immunesystem has various mechanisms to suppress theimmune response to the self, and the distur-bance of these mechanisms results in auto-immune diseases.

Autoimmunity andAutoimmune Diseases

The conventional clonal deletion theory

Mechanisms of Autoimmunity—Recent concept—JMAJ 47(9): 403–406, 2004

Kazuhiko YAMAMOTO

Professor, Department of Allergy and Rheumatology, The University of Tokyo

Abstract: Autoantibodies and autoreactive T cells, which exist even in healthyindividuals, are usually regulated by a mechanism called immunological tolerance.For example, peripheral T cells are subject to various types of regulatorymechanisms, including clonal deletion, anergy, clonal ignorance, and T cells withregulatory functions. It is believed that autoimmune response may initiate whensuch regulated immune responses are pathologically activated by a certain trigger,probably a limited antigenic stimulation. Thereafter, other factors that promoteautoimmune responses combine to develop an autoimmune disease. It is esti-mated that T cells are closely involved in these reactions.

Key words: Immunological tolerance; Molecular mimicry; Epitope spreading

assumes that the immune system definitelydistinguishes between self and non-self, andthat autoreactive B and T cell clones areeliminated before they mature. However,recent studies have demonstrated that thistheory, although basically correct, does notalways hold true. B and T cells that react withautoantigens exist in the peripheral blood ofhealthy individuals.

For example, T cells that react with auto-antigens, such as myelin basic protein (MBP)of myelin sheath and type II collagen of car-tilage, can be separated from the peripheralblood of healthy individuals. Furthermore, auto-immune diseases such as thyroiditis can beinduced in normal animals by immunizing themwith organ-specific antigens such as thyro-

� Autoimmune Diseases

404 JMAJ, September 2004—Vol. 47, No. 9

Mechanisms ofImmunological Tolerance

Immunological tolerance is defined as a statein which the immune system does not posi-tively respond to autoantigens. The concept ofimmunological tolerance for autoreactive Tand B cells has been changing rapidly as newexperimental systems have been established.

T cells, which play a central role in acquiredimmunity, undergo clonal deletion by apo-ptosis when they are exposed to a sufficientamount of autoantigens in the thymus wherethey differentiate. This is called central toler-ance. It has been revealed recently that somemolecules previously considered to be expressedonly in a specific organ are also expressed inmedullary epithelial cells of the thymus. Thisindicates that the thymus is intended to expressas many autoantigens as possible in the bodyto induce tolerance for them. However, thismechanism is limited by the fact that not allautoantigens are expressed in the thymus.Furthermore, T cells that weakly react withautoantigens can migrate into peripheral tissue.Each antigen should have multiple amino acidsequences that can bind to antigen-presentingMHC molecules. These sequences are calledepitopes or antigenic determinants. However,some epitopes are not presented as antigensunder usual conditions probably due to therelationship with other epitopes or proteolysisin the cells. Such epitopes are called “crypticepitopes,” which means hidden antigenic deter-minants. T cells cannot become tolerant tothem.1)

T cells that migrate into peripheral tissuesundergo clonal deletion by apoptosis in thesimilar way as in the thymus when the stimulusof autoantigens is strong. When the stimulus isnot strong enough, T cells undergo clonalanergy (clonal paralysis). When the amount ofautoantigens is further reduced, T cells becomeignorant (non-tolerant and unresponsive). Inthis regard, it is important that naïve T cellscirculate only in lymphoid organs without

K. YAMAMOTO

globulin, indicating that lymphocytes that reactwith the autoantigens exist in normal animals.Therefore, it is believed that the existence ofautoantibodies or autoreactive T cells is notenough to elicit autoimmune diseases. Inaddition, it has been recently speculated thatauto-reactivity at a low level is physiologicaland necessary for a normal immune response.It has been reported that the weak reactivityto autoantigens presented by major histo-compatibility complexes (MHC; for humans,HLA) might be necessary for the survival ofperipheral mature T cells and maintenance ofhomeostasis.

Considering these factors, it is important todistinguish specific autoimmune responses thatcause various autoimmune diseases from theexistence of autoreactive lymphocytes or simpleautoimmune response. For example, injectionof spermatozoa into an animal results only inthe production of autoantibodies against sper-matozoa, but it does not cause any disease.However, the immunization of an animal withspermatozoa mixed with an adjuvant thatstrongly stimulates an immune response resultsin autoimmune testitis. Therefore, autoimmunediseases are distinguished from mere auto-immune response not by the presence/absenceof autoimmune response, but by the differentquality and quantity of the autoimmuneresponse.

Autoimmune diseases are divided into twogroups: the organ-specific autoimmune diseases,in which the target antigens and the tissue dis-orders are localized in one organ, and thesystemic autoimmune diseases, in which theresponse to a certain type of antigens that areexpressed widely in the body, such as anintranuclear antigen and multiple organs areinvolved. There are several autoimmune dis-eases that stand between these two groups. Itremains unclear whether these two groups ofautoimmune diseases result from the same orsubstantially different mechanisms.


MECHANISMS OF AUTOIMMUNITY

entering other organs to maintain the state ofignorant.

It has also been reported that tolerance maybe actively suppressed by regulatory T cells.Recent studies have reported T cells with vari-ous regulatory functions, including those thatproduce cytokines with suppressive effects,such as interleukin (IL)-10 and transforminggrowth factor (TGF)-�, and those that haveCD4� and CD25� surface markers and pro-vide suppressive effect through cell-cell contact.These various suppressive T cells may playdifferent roles, depending on the activation ofautoreactive T cells.

Thus, autoreactive T cells are under sub-stantially different conditions of tolerance,depending on the quality and quantity of auto-antigens. For example, many autoantigens aretoo isolated from the immune system to activatepotential autoreactive T cells. Autoantigensexpressed on non-hematopoietic cells may notstimulate T cells because they do not have co-stimulatory molecules. Another mechanismhas also been revealed in which the lymphnodes around organs have dendritic cells thattake antigens to induce tolerance of auto-reactive T cells in the steady state condition.

B cells have been reported to undergo anergyin response to soluble autoantigens and clonaldeletion in response to stronger autoantigens,such as those on cell surfaces in the bonemarrow where they differentiate. B cells thatstrongly react with soluble antigens such asself-molecules at the germinal center of periph-eral tissues are also deleted through apoptosis.B cells have been reported to cause a phenom-enon called receptor editing in which B cellsthat react with an autoantigen rearrange thegene of the antigen receptor (immunoglobulin)once again to make another non-autoreactivereceptor.

Mechanism of Initiation ofAutoimmunity

It is generally believed that autoimmunity is

triggered by the development or activation ofCD4� helper T cells that react with a specificautoantigen. Based on various evidence, it isnow proposed that a specific antigenic stimulusis the first trigger of autoimmunity. This iscalled the “single initiating antigen hypoth-esis”.2) For example, molecular mimicry inwhich immune response occurs to both anexternal microbial antigen and an autoantigenbecause of their homology is considered one ofthe mechanisms of initiating autoimmunity.

Microbial infection may initiate autoimmuneresponse not only through molecular mimicry,but also with polyclonal activation and releaseof isolated autoantigen. Lipopolysaccharide(LPS), a product of infectious microbes, bac-terial DNA, and viruses serve as an adjuvantto immune response. They bind to Toll-likereceptors (TLRs) on the surface of macro-phages or dendritic cells to stimulate naturalimmunity and inflammatory cytokine pro-duction, enhancing immune response by in-creasing the expression of MHC antigen orco-stimulatory molecules, such as B7-2 andOX40L. These responses are usually helpful forinducing acquired immunity, but may stimulatepotential autoreactive T cells. Through theseprocesses, it is also possible that cryptic epitopesnot expressed under usual conditions areexpressed to trigger an autoimmune response.

Non-infectious factors are also consideredas a trigger of autoimmunity. For example,estrogen exacerbates systemic lupus erythema-tosus (SLE) in a mouse model, while drugs,such as procaine amide and hydralazine, inducethe production of antinuclear antibodies, caus-ing an SLE-like pathologic state. The amountof iodine intake is an important environmentalfactor in autoimmune thyroid disease.

Mechanisms of Development ofAutoimmune Diseases

Triggering autoimmunity alone probablyresults in a transient event and is insufficient toinduce autoimmune disease. Studies in mouse


models have shown that CD4� T cells may berequired to complete the pathological state ofmost autoimmune diseases. Animal experimentshave demonstrated that the onset of auto-immune diseases can be suppressed by removingor inhibiting the function of CD4 cells withanti-CD4 monoclonal antibodies. Furthermore,the importance of antigen-specific CD4 cells inpathological autoimmune condition has beensuggested from the association with MHC classII antigens (such as DR antigen of HLA inhumans), infiltration of CD4� cells in manyorgan-specific autoimmune diseases, and pro-duction of autoantibodies of IgG type.

Although various factors are associated withthe progression of autoimmune diseases, one ofthe important phenomena is epitope spreading.Epitope spreading refers to a phenomenonin which autoantigens (antigen determinants)detected by T and B cells increase during theprocess from the initial activation of auto-reactive lymphocytes to the chronic phase. Thisconcept is important for explaining, for example,the mechanism by which autoimmune responseinduced by one cryptic epitope leads to com-plete autoimmune response. Both B and T cellsare involved in this phenomenon. Particularly,B cells play an important role as antigen-presenting cells for T cells.

In contrast, a study using non-obese diabetic(NOD) mice as a type I diabetes model showedthat autoimmune disease may progress throughthe avidity maturation and selective expansionof a particular antigen-specific T cell clone. We

have also shown from the analyses of T cellclonality infiltrating into organs that reactiveepitope is not always spread during the prog-ress of a disease. Probably, such positive andnegative balance of immune responses withregard to reactive epitopes may be involvedin the persistence and progression of auto-immune diseases.

Conclusions

Autoimmune disease is generated throughthe disturbance of immunological tolerance.Activation of autoreactive lymphocytes, andvarious positive and negative immune responsesare involved in each of these processes. Geneti-cally, individuals with lower threshold to theseresponses are more susceptible to autoimmunedisease, although various environmental factorsthat induce such immune responses are alsosignificant. It is thus necessary to understand indetail autoimmune phenomena in each patientto establish a proper therapy that suppresspathological immune responses without affect-ing normal immune functions.

REFERENCES

1) Sercarz, E.E. et al.: Dominance and crypticityof T cell antigenic determinants. Annu RevImmunol 1993; 11: 729–766.

2) Marrack, P. et al.: Autoimmune diseases: whyand where it occurs. Nat Med 2001; 7: 899–905.

K. YAMAMOTO



Fundamentals of Treatment forAutoimmune DiseasesJMAJ 47(9): 407–411, 2004

Seiji MINOTA

Professor and Chief, Division of Rheumatology and Clinical Immunology,Jichi Medical School

Abstract: Autoimmune diseases are dichotomized into organ-specific and sys-temic one. Hashimoto’s disease, Addison’s disease, and pernicious anemia are therepresentatives of the former and systemic lupus erythematosus of the latter.Systemic disease is treated mainly by rheumatologists and organ-specific diseaseis in the hands of the specialists to the organs involved. Autoantigens specific to theorgans involved are targeted in organ-specific disease, and, nuclei without organ-specificity are the main targets in systemic disease. Although more concreteevidence of autoimmune phenomena for their pathogenesis is obtained in organs-specific disease than systemic disease, immunosuppression by glucocorticoidsand immunosuppressants is applied only to the latter. It is very difficult to determinethe amount of glucocorticoids least but sufficient to suppress the disease, and, itis sometimes based upon the doctors’ experience. This is why it is called “artinstead of science” how to use glucocorticoids. On the other hand, hormonereplacement therapy is the treatment-rule for organ-specific disease instead ofimmunosuppression and it might be even forgotten that autoimmune processunderlies there. These two categories of autoimmune disease are in striking con-trast in terms of both pathogenesis and treatment.

Key words: Systemic autoimmune disease;Organ-specific autoimmune disease; Glucocorticoid;Immunosuppressive agent; Pernicious anemia

larly. Organ-specific autoimmune disease is theone usually not in hands of rheumatologists butin those of the specialists for the organs in-volved, such as endocrinologists, neurologists,gastroenterologists, and so on.

There are two interesting features between the

Introduction

Autoimmune diseases are roughly dividedinto two categories: systemic and organ-specific.The former is a group of diseases, which iscalled collagen-vascular diseases more popu-



S. MINOTA

two groups. First, organ-specific autoimmunediseases have more concrete evidence for theinvolvement of autoimmune processes thansystemic ones, such as the evidence for exist-ence of autoantigen-specific T lymphocytes.1)

Secondly, in spite of this, immunosuppressionby glucocorticoids or immunosuppressive agentsis applied to only systemic autoimmune dis-eases and almost never to organ-specific ones.As a matter of fact, it is sometimes forgottenthat organ-specific autoimmune diseases haveautoimmune mechanisms underlain for thepathogenesis.

These aspects are easier to understand whenwe review the characteristics of the two groupsof autoimmune diseases.

Characteristics of SystemicAutoimmune Diseases(Organ-Nonspecific AutoimmuneDiseases, So-Called Collagen VascularDiseases)

Let’s look at the disease character of systemiclupus erythematosus (SLE) as a representativeof systemic autoimmune diseases. It is well-known that patients with SLE have anti-nuclear antibodies in their circulation as themost paramount feature. Every nucleated cellin the body has a nucleus inside, and there is noorgan-specificity in this regard. Anti-nuclearantibodies interact with nuclei and elicit inflam-mation by consuming complements whennucleated cells are destroyed and release thenuclear materials in the circulation or in thetissue fluids.

Kidney is the organ targeted most frequentlyin SLE and the resultant glomerulonephritis iscalled “lupus nephritis”. Sixty to seventy per-cent of the patients with SLE develop lupusnephritis, although autoantibodies strictly spe-cific to glomeruli are scarcely seen. As men-tioned above, lupus nephritis develops as aresult of immune complexes formed in the cir-culation or in situ, which eventually accumulatein glomeruli.

There are three major anatomical character-istics of the kidney in this regard. First, kidneysreceive �25% of the blood that is pumped upby the heart every minute. That is, they receive�50 times more blood than other organs in thebody based upon weight by weight. Therefore,the kidney is an organ quite rich in blood flow.Second, glomerular vascular structure is com-posed of afferent arterioles, glomerular capil-laries, and efferent arterioles. As a matter offact, glomerular capillaries are sandwiched bythe arterioles. Probably due to this anatomicalcharacteristic, pressure in the glomerular cap-illary is �4 times higher than the one in thecapillaries elsewhere. Thirdly, the kidney isan apparatus for filtering body fluid and itmakes �150 l/day of glomerular filtration.Immune complexes could passively be depos-ited in the glomeruli from patients with SLE asa result of these anatomical and physiologicalcharacteristics.

There are many reports indicating that anti-dsDNA antibodies, in particular, have strongglomerulonephritogenic activities. Thus, treat-ment modality has been developed to eliminateB cells specific for anti-dsDNA antibodies,although it is not widely prevailed. A part ofanti-dsDNA antibodies might indeed morepreferentially be deposited in the glomerulithan autoantibodies specific for other auto-antigens, it is quite difficult to ascribe lupusnephritis to only one autoantigen-autoantibodysystem. Because anti-dsDNA antibodies arehighly specific to SLE and reflect the diseaseactivities in most cases, lots of autoantibodies,in terms of both quality and quantity, specific tomany cell components are produced by the timeanti-dsDNA antibodies emerge and, conse-quently, higher amount of immune complexesare deposited in the glomeruli.

Because T lymphocytes are indispensable forantigen-specific antibody formation, it is widelybelieved that they play a pivotal role also inautoantibody production in SLE. However,one of the most perplexing things in systemicautoimmune diseases is the difficulty in show-


TREATMENT OF AUTOIMMUNE DISEASES

ing the existence of such T lymphocytes inSLE.2) We are only speculating indirectly thepresence of such T lymphocytes by analyzingthe molecular characteristics of autoantibodiesincluding anti-nuclear antibodies.3) Questionsremain to be answered as to autoantigen whichinitiates the autoimmune process.

Fundamentals for the Treatment ofSystemic Autoimmune Diseases

Because of the reasons mentioned above, itis impossible, at this moment, to utilize auto-antigens or a part of an autoantigen to elimi-nate pathogenic and antigen-specific T or Blymphocytes. Therefore, overall immunosup-pression is needed to achieve sizable effects inthe treatment of systemic autoimmune diseases.

1. Glucocorticoids (Corticosteroids)After all, glucocorticoids are most frequently

used for the treatment of systemic autoimmunediseases. How to use glucocorticoids in treatingautoimmune disease is largely based uponone’s experience and this is why it is called“art instead of science” to use glucocorticoids.They have both anti-inflammatory and immuno-suppressive effects. For example, prednisoloneless than 30 mg/day exerts mainly anti-inflammatory activity, while immunosuppres-sive effects seem to appear when it is used atthe dose of more than 50 mg/day. Glucocorti-coids show their effects by binding to the recep-tor located in the cytoplasm and, after migrat-ing to the nucleus, the complexes bind to thespecific sites of the glucocorticoid-respondinggenes with the resultant protein production.4)

However, anti-inflammatory effects would bebrought about not by inducing glucocorticoid-inducible proteins but by the mechanisms thatfollow. Transcription factors such as AP-1 andNF-�B are required in order for cells to pro-duce inflammation-inducing proteins that wouldbe released into their microenvironment. Thetranscription factors accelerate enormously thetranscription rate of the inflammatory proteins

by binding to the upstream of those genes.Complex molecules composed of glucocorti-coids and their receptors bind directly to AP-1and NF-�B in the nucleus and block the lattermolecules to bind their specific transcriptionsites, thereby inhibiting the production ofinflammation-inducing proteins.

On the other hand, immunosuppressiveeffects of glucocorticoids would be due to thealteration qualitatively and quantitatively inthe function of T lymphocytes and antigenpresenting cells. Thus, prednisolone less than30 mg/day is used when anti-inflammatoryeffects are pursued and more than 50�60 mg/day of prednisolone are needed to achieveimmunosuppressive effects. There are big vari-ations among artificial glucocorticoids in theirhalf-lives when given in vivo, and we needto understand that the longer the half-lives,the more potent in both their beneficial anddeleterious effects. Glucocorticoids show anti-inflammatory effects very swiftly, while immu-nosuppression is a late effect.

2. Immunosuppressive agentsA group of drugs classified as immuno-

suppressive agents is usually used as an adjunctto glucocorticoids instead of being used solely.They are slow-acting compared to glucocorti-coids. Azathioprine and cyclophosphamide aremore frequently used than cyclosporine A andFK506 in Japan. However, the latter two arerequired to suppress T-lymphocyte functionmore specifically. Cyclophosphamide is usedeither per os every day or intravenously as apulse-therapy once a month. The latter isbelieved to be less toxic with almost equalbeneficial effects.5)

Outline of Organ-Specific AutoimmuneDiseases and Fundamentals ofthe Therapy Thereof

Organ-specific autoimmune diseases are di-chotomized from the therapeutic point of view.Hashimoto disease, Addison disease, pernicious


anemia, and type I diabetes mellitus compriseone side and the other side includes multiplesclerosis for example.

Let’s look at the pernicious anemia causedby deficiencies of vitamin B12 or folic acid. Vita-min B12 needs to couple to the intrinsic factor,which is released from the parietal cell of thestomach, to be absorbed via the specific recep-tor located in the ileum. There are two kinds ofautoantibody found in pernicious anemia: theone which inhibits the binding of vitamin B12 tothe intrinsic factor6) and the other which blocksthe binding of vitamin B12-intrinsic factor com-plex to the receptor in ileum.7) Production ofintrinsic factor is decreased in atrophic gas-tritis, where antibody- and cell-mediated auto-immune mechanisms are operative in destroy-ing parietal cells in the stomach.

Although pernicious anemia is induced byan autoimmune mechanism, its specific therapyis intramuscular injection of vitamin B12. Gluco-corticoids or immunosuppressants are neverused to suppress the autoimmunity whichunderlies pernicious anemia. This principleholds true in Hashimoto’s disease, Addison’sdisease, and type I diabetes mellitus. Replace-ment therapy with thyroid hormone and insulinis applied to Hashimoto’s disease and type Idiabetes, respectively. Although glucocorticoidsare indeed used for treatment of Addison’sdisease, this is not for suppression of auto-immune mechanism but for the replacementof the adrenal hormone. Therefore, gluco-corticoids in high amount are never used inAddison’s disease. Even if the function ofthese endocrine organs is destroyed completelythrough autoimmune mechanism, replacementtherapy with the corresponding hormone is pos-sible and much safer than aggressive immuno-suppressive therapy.

The situation is quite different in multiplesclerosis and replacement therapy is not appli-cable here. Autoimmune process per se must bestopped to improve central nervous systemfunction and we need to resort to glucocorticoidsin high dose or immunosuppressants just like in

systemic autoimmune diseases.Number of autoantigens eliciting autoimmune

process is fewer in organ-specific autoimmunediseases than in systemic autoimmune diseasesand the identification of their molecular natureis rapidly progressing. We hope, in the nearfuture, to suppress autoimmune process by thespecific autoantigens or the epitopes thereof.

Conclusion

Most organ-specific autoimmune diseases aretreated by endocrinologists and the replace-ment of hormone is the treatment principle.It is sometimes forgotten that autoimmunemechanisms are operative in these organ-specific autoimmune diseases.

On the other hand, many organs are involvedin systemic autoimmune diseases and theintroduction of high dose glucocorticoids orimmunosuppressants is the treatment rule.Glucocorticoids also have adverse effects sys-temically and it is quite important to use thesmallest amount required to suppress diseaseprocesses. However, this is very difficult toachieve and it is often referred to as “artrather than science” to decide the amount ofglucocorticoids to be used. It might be a trick tostart treatment with enough amount of gluco-corticoids and to taper as swiftly as possible.We need to be alert to opportunistic infectionsaround 4 weeks from the initiation of the treat-ment and prophylactic measures should betaken by checking and referring to the numberof total lymphocytes or CD4� T lymphocytes.

REFERENCES

1) Haskins, K. and Wegmann, D.: DiabetogenicT-cell clones. Diabetes 1996; 45: 1299–1305.

2) Mohan, C., Adams, S., Stanik, V. and Datta,S.K.: Nucleosome: a major immunogen forpathogenic autoantibody-inducing T cells oflupus. J Exp Med 1993; 177: 1367–1381.

3) Sontheimer, R.D. and Gilliam, J.N.: DNA anti-body class, subclass, and complement fixationin systemic lupus erythematosus with and

S. MINOTA


without nephritis. Clin Immunol Immuno-pathol 1978; 10: 459–467.

4) Buckbinder, L. and Robinson, R.P.: The gluco-corticoid receptor: molecular mechanism andnew therapeutic opportunities. Curr DrugTargets Inflamm Allergy 2002; 1: 127–136.

5) Boumpas, D.T., Austin, H.A., 3rd, Vaughn,E.M. et al.: Controlled trial of pulse methyl-prednisolone versus two regimens of pulsecyclophosphamide in severe lupus nephritis.

TREATMENT OF AUTOIMMUNE DISEASES

Lancet 1992; 340: 741–745.6) Pruthi, R.K. and Tefferi, A.: Pernicious ane-

mia revisited. Mayo Clin Proc 1994; 69: 144–150.

7) Gueant, J.L., Safi, A., Aimone-Gastin, I. et al.:Autoantibodies in pernicious anemia type Ipatients recognize sequence 251–256 in humanintrinsic factor. Proc Assoc Am Physicians1997; 109: 462–469.



Introduction

Idiopathic thrombocytopenic purpura (ITP),autoimmune hemolytic anemia (AIHA), andpernicious anemia are autoimmune hemato-logical diseases associated with autoantibodiesagainst platelets, RBCs, and gastric mural cellsand intrinsic factor, respectively.

Autoimmune Hematological DiseasesJMAJ 47(9): 412–418, 2004

Kenji YOKOYAMA* and Yasuo IKEDA**

*Assistant, **Professor, Department of Internal Medicine,Keio University School of Medicine

Abstract: Idiopathic thrombocytopenic purpura (ITP), autoimmune hemolyticanemia (AIHA), and pernicious anemia are autoimmune hematological diseasesassociated with autoantibodies against platelets, red blood cells, and gastric muralcells and intrinsic factor, respectively. The diagnosis of ITP requires thrombo-cytopenia with normal morphology of red blood cells and white blood cells (exceptfor cases complicated with AIHA or iron-deficiency anemia). Bone marrow exami-nation indicates a normal or increased number of megakaryocytes. The first-linetreatment is the administration of glucocorticoids, and splenectomy is performed inpatients who are unresponsive to initial glucocorticoid therapy. The diagnosis ofAIHA requires findings indicating hemolysis and serological evidence of anti-redblood cell (RBC) autoantibodies. Like ITP, the first-line treatment is the administra-tion of glucocorticoids. Splenectomy and the administration of immunosuppressiveagents are considered in patients who are unresponsive to initial glucocorticoidtherapy. Neurological symptoms in addition to anemic symptoms are common inpatients with pernicious anemia. The diagnosis of pernicious anemia requiresfindings of dyserythropoiesis and low vitamin B12 value. Anti-intrinsic factor and/oranti-gastric mural cell antibodies are often positive. Pernicious anemia is treatedwith the intramuscular injection of vitamin B12.

Key words: Idiopathic thrombocytopenic purpura;Autoimmune hemolytic anemia; Pernicious anemia

This paper discusses these three diseases.

Idiopathic ThrombocytopenicPurpura (ITP)

ITP is one of the hematological diseasesassociated with thrombocytopenia. ITP is anautoimmune thrombocytopenic disorder in



observed. ITP patients who are found to havethrombocytopenia at routine medical checkupsare often asymptomatic.

Peripheral blood cell count and morpho-logical examination of blood cells should firstbe performed to diagnose ITP. It is also nec-essary to exclude pseudothrombocytopenia.Pseudothrombocytopenia occurs when plateletcount with an automatic hemocytometer mis-takenly reads a low value due to platelet agglu-tination in a test tube containing ethylenedi-aminetetraacetic acid (EDTA), an anticoagulant.Pseudothrombocytopenia is reported to occurin about 0.1% of adults and should be sus-pected in patients with a low platelet value

which antiplatelet antibodies bind to plateletsand cause accelerated platelet destruction bythe reticuloendothelial system, including thespleen. ITP is often diagnosed in patients whovisit a clinic with a complaint of bleeding tend-ency, such as purpura, or who visit a clinicbecause thrombocytopenia were found at rou-tine medical checkups.

1. Diagnosis of ITPPatients with ITP often show subcutaneous

or submucosal bleeding, although the severityof bleeding symptoms varies. Intrajoint orintramuscle hematomas, as observed in dis-eases associated with coagulopathy, are rarely

Table 1 Diagnostic Criteria of Idiopathic Thrombocytopenic Purpura (ITP)(Investigation and research group of disease specified by the Ministry of Health and Welfare; revised in 1990)

1. Bleeding symptoms are observed.The main bleeding symptom is purpura (petechia and ecchymosis), and other symptoms include stomatorrhagia,rhinorrhagia, melena, hematuria, and hypermenorrhea. Usually, no intrajoint bleeding is observed. ITP may be detected inasymptomatic patients found to have thrombocytopenia at a medical checkup.

2. The following laboratory findings are observed.1) Peripheral blood

(1) Thrombocytopenia with platelet count of 100,000/�l or less. Attention should be paid to the possibility ofpseudothrombocytopenia when the result is obtained with an automatic hemocytometer.

(2) Erythrocytes and leucocytes are quantitatively and morphologically normal. Blood loss-induced or iron-deficiencyanemia is sometimes observed. A slight fluctuation of leukocyte count may be observed.

2) Bone marrow(1) Megakaryocyte count in the bone marrow is normal or increased. Many of megakaryocytes are lacking in platelet

adhesion.(2) The cellularity and the morphology of both the erythroid and myeloid series are normal. The myeloid/erythroid ratio

(M/E ratio) is normal.(3) Platelet-associated immunoglobulin G (PAIgG) is increased.

The increase in PAIgG is sometimes not observed, while it can be observed in thrombocytopenia associated withother diseases.

3. Other diseases associated with thrombocytopenia can be excluded.Note)

4. Idiopathic thrombocytopenic purpura may be diagnosed when a patient meets the above characteristics of (1) and (2) and theabove requirement of (3). The shortage of platelet life may be helpful to exclude ITP.

5. Disease type differentiation criteria1) Acute type: ITP resolved in 6 months of the estimated onset or diagnosis2) Chronic type: ITP that persist for more than 6 months of the estimated onset or diagnosis.However, ITP may be considered as the acute type in infants when it develops acutely with prior viral infection.

Note: Diseases that can cause thrombocytopenia include drug or radiation disorder, aplastic anemia, myelodysplastic syndrome,paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, leukemia, malignant lymphoma, bone marrow metastasisof cancer, disseminated intravascular coagulation syndrome, thrombotic thrombocytopenic purpura, hypersplenism, megaloblas-tic anemia, sepsis, tuberculosis, sarcoidosis, and hemangioma. For infection, thrombocytopenia after viral infection or viral livevaccine inoculation in infants may be included in ITP. Congenital types of thrombocytopenia include Bernard-Soulier syndrome,Wiskott-Aldrich syndrome, May-Hegglin syndrome, and Kasabach-Merritt syndrome.

(Kuramoto, A. et al.: 1990 Research Report of Specific Disease Specific Organopathy Investigation and Research Groupof Ministry of Health and Welfare. 1991; pp.59–61)

AUTOIMMUNE HEMATOLOGICAL DISEASES


without clinical symptoms, including bleedingtendency. In such cases, platelet count shouldbe verified to eliminate the possibility of pseu-dothrombocytopenia by (1) visually checkingperipheral blood smear specimens and (2) col-lecting blood with other anticoagulants such ascitric acid and heparin.

Peripheral blood smears from typical ITPpatients show thrombocytopenia and normalor slightly larger platelets, with no giant plate-lets being observed. Erythrocytes and leuco-cytes are morphologically normal.

When ITP is suspected from peripheralblood smears, further examinations should beperformed. According to American Society ofHematology guidelines, suspected patients ofless than 60 years of age can be diagnosed asITP without bone marrow examination, unlessfindings inconsistent with ITP are observed inmedical history, physical examinations, andperipheral blood count or morphology.1)

In Japan, however, bone marrow examina-tion is usually performed to verify the normalor increased number of megakaryocytes and toconfirm that erythroid and myeloid cells arequantitatively and morphologically normalaccording to the diagnostic criteria proposedby a research group of the former Ministry ofHealth and Welfare (currently, the Ministry ofHealth, Labour, and Welfare), as shown inTable 1. Further examinations may be per-formed as required for differentiating ITP fromother possible diseases listed in the Note ofTable 1.2)

2. Treatment of ITPTreatment is not always necessary in patients

diagnosed as having ITP. The need for treat-ment depends on platelet count and severity ofbleeding tendency. Although no definite cri-teria have been established for the indication fortreatment, asymptomatic patients or patientswith mild purpura who have a platelet count of50,000/�l or higher at the first presentation areoften followed without specific treatment.

In contrast, treatment is necessary for patients

K. YOKOYAMA and Y. IKEDA

with a platelet count less than 20,000/�l, irre-spective of symptoms, or those with evidentsubmucosal bleeding and a platelet count lessthan 50,000/�l. The need for treatment inpatients with mild bleeding tendency and aplatelet count between 20,000 and 50,000/�l isoften examined on a case-by-case basis in con-sideration of other hemorrhagic risk factors,such as blood pressure and peptic ulcer.

Patients with fatal hemorrhage irrespectiveof platelet counts, or those with evident sub-mucosal hemorrhage and a platelet count lessthan 20,000/�l have to be immediately hospi-talized for treatment.

The following treatments are available forITP.(1) Standard treatment

(i) Glucocorticoids: Glucocorticoids are thefirst-line therapy for ITP. Usually, oral predoni-solone (PSL) is used. It is started at 1 mg/kg/day and continued for at least 3 to 6 weeks.Subsequently, the dose is gradually reduced,depending on its effect.

(ii) Splenectomy: Splenectomy is indicatedin patients who do not respond to glucocorti-coids or those who require 0.1 mg/kg/day orhigher of PSL to maintain a safe platelet count.Previous reports showed that platelet countreturned to normal levels in 60–70% of patientswho received a splenectomy.(2) Emergency treatment

(i) Immunoglobulin: Earlier studies reportedthat administration of an intact type of immuno-globulin at 0.4 g/kg/day for 5 days increasedplatelets in about 75% of patients with ITP.However, this is usually a transient increase,and the platelet count often returns to theprevious level in 3 to 4 weeks.

The administration of immunoglobulin isindicated in patients with a platelet count lessthan 50,000/�l and fatal hemorrhage, or thosewho require a transient increase of plateletsfor surgery.

(ii) Platelet transfusion: Platelet transfusionis performed as an emergency measure forpatients complicated with fatal hemorrhage.


However, the effect is temporary because anti-platelet antibodies bind to transfused plateletsand cause platelet destruction.(3) Treatment for intractable cases

(i) Immunosuppressive agents: Immunosup-pressive agents (cyclophosphamide, azathioprineand cyclosporine) have been administered inpatients with refractory ITP. Vincristine anddanazol are also used. However, their effect is

variable.(ii) H. pylori eradication therapy: Recent

clinical trials in ITP patients positive for Heli-cobacter pylori reported that platelet countsincreased after H. pylori eradication therapy.3–5)

Although it remains unclear how H. pylori isinvolved in the onset of ITP, the therapydeserves further investigation.

Table 2 Diagnostic Criteria of Autoimmune Hemolytic Anemia (AIHA)(Investigation and research group of disease specified by the Ministry of Health and Welfare; revised in 1990)

1. The diagnostic criteria of hemolytic anemia are met.

2. The direct Coombs’ test using wide spectrum antiserum is positive.

3. Alloimmune hemolytic anemia (incompatible blood transfusion and hemolytic disease of the newborn) and drug-inducedimmune hemolytic anemia are excluded.

4. A diagnosis of AIHA is made with the above 3 criteria. AIHA is then further classified into the following 3 disease types bythe optimal temperature for the reaction of anti-erythrocyte autoantibodies.

(1) Warm AIHAWarm AIHA clinically varies among patients. In principle, IgG alone, or the combination of IgG and a complementfactor is detected in the direct Coombs’ test at 37°C using specific antiserum. However, there may be cases positive onlyfor anti-complement or wide spectrum antiserum. This type of AIHA may be diagnosed by excluding the following (2)and (3).

(2) Cold agglutinin syndrome (CAS)Serum cold agglutinin is increased, and exacerbated hemolysis by the exposure to cold or chronic hemolysis isobserved. Complement components are detected at the direct Coombs’ test at 4°C.

(3) Paroxysmal cold hemoglobinuriaHemoglobinuria and detection of serum biphasic hemolysin (Donath-Landsteiner antibody) characterize this disease.

5. The clinical course and cause of AIHA are classified as follows:Acute type: Resolved within 6 months of the estimated onset or diagnosis.Chronic type: Persisted for more than 6 months of the estimated onset or diagnosis.Idiopathic type: No underlying disease is observed.Secondary: A prior or concomitant underlying disease is observed.

6. Remarks1) Morphological findings of erythrocytes (spherocytes and hemagglutination) are helpful for making a diagnosis of AIHA.2) Occasionally, the direct Coombs’ test by the common method is negative in some cases with warm AIHA.3) Idiopathic warm AIHA may be complicated with idiopathic thrombocytopenic purpura (ITP).4) Hemolysis of cold agglutinin syndrome does not always occur in parallel with cold agglutinin titer: hemolytic symptoms

may occur even at a low titer.5) Antibody emigration technique is used to determine the properties of autoantibodies. Further examination may be per-

formed, as required, because some autoantibodies may show special properties, depending on the type of immunoglobulinand immunobiological activity.

6) Underlying diseases include autoimmune diseases, rheumatic diseases, lymphoproliferative disorders, immunodeficiencysyndrome, tumors, and infections (mycoplasma and virus). These diseases may become evident during the clinical courseof patients with idiopathic AIHA. AIHA associated with prior viral infection in infants shall be considered idiopathic. Coldagglutinin syndrome associated with mycoplasma or viral infection shall be considered secondary.

7) Attention should be paid to the fact that the direct Coombs’ test with wide spectrum antiserum is positive in drug-inducedimmune hemolytic anemia. It is helpful for making a diagnosis of the drug-induced anemia to examine the clinical courseand effect of the discontinuation of the potentially responsible drug. Except for the autoimmune type (�-methyldopa), drugspecificity of antibodies can be proved with appropriate techniques. For the autoimmune type, the direct Coombs’ test maybecome positive after the long-term administration of the responsible drug, and warm AIHA may occur in some patients.

(Maekawa, T.: Research Report of Diseases Specified by the Ministry of Health and Welfare: Idiopathic Hematopoietic Disorder.1991; pp.64–70)



Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA)develops because anti-RBC autoantibodies(IgC or IgM) bind to RBCs and cause acceler-ated RBC destruction by the reticuloendo-thelial system, including the spleen. AIHA isclassified by the characteristics of autoanti-bodies into warm AIHA, which has warm-typeIgG antibodies, cold agglutinin syndrome(CAS), which has cold-type IgM antibodies,and paroxysmal cold hemoglobinuria (PCH),which has biphasic IgG antibodies (Donath-Landsteiner (D-L) antibodies).

1. Diagnosis of AIHAPatients with AIHA often complain of

anemic symptoms, including palpitations anddypnea on exertion, although their severitydiffers by patient. Physical examination of theAIHA patient reveals anemia, jaundice, andsplenomegaly. To make a diagnosis of AIHA, itis necessary to (1) detect clinical or laboratoryfinding(s) suspected to indicate hemolysis, and(2) serologically demonstrate anti-RBC anti-bodies. The diagnostic criteria of the researchgroup of the former Ministry of Health andWelfare (currently the Ministry of Health,Labour, and Welfare), revised in 1990,6) areused in Japan. See Table 2.

Laboratory findings suggesting hemolysisinclude anemia, increased reticulocytes, in-creased bilirubin with the predominant increaseof indirect bilirubin, increased LDH, andreduced haptoglobin. Anti-RBC antibodiescan be demonstrated by detecting immuno-globulins or complement components com-bined with RBC membrane using directCoombs’ test.

When the direct Coombs’ test is negativein patients with typical AIHA findings, it isnecessary to quantitatively determine immu-noglobulin combined with RBCs. It is alsonecessary to perform the direct Coombs’ testat different temperatures because AIHA isclassified into subtypes by the temperature at

which antibodies become active.AIHA is classified into warm AIHA when

antibodies (IgG) become active around 37°C;into CAS when cold-type IgM antibodies showstrong activity at as low as 0 to 4°C with almostno activity at physiological temperature; andinto PCH when D-L antibodies (IgG) that bindto RBC at 0 to 4°C and dissociate from RBC at37°C. However, prior to dissociation, D-L anti-bodies initiate complement activation andcause homolysis.

It is important to ask patients about theirmedical history because AIHA may develop inpatients with an underlying disease (systemiclupus erythematosus, malignant lymphoma, orchronic lymphocytic leukemia) or infection(such as mycoplasma) or those who are takingdrugs (such as �-methyldopa).

2. Treatment for AIHA(1) Treatment for warm-type AIHA

Usually, folic acid is administered to increasehematopoiesis. The need for further treatmentdepends on the severity of hemolysis. The first-line therapy is the administration of gluco-corticoids: usually 1 mg/kg/day of oral PSL isadministered. Hemolysis is usually amelioratedwithin 3 weeks, and PSL is gradually reducedafter 4 to 6 weeks of treatment. Although PSLcan be discontinued in some patients, a main-tenance dose of 10 to 15 mg/day is oftenrequired. Splenectomy and/or administrationof an immunosuppressive agent is performedon patients who do not respond to PSL or thosewho require a high dose of PSL to maintainRBCs, as in the treatment for ITP.(2) Treatment for CAS

CAS develops both primarily and second-arily. Primary CAS is often associated withmild anemia, and is therefore treated merelyby instructing patients to avoid cold stimuli.Severe patients may be treated with an immu-nosuppressive agent or plasmapheresis, whilethe administration of glucocorticoids or sple-nectomy are not so effective. Patients withsecondary CAS associated with advanced



hemolysis require the treatment of their under-lying diseases.(3) Treatment for PCH

Usually, PCH does not require any specifictreatment except for avoiding cold stimuli.However, plasmapheresis is indicated in seri-ous cases with fatal risk. Underlying syphilisshould be suspected in patients with chronicPCH.

Pernicious Anemia

Pernicious anemia results from vitamin B12

deficiency. Although vitamin B12 deficiency canoccur from insufficient intake, gastrectomy, orsmall intestine disease, only the anemia associ-ated with vitamin B12 deficiency by chronicatrophic gastritis is called pernicious anemia.

1. Diagnosis of pernicious anemiaPernicious anemia develops and progresses

slowly. The diagnosis of pernicious anemia isoften made in patients around 60 years of age.In addition to anemic symptoms, this disease isassociated with neurological symptoms (abnor-mal sense of perception, vibration, and positionas well as positive Romberg’s sign, reducedmuscle strength, and spastic gait) and lingualpapilla atrophy (Hunter’s glossitis). Peripheralblood testing indicates macrocytic anemia andhypersegmented neutrophils often associatedwith leukopenia and thrombocytopenia.

Since hematopoiesis is ineffective, biochem-ical tests show increased LDH, increasedindirect bilirubin, and reduced haptoglobin.Vitamin B12 is low. The diagnosis of perniciousanemia can be confirmed in the Schilling testindicating that the absorption of vitamin B12 islow and recovered with the addition of thegastric intrinsic factor.

Furthermore, patients with pernicious ane-mia show immunological abnormalities, suchas the development of anti-intrinsic factorantibody (highly specific because it is positivein about 70% of patients) and anti-gastricmural cell antibody (positive in about 90% of

patients).Bone marrow examination indicates mega-

loblastic cells, giant metamyelocytes, and giantrod nuclear cells, although diagnostic bonemarrow examination is not necessarily requiredin typical cases.

2. Treatment for pernicious anemiaThe first-line therapy for pernicious anemia

is the intramuscular injection of vitamin B12:usually, 1,000�g/day of hydroxocobalamin ormethylcobalamin is administered for about 2weeks continuously, which improves anemiaand replaces a sufficient amount of vitamin B12.Subsequently, maintenance therapy is neces-sary every 2 to 3 months. An earlier studyreported that there is another vitamin B12

absorption route that does not require thegastric intrinsic factor, and that the oral admin-istration at 2,000�g every day was comparableto, or more effective than, the intramuscularinjection of 1,000�g once a month.7)

Conclusion

This paper explains the latest view of thediagnosis and treatment of ITP, AIHA, andpernicious anemia. We hope that this paper willbe helpful for those who encounter clinicalcases suspected to have the diseases.

REFERENCES

1) George, J.N. et al.: Idiopathic thrombocyto-penic purpura: A practice guideline developedby explicit methods for the American Societyof Hematology. Blood 1996; 88: 3–40.

2) Kuramoto, A. and Fujimura, K.: Examinationof diagnostic criteria of idiopathic thrombo-cytopenic purpura. 1990 Research Report ofInvestigation and Research Group of DiseaseSpecified by the Ministry of Health and Wel-fare: Idiopathic Organopathy. 1991; pp.59–61.(in Japanese)

3) Gasbarrini, A., Franceschi, F., Tartaglione, R.et al.: Regression of autoimmune thrombo-cytopenia after eradication of Helicobacter



Pylori. Lancet 1998; 352: 878.4) Kohda, K., Kuga, T., Kogawa, K. et al.: Effect

of Helicobacter pylori eradication on plateletrecovery in Japanese patients with chronicidiopathic thrombocytopenic purpura andsecondary autoimmune thrombocytopenicpurpura. Br J Haematol 2002; 118: 584–588.

5) Emilia, G., Longo, G., Luppi, M. et al.: Helico-bacter pylori eradication can induce plateletrecovery in idiopathic thrombocytopenic

purpura. Blood 2001; 97: 812–814.6) Maekawa, T.: Report of Chairperson of

Hemolytic Anemia Sub-committee. ResearchReport of Disease Specified by the Ministry ofHealth and Welfare: Idiopathic HematopoieticDisorder. 1991; pp.64–70. (in Japanese)

7) Kuzminski, A.M., Del Giacco, E.J., Allen,R.H. et al.: Effective treatment of cobalamindeficiency with oral cobalamin. Blood 1998;92: 1191–1198.




Introduction

It is generally recognized that endocrineorgans may contract various organ-specificautoimmune diseases, which, except for Base-dow’s disease (Graves’ disease) in which auto-antibodies possess endocrine gland-stimulatingactivity, present diverse clinical features due toendocrine hypofunction through autoimmunemechanisms. Widely known among these disor-ders is polyglandular autoimmune syndromeinvolving autoimmune endocrine diseases of

Autoimmune Endocrine DiseasesJMAJ 47(9): 419–424, 2004

Hiroki SHIMURA* and Tetsuro KOBAYASHI**

*Lecturer, **Professor, Third Department of Internal Medicine,School of Medicine, University of Yamanashi

Abstract: Autoimmune endocrine diseases occur most frequently amongvarious autoimmune diseases. Among autoimmune endocrine diseases, Graves’disease, Hashimoto’s disease, type 1 diabetes mellitus, and Addison’s disease areespecially frequent in daily clinical practice. Graves’ disease produces thyro-toxicosis due to the effects of the anti-TSH receptor antibody upon the thyroid glandand diverse symptoms due to its effects on extrathyroid tissues. Hashimoto’sdisease is the most frequently encountered autoimmune disorder, and cellularimmunity is thought to be involved. Guidelines for the diagnosis of these thyroiddiseases have been provided by the Japan Thyroid Association. Autoimmunemechanisms are involved in many cases of type 1 diabetes mellitus. Type 1 diabetesmellitus has a wide spectrum of clinical disease states ranging from the rapid onsetform, which develops diabetes mellitus within several days, to SPIDDM, whichslowly progresses over years. Addison’s disease is also an autoimmune disorderin many cases and may present polyglandular autoimmune syndrome with compli-cations by other organ-specific autoimmune disorders.

Key words: Graves’ disease; Hashimoto’s disease; Type 1 diabetes mellitus;Addison’s disease

several organs.This paper presents brief accounts of Graves’

disease, Hashimoto’s disease, type 1 diabetesmellitus, and Addison’s disease, which are fre-quently seen autoimmune endocrine diseasesin daily clinical practice.

Graves’ Disease

1. PathophysiologyThe disease is characterized by the presence

of an autoantibody that recognizes the TSH



thyroid with low internal echo level. Enhancedinternal blood flow is noted on Dopplerultrasonography.

4. Essentials of diagnosisGuidelines for the diagnosis of thyroid dis-

eases (the sixth draft) have been provided bythe Japan Thyroid Association.2) The associ-ation’s guidelines for the diagnosis of Graves’disease are cited in Table 1. These guidelinesare available at the Japan Thyroid Association’swebsite (http://thyroid.umin.ac.jp/flame.html).

5. Treatment(1) Antithyroid drugs: These drugs are

H. SHIMURA and T. KOBAYASHI

receptor and stimulates the thyroid gland (i.e.,anti-TSH receptor antibody), goiter, and signsof thyrotoxicosis. Exophthalmos and pretibialmyxedema, which are also characteristic fea-tures of Graves’ disease, cannot be explainedby excess thyroid hormones and currently areconsidered to be ascribable to the reactions ofantibody to TSH receptors in adipocytes, etc.1)

2. Clinical features and physical findingsMerseburg’s triad (palpitations, struma, and

exophthalmos) is important as symptoms andfindings in Graves’ disease. Other major symp-toms include weight loss (with an associatedincrease in appetite), fatiguability, shortness ofbreath, hyperidrosis, finger tremors, diarrhea,periodic paralysis (male), and muscle weakness.

Physical findings include (1) diffuse struma(vascular murmurs audible); (2) ocular symp-toms exophthalmos, lid lag and Graefe’s sign;(3) tachycardia and atrial fibrillation; (4) warmmoist skin; (5) tremors; and (6) pretibialmyxedema.

3. Laboratory findings(1) Routine examination: Elevation in serum

ALP (bone type isozyme), a slight increase inAST/ALT, low serum cholesterol level, and aslight increase in blood glucose are noted.

(2) Endocrine tests: Low serum TSH leveland elevations in free T3 and free T4 in serumare observed. Patients show elevated radio-active iodine uptake (30% or more).

(3) Immunological tests: Patients are posi-tive for anti-TSH receptor antibody. For serumanti-TSH receptor antibody determination, twodifferent assay methods are currently avail-able: 1) measurement of the degree of inhibi-tion of binding to labeled TSH receptor (TBII,TRAb) and 2) measurement of cAMP produc-tion in cultured thyroid cells (TSAb). Usually,one or the other of the tests is performed first,and if the test is found negative, then the othertest is undertaken.

(4) Imaging diagnosis: Ultrasonographicexamination reveals diffuse enlargement of the

Table 1 Guidelines for the Diagnosis of Graves’ Disease

a) Clinical findings1. Signs of thyrotoxicosis such as tachycardia,

weight loss, finger tremor, and sweating2. Diffuse enlargement of the thyroid gland3. Exophthalmos and/or specific ophthalmopathy

b) Laboratory findings1. Elevation in serum free thyroxine (FT4) level2. Suppression of serum thyroid stimulating

hormone (TSH): less than 0.1�U/ml3. Positive for anti-TSH receptor antibody (TRAb or

TBII) or thyroid stimulating antibody (TSAb)4. Elevated radioactive iodine (or 99mTcO4

�) uptaketo the thyroid gland

1) A patient shall be said to have Graves’ disease if he/shehas satisfied at least one of the clinical findings and all 4laboratory findings.

2) A patient shall be said probably to have Graves’ diseaseif he/she has satisfied at least one of the clinical findingsand 3 laboratory findings 1 through 3.

3) A patient is suspected to have Graves’ disease if he/shehas satisfied at least one of the clinical findings and 2laboratory findings 1 and 2. Elevation in serum FT4 haveusually been present for at least 3 months.

Notes1. Decrease of serum cholesterol and increase of serum alkaline

phosphatase are often observed.2. There are rare cases with free triiodothyronine (FT3) elevation

alone and normal FT4.3. A patient shall be said to have “euthyroid Graves’ disease” or

“euthyroid ophthalmopathy”, if he/she has ophthalmopathy andis positive for TRAb or TSAb, but shows normal FT4 and TSH.

4. In an elderly patient, clinical symptoms and signs including anenlargement of the thyroid gland, may not be clear.

5. In children, decreased scholastic ability, accelerated growth,restlessness and other symptoms are observed.


AUTOIMMUNE ENDOCRINE DISEASES

often used as drugs of first choice for thetreatment of Graves’ disease in Japan. Usually,methimazole (MMI) with a slightly higherpotency is instituted at a dosage level of 15–30 mg/day, followed by a gradual dose reduc-tion over several years. In case of any adversereaction occurring (except for agranulocytosis)or during lactation, the drug is replaced withpropylthiouracil (PTU). Antithyroid drugs aredrugs of first choice for pregnant women.

(2) Radioactive iodine therapy: Patients inwhom antithyroid drugs cannot be used andmiddle-aged and older patients who respondpoorly to the therapy regimens are better indi-cated for the use of radioiodine. At present,the therapy is feasible at outpatient services.Therapeutic effects become evident about 6months after the start of medication, with sub-sequent development of late hypothyroidismin many cases.

(3) Subtotal thyroidectomy: This is pre-ferred for refractory juvenile cases of Graves’disease with notable enlargement of the thyroid.

Hashimoto’s Disease

1. PathophysiologyThis disease occurs in nearly one out of

every ten middle-aged women and is an organ-specific autoimmune disorder with the highestprevalence. The etiology remains unclear,although cellular immunity and antibody-dependent cytotoxicity are generally thoughtto be involved.

2. Clinical features and physical findingsFirm diffuse enlargement of the thyroid is

the only finding if thyroid hypofunction is notpresent. The disease progresses into hypothy-roidism to produce generalized edema, weightgain, subjective symptoms such as fatiguability,sensitivity to the cold and diarrhea, and physi-cal findings such as hoarseness, dry skin, fallingof the lateral one-third of both eyebrows, bra-dycardia, and a prolonged relaxation phase ofthe Achilles tendon reflex.

3. Laboratory findings(1) Routine examination: Increased ESR,

elevation in serum �-globulin (increased ZTTand TTT values), elevations in CPK and LDH,and high serum cholesterol level are noted.

(2) Endocrine tests: Free T3 and free T4 inserum are lowered and TSH is elevated. Latenthypothyroidism with a normal thyroid hormonelevel and with elevation in TSH alone is alsofrequently observed.

(3) Immunological tests: Patients are posi-tive for anti-thyroid peroxidase (TPO) antibodyand for anti-thyroglobulin (Tg) antibody.

4. Essentials of diagnosisThe diagnosis guidelines (the sixth draft)

provided by the Japan Thyroid Association2)

are shown in Table 2. Occasionally, patientsmay present transient symptoms of thyro-toxicosis, which is called painless thyroiditis.

5. TreatmentReplacement therapy with T4 preparations is

Table 2 Guidelines for the Diagnosis of ChronicThyroiditis (Hashimoto’s Disease)

a) Clinical findings1. Diffuse swelling of the thyroid gland without any

other cause (such as Graves’ disease)

b) Laboratory findings1. Positive for anti-thyroid microsomal antibody or

anti-thyroid peroxidase (TPO) antibody2. Positive for anti-thyroglobulin antibody3. Lymphocytic infiltration in the thyroid gland

confirmed with cytological examination

1) A patient shall be said to have chronic thyroiditis if he/she has satisfied clinical criterion and any one laboratorycriterion.

Notes1. A patient shall be suspected to have chronic thyroiditis, if he/she

has primary hypothyroidism without any other cause to inducehypothyroidism.

2. A patient shall be suspected to have chronic thyroiditis, if he/shehas anti-thyroid microsomal antibody and/or anti-thyroglobulinantibody without thyroid dysfunction nor goiter formation.

3. If a patient with thyroid neoplasm has anti-thyroid antibody bychance, he or she should be considered to have chronic thyroiditis.

4. A patient is possible to have chronic thyroiditis if hypoechoicand/or inhomogeneous pattern was observed in thyroidultrasonography.


performed in patients with hypothyroidism. Itis a common practice to use a low dose level forinitiating T4 drug therapy, with subsequentgradual dosage increase until serum TSH levelbecomes normalized. The therapy should bestarted at a dose level of 12.5�g/day especiallyin elderly patients and severe cases becauseof the potential risk of angina pectoris or car-diac failure.

Type 1 Diabetes Mellitus

1. PathophysiologyThe diagnostic criteria and classification of

diabetes mellitus into two types depictingdisease states — insulin-dependent diabetesmellitus (IDDM) and non-insulin-dependentdiabetes mellitus (NIDDM) — were revisedin 1999 to those classifying the disease intofour types based on etiology, i.e., types 1 and2, other particular mechanisms or disorders(inclusive of genetic abnormalities), and ges-tational diabetes.

Type 1 diabetes denotes diabetes mellitus,which develops due to destruction of pan-creatic � cells. The disease under this categoryis further classified into type 1A, which arisesthrough autoimmune mechanisms, and type1B, which is of non-autoimmune nature.

Type 1A disease of autoimmune etiologyincludes the slow-progressing insulin-dependentdiabetes mellitus (SPIDDM) besides the rapid-onset type, which is typical of conventionalIDDM. SPIDDM is a disease form that pre-sents clinical features close to type 2 diabetesmellitus but progresses over several years withdepression of pancreatic � cell function andultimately into an insulin-dependent status. Inboth these forms of type 1A, the anti-islet auto-antibody (to be described below) is detected.The anti-islet autoantibody is not demonstratedin cases of type 1B disease.

Recently, attention has been focused on thepresence of fulminant type 1 diabetes mellitusin which ketoacidosis develops in a period ofseveral days (mean: 4 days), occasionally tak-

ing a fatal clinical course.

2. Clinical features and physical findingsThere are no symptoms/findings specific to

type 1 diabetes mellitus. Most patients are non-obese, with more severe symptoms of weightloss, polyuria and thirst due to marked hyper-glycemia, and are prone to diabetic coma. Infulminant type 1 diabetes mellitus, about 70%of patients develop common cold-like symp-toms such as upper abdominal pain, fever, andheadache before the onset of diabetes mellitus.

3. Laboratory findings(1) Routine examination: A diagnosis of

diabetes mellitus can be established accordingto the diagnostic criteria for diabetes mellitus.HbA1c is usually elevated but this parameterremains at normal to a slight elevation in casesof the fulminant form of type 1B disease. Exo-crine pancreatic enzymes such as elastase I andamylase are elevated in the fulminant form.Acidosis is often present among cases of type 1disease other than SPIDDM.

(2) Endocrine tests: The fasting serum Cpeptide level (�0.5 ng/ml) and urinary C pep-tide output (�10�g/day) are lowered due todepressed insulin secretory function. These arenot the case with SPIDDM.

(3) Immunological tests: Patients with type1A disease are positive for anti-glutamic aciddecarboxylase (GAD) antibody being anti-isletautoantibody, islet cell antibody (ICA), anti-insulin autoantibody (IAA), and IA-2 antibody.3)

Patients with the fulminant form of type 1 dia-betes are negative for these autoantibodies.Of human leukocyte antigens, patients oftenpossess HLA-DR4 or -DR9 and are negativefor HLA-DR2.

4. Essentials of diagnosisAnti-GAD antibody can be measured rou-

tinely and must be determined positively whentype 1 diabetes mellitus is suspected. In thefulminant form, common cold-like symptomsfrequently precede the onset of the disease,



so urine tests for glucose (and ketones) areessential in patients with colds complainingof lassitude.

5. TreatmentUsually, an intensive insulin therapy regimen

consisting of a dose of a regular (or rapid-acting) insulin is undertaken before every mealand a dose of an intermediate-acting (or long-acting) insulin at bedtime. If the blood glucoselevel is still poorly controlled with this regimen,then continuous subcutaneous insulin infusion(CSII) is performed. It has been shown thatlow-dose insulin provides a protective effectfor pancreatic � cells, and replacement withinsulin therapy is required in patients withSPIDDM receiving sufonylureas.

Addison’s Disease

1. PathophysiologyAddison’s disease is caused by destruction

of the adrenal cortices resulting in chronicadrenocortical insufficiency. Leading causes areautoimmune destruction, termed idiopathic,and tuberculosis. In the idiopathic entity, thedisease may present polyglandular autoimmunesyndrome involving complications by otherorgan-specific autoimmune disorders (i.e., type1 diabetes mellitus, Hashimoto’s disease, idio-pathic hypoparathyroidism, gonadal hypofunc-tion, mucocutaneous candidiasis, and perniciousanemia). These are classified into type I causedby juvenile-onset autoimmune regulator (AIRE)gene abnormality, type II, being an adult-onsetdisease without associated non-endocrine dis-order, and type III, which does not involveAddison’s disease.4)

2. Clinical features and physical findingsHyperpigmentation due to increased secre-

tion of ACTH is a characteristic clinical feature.Aldosterone-cortisol-adrenal androgen deficitsymptoms are also noted.

3. Laboratory findings

(1) Routine examination: Hypoglycemia,hyponatremia, hyperkalemia, and peripheralblood eosinophilia are present.

(2) Endocrine tests: Diagnostic findingsinclude elevated plasma ACTH, low plasma andurine cortisol levels, low plasma aldosteronelevel, low plasma DHEA-S value, decrease inurinary 17-OHCS/17-KS, and no or low plasmacortisol in the rapid ACTH test.

(3) Immunological tests: Autoantibodiesrecognizing steroid-synthesizing enzymes aredetected but these laboratory tests have notbeen generally adopted to date.

4. Essentials of diagnosisWhen there are diverse nonspecific symp-

toms, the disease must be deduced from skinpigmentation and routine laboratory test data.Caution must be exercised because if the dis-ease is left undiagnosed and without adequatesteroid substitution therapy, some types of stressmay precipitate adrenal crisis (acute adrenalinsufficiency) with a fatal outcome.

5. TreatmentReplacement therapy with hydrocortisone

at 20 mg/day is a common practice. A divideddose in the morning may be greater than theone given in the early evening to be in harmonywith circadian rhythm in cortisol secretion. Thedose of hydrocortisone should be raised 2- to3-fold the usual dose (40–60 mg/day) in case ofcommon cold with pyrexia or other infections,trauma, or surgery.

Conclusions

Endocrine diseases in which autoimmunemechanisms are considered to be involved,besides the four above-mentioned diseases,include lymphocytic adenohypophysitis, lym-phocytic infundibuloneurohypophysitis, andidiopathic hypoparathyroidism. Autoimmuneendocrine disorders are most frequent amongvarious autoimmune diseases, so it is of impor-tance to always keep this fact in mind in daily

AUTOIMMUNE ENDOCRINE DISEASES



clinical practice to achieve diagnosis and treat-ment in such cases.

REFERENCES

1) Endo, T.: Approaches to thyroid disorders.—The pathogenetic mechanisms of Graves’ dis-ease and basic strategies for pharmacotherapyand management. Medical Practice 2002; 19:196–202. (in Japanese)

2) Mitsuma, T., Shishiba, Y., Uchimura, H. et al.:Guidelines for the diagnosis of thyroid diseases:

Basedow’s disease, hypothyroidism, indolentthyroiditis/chronic thyroiditis (Hashimoto’sdisease) and subacute thyroiditis. Horumon-to-Rinsho 2002; 50: 643–653. (in Japanese)

3) Kobayashi, T.: Pathophysiology and immunesystems in type 1 diabetes mellitus. Karadano-kagaku 2001; Special Issue (Diabetes Mellitus2001): 54–57. (in Japanese)

4) Kudo, J. and Shimizu, N.: Genetic autoimmunedisorder (APECED): Polyglandular auto-immune endocrinopathy type I. Naibunpitsu-Tonyobyoka 1999; 9: 527–533. (in Japanese)



Introduction

This paper describes some representativeautoimmune neurological diseases. As describedlater, the common types of the diseases inJapan are different from those in Westerncountries; for example, the optic-spinal formof multiple sclerosis and the axonal form ofGuillain-Barré syndrome are more common inJapan than in Western countries. This suggeststhat the development of autoimmune neuro-logical diseases varies among races and issubstantially influenced by environmental fac-tors. Therefore, care is needed in interpretingmedical textbooks and literature published inWestern countries.

Autoimmune Neurological DiseasesJMAJ 47(9): 425–430, 2004

Fumihito YOSHII* and Yukito SHINOHARA**

*Associate Professor, **Professor,Department of Neurology, Tokai University School of Medicine

Abstract: Multiple sclerosis, myasthenia gravis, and Guillain-Barré syndromeare neurological diseases induced by abnormal autoimmunity. Since these dis-eases show characteristic clinical courses and neurological symptoms, they can bediagnosed with appropriate examinations. However, it is necessary to note that thecommon types of these diseases in Japan are not always the same as those inWestern countries. Based on an increasing knowledge of the pathological mecha-nisms of the diseases, various immune therapies are being developed.

Key words: Autoimmune neurological diseases; Multiple sclerosis;Myasthenia gravis; Guillain-Barré syndrome

Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) ismade according to the conventional clinicaldescription of “spatially and temporally sep-arated multifocal central nervous lesions”.1)

Pathologically, MS presents perivascular in-flammation and myelin sheath destruction(demyelination plaques) in the white matter.

The prevalence of the disease in Caucasiansis 40 to 100 per 100,000 individuals, while it isonly about one-tenth of this figure among theJapanese. The disease type is also differentbetween Caucasians and Japanese — the cere-bral and optic-spinal forms are predominant inthe former and the latter, respectively.



The examination of evoked potential isuseful for detecting clinically asymptomaticpotential lesions that cannot be read in MRimages. It is performed for visual, auditory, andsomatic sensation — when any of the sensorypathways is abnormal, its signal latent time isprolonged.

2. Clinical courseMS mainly develops in patients in their

twenties to fifties, with a peak being notedbetween 25 and 30 years. Most patients areclassified into relapsing/remitting MS in whichperiods of exacerbation and periods of stableor improved clinical state occur alternately.Symptoms may recur from several times a yearto only once every several years.

Primary progressive MS that progresseschronically from the onset has been reported inabout 10 to 15% of Western patients,2) but onlyin 5% of Japanese patients. This form of MS hasto be differentiated from neurodegenerativediseases or cerebral tumors.

In about 10% of patients with relapsing/remitting MS, the disease gradually becomesprogressive within 10 years (secondary pro-gressive MS). Although this form of MS isobserved in 20 to 40% of patients in Westerncountries, it is less frequently observed inJapan.

3. Neurological symptomsMS has a large variety of neurological symp-

toms. It often occurs with vision disorder oracute transverse myelitis in Japanese becausemany Japanese MS patients are classified intooptic-spinal MS. The symptoms that maydevelop during the clinical course of MSinclude reduced vision, double vision, dys-kinesia/paresthesia, spasm, dysuria, ataxia,tremor, cognitive dysfunction, and Lhermitte’ssign (an electric shock-like sensation runningfrom the back to the limbs when the neck isbent forward, and associated with lesions in thecervical-spinal cord posterior funiculus). Inaddition, paroxysmal symptoms may occur,

F. YOSHII and Y. SHINOHARA

1. Diagnostic examinationMRI shows demyelination plaques in the

white matter around the cerebral ventricles,brain stem, cerebellum, and spinal cord as highsignal intensity areas in T2-weighted or fluidattenuated inversion recovery (FLAIR) images(Fig. 1). However, attention should be paid tothe fact that similar findings may also beobserved in patients with other inflammatorydiseases, ischemia, metabolic diseases, andtumors.

Cerebrospinal fluid examination shows in-creased IgG in about 70% of the patients, witha resultant increase of the IgG index (obtainedby dividing the ratio of IgG to albumin in thecerebrospinal fluid by the corresponding ratioin the serum). The positive rate of oligoclonalbands of about 35 to 46% in Japanese patientsis lower than in Westerners. Furthermore,although the number of cells in the cerebro-spinal fluid of MS patients should be less than50/mm3, the cell numbers exceed 50/mm3 in aconsiderable number of Japanese patients.

Fig. 1 Head MRI (FLAIR) image of a patient withmultiple sclerosis: multiple high-density areasare observed in the white matter around thelateral ventricles.


AUTOIMMUNE NEUROLOGICAL DISEASES

including trigeminal neuralgia, paroxysmalarticulation disorders, and dystonic paroxysm(often called tonic convulsions).

4. TreatmentAdrenocortical steroids have long been used

for the treatment of relapsing/remitting MS.The most reliable therapy is the intravenousdrip infusion of 1,000 mg of methylpredniso-lone (for 3 days), followed by the oral admin-istration of prednisolone. Although these ster-oids shorten the periods of administration orsymptomatic relapse, they do not reduce therelapse rate or change the long-term prognosis.Plasmapheresis may be effective for patientswho do not respond to a massive dose ofmethylprednisolone.

Amantadine and selective serotonin reup-take inhibitors serve as useful symptomatictreatment for relieving fatigue. Carbamazepineis often effective for trigeminal neuralgia andLhermitte’s sign. Carbamazepine or phenytoinis used to treat dystonic paroxysm.

Interferon �-1b (Betaferon®) was approvedin Japan in September 2000 for relapsing/remitting MS and secondary progressive MS toreduce the relapse rate. It is also effective foroptic-spinal MS. It is used by subcutaneouslyinjecting 8 MIU (million international units)every other day. It has been reported to causeadverse effects such as influenza-like symp-toms, redness/pain/necrosis at the injectionsite, and depression.

Myasthenia Gravis

The prevalence rate of myasthenia gravis(MG) has been reported to be 5 to 7 per100,000 people. It occurs relatively frequentlyin females in their twenties and thirties, buttends to more frequently occur in males in theirforties or older.

1. Clinical symptomsThe most evident symptom is tiring easily.

The repeated use of muscles causes muscular

weakness, which quickly becomes evident asfatigue. The fatigability may be improved bytaking a rest. In addition, MG is subject tointraday or interday variation (for example,it is more severe in the evening than in themorning).

MG often develops with blepharoptosis anddouble vision owing to extraocular muscleweakness, although it may develop with bulbarparalysis (articulation disorders and dyspha-gia) or muscular weakness of the limbs (withproximal muscles being dominant). The symp-toms are not always symmetrical.

2. Diagnosis(1) A diagnostic test is performed with

edrophonium hydrochloride (Tensilon®), ashort-acting anticholinesterase agent. Its solu-tion (dissolved in 9 ml of physiological salineat 10 mg/ml) is intravenously administered todetermine whether it improves muscular weak-ness or not.

(2) A repeated stimulation test using asurface electromyogram is performed at 1, 3, 5,10, and 20 Hz. The patients with MG show awaning phenomenon (reduced amplitude ofprovoked potential as compared with the firsttrial) in response to either high or low fre-quency stimuli.

Fig. 2 Chest CT of myasthenia gravis.Thymoma (arrow) is apparent in the anteriormediastinal region.


(3) A blood test is performed for anti-acetylcholine receptor antibody. The antibodyis positive in about 80% of MG patients,although the antibody titer does not alwayscorrelate with the severity of the disease.

(4) Imaging diagnosis (CT or MRI) is per-formed for the anterior mediastinal regionbecause MG is often complicated with thy-moma or thymic hyperplasia (Fig. 2).

3. TreatmentAn appropriate treatment should be selected,

depending on the symptoms of each patient.Basically, MG is treated with anticholin-esterase agents or adrenocortical steroids tobe administered every other day, or thymec-tomy. Oral anticholinesterase agents, such asMestinon® and Mytelase®, inhibit acetylcholin-esterase, and mild MG may be resolved withanticholinesterase therapy alone.

However, they do not treat the basic mecha-nism of MG lesions, that is, they are noteffective for the actions of the autoantibodiesagainst postsynaptic receptors or adjacent mus-cle membrane. Therefore, an adrenocorticalsteroid is administered every other day for MG,except the ocular muscle form. It is started at adose of 20 to 30 mg/day and maintained at 60to 100 mg/day for several weeks followed bygradual dose reduction.

Immunosuppressive agents such as aza-thioprine and cyclosporin can be used inintractable cases that do not respond to anti-cholinesterase agents or adrenocortical ster-oids. (These immunosuppressive agents are notcovered by the Japanese medical insurancescheme.)

In September 2000, tacrolimus (Prograf®)was approved for coverage by Japanesemedical insurance for patients who do notrespond well to steroids or for whom steroidsare contraindicated. A recent study reportedthat the drug was markedly effective in somecases.3)

Plasmapheresis or massive �-globulin admin-istration (intravenous immunoglobulin: IVIG)

is performed in severe cases or in those whodeveloped a crisis. The effects of plasma-pheresis are not significantly different betweenthe double filtration and immune adsorptiontechniques. IVIG is generally administered at400 mg/kg for 5 days.

Thymectomy is essential for patients withthymoma. In patients without thymoma, resid-ual fat tissue in the anterior mediastinal regionis removed.

Guillain-Barré Syndrome

It is important to differentiate the demyelin-ating and axonal forms of polyneuropathy byperforming a nerve conduction test and check-ing for F wave abnormality. The most commontype of demyelinating polyneuropathy resultsfrom the inflammation of myelin sheaths and istherefore called inflammatory demyelinatingpolyneuropathy. Its acute form is Guillain-Barré syndrome (GBS). It should be noted thatGBS is different in Japanese and Westerners —the axonal form accounts for about 30% inJapanese patients.

1. Clinical course and prognosisIn typical patients with GBS, tetraplegia

rapidly progresses and the progression stopswithin 4 weeks. After an average plateauperiod of 2 weeks, the patients start to recover.However, some patients may show differentclinical courses, including the suspension of theprogression, phased exacerbation of tetra-plegia, and recurrence of symptoms duringrecovery.

Although plasmapheresis and IVIG, whichare described later, may modify these clinicalcourses, the prognosis of GBS is poor in theelderly, patients with rapidly progressing symp-toms, those requiring artificial respiration, andthose with electrophysiologically low ampli-tude of complex muscular action potential.Further, the patients with axonal GBS gener-ally have a poorer prognosis than those withdemyelinating GBS.



Although more than 75% of GBS patientshave complete functional recovery within 6months of its onset, about 15% have sequelaethat limit daily activities. GBS recurs infre-quently, with a recurrence rate of 5% or lower.

2. Etiology and mechanismAbout two-thirds of patients with GBS have

a history of prior infections (such as upper res-piratory inflammation or diarrhea). The patho-gens involved include Campylobacter jejuni,cytomegalovirus, Epstein-Barr (EB) virus, myco-plasma, HIV, and influenza bacillus.

The most common in Japan is infectionwith C. jejuni, which is an important bacteriumresponsible for bacterial diarrhea. It should benoted that GBS associated with C. jejuniinfection is frequently observed in China. GBSassociated with C. jejuni often develops as apurely motor axonal form.4)

The annual prevalence of GBS in Japan is 1to 2 individuals per 100,000, which is compa-rable to that in Western countries.

3. TreatmentThe main treatment for GBS is to remove

anti-ganglioside antibodies and TNF-�, whichare considered to be involved in the onset ofGBS and increase in the acute phase of thedisease. Adrenocortical steroid therapy hadpreviously been used, but it was provedineffective when administered alone. There-fore, plasmapheresis, IVIG, and pulse therapywith methylprednisolone are currently used.Other standard treatments include those forrespiratory disorders, arrhythmia, abnormalblood pressure, and complications such asinfections and pulmonary infarction, as well asrehabilitation during the recovery phase.

Plasmapheresis is roughly divided intosimple plasmapheresis, plasmapheresis basedon double filtering, and plasma adsorptionusing an immune adsorber. Plasmapheresisinhibits exacerbation, shortens the morbidperiod (including artificial respiration periodor period until the patient can walk), and

relieves sequelae.Plasmapheresis is generally indicated for the

following patients:(1) Patients with moderate or severe symp-

toms (Grade 4 or higher as evaluated withthe Hughes’ functional grade (Table 1))or those classified into Grade 3 who haveprogressive muscular weakness

(2) Patients within 14 days of onset(3) Patients without serious circulatory, renal

or hepatic diseases(4) Patients at 16 years old or older without

septic shock, a history of myocardialinfarction within 6 months, markedautonomic disorder, or tendency tohemorrhage.

The following frequency is considered appro-priate for plasmapheresis depending onseverity.5)

(1) Two times for mild patients (who canwalk and stand, but cannot run)

(2) Four times for moderate patients (whoneed assistance standing) and severepatients (who need artificial respiration)

Any of the above plasmapheresis techniquesusually improves GBS symptoms and suspendsthe progression of GBS within one week afterthe start of the treatment.

IVIG has been demonstrated to improvemotor function, shorten the morbid period,and reduce the rate of patients who need artifi-cial respiration 4 weeks after the start of the

AUTOIMMUNE NEUROLOGICAL DISEASES

Table 1 Hughes’ Functional Grade

Grade 0 Normal

Grade 1 Has mild neurological symptoms

Grade 2 Can walk for 5 meters without a cane

Grade 3 Can walk for 5 meters with a cane orsupporting device

Grade 4 Is restricted to bed or wheelchair

Grade 5 Requires assisted ventilation

Grade 6 Dead



Fig. 3 General guide to Guillain-Barré syndrome

treatment. IVIG is expected to provide analmost comparable effect to plasmapheresis.IVIG is performed by intravenous drip infu-sion of 400 mg/kg/day of a human immuno-globulin preparation (Venilon-I®) for 4 to 6hours once daily for 5 straight days.

The pulse therapy with methylprednisoloneis not effective when given alone. However,it has been reported to improve motor functionat week 4 or to shorten the period until inde-pendent gait when combined with IVIG. Thepulse therapy is performed by the intravenousdrip infusion of 500 mg/day of methylpred-nisolone together with human immunoglobulinpreparation for 5 days continuously.

Because of the low prevalence rate, it is

difficult for patients and their families or otherpeople, including paramedical staff, to obtaindetailed information on GBS. With supportfrom the Guillain-Barré Syndrome FoundationInternational, an international GBS organiza-tion, we have prepared a General Guide toGuillain-Barré Syndrome (Fig. 3), which isavailable at no cost.

Conclusion

This paper discussed three autoimmuneneurological diseases, multiple sclerosis, myas-thenia gravis, and Guillain-Barré syndrome.We would like to emphasize again the impor-tance of understanding their specific character-istics in Japanese patients in order to provideappropriate treatment.

REFERENCES

1) McDonald, W.I., Compston, A., Edan, G.et al.: Recommended diagnostic criteria formultiple sclerosis: guidelines from the Inter-national Panel on the diagnosis of multiplesclerosis. Ann Neurol 2001; 50: 121–127.

2) Thompson, A.J., Montalban, X., Barkhof, F.et al.: Diagnostic criteria for primary progres-sive multiple sclerosis: a position paper. AnnNeurol 2000; 47: 831–835.

3) Evoli, A., Di Schino, C., Marsili, F. et al.:Successful treatment of myasthenia graviswith tacrolimus. Muscle Nerve 2002; 25: 111–114.

4) Ogawara, K., Kuwabara, S., Mori, M. et al.:Axonal Guillain-Barré syndrome: relation toanti-ganglioside antibodies and Campylo-bacter jejuni infection in Japan. Ann Neurol2000; 48: 624–631.

5) The French Cooperative Group on PlasmaExchange in Guillain-Barré Syndrome:appropriate number of plasma exchanges inGuillain-Barré syndrome. Ann Neurol 1997;41: 298–306.



Autoimmune Bullous Diseases

1. ConceptIn autoimmune bullous diseases, antibodies

against epidermal antigens damage the epi-dermis, resulting in bullous formation. Auto-immune bullous diseases are divided into twogroups: the pemphigus group with antibodiesagainst substances between epidermal cells,and the pemphigoid group with antibodiesagainst epidermal basement membrane.

Desmosome and hemidesmosome are con-sidered to play important roles in the adhesionof epidermal cells. Recent molecular-biologicalstudies have shown that the antigens of all auto-immune bullous diseases are the componentsof desmosome and hemidesmosome. Figures 1

Autoimmune Diseases in DermatologyJMAJ 47(9): 431–435, 2004

Hiroo YOKOZEKI* and Kiyoshi NISHIOKA**

*Associate Professor, **Professor, Tokyo Medical and Dental University

Abstract: This article summarizes the concept, clinical characteristics, and treat-ment of bullous diseases and erythema nodosum, which are typical autoimmunediseases in the field of dermatology. Autoimmune bullous diseases are classifiedinto the pemphigus group, with antibodies against substances between epidermalcells, and the pemphigoid group, with antibodies against epidermal basementmembrane. The causative antigens for each group have recently been identified.Type-III allergic reaction induced by bacteria, medicine, etc. as causative antigensis thought to be involved in the development of erythema nodosum. The treatmentof the diseases chiefly consists of removal of causative antigens and steroidhormone therapy.

Key words: Pemphigus; Bullous pemphigoid; Erythema nodosum;Autoimmune disease

and 2 show the structure and componentproteins of hemidesmosome and desmosome,respectively.

Desmosome exists in epidermal cell mem-brane. Keratin intermediate-sized filamentscombine with the intracellular adhesion plate.Two membrane proteins of desmoglein anddesmocollin maintain intercellular adhesion,each of which is subdivided into Types 1 to 3.Intracellular adhesion is based on desmo-plakin (DPL), envoplakin (EPL), periplakin(PPL), placoglobin (PG), and placophilin.Types 1 and 3 desmoglein are the target anti-gens of pemphigus.1–3)

Keratin intermediate-sized filaments alsocombine with the adhesion plate of hemi-desmosome. Intracellular adhesion plate pro-



2. Pemphigus(1) Definition and classification

Pemphigus is a representative autoimmunedermal disease associated with autoantibodiesagainst substances between epidermal cells. Itis divided into four classic types — pemphigusvulgaris, pemphigus vegetans, pemphigus foli-aceus, and pemphigus erythematosus — as wellas other types of herpetiform, drug-induced,tumor-associated, and IgA pemphigus. Theantigens of each type of pemphigus are listedin Table 1.(2) Clinical symptoms and pathological

findingsPemphigus vulgaris often develops as in-

tractable diffuse oral lesions, followed by loosebullae and erosions on the skin (Fig. 3). Thebullae and erosions tend to develop at inter-triginous sites and be epithelialized withoutscarring.

Pemphigus vulgaris is associated with thebullous formation on mechanically stimulatednormal skin, which is called “Nikolsky’s sign.”Histopathologically, acantholysis (epidermalcells are separated from each other to form

H. YOKOZEKI and K. NISHIOKA

teins include BP230 and plectin that belong tothe plakin family. Trans-membrane proteinsinclude BP180 and �6�4 integrin. BP180 andBP230 are the target antigens of bullouspemphigoid.1,4)

Keratin intermediate-sized filaments

Basal cells

Adhesion plate

Cellmembrane

Clear layer

Basallamina

Dermis

Reserved fibersType VII collagen

Type IV collagen

Dermal collagen

�6�4integrin

Laminin 5(Epiligrin)

Hemidesmosome

N N N

C

CC C

NN

�6�4�6�4

Ple

ctin

BP

230

BP

180

Fig. 1 Structure of hemidesmosome (see Reference 1)

Fig. 2 Structure of desmosome (see Reference 1)(EPL: Envoplakin, PG: Placoglobin, DPL: Desmoplakin, PPL: Periplakin)

Adhesion plate Adhesion plate

EPL

DPL I

DPL II

DPL I

DPL II

PPL

PG

PG

Inside of cell

Keratin intermediate-sized filaments

Outside of cell

Cell membrane

Inside of cell

Cell membrane

Desmoglein 1 to 3(Dsg 1 to 3)

Desmoglein 1 to 3(Dsg 1 to 3)

Desmocollin 1 to 3(Dsc1to 3)

Desmocollin 1 to 3(Dsc1to 3)


AUTOIMMUNE DISEASES IN DERMATOLOGY

intraepidermal bullae) is observed over thebasal layer. Skin biopsy using a fluorescentantibody technique shows the deposition ofIgG and C3 between epidermal cells.

Pemphigus vegetans is a subtype of pem-phigus vulgaris and appears as a verruciformskin elevation associated with epidermal hyper-trophy by the long-term mechanical stimuli atintertriginous sites.

Pemphigus foliaceus causes shallow ero-sions, squamae, and crusts at seborrheic sites ofthe head, face, chest, and back. The erosionsare quickly resolved, although pigmentationremains. This type of pemphigus is usually not

associated with oral lesions.Pemphigus erythematosus is a subtype of

pemphigus foliaceus. It causes exanthema atseborrheic sites as in pemphigus foliaceus.Furthermore, it causes a butterfly erythemaassociated with keratose erosions on the face.It may be positive for antinuclear antibodiesand complicated with thymoma. The biopsy ofpemphigus foliaceus and erythematosus showssubcorneal bullae associated with acantholysis.(3) Diagnosis

Pemphigus can be easily diagnosed based onclinical symptoms, histopathological exami-nation, fluorescent antibody technique, andenzyme-linked immunosorbent assay (ELISA).It has to be differentiated from other auto-immune bullous diseases, drug eruption, andimpetigo contagiosa.(4) Treatment

Pemphigus vulgaris or vegetans should betreated with steroid hormones at an initial doseof 40 to 60 mg/day (the dosage is based onpredonisolone®). If the disease does notrespond, the dose should be increased 1.5 to 2times or steroid pulse therapy performed.Previous studies reported that the combina-tion with immunosuppressive agents (such ascyclosporin and MTX), plasmapheresis, andmassive �-globulin therapy was effective for

Table 1 Classification and Antigens of Pemphigus

Subtype Immunoglobulin Antigen

Pemphigus vulgaris IgG Desmoglein 3 (DG3)

Pemphigus vegetans IgG DG3

Pemphigus foliaceus IgG DG1

Pemphigus erythematosus IgG DG1

Herpetiform pemphigus IgG DG1 (DG3)

Drug-induced pemphigus IgG Various

Tumor-associated pemphigus IgG Desmoplakin, envoplakin, periplakin, BP230,DG1 and 3, and 170 kDa protein

IgA pemphigus IgA Desmocollin 1

(Quoted from Hashimoto, T.: Hydroa. Easy Dermal Immunology (Nishioka, K. ed.) 2002;pp.199–208) (in Japanese)

Fig. 3 Clinical case with pemphigus vulgaris


intractable pemphigus. Pemphigus foliaceusoften requires a smaller oral dose of steroidhormone than pemphigus vulgaris: an initialdose of 20 to 40 mg/day (based on predo-nisolone®) may be enough.

3. Bullous pemphigoid(1) Concept and definition

Bullous pemphigoid is an autoimmune bullousdisease in which autoantibodies react with230 kDa and 180 kDa pemphigoid antigens inhemidesmosome to cause subepidermal bullae.Tense and filled bullae on severely itchingedematous erythema in the elderly clinicallycharacterize the disease.(2) Clinical symptoms and pathologic findings

As described above, bullous pemphigoidtends to develop in the elderly. At first,urticaria-like or exudative erythema associatedwith severe systemic itching develops, followedby the gradual formation of tense and filledlarge bullae on erythema. The bullae, whenruptured by scratching, cause erosions thatlook like burns on the whole body. Severebullous pemphigoid may be complicated withfever, body weight loss, and anemia. Histo-pathologically, subepidermal bullae associatedwith eosinophilic and neutrophilic infiltrationcharacterize the disease. Fluorescent antibodytechnique shows the linear deposition of IgGand C3 along the basement membrane.(3) Treatment and prognosis

Mild bullous pemphigoid may be resolvedonly with the external application of steroidhormone. However, the disease is basicallytreated with the oral administration of steroidhormone: an initial dose of 40 mg/day (basedon predonisolone®) is often used. Sulfa agents,such as diaminodiphenyl sulfone (DDS) anddiaphenylsulfone (Lectisol®), or the combina-tion therapy of minocycline and nicotinamidehave been reported to be effective.

The prognosis of the disease is good, and thedisease can be controlled with the oral admin-istration of steroids. However, since manypatients with the disease are elderly, attention

should be paid to possible infections andmalignant tumors.

Erythema Nodosum

1. ConceptErythema nodosum is a painful erythema

that develops on the extensor side of the leg.Histologically, septal panniculitis at the septumbetween subcutaneous fat and connectivetissue characterizes the disease.

2. EtiologyEtiologic factors of erythema nodosum

include infection with bacteria including hemo-lytic streptococcus, Mycobacterium tuberculosis,Mycobacterium leprae, and viruses, as well asdrugs, Behçet’s disease, sarcoidosis, and ulcer-ative colitis. Among them, the infection withhemolytic streptococcus, such as tonsillitis,is considered the most important factor.Although it has been suggested that Type IIIallergic reaction to these antigens may beinvolved in the development of the disease,this hypothesis has not been fully examined.Erythema nodosum is considered to occur in10 to 15% of patients with Sweet’s disease and80% of those with Behçet’s disease.

3. Clinical symptomsErythema tends to occur on the extensor

side of the leg, although it may occur on thefemoral region and forearm. Erythema appearsas a painful and poorly defined mild elevationat which subcutaneous induration is palpable(Fig. 4). It is associated with heat, but not witherosions and ulcers. Erythema disappears inseveral weeks, but pigmentation remains. It isoften associated with fever and may be asso-ciated with articular pain of the knee.

4. Histopathological findingsMaking a diagnosis of erythema nodosum

needs a skin biopsy to histopathologicallyexamine the erythematous lesion. The lesionextends from the dermal substratum to sub-

H. YOKOZEKI and K. NISHIOKA


AUTOIMMUNE DISEASES IN DERMATOLOGY

Fig. 4 Clinical case with erythema nodosum

cutaneous tissue and mainly results from septalpanniculitis or inflammation of fat tissue at theseptum with connective tissue. In the earlystage, the disease shows neutrophilic and lym-phocytic infiltration and fibrin precipitation infat tissue. It then gradually presents chronicgranulomatosis-like findings, such as infiltra-tion of histiocytes and giant cells, hyperplasiaof capillary vessels, and increase in fibroblasts.

5. Laboratory findingsErythema nodosum is associated with inflam-

matory findings including increased white bloodcell count, blood sedimentation rate and CRP.Increased ASO and ASLO are observed inpatients infected with hemolytic streptococcus.

To examine the possible complication bypulmonary tuberculosis and sarcoidosis, it isalso necessary to perform chest X-rays and atuberculin test.

6. Diagnosis and differentiationAny painful erythema associated with sub-

cutaneous induration on the leg has to bepathologically examined with skin biopsy todifferentiate it from the following diseases.(1) Erythema induratum (Bazin)

This type of erythema can be clinically differ-entiated by ulcerative erythema on the legwith persistent scars. Histopathologically, thediagnosis of the disease can be made with histo-logical findings of lobular panniculitis, in whichinflammation occurs mainly in fat tissue lob-ules, and epithelioid cell-like granuloma andcaseation necrosis.(2) Thrombophlebitis

Restiform induration clinically characterizesthrombophlebitis. This disease can be histo-pathologically differentiated from erythemanodosum.(3) Periarteritis nodosa (cutaneous type)

Subcutaneous induration consistent with thecrossings of livedo reticularis clinically charac-terizes the disease. Pathologically, this diseaseappears as necrotic angitis.

7. TreatmentErythema nodosum improves only by ele-

vating the leg and allowing the patient to rest.At first, an infectious focus of tonsillitis islocated. When an infection with hemolyticstreptococcus is suspected, it is necessary toadminister a penicillin antibiotic. An under-lying disease such as tuberculosis, fungal infec-tion, sarcoidosis, or Sweet’s disease, if any, istreated. Temporary systemic administration ofsteroid hormone is attempted in patients withsevere fever and arthralgia without infectiousfocus and underlying disease, although thisshould be done carefully.

REFERENCES

1) Hashimoto, T.: Hydroa. Easy Dermal Immu-nology (Nishioka, K. ed.) 2002; pp.199–208.

2) Amagai, M. et al.: Autoantibodies against anovel epithelial cadherin in pemphigus vulgaris,a disease of cell adhesion. Cell 1991; 67: 869–877.

3) Amagai, M. et al.: Absorption of pathogenicautoantibodies by the extracellular domain ofpemphigus vulgaris antigen (Dsg3) producedby baculovirus. J Clin Invest 1994; 94: 59–67.

4) Korman, N.J.: Bullous pemphigoid. ArchDermatol 1998; 134: 1137–1141.


Current System for Regulation ofHealth Foods in JapanJMAJ 47(9): 436–450, 2004

Heizo TANAKA*, Fumi KANEDA**,Reiko SUGURO*** and Hiroko BABA****

* Director-general, National Institute of Health and Nutrition** Division of Health and Nutrition Monitoring,

National Institute of Health and Nutrition*** Japanese Society of Nutrition and Dietetics

**** Medical Research Institute, Tokyo Medical and Dental University

Abstract: The current Japanese system for regulation of “health foods” callsthem “Foods with Health Claims” and divides them into two categories. One is“Foods with Nutrient Function Claims.” The label can be freely used if a productsatisfies the standard for the minimum and maximum daily levels of consumption.Twelve vitamins and five minerals are presently standardized. The other is “Foodsfor Specified Health Uses.” They contain dietary ingredients that have beneficialeffects on physiological functions of the human body to maintain and promotehealth and to improve health-related conditions. Health claims for these foodscorrespond to the enhanced or “other” function claims of Codex Alimentarius orstructure/function claims of the United States. However, disease risk reductionclaims are not allowed. After the Food Safety Commission examines the safety ofthe product and the Pharmaceutical Affairs and Food Sanitation Council evaluatesthe effectiveness, the Ministry of Health, Labor and Welfare gives official approval,allowing the manufacturer to carry the structure/function claims and mark on theproduct. In order to maintain and improve people’s health and to prevent chronicnon-communicable diseases, a well-balanced diet is much more important than“health foods,” including “Foods with Health Claims.”

Key words: Dietary supplement; Foods with health claims;Foods with nutrient function claims;Foods with specified health uses;Disease risk reduction claims

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 126, No. 6, 2001, pages 792–805).The Japanese text is a transcript of a lecture originally aired on June 13, 2001, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

� Health Foods


REGULATION OF HEALTH FOODS IN JAPAN

Introduction

The purpose of the present paper is todescribe the current regulatory system for“health foods” in Japan. In 2004, however, thesystem may be amended based on the report ofthe Advisory Committee of the New Systemfor Regulation of “Health Foods” (Chairman:H.T.), the Japanese Ministry of Health, Laborand Welfare (called the Ministry of Health andWelfare until 2001). Some points that werebeing debated by the Committee will also bementioned in this paper.

The term “health food” is often used inJapan, although a clear definition of “healthfood” has not been established.1) Accordingto the US Dietary Supplement Health andEducation Act (DSHEA) of 1994,2) dietarysupplements can be extracts or concentrates,and may be found in many forms such astablets, capsules, softgels, gelcaps, liquids, orpowders. On the other hand, Japanese “healthfoods” can not only be produced in forms thatresemble drugs, but may also take the form ofconventional or processed foods such as ‘tofu’(bean curd), noodles, Hamburg steak, sau-sages, crackers, yogurt, beverages and confec-tionery. The difference in forms is the mainreason why the term “health food” is usedinstead of dietary supplement in Japan. There isno major difference in the dietary ingredientsof the two. As defined in the DSHEA,2) a“health food” is a product taken orally thatcontains a dietary ingredient intended tosupplement the diet. The dietary ingredients inthese products may include: vitamins, minerals,amino acids or proteins, fatty acids or oil, herbsor other botanicals, and substances such asenzymes, organ tissues, glandulars, and metabo-lites. “Health food” is a generic term for foodproducts, whether foods, drinks or dietarysupplements, that carry nutrient function andhealth claims or that are designed to be moreeffective than common foods in helping peoplemaintain and promote their health, or at leastare expected to have such an effect.1) But

“health foods” do not include organically pro-duced foods.

A Tentative Classification of“Health Foods”

Primitive humans, who evolved approxi-mately 1 million to 200,000 years ago, gatheredwild plants, animals, and minerals that theyknew to be edible through experience.1,3) Thenour ancestors deliberately cultivated anddomesticated particular species of plants andanimals. Processed foods were also introducedin order to preserve food quality, achieve morecomplete use, and provide a stable supply offoodstuffs. Recently, recombinant gene tech-nology has allowed the creation of new species,giving rise to plants rich in �-carotene andother special nutrients (enriched products),and even cloned cows. We prepare these con-ventional foods for eating by boiling, broiling,frying, and seasoning them. We usually eatcooked foods.

A conventional food contains more than onenutrient. “Health foods” that are rich in a spe-cific nutrient are identified, and then manynutrient-products are made by extraction, fer-mentation, enzyme activation and synthesis. Ifthey are found to have physiologically activefunctions other than nutrient functions, e.g.,antioxidation or immune system enhancement,they are recognized as a group of “healthfoods” (1 in Table 1) and authorized as “Foodswith Nutrient Function Claims” in Japan.4)

A conventional plant food generally hastwo components: nutrients and non-nutrients.Among non-nutritive components are chloro-phyll, isoprenoids or terpenoids, tannins, ste-roids, flavonoids, carotenoids, organosulfurcompounds, organic acids and others that canhave physiological effects beyond the tradi-tional nutritional effects: immunity enhance-ment, antioxidation, anticoagulation and others,or the reduction of the risk of a disease. Thesefall under the second group of “health foods”called biogenics, a kind of functional food [2-2)


in Table 1].Prebiotics and probiotics are the third group

of “health foods,” some of which are legallyapproved as “Foods for Specified Health Uses”or “foods with structure/function claims2)

or enhanced or ‘other’ function claims5)” inJapan.6–8) A prebiotic is defined as a non-digestible food ingredient that beneficiallyaffects the host by selectively stimulatingthe growth and/or activity of one or a limitednumber of bacteria in the colon [2-1) in Table1], and a probiotic is defined as a live microbialfood ingredient that is beneficial to health (5 inTable 1).

Drugs and foods share the same origin. TheChinese concept that medicine and food areessentially the same may be partly based onthis fact.1,3) While humans were hunting wild

animals and gathering plants and minerals forfood, they discovered roots, leaves, and barksof plants (medicinal herbs), organs and tissues(including stones) of animals, and someminerals that were effective against diarrhea,pain, bleeding, etc. Our ancestors collected andstored such useful natural products. Also, infor-mation about useful natural products waspassed from generation to generation in differ-ent areas and by different ethnic groups. It wasin China that herbal medicines or Chinesemedicines were developed, and some books onthem were written between the first and thirdcenturies.1,9) They have been widely used ascrude drugs in Japan as well as in China sincethat time. With the technological progress ofscience in the 20th century, it was found thatsome of them had specific components with

Table 1 Biologically Active Ingredients in “Health Foods” Used Mainly in Japan

1. Nutrient1) Nutrient function Vitamin. Mineral. Protein.

2) Other function Vitamin C, E (Antioxidation). Rice, wheat, barley and adlay germ. Branched chain amino acid.Lacto-tripeptide, sardine-peptide and oligo-peptide from dried bonito (Inhibitor of angiotensin converting enzyme).EPA, DHA, �-, �-linoleic acid, oleic acid, diacylglycerol, and medium chain fatty acid. Coenzyme Q10

2. Non-Nutrient1) Prebiotics Dietary fiber (Indigestible dextrin, blond psyllium husk, algin, etc.).

Polysaccharide (Chitosan, glucosamine, chondroitin, etc.).Oligosaccharide (Lacto-sucrose, fructo-oligosaccharide, galacto-oligosaccharide, lactulose, etc.).Sugar alcohol (Xylitol, maltitol, lactitol, sorbitol, mannitol, etc.).

2) Biogenics Isoprenoid (Glycyrrhizin, triterpenoid saponins in Panax ginseng, gymnema, etc.).(Phytochemicals) Tannin (Catechin in green tea, etc.). Steroid (Sitosterol, etc.).

Flavonoid (Flavonoid glycoside in ginkgo leaf, daidzin, genistein, etc. in soy, anthocyanin in blueberry, etc.).Carotenoid (�-, �-carotene in palm kernel oil, etc.).Organosulfur compound (Alliin, allicine, etc. in allium vegetables, etc.).Organic acid (Hydroxycitric acid in garcinia, etc.).Chlorophyll (Chlorophyll in chlorrella and spirulina, etc.).

3. Specific ingredient Anthraquinones in Aloe arborescens natalenis and Aloe vera.(Crude drug origin) Curcumin in turmeric. Hypericin in St. John’s wort. Betaine, zeaxanthin, beta-sitosterol, etc. in dried berries and

root bark of lycium. Gutta-percha, eucommial, etc. in bark of Eucommia ulmoides, etc.

4. Multiple ingredients1) Plant origin Agaricus blazei, Ganoderma lucidum, Phellinus linteus, Zizania latifalia, kale, saw palmetto, prune, raspberry,

fucoidan, etc.

2) Animal origin Royal jerry, propolis, etc.

3) Mineral origin Bittern, etc.

5. Probiotics and Lactobacillus, bifidobacterium, etc.microorganisms Beer yeast, Bacillus subtilis natto, etc.

Jar vinegar, husked rice vinegar, etc.

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medicinal effects, which were neither nutritivenor non-nutritive. The specific components andtheir derivatives were isolated and purified,and became ethical drugs: morphine wasobtained from opium, quinine from cinchona,salicin (its derivative is acetyl salicylic acid)from the bark of certain poplars and willows,steroids from animal adrenal cortex, prostag-landins from semen, etc.9) In 1971, the Directorof the Pharmaceutical Bureau, the Ministry ofHealth and Welfare, issued the notification,“Instruction and Regulation for DisapprovalDrugs,” in which approximately 170 ingredi-ents that originated from plants and animalswere defined as foods, because they weremildly effective and probably safe.10) Hence, aslong as indications and actions are not claimed,they are not regarded as drugs. They are thefourth group of “health foods” (3 in Table 1).

The fifth group is complicated (4 in Table 1).There are some food products that originate innatural resources, plants or animals, and carryhealth benefits. But the effective ingredient isnot identified. Although all of the dietary ingre-dients in a food product are identified, we donot know which ingredient is effective. If manynutritive, non-nutritive and specific compo-nents coexist in a food, their interaction maycontribute to promoting health or reducing therisk of disease.4) Some of them have been soldin the market for more than 10 years and havebeen presumed safe: agaricus, chlorella, propo-lis, royal jelly, etc. And it is difficult to distin-guish them from the second, third and fourthgroups of “health foods.”

Changes in Japanese Regulations on“Health Foods”

The concept of functional foods first evolvedin Japan in the mid-1980s.11,12) Japanese foodscientists who were members of research teamson functional foods sponsored by the Ministryof Education, Science and Culture, proposedthat, while the primary role of food was toprovide adequate nutrients to meet metabolic

requirements and the secondary role was toprovide gustatory and olfactory satisfaction,there existed the tertiary function of promotinga state of well-being and better health and reduc-ing the risk of disease. The scientists definedfunctional foods as those that emphasized thetertiary element or those that were designed toprovide beneficial health effects: enhancementof gastrointestinal functions, immunomodu-lation, antioxidation, antimutation, antitumoraction, hematopoiesis, antithrombogenesis,reduction of blood pressure, blood lipids andblood sugar, neuroregulation, etc. Functionalfoods can fall into the second, third or fifthgroup of “health foods” mentioned in the pre-vious section.

The idea of functional foods attracted thegreat interest of companies in the health foodindustry, which were looking for products withhigh added value.12) Companies in the industrysaw a bright future for functional foods andbegan research and development activities. Asthe health food market expanded, the formerEnvironment Health Bureau, the Ministry ofHealth and Welfare, set up the Office of HealthPolicy on Newly Developed Foods in 1988 andthe Advisory Committee on “Functional Foods”in order to build up the regulatory system for“health foods.”

A system for “Foods for Special DietaryUses” had already been enforced under theNutrition Improvement Act (Health Promo-tion Act at present). They included food thatclaimed to be suitable for special dietary uses,e.g., formulated and dried milk for infants,dried milk for pregnant women and lactatingmothers, foods for the elderly with masticatingor swallowing disorders, and medical foodsfor the sick. Because the permission of theMinistry of Health was required to marketthe foods, the Office of Health Policy on NewlyDeveloped Foods decided in 1991 that some ofthe “health foods” would be categorized as“Foods for Special Dietary Uses” and named“Foods for Specified Health Uses” accordingto the report of the Advisory Committee of



Functional Foods.10,13) However, only “healthfoods” produced in conventional form wereincluded in this category.

Due to the deregulation and opening of themarket for foreign products, the Ministry ofHealth, Labor and Welfare started to revise theguidelines on foods and drug classifications,and to organize an advisory committee fordietary supplements.13) In March 1995, thefollowing deregulation plan was adopted at aCabinet meeting: 1) Some vitamins and miner-als should be marketed as foods even if theyare in the form of tablets or capsules; 2) Someherbs should be recategorized from drugs tofoods.

In October 1995, the American Chamber ofCommerce in Japan submitted a proposal tomarket dietary supplements as foods in Japan.In the following year, in March 1996, the Officeof Trade and Investment Ombudsman (OTO)decided to open up the market for dietarysupplements based on the following: 1) A newcategory should be set up for dietary supple-ments; 2) The restrictions on the formulation ofdietary supplements should be abolished orlargely deregulated; 3) The restrictions on thestructure/function claims of dietary supple-ments should be deregulated.1,12)

Based on the background described above,the Pharmaceutical and Food Safety Bureau,the Health Ministry, issued notifications andapproved the following ingredients as foods,even if they are supplied as tablets and cap-sules: 13 vitamins in 1997, 8 herbs in 1998, 8

Fig. 1 Current system for regulation of “health foods” in Japan

Drugs,including quasidrugs

Foods forSpecified Health Uses(Individual approval system)

Foods with Health Claims

Foods withNutrient Function Claims(Standard regulation system)

Nutrient and ingredient contents

Structure/function health claim

Attention and warning

Nutrient contents

Nutrient function claim

Attention and warning

Conventional foods,including “so-calledhealth foods”

minerals in 1999 and 5 minerals in 2000.10) InApril 2001, a new regulatory system for “healthfoods,” the System of Foods with HealthClaims, was enforced in accordance with thereports of two advisory committees on Regula-tions of Dietary Supplements and Revision ofClassification of Drugs and Foods.

System of “Food with Health Claims”

“Foods with Health Claims” are health foodsthat conform to the safety and efficacy stan-dards set by the Ministry of Health. They con-sist of two categories: “Foods with NutrientFunction Claims” and “Foods for SpecifiedHealth Uses” (Article 5, Enforcement Regula-tions, Ministerial Ordinance, of Food Sanita-tion Act, 2001. Fig. 1).

1. “Foods with Nutrient Function Claims”The Advisory Committee on Regulations of

Dietary Supplements (Chairman: H.T.), notonly studied nutrients, i.e., vitamins, minerals,amino acids, and fatty acids, but also someherbs or crude drugs, and dietary fibers as can-didates ingredients for regulation as dietarysupplements.10,13) Among them, however, theHealth Ministry chose only the nutrients andclassified them as a new category, i.e., “Foodswith Nutrient Function Claims.”

“Foods with Nutrient Function Claims” areintended to supplement or complement thedaily diet, in cases where the dietary intake isinsufficient due to increased age and unhealthy

H. TANAKA et al.


dietary practices or where consumers feelthat their diet requires supplementing. At thepresent time, the definition is the same as thatof vitamin and mineral food supplements inthe report of the 25th Session of the CodexCommittee on Nutrition and Foods for SpecialDietary Uses, November 2003,5) although“Foods with Nutrient Function Claims” canbe marketed not only in tablet and capsuleform, but also as conventional food, excludingperishable foods.

Twelve vitamins (vitamin A, E, D, B1, B2,B6 and B12, folid acid, niacin, pantothenicacid, biotin, and vitamin C) and two minerals(calcium and iron) were standardized as“Foods with Nutrient Function Claims” in2001, because the daily requirements for thesevitamins and minerals were defined in the sixthrevision of the “Recommend Dietary Allow-ance (RDA) for the Japanese”14) and the maxi-mum quantities were determined as “over-the-counter” drugs and quasidrugs. In addition,zinc, magnesium and copper were standardizedin 2004. The standardization of fatty acids andamino acids is under consideration.

The minimum level of each vitamin ormineral contained in the daily consumption

level of “Foods with Nutrient Function Claims”as suggested by the manufacturer should beone-third of the RDA for the Japanese. Themaximum level is the same as the maximumamount of nutrient items in “over-the-counter”drugs and quasidrugs.

The eight information statements that aremandatory for “Foods with Nutrient FunctionClaims” are listed in Table 2.10,13)

The nutrient content should be stated inaccordance with conventional nutrition label-ing standards (Notification on Nutrition Label-ing Standards, 2001).10,13) With respect to nutrientfunction claims, only the statements given inTable 3 are permitted.10,13)

“Foods with Nutrient Function Claims” donot need to be approved by the Ministry ofHealth before they are marketed. The manu-facturers do not need to register their productswith the Ministry of Health before producingor selling them.

2. “Foods for Specified Health Uses”“Foods for Specified Health Uses” are those

that contain dietary ingredients that havebeneficial effects on the physiological functionsof the human body to maintain and promote

Table 2 Mandatory Statements on the Label of “Foods with Health Claims” in Japan

“Foods with Nutrient Function Claims”

1. “Food with Health Claim (Food with Nutrient FunctionClaim)”

2. Nutrient contentEnergy, protein, lipid, carbohydrate, sodium, andthe mineral or vitamin claimed for function

3. Nutrient function claim

4. Dosage and administration5. Method of consumption6. Percentage of the daily portion of consumption to

the recommended dietary allowance

7. Attention and warning8. “Unlike food with specified health uses, this product has

not undergone individual evaluation by the Ministry ofHealth, Labor and Welfare.”

“Foods for Specified Health Uses”

1. “Food with Health Claim (Food for Specified Health Use)”

2. Nutrient contentEnergy, protein, lipid, carbohydrate, sodium, andthe ingredient claimed for function

3. Structure/function health claim or enhanced health claimapproved

4. Dosage and administration5. Method of consumption6. Percentage of the daily portion of consumption to

the recommended dietary allowance, if RDA is availablefor the ingredient

7. Attention and warning



Table 3 Nutrient Function Claims, and Attention and Warnings for “Foods with Nutrient Function Claims” in Japan

Nutrient Approved Statements for Nutrient Function Claims Attention and Warnings

Vitamin A Vitamin A is a nutrient that helps in the maintenance of Taking large amounts of this product will not curenocturnal visual acuity. disease or promote health. The indicated daily intakeVitamin A is a nutrient that helps to keep skin and mucosa should be followed. Women who are in the firsthealthy. trimester of pregnancy or desire to become pregnant

should not take this product excessively.

Vitamin D Vitamin D is a nutrient that increases the absorption of Taking large amounts of this product will not curecalcium in the intestine and helps the formation of bone. disease or promote health. The indicated daily intake

should be followed.

Vitamin E Vitamin E is a nutrient that helps to protect lipids in dittothe body from oxidation by antioxidative activity andto keep cells healthy.

Vitamin B1 Vitamin B1 is a nutrient that helps to produce energy dittofrom carbohydrates and to keep skin and mucosa healthy.

Vitamin B2 Vitamin B2 is a nutrient that helps to keep skin and mucosa dittohealthy.

Niacin Niacin is a nutrient that helps to keep skin and mucosa dittohealthy.

Vitamin B6 Vitamin B6 is a nutrient that helps to produce energy from dittoprotein and to keep skin and mucosa healthy.

Folic acid Folic acid is a nutrient that helps red blood cell formation. dittoFolic acid is a nutrient that contributes to the normal Although this product is a nutrient that contributesgrowth of the fetus. to the normal growth of the fetus, better development

of the fetus will not ensue from taking large amounts.

Vitamin B12 Vitamin B12 is a nutrient that helps red blood cell Taking large amounts of this product will not cureformation. disease or promote health. The indicated daily intake

should be followed.

Biotin Biotin is a nutrient that helps to keep skin and mucosa dittohealthy.

Pantothenic acid Pantothenic acid is a nutrient that helps to keep skin and dittomucosa healthy.

Vitamin C Vitamin C is a nutrient that not only helps to keep skin dittoand mucosa healthy but also has an antioxidative activity.

Calcium Calcium is a nutrient necessary for the formation of bones dittoand teeth.

Iron Iron is a nutrient necessary for the formation of red blood dittocells.

Zinc Zinc is a nutrient necessary to keep the sense of taste Taking large amounts of this product will not curenormal. disease or promote health. Because excess intake ofZinc is a nutrient that helps to keep skin and mucosa healthy. zinc can inhibit the absorption of copper, excessZinc is a nutrient useful for maintaining health by taking intake should be avoided. The indicated daily intakepart in the metabolism of protein and nucleic acid. should be followed. Infants and children should not

take this product.

Copper Copper is a nutrient that helps red blood cell formation. Taking large amounts of this product will not cureCopper is a nutrient that helps the normal activity of many disease or promote health. The indicated daily intakeenzymes in the body and bone formation. should be followed. Infants and children should not

take this product.

Magnesium Magnesium is a nutrient necessary for the formation of Taking large amounts of this product will not curebones and teeth. Magnesium is a nutrient that helps disease or promote health. Loose stool or diarrheathe normal activity of many enzymes in the body and can occur by taking large amounts. The indicatedenergy production, and it is necessary to keep the blood daily intake should be followed. Infants and childrencirculation normal. should not take this product.

Beta-carotene, a precursor of vitamin A, is allowed to state the same nutrient function claims as vitamin A. In this case, the followingstatement is not required: “Women who are in the first trimester of pregnancy or desire to become pregnant should not take this productexcessively.”

H. TANAKA et al.


health and to improve specific health-relatedconditions (Article 12, Enforcement Regula-tions, Ministerial Ordinance, of Health Pro-motion Act, 2003. Article 5, EnforcementRegulations of Food Sanitation Act, 2001.10,13)).In 1991, when the regulatory system for “Foodsfor Specified Health Uses” started, they werein conventional food form or processed foods.In 2001, however, the regulatory range wasbroadened to include capsules, tablets, etc.

The seven information statements that aremandatory for “Foods for Specified HealthUses” are shown in Table 2. Health claimscorrespond to the Enhanced (or other) Func-tion Claims of the Codex Alimentarius5) orStructure/Function Claims of the US.2) Thestatements must be based on current relevantscientific substantiation, but they cannot statethat a “food for specified health use” can beused to diagnose, prevent, treat, or cure a spe-cific disease. The Council of PharmaceuticalAffairs and Food Sanitation indicated theappropriate health claims as follows.10)

1) Because Food X contains substance A,Food X may maintain or improve a physi-ological condition marker that can be easilymeasured. The marker must be one thatpeople can evaluate by themselves or that ismeasured in a screening test.Statements that are allowed are:“Food X helps maintain blood pressure

(blood sugar, triglycerides or cholesterol)at normal levels.”

“Food X accelerates the breakdown of bodyfat.”

A statement that is prohibited is:“Food X improves hypertension.”

2) Food X may maintain or improve physi-ological and tissue functions of the humanbody.Statements that are allowed are:“Food X improves bowel movements.”“Food X increases the absorption of calcium.”Statements that are prohibited are:“Food X is effective for detoxification.”“Food X is effective for activation of lipid

metabolism.”3) Food X may improve subjective and tempo-

rary physical disorders, but not those thatare persistent or chronic.Statements that are allowed are:“Food X is good or useful for persons who

feel physical fatigue.”A statement that is prohibited is:“Food X helps prevent aging.”

Claims of reduced disease risk are notallowed for “Foods for Specified Health Uses”in Japan. Since claims of reduced disease risk asdefined by the Codex Alimentarius5) are diffi-cult to distinguish from medical claims, furtherconsideration is necessary to approve theclaims for “Foods for Specified Health Uses.”From the viewpoint of preventive medicine,“reduced cancer risk through dietary improve-ment” and “control of hypertension, hyper-lipidemia, abnormal glucose tolerance etc.through lifestyle modifications” are the pri-mary prevention of chronic non-communicablediseases.1) In Japan as in other countries, thePharmaceutical Affairs Act prohibits the use ofterms such as disease, prevention, treatment,cure, and diagnosis for food products. As men-tioned above, the statement, “Food X improveshypertension,” is a claim of reduced diseaserisk using the disease name, “hypertension.”Therefore, this statement is not permitted inJapan. Statements such as “food X is good forpersons whose blood pressure tends to be alittle high” and “food X is good for personswho are concerned about their blood pres-sure,” are acceptable.1,10) Some members ofthe Advisory Committee on Regulations ofDietary Supplements said that such claims on“Foods for Specified Health Uses” were thesame as disease risk reduction claims.1)

Application for “Foods for SpecifiedHealth Uses”

In order to market a product as a “Food forSpecified Health Use,” the manufacturer isrequired to submit two documents to the Office



of Health Policy on Newly Developed Foods,the Ministry of Health, Labor, and Welfare(� and � in Fig. 2): “Application for LabelingApproval” under the Health Promotion Act,and “Application for Judgment on the Safetyand Effectiveness of the Food” under theRegulatory Standards for Foods, Food Addi-tives, etc. (Ministerial Ordinance).10,13) First, theNovel Food Expert Committee, Food SafetyCommission, the Cabinet Office, examinesproduct safety (� and � in Fig. 2).

Secondly, the Newly Developed Food ExpertSubcommittee, the Newly Developed FoodExpert Committee, the Food Sanitation Sub-council, and the Pharmaceutical Affairs andFood Sanitation Council, in this order, evaluateproduct effectiveness (� and � in Fig. 2). TheNewly Developed Food Expert Subcommitteestrictly and impartially decides whether the

product should be accepted as a “Food forSpecified Health Use.” In addition, the NationalInstitute of Health and Nutrition or anotherlaboratory authorized by the Health Ministrydetermines the contents of the effective ingre-dient in the candidate food (�’, �’ and �’

Applicant (Manufacturer)

Office of Health Policy on Newly Developed FoodsMinistry of Health, Labor and Welfare

National Institute of Health and Nutrition, andOthers(Analysis of ingredients)

Novel Food Expert CommitteeFood Safety Commission(Examination of safety)

Newly Developed Food Expert SubcommitteeNewly Developed Food Expert CommitteeFood Sanitation SubcouncilPharmaceutical Affairs and Food Sanitation Council(Evaluation of effectiveness)

� �’ �’��

� � � �

�’

� Two documents, “Application for Labeling Approval” and “Application for Judgment on the Safety and Effectiveness of theFood”, are sent to the Office of Health Policy on Newly Developed Foods through Public Health Center and Prefectureor Major City Designated by Government Ordinance or Tokyo Metropolitan Ward.

� The Office checks the two documents before receiving them officially.� The Office asks the Novel Food Expert Committee to examine the safety.� The Committee notifies the safety confirmation to the Office.� The Office consults the Newly Developed Food Expert Subcommittee and three others to evaluate the effectiveness and

safety of the candidate product. The subcommittee or the Office conducts hearing from the manufacturer, if necessary.� The Pharmaceutical Affairs and Food Sanitation Council submits the report to the Office.� The Ministry of Health, Labor and Welfare approves the product as a “Food for Specific Health Use”, after confirming the

analytical findings of the physiologically active ingredient and nutrients which are measured by the National Institute ofHealth and Nutrition or another laboratory.

Fig. 2 Flow from application to approval for “Food for Specified Health Use”

Fig. 3 Mark of “Food for Specified Health Use”

H. TANAKA et al.


Table 4 Foods for Specified Health Use, Japan (March 2004)

Approved Use Biologically Active Component Product % Effectiveness15) Safety15)

for • • • • No.

Bowel movement Dietary fiber 74 17.5Indigestible dextrin 37 (1) (1)Blond psyllium husk 19 effective likely safeOthers 18

Oligosaccharide 62 14.6Lactosucrose 28 (2) (2)Others 34

Probiotics 62 14.6Lactobacillus 44 likely effective likely safeBifidobacterium 15 possibly effective possibly safeOthers 3

Subtotal 198 46.7%

Serum Dietary fiber 36 8.5cholesterol Low molecular sodium alginate 16 Algin: possibly effective Algin: likely safe

Blond psyllium husk 12 likely effective likely safeOthers 8

Soy Protein 18 4.2 likely effective likely safePhytosterol 4 0.9 Beta-sitosterol: likely effective Beta-sitosterol: likely safePhytostanol 1 0.2 Sitostanol: likely effective Sitostanol: likely safeOthers 2 0.5

Subtotal 61 14.1%

Serum triglyceride, Diacylglycerol 10 2.4 — —Body fat Others 7 1.7

Subtotal 17 4.0%

Blood glucose Dietary fiber 44 10.4Indigestible dextrin 43 (3) (3)Others 1

Others 9 2.1

Subtotal 53 12.5%

Blood pressure Sardine peptide 22 5.2 — —(Valyl-tyrosine)Oligopeptide from dried bonito 6 1.4 — —Lacto-tripeptide 3 0.7 — —Others 8 1.9

Subtotal 39 9.2%

Dental Health Sugar alcohol 18 4.2Xylitol 13 likely effective possibly safeOthers 5

Casein phosphopeptide 8 1.9 — —-Amorphous calciumphosphate*Others 4 0.9

Subtotal 30 7.3%

Bone health Soy isoflavone 7 1.7 possibly effective possibly safeOthers 5 1.2

Subtotal 12 2.8%

Mineral Calciumabsorption Casein phosphopeptide 3 0.7 — —

Calcium citrate malate 2 0.5 likely effective likely safeOthers 1 0.2

Ironheme iron 4 0.9 effective likely safe

Others 4 0.9

Subtotal 14 3.2%

Total 424 .100%

Fourteen of 424 products have just been approved by the Newly Developed Food Expert Committee,but not by the Ministry of Health, Labor and Welfare (http://www.mhlw.go.jp/topics/0102/tp0221-2.html).(1) Although “indigestible dextrin” does not appear in the Natural Medicines Comprehensive Database,15)

it is considered to be likely effective and likely safe based on the description of other dietary fibers.(2) “Lactosucrose” is considered to be possibly safe based on the description of “fructo-oligosaccharides.”

Although fructo-oligosaccharide may relieve constipation, more evidence is needed to rate it for this use.(3) “Indigestible dextrin” is considered to be possibly effective and likely safe.—: There is no description of the ingredient or its related component.*: “Calcium phosphate” is effective and likely safe.



in Fig. 2). After the final evaluation by thePharmaceutical Affairs and Food SanitationCouncil, the Ministry of Health officiallyapproves the manufacturer’s enhanced func-tion claim and the marking (Fig. 3) on theproduct (� and � in Fig. 2).

Effectiveness and Safety of“Foods for Specified Health Uses”

The manufacturer who applies to thegovernment for approval as “Food for Speci-fied Health Uses” for its product must tabulateboth published literatures and unpublishedor internal office reports on the effectivenessof the product and/or its ingredients, and pro-vide a summary of each literature or report.10,13)

The table must include in vitro metabolic andbiochemical studies, in vivo studies, and humanrandomized controlled trials (RCT). At theleast, one RCT is required and should appearin a journal with a peer review system. Further-more, the identification of the single, specificactive ingredient of the product is required,and the exact mechanism of action should beclarified.

Table 4 shows the effectiveness and safety ofthe major “Foods for Specified Health Uses”according to the Natural Medicines Com-prehensive Database.15) Most of the productsare possibly or likely to be effective and safe.However, the products or their physiologicallyactive components, which were first manu-factured in Japan, e.g., indigestible dextrin,lactosucrose, sardine, dried bonito and lacto-peptides (which may inhibit the activity ofangiotensin converting enzyme), and caseinphosphopeptide, are not listed in the data-base.15) According to international standards,they will be rated as having insufficient reliableinformation about its effectiveness and safety.On the other hand, calcium and iron productsshould be moved from the “Foods for SpecifiedHealth Uses” to “Foods with Nutrient FunctionClaims.”

In contrast to dietary supplements in the

US,2) the “Foods for Specified Health Uses” intablet or capsule form are less than 1%, andalmost all of them are found in the form ofconventional foods: 35% for beverages, 19%for fermented milk and 13% for confectionery.

Some Issues under Discussion

The Advisory Committee of the New Systemfor Regulation of “Health Foods” (Chairman:H.T.) was set up in April 2003, and submittedan amendment of the regulatory system to thegovernment in June 2004. Some issues pro-posed by the Committee are as follows.16)

1) Establishment of the New Regulatory Act“Health foods” are regulated by several acts,

including the Health Promotion Act, FoodSanitation Act and Pharmaceutical Affairs Act.Health food manufacturers and their associa-tions were demanding the regulation of “healthfoods” under a single act. There are many“health foods” that have been used for morethan ten years, and, therefore, they are con-sidered to be safe: royal jelly, propolis, agaricus,spirulina etc. Some of them are of good qualityunder the Good Manufacturing Practice(GMP). The manufacturers also demandedthat quality products be authorized under thenew act. However, consumer organizations, theJapan Medical Association and other profes-sional societies were opposed to the planbecause more evidence was needed to rate theeffectiveness of the products. Thus, the Advis-ory Committee could not obtain the consensusof the members on the new act.

2) “Foods with Nutrient Function Claims”As mentioned earlier, 12 vitamins and five

minerals were standardized as “Foods withNutrient Function Claims” as of March 2004.The health food manufacturers claimed thatvitamin K, manganese, selenium, chromium,molybdenum and other minerals whose dietaryreference intakes were determined in the currentRDA for Japanese14) should be standardized.

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The daily intake of minerals cannot be esti-mated due to the lack of Japanese Food Com-position Table17) for these minerals. Therefore,it is difficult to assess whether a consumermeets the requirements for the minerals, and itis also difficult to set the maximum amount ofintake from the supplement. Thus, the Com-mittee did not standardize the vitamin andminerals for “Foods with Nutrient FunctionClaims.”

Suppose that an extract contains substanceA which may reduce the risk of osteoporosis,but which is not approved as a “Food for Spe-cific Health Use.” The manufacturer enrichesthe extract with one to two vitamins (e.g.,vitamin D) or minerals (e.g., calcium), andlabels it “Food with Nutrient Function Claim.”Althouth the labeling is not currently illegal,the labeling is misleading. Consumers may beled to believe that the extract or substance Aitself is authorized as the “Food with NutrientFunction Claim.” Thus, consumer organiza-tions say that the government must prohibitthe sales under the new regulatory act. InMarch 2004, the Office of Health Policy onNewly Developed Foods, the Ministry of Health,warned health food manufacturers that theyshould enforce the autonomous regulation forlabeling more severely, as the number of suchproducts increased. Later, the Advisory Com-mittee decided to prohibit the labeling on thefoods.

3) “Foods for Specified Health Uses”When the Newly Developed Food Expert

Subcommittee evaluates the effectiveness andsafety of a candidate for “Food for SpecifiedHealth Use,” the rating method is not alwaysclarified, although it is evidence-based. Bothmanufacturers and consumers say that thepractical ratings should be standardized.

For many “health foods,” there has beenlittle scientific inquiry into the active ingredi-ents and the exact mechanism of action.14) Most“health foods” are a combination of manyingredients. It is quite possible that “health

foods” work through the combined effects ofmultiple ingredients, which means the approachof identifying a single, specific active ingredientis flawed. Thus, the Advisory Committee decidedto exempt the manufacturer from submittingdata on the action mechanism for a candidateproduct for “Food for Specified Health Use.”

Because a re-evaluation system after mar-keting “Foods for Specified Health Uses” hasnot been established, consumers, physicians,pharmacists and dieticians expect to have asystem that will monitor the effectiveness andstop the sales of ineffective products.

Health food manufacturers have asked thegovernment to allow the disease risk reductionclaims on “Foods for Specified Health Uses.”The government intends to allow this in linewith the Codex alimentarius, the US andothers. However, the Japan Medical Associa-tion opposes this because physicians are afraidthat if a patient who has to take antihyper-tensive agents uses a “Food for Specified HealthUse” with a risk reduction claim instead, his/her blood pressure will not be well-controlled,and the person may suffer a stroke or heartattack. It will be difficult for Japanese con-sumers to differentiate a food with disease riskreduction claims from a drug that is effectivefor the same disease.

The proposal of the Advisory Committeereflects a compromise reached by mutualconcession. If the scientific evidence supportsthe relationship between a food or ingredientand a disease or health-related condition, andprovides a very high level of confidence in itsvalidity, claims of disease risk reduction will beallowed for the food. The only disease riskreduction claims permitted will be thoserelated to nutrient to disease for the time being.For example, “Calcium may reduce the risk ofosteoporosis. Food X is high in calcium.” Asshown in this example, the claim must consistof two parts5):(1) Information on an accepted diet-health

relationship, followed by(2) information on the composition of the



product relevant to the relationship.According to the proposal of the Advisory

Committee, the Office of Health Policy onNewly Developed Foods may classify “Foodsfor Specified Health Uses” into three groups.The first group mainly consists of prebioticsand probiotics. Because they make up almosthalf of the “Foods for Specified Health Uses,”and are likely to be rated as safe and effective,they can be easily standardized and named“Foods for Specified Health Uses under Stan-dard Regulation System.” The others may bedivided into two on the basis of the strength ofthe evidence behind the structure/functionclaims or enhanced function claims. Foods withdefinite or probable effectiveness based onrandomized controlled trials will be simplycalled “Foods for Specified Health Uses” underthe current regulatory process. If the evidencefor the claims is tested by studies with a rela-tively low rating for design (cohort studies,nonrandomized intervention trials with con-current or historical controls, and case-controlstudies), the foods, the third group, will becalled “Foods for Specified Health Uses withQualified Structure/function Claims.” There-fore, they will be required to carry a disclaimer(i.e., the evidence is limited and not conclusive)like dietary supplements of the third level or Ccategory in the qualified health claims of theUnited States.2) However, an evidence-basedranking system for scientific data will be dis-cussed and determined by a group of experts.

4) Health Food Professionals“Health foods” fall somewhere between

conventional foods and drugs, but the bound-ary between health and conventional foods orbetween health foods and drugs is not clear.Dieticians deal with conventional foods andpharmacists with drugs. Therefore, “healthfood” professionals that could provide con-sumers with the correct information are neededin Japan. The government entrusts the trainingor education of these professionals to the pri-vate sector, but does not grant them national

certification.18)

5) Risk CommunicationThe National Institute of Health and Nutri-

tion is creating a database of evidence-basedinformation on the effectiveness, safety, inter-actions with drugs and others, etc. of “healthfoods” that are manufactured and marketedmainly in Japan.19) Users will be able to accessthe database on the Internet, free of charge,from July 2004.

Many “health foods” that are unknown evento specialists are marketed at shops, mail-ordered, sold door-to-door and imported pri-vately using the Internet in Japan. Some ofthem may carry illegal health claims, and othersmay contain harmful medicinal or chemicalingredients. More priority should be given tosafety rather than effectiveness. The NationalInstitute of Health and Nutrition19) is operatinga network center to gather reports from moni-tors on the adverse effects of “health foods.”The number of monitors is approximately 1,500(as of May 2004), most of whom are dieticiansand pharmacists. If several cases with a specificadverse effect are reported to the center,the cause or the “health food” can be easilyidentified. The information is then reportedto consumers through the monitors. Thus, it isexpected that the system will prevent a large-scale epidemic.

Conclusion

The current Japanese system for regulationof “health foods,” called “Foods with HealthClaims,” consists of two categories: “Foods withNutrient Function Claims” and “Foods forSpecified Health Uses.”

The label “Food with Nutrient FunctionClaim” can be freely used if a product satisfiesthe standard for the minimum and maximumlevels for daily consumption. The minimumlevel should be one-third of the Japanese rec-ommended dietary allowance for each vitaminor mineral. The maximum level is set as the

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maximum amount of nutrients in quasidrugs.Twelve vitamins (vitamins A, E, D, B1, B2, B6

and B12, folic acid, niacin, pantothenic acid,biotin and vitamin C) and five minerals (cal-cium, magnesium, zinc, iron and copper) arecurrently standardized (as of April 2004).

“Foods for Specified Health Uses” are thosethat contain dietary ingredients that have ben-eficial effects on physiological functions of thehuman body so as to maintain and promotehealth and to improve health-related condi-tions. Health claims for these foods correspondto the enhanced or “other” function claims ofthe Codex Alimentarius or structure/functionclaims in the US. However, disease risk reduc-tion claims are not allowed. The Ministry ofHealth, Labor and Welfare gives officialapproval on a case by case basis allowing themanufacturer to carry the claim and mark onthe product, after the Food Safety Commissionexamines the safety of the product and thePharmaceutical Affairs and Food SanitationCouncil evaluates the effectiveness. The num-ber of “Foods for Specified Health Uses” was424 as of March 2004, and 65% of them areprobiotics or prebiotics.

One reason for the establishment of the sys-tem is to provide consumers with the necessaryinformation to choose a good product fromnumerous health foods. In order to make thesystem beneficial for consumers, it is veryimportant to train experts who are able toeducate, teach, and give advice about “healthfoods.”

In order to maintain and improve people’shealth and to prevent chronic non-communi-cable diseases, a key element is a balanced dietof staple foods (e.g., steamed rice), main dishes(fish, meat, chicken, eggs, tofu etc.), and sidedishes (vegetables etc.). Healthy individualsshould obtain all necessary energy, nutrientsand non-nutritious components from regularmeals. They should never take quasidrugs con-taining vitamins and minerals and “healthfoods,” including “Foods with Health Claims,”in place of the daily diet and regular meals.

REFERENCES

1) Tanaka, H:. Problems with the creation of asystem for regulation of foods with healthclaims, drugs and so-called dietary supple-ments. J Japan Med Associ 2001; 126: 792–805.(in Japanese)

2) http://www.cfoan.fda.gov/~dms/dietsupp.html3) Hitachi Systems & Sevices: CD-ROM, World

Encyclopedia, 2nd Ed. Hitachi Systems & Ser-vice, Tokyo, 2000.

4) Tanaka, H.: Safety of health foods. J ScienceCouncil of Japan 2003; 8(11): 47–53. (inJapanese)

5) http://www.codexalimentarius.net/reports.asp6) Mitsuoka, T.: Intestinal flora and the host.

Pharmacia 1969; 5: 608–609.7) Salminen, S., Bouley, C., Boutron-Runault,

M.C. et al.: Functional food science and gas-trointestinal physiology and function. Br JNutr 1998; 80 (suppl): S147–S171.

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9) Yamakawa, K.: History of International Phar-macy and Society. Nankodo, Tokyo, 2000. (inJapanese)

10) Research Group of Newly Developed Foods:A Collection of Laws, Ordinances and Notifi-cations on Health Foods and Foods withHealth Claims. Chuo-Hoki, Tokyo, 2004. (inJapanese)

11) Shimizu, T.: Health claims on functional foods:The Japanese regulations and an internationalcomparison. Nutr Research Review 2003; 16:241–252.

12) Hosoya, N.: Health Claims, Primary Careof Lifestyle-related Diseases (Disorders) withFoods. Dai-Ichi-Shuppan, Tokyo, 2001. (inJapanese)

13) Research Group of Newly Developed Foods:Manual for Regulatory System of “Foods withHealth Claims.” Shin-Nihon-Hoki, Nagoya,2001. (in Japanese)

14) Ministry of Health and Welfare: The 6th Revi-sion of Recommended Dietary Allowances—Dietary Reference Intakes for Japanese.Office of Lifestyle-related Disease Control,Ministry of Health and Welfare, Tokyo, 1999.(in Japanese)



15) Jellin, M., Gregory, P.J., Batz, F., Hitchens, K.et al.: Pharmacist’s Letter/Prescriber’s Letter/Natural Medicines Comprehensive Database,5th Ed. Therapeutic Research Faculty, Stock-ton, CA, 2003.

16) http://www.mhlw.go.jp/shingi/2003/10/s1017-1.html

17) Resources Council, Science and TechnologyAgency: Standard Tables of Food Compositionin Japan, 5th Revised Ed. Printing Bureau,Ministry of Finance, Tokyo, 2000.

18) http://www.nih.go.jp/eiken/info/info_nr.html19) http://humpty.nih.go.jp/food/

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