CONTENTS · JMAJ, August 2004—Vol. 47, No. 8351 This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129,

Vol.47, No.8 August 2004

CONTENTS

Trace Elements

What are Trace Elements?—Their deficiency and excess states—

Osamu WADA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

Zinc Deficiency and Clinical Practice

Hiroyuki YANAGISAWA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

Copper Deficiency and the Clinical Practice

Tsugutoshi AOKI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

Iodine Deficiency Disorder and Clinical Practice

Makoto IITAKA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Trace Element Deficiency in Infants and Children—Clinical practice—

Hiroko KODAMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

Deficiencies of Trace Elements among the Aged and Clinical Aspects

Yoshinori ITOKAWA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

Sensory Dysfunctions due to Trace Element Deficienciesand the Clinical Aspects—Taste and olfactory disorders—

Minoru IKEDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Trace Elements and Cancer

Hiroyuki FUKUDA et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Trace Elements and Nervous and Mental Diseases

Tameko KIHIRA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

JMAJ, August 2004—Vol. 47, No. 8 351

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 129, No. 5, 2003, pages 607–612).

What are Trace Elements?

The human body is composed of elementswhich can be roughly divided into abundantelements and trace elements. Abundant ele-ments consist of the major elements that areinvolved in the formation of covalent bonds

What are Trace Elements?—Their deficiency and excess states—JMAJ 47(8): 351–358, 2004

Osamu WADA

Professor Emeritus, University of Tokyo

Abstract: Elements which are detected in small but not precisely known amountsin the living body were called “trace elements” in the past. Recent advances inanalytical technologies, such as the development of atomic absorption spectrom-etry, have made it possible to measure these elements precisely and to determinetheir functions and the characteristics of their deficiency and excess states.The so-called vitamin boom has passed, and it now appears to be boom-time fortrace elements. Nowadays, cases with trace element deficiencies are oftenencountered clinically, especially during high-calorie parenteral therapy or enteralnutrition, and congenital abnormalities of trace element metabolism have beenclarified successively. Thus, knowledge of the clinical aspects of trace elements isbecoming indispensable for front-line clinicians.1) Meanwhile, epidemiologicalsurveys and animal studies have suggested the possibility that some trace elementdeficiencies are associated with a reduced anti-oxidant potential in organisms(which is believed to possibly underlie the onset of cancer and atherosclerosis),accelerated aging, developmental retardation in children, and an increased inci-dence of abnormal pregnancies, immunological abnormalities, and lifestyle-relateddiseases. Thus, from the viewpoint of prophylactic medicine, study, survey, andprophylaxis of trace elements are also attracting close attention.

Key words: Trace element; Trace element deficiency; Excess of trace elements;Congenital abnormality in trace element metabolism

and are important constituents of tissues(oxygen, carbon, hydrogen, nitrogen, etc.), andsemi-major elements, which often exist in theionic state, and are involved in functions of theliving body through maintenance of osmoticpressure and membrane potentials (potassium,sodium, etc.). Major elements account for 96%

�Trace Elements

352 JMAJ, August 2004—Vol. 47, No. 8

Table 1 Functions of Trace Elements and Symptoms of Their Deficiency and Excess States

TraceEnzymes containing

elementthe elements and Physiological functions Symptoms of deficiency state Symptoms of excess state

active forms

Carbonic anhydrase Protein metabolism Major symptoms: Acute:Peptidase Lipid metabolism Gradually exacerbating Relative Fe-Cu deficiency,Alcohol dehydrogenase Carbohydrate metabolism eruptions, first affecting nausea, vomiting,Alkaline phosphatase Bone metabolism the face and perineum abdominal pain, melena,Polymerase Associated symptoms: hyperamylasemia,Zinc finger Stomatitis, glossitis, alopecia, somnolence, hypotension,

Zinc etc. nail changes, abdominal lung edema, diarrhea,symptoms (diarrhea, vomiting), jaundice, oliguriafever Chronic:

Delayed wound healing, dwarfism Reduced reproductiveGrowth retardation, negative function, dwarfism,

N balance, taste disorder, hyposmia,Immunosuppression, anemiaMental symptoms (depression),Taste disorder, anorexia

Ceruloplasmin Hemopoiesis Anemia Nausea, vomiting,Monoamine oxidase Bone metabolism Leukopenia heartburn, diarrhea,Cytochrome oxidase Connective tissue Neutropenia jaundice, hemoglobinuria,Ascorbic acid oxidase metabolism Disturbed maturation of hematuria, oliguria,

Copper Dopamine �-hydroxylase myeloleukocytes anuria, hypotension, coma,Superoxide dismutase Bone changes (children): melenaetc. Reduced osseous age,

irregular/spurring metaphysis,bone radiolucency,bone cortex thinning

Glucose tolerance factor Carbohydrate metabolism Abnormal glucose tolerance Nausea, vomiting,Cholesterol metabolism Reduced respiratory quotient peptic ulcer, CNS disorder,Connective tissue Weight loss Liver/kidney dysfunction,

Chromiummetabolism Peripheral neuropathy growth retardation

Protein metabolism Increased serum free fatty acidsAbnormal nitrogen balanceMetabolic consciousness

disturbance

Glutathione peroxidase Antioxidant action Myalgia (lower extremities) Selenosis (alopecia, nail(GSH-Px) T4�T3 conversion Cardiomyopathy detachment, CNS disorder)

Selenium 5�-deiodinase (type I) Reduced carcinogenicity (myocardial cell collapse,Various selenoproteins action fibrosis)

Nail bed whitening

Arginase Bone metabolism Reduced serum cholesterol Parkinsonian syndromePyruvate carboxylase Carbohydrate metabolism Reduced coagulation Early chronic:Superoxide dismutase Lipid metabolism Hair reddening Impotence, loss of vigor,

Manganese Glycosyltransferase Reproduction Dermatitis (miliaria crystallina) somnolence, anorexia,Immunity Growth retardation edema, myalgia, headache,

Increased radiolucency at the excitation, fatigueepiphyses of long bones Advanced stage:

Extrapyramidal disorder

Xanthine oxidase Amino acid metabolism Tachycardia Hyperuricemia, goutXanthine dehydrogenase Uric acid metabolism PolypneaAldehyde oxidase Sulfuric acid/sulfurous Night blindness

MolybdenumNitrous acid oxidase acid metabolism Scotoma

IrritabilitySomnolenceDisorientationComa

CobaltVitamin B12 Hemopoiesis Pernicious anemia Cobalt poisoning

Methylmalonic acidemia

Iodine Thyroid hormone Tissue metabolism Goiter, hypothyroidism Goiter, hypothyroidism

(Summary of many reports)

O. WADA


of the total body weight, and the semi-majorelements account for 3 to 4% of the total bodyweight. Deficiency of major elements can leadto nutritional disorders, and their presence inexcess can cause obesity. Deficiencies or excessstates of semi-major elements often result inwater and electrolyte abnormalities.

Essential trace elements of the human bodyinclude zinc (Zn), copper (Cu), selenium (Se),chromium (Cr), cobalt (Co), iodine (I), manga-nese (Mn), and molybdenum (Mo). Althoughthese elements account for only 0.02% of thetotal body weight, they play significant roles,e.g., as active centers of enzymes or as tracebioactive substances. A major outcome of traceelement deficiencies is reduced activity of theconcerned enzymes. However, since each traceelement is related to so many enzymes, defi-ciency of a single trace element is often notassociated with any specific clinical manifesta-tions, but rather manifests as a combination ofvarious symptoms. Because of the presence oftrace elements in very small amounts and theabsence of specific clinical features associatedwith their deficiency, it is often difficult forclinicians to identify deficiencies of some par-ticular trace elements.

Table 1 lists the enzymes containing traceelements, and summarizes the physiologicalfunctions of trace elements and the character-istics of their deficiency and excess states.

Trace Elements as Nutrients orMedicines2)

Like vitamins, trace elements were alsooriginally viewed as nutrients. They are listed inthe Japanese recommended dietary allowance(RDA). Because of the tendency in recenttimes towards unbalanced food intake, exces-sive purification of crops, and dieting practicedwidely to reduce body weight, deficiency ofzinc (a trace element abundantly contained inanimal foods and crops) are encountered rela-tively frequently.

Trace elements exert pharmacological actions

if they are ingested in amounts several to tentimes higher than the nutritional requirements.Excessive ingestion of trace elements as medi-cines has also been reported, which may occa-sionally lead to poisoning. To avoid such poison-ing, the RDA table displays also the referencedose (RfD, i.e., the highest permissible dose) foreach element. However, the RfD shown in theRDA table is relevant as reference values onlywhen trace elements are ingested as ordinarynutrients. Table 21) lists the pharmacologicallyeffective actions of trace elements when theyare consumed in excess. However, when deal-ing with trace elements, caution must be exer-cised to avoid excessive dosage.

Daily Intake, Recommended DietaryAllowance, Reference Dose, andSafety Margin of Trace Elements, andCauses of Deficiency States

Table 32) summarizes these parameters in

DEFICIENCY AND EXCESS OF TRACE ELEMENTS

Table 2 Trace Elements and the Potential Effects ofReplenishment, Prophylaxis, andPharmacological Effects

Trace element Potential effects of replenishment,prophylaxis, and pharmacological effects

IronCorrection of latent iron deficiencyResistance to infections

Wound healingImproved resistance to infections and

Zincimmune functions

Correction of developmental retardationand gonadal hypoplasia

Correction of taste disorder

ChromiumCorrection of carbohydrate metabolismPrevention of atherosclerosis

Anti-cancer activitySelenium Prevention of ischemic heart disease

Vitamin E-like activity

Fluorine Prevention of dental caries

Iodine Correction of latent iodine deficient goiter

(Quoted from Wada, O. et al.: Trace elements and theirabnormalities. Integrated Handbook of Internal Medicine 6,Nakayama-Shoten Co., Ltd., Tokyo, 1995; pp.253–263.)


relation to trace elements. It is noteworthythat the mean daily intake and the RDA areapproximately the same for most trace ele-ments. This can be interpreted as evidence thatover the long history of humankind, dietarystyles allowing approximately stable supply oftrace elements have become established, andthat the amounts of trace elements ingested viafood represent the appropriate levels. In otherwords, trace element deficiencies are unlikely

to occur unless the dietary patterns of indi-viduals change dramatically, or the metabolismof trace elements is disturbed. Table 4 showsthe major causes of trace element deficiencies.High-calorie parenteral therapy and enteralnutrition can be viewed as representing dra-matic alterations of the dietary pattern, whileextremely low intake and congenital metabolicabnormalities can be viewed as representingdisturbed metabolism of trace elements. Inrecent years, the prevalence of these metabolicabnormalities has been on the increase, andtheir pathophysiology has been clarified indepth, highlighting the importance of traceelements in clinical practice.

It is also important to note that the ratioof the RfD to RDA, i.e., the safety margin, isnot very large. Amidst the tendency of peopleto consume health promotion foods based ontheir distrust of medicines, preparations oftrace elements are available commercially, andinappropriate use of these preparations cancause excess states of these trace elements.It is also noteworthy that the doses at whichtrace elements exert pharmacologically effec-tive actions are much higher than the RfD.

Table 3 Daily Dietary Requirements of Trace Elements in Adult Japanese Males (body weight: 50kg)

“No “Lowest Effective Recommended ReferenceTrace element Mean daily adverse adverse replenishment/ dietary dose RfD/

intake effects” level effect” level pharmacological allowance (RfD) RDA(NOAEL) (LOAEL) dose (RDA)

Zinc 7�11mg 30mg* 600mg �200mg 9.6mg 30mg 3(immune functions, etc.)

Copper 1�4mg 9mg* 10mg — 1.8mg 9mg 5

Chromium (III) 28�62�g 1,000�g* — 150�1,000�g 35�g 250�g 7(diabetes mellitus, etc.)

Selenium 41�168�g 400�g 750�g* �200�g 55�g 250�g 4.5(cancer prevention, etc.)

Manganese 3�4mg 10mg* — — 4mg 10mg 2.5

Molybdenum 135�215�g 350�g 7mg* — 30�g 250�g 8

Iodine 200�30,000�g 3,000�g* 23,000�g — 150�g 3,000�g 20

Arsenic 10�34�g 40�g* 700�g — 10–34�g 140�g 4

*Basis for calculation of RfD• The mean daily intake is approximately equal to the RDA.• RfD/RDA indicates the safety margin between daily requirements and toxic levels, and is not very large.

(Quoted from Wada, O.: Usefulness and safety of trace chemicals. Proceedings of Trace Nutrients Research 2001; 18: 1–10.)

Table 4 Major Causes of Trace Element Deficiency

1. Inadequate supply1) Congenital metabolic disorders:

Acrodermatitis enteropathica (zinc),Menkes disease (copper)

2) Inadequate intake: Unbalanced nutrition, excessivepurification of crops, ingestion offoods poor in trace elements,undevelopment of the foodtransportation system

2. Iatrogenic: High-calorie parenteral therapy, chelatingdrugs, surgery, etc.

3. Diseases, etc.: Pregnancy, excessive alcohol consump-tion, liver disease, nephropathy

Note: Underlined factors are predominant.

O. WADA


Figure 1 graphically represents these rela-tionships for zinc.3)

Deficiency and Excess States ofTrace Elements

As shown in Table 5, deficiency and excessof trace elements are either congenital oracquired. Deficiency states of trace elementsare most frequently seen during high-calorieparenteral therapy or enteral nutrition. Zincdeficiency can develop within 2 weeks afterthe start of such therapies.4) Therefore, whileadministering these therapies, caution must beexercised to ensure that all trace element defi-ciencies are prevented.

Congenital abnormalities of trace elementmetabolism are rare. Abnormal intestinal absorp-tion or disturbed transport of absorbed trace

elements more often lead to deficiency of traceelements. Acrodermatitis enteropathica due todisturbed zinc absorption and Menkes diseasedue to abnormal copper transport through theintestinal mucosa5) are some examples of suchconditions.

If the site of uptake of trace elements into anactive form is disturbed, the trace element ispooled there, causing excess of the element. Incases of Wilson disease characterized by dis-turbed uptake of copper into ceruloplasmin,5)

tissue damage and fibrosis due to copper occurin the liver and other sites.

Trace Element Deficiencies as Viewedfrom the Standpoint of ProphylacticMedicine

Many epidemiological surveys and animal

Fig. 1 Toxic levels, recommended daily dietary allowance, effective replenishment dose, and“no adverse effect” level of zinc (amounts of zinc�absolute level)

The effective replenishment level (pharmacological level) is higher than toxic levels. The amount ordinarily ingested is slightlylower than the recommended daily dietary allowance.(Quoted from Wada, O.: Usefulness and safety of trace chemicals. Proceedings of Trace Nutrients Research 2001; 18: 1–10.)

(Toxic Levels and Recommended Daily Dietary Allowance)

Nauseant level (455 mg)

Elevated serum LDL (300 mg)

Reduced immune functions (300 mg)

Causing gastrointestinal symptoms (100 mg)

NOAEL for immunosuppression (100 mg)

LOAEL for serum HDL reduction (75 mg)

NOAEL for serum HDL reduction (50 mg)

Suppressing copper and iron absorption (50 mg)

RfD for adult Japanese (30 mg)

RfD by US EPA (18�20 mg/60 kg/day)

RDA for adult US males (15 mg)

RDA for adult US females (12 mg)

RDA for adult Japanese males (9.6 mg)

RDA for adult Japanese females (7.8 mg)

Minimum balancing level (5.5 mg)

(100)

(10)

(0)

(1,000) amounts of zinc mg/day

(Effective Replenishment and “No Adverse Effect”)

LDL-decrease and HDL-increase in patients with ischemic heart disease (240 mg)

LDL-decrease in females (150 mg)

No effects on immune functions (100 mg)

Improved immune functions (14�200 mg)

Treatment of gastric ulcer (48 mg)

Treatment of various diseases (30�45 mg)

Improved the sense of taste (30 mg)

Favorable effects on pregnancy and labor (30 mg)

Improved dark adaptation (25 mg)

No antagonism against copper and iron (8�24 mg)

Am

ount

s ta

ken

with

sup

plem

ent b

y th

e U

S p

opul

atio

n (0

.15�

100

mg)

No

effe

cts

on li

pids

(20�

150

mg)

Am

ount

s in

gest

ed b

y Ja

pane

se(7

.5�

12 m

g)



Table 5 Clinical Deficiency and Excess States of Trace Elements

Trace elementDeficiency Excess

Congenital Acquired Congenital Acquired

Iron Atransferrinemia Iron-deficiency anemia Hemochromatosis Iron poisoning

Zinc Acrodermatitis High-calorie parenteral Zinc fume fever,enteropathica therapy, enteral nutrition, zinc poisoning

drugs (chelating agents),inadequate intake

Copper Menkes disease High-calorie parenteral Wilson disease Copper fume fever,Aceruloplasminemia therapy, enteral nutrition copper poisoning

Manganese High-calorie parenteral Parkinsonian syndrometherapy (1 case)

Selenium Some types of High-calorie parenteral Selenosispancreatic cysts therapy (several cases),

dietary Keshan disease,Kaschin-Beck disease,ischemic heart disease,cancer

Chromium High-calorie parenteral Chromium poisoning,therapy (several cases), lung cancerdiabetes mellitus,atherosclerosis

Iodine Abnormal iodine Goiter Goitermetabolism

Cobalt Pernicious anemia Cobalt poisoning

Molybdenum High-calorie parenteral Gout, molybdenumtherapy (1 case) poisoning

Table 6 Trace Element Deficiency as Viewed fromthe Standpoint of Preventive Medicine

What needs to be prevented Elements involved

Reduction in Zinc, iron, manganese,anti-oxidant potential selenium, copper

Promotion of aging and Zinc, copper, selenium,its cause chromium

Developmental retardation Zincof children

Abnormal pregnancies, Zincinfertility, fetal abnormalities

Immunodeficiency Zinc, iron, copper,selenium

Increased carcinogenicity Zinc, copper, selenium

Promoted atherosclerosis Zinc, selenium, iron,copper, chromium

Increased incidence of Chromium, zinc,diabetes mellitus selenium, vanadium

Predisposition to hypertension Copper, zinc, selenium

Predisposition to senile dementia Zinc

Predisposition to taste disorder Zinc

Predisposition to dental caries Fluorine

Predisposition to goiter Iodine

MicrosomeNucleus

Peroxisome Mitochondria

Biomembrane

Lysosome

Catalase(Fe)

Cu/ZnSOD

MnSOD�GSHPx (Se)

GSHGSHPx

(Se)

O3�2H� H2O�O2

2H2O�O2

2H2O�GSSG

H2O2�H2O2

H2O2�2GSH

Cu/Zn, MnSOD

FeCatalase

SeGSGPx

LOOH�2GSH LOH�GSSG�H2OSe

GSHPx

(SOD: Superoxidase dismutase, GSHPx: glutathione peroxidase)

Fig. 2 Anti-oxidative actions of trace elementsThe characteristics of trace element deficiency, especially inthe case of adults, may be explained by a reduction in the anti-oxidant actions.(Quoted from Wada, O.: Trace elements and sugar and lipidmetabolism—Overview. Endocrinology & Diabetology 1998;6: 109–117.)

O. WADA


studies have demonstrated that health prob-lems are caused by deficiency of trace elements(Table 6).6) It has been shown that the defi-ciency of many trace elements, especially zinc,is associated with accelerated aging,7) immuno-deficiency,8) accelerated progression of HIV in-fection,9) increased incidence of abnormalpregnancies,10) developmental retardation inchildren,11) and taste disorder.12) It has alsobeen shown that deficiency of chromium13) isrelated to the development of diabetes mellitusand atherosclerosis, and that selenium defi-ciency14) is associated with the increase ofcancer and ischemic heart disease. Clarifyingthese abnormalities clinically and establishingcountermeasures against them are importantissues that must be addressed by regionalhospitals engaged in both prophylactic medi-cine and clinical medicine. Studies in this fieldmay be expected to advance rapidly from nowon and contribute to improving the dietaryhabits of populations in local communities.

Decreased anti-oxidant potential of the liv-ing body, which is a subject that has recentlyattracted close attention, is thought to underliethe development of numerous lifestyle diseaseconditions. Several trace elements have beenshown to be involved in the anti-oxidant effi-cacy of the body (Fig. 2).13)

Conclusion

In this article, the basic biology of traceelements and features of their deficiency andexcess states have been presented to providean overview of these elements. Clinically, aswell as in nutritional evaluations, one of themost difficult problems concerning trace ele-ments is the difficulty of diagnosing traceelement deficiencies. Although the currentlyavailable methods of diagnosis are listed inTable 7, there are few methods that allowaccurate diagnosis, especially in cases with mildto moderate deficiency. The development ofmore accurate methods is an issue that must beaddressed in future.

REFERENCES

1) Wada, O. et al.: Trace elements and theirabnormalities. Integrated Handbook of Inter-nal Medicine 6, Nakayama-Shoten Co., Ltd.,Tokyo, 1995; pp.253–263. (in Japanese)

2) Wada, O.: Usefulness and safety of tracechemicals. Proceedings of Trace NutrientsResearch 2001; 18: 1–10. (in Japanese)

3) Wada, O. and Yanagisawa, H.: Trace elements,with special reference to the usefulness andsafety of zinc. Medicine and Drug Journal1997; 33(12): 126–134. (in Japanese)

Table 7 Diagnosis of Trace Element Deficiency

1. Trace element deficiency is one of the most difficult conditions to diagnose.Few valid methods are available (due to the wide overlap between the normal state and the deficiency state).

2. Methods currently used1) Measurement of trace element concentrations in samples:

serum, erythrocytes, leukocytes, lymphocytes, hair (for many elements); urine (for iodine)2) Measurement of the activity of enzymes containing trace elements in their core:

alkaline phosphatase (zinc), 5�-nucleotidase (zinc), ACE ratio (zinc),ceruloplasmin (copper), thyroid hormone (iodine), glutathione peroxidase (selenium), etc.

3. Function tests: dark adaptation (zinc), taste test (zinc), electroretinogram (zinc)4. Balance studies: many elements, not practical5. Analysis of daily intake: not practical, large variance (many elements)6. Checking for alleviation of symptoms following replenishment:

most reliable method of diagnosing deficiency (many elements)

Note: Underlined methods are the most frequently used.(Quoted from Wada, O. et al.: Trace elements and their abnormalities. Integrated Handbook of Internal Medicine 6,Nakayama-Shoten Co., Ltd., Tokyo, 1995; pp.253–263.)



4) Takagi, Y. and Okada, T.: Metabolism of traceelements. Japanese Journal of Clinical Medicine2001; 59(extra issue): 401–412. (in Japanese)

5) Okabe, M. et al.: Front-line of research on cop-per. Vitamin 2001; 75: 557–563. (in Japanese)

6) Wada, O. et al.: Trace element deficiencyin humans. JJPEN 1990; 12: 419–424. (inJapanese)

7) Wada, O.: The role of trace elements in agingprocess. In Nutrition and Aging, Intnl Life SciInstitute, Tokyo, 1995; p.85.

8) Kodama, H.: Role played by essential traceelements in maintenance of immune function.Japanese Journal of Clinical Medicine 1996; 54:46–51. (in Japanese)

9) Patrick, L.: Nutrients and HIV: Part two-vitamins A and E, zinc, B-vitamins, and mag-

nesium. Altern Med Rev 2000; 5: 39–51.10) Shah, D. and Sachdev, H.P.: Effect of gesta-

tional zinc deficiency on pregnancy outcomes.Br J Nutr 2001; 85(Suppl 2): S101–S108.

11) Bhandari, N. et al.: Effect of micronutrientsupplementation on line on growth of chil-dren. Br J Nutr 2001; 85(Suppl 2): S131–S137.

12) Tomita, H.: Taste disorder and diet.Kodansha��Book, Kodansha, Ltd., Tokyo,2002. (in Japanese)

13) Wada, O.: Trace elements and carbohydrateand lipid metabolism—Overview. Endo-crinology & Diabetology 1998; 6: 109–117. (inJapanese)

14) Schrauzer, G.N.: Anticarcinogenic effects ofselenium. CMLS 2000; 57: 1864–1873.

O. WADA



Introduction

The number of patients visiting outpatientclinics with complaints of abnormal sense oftaste or olfaction (most frequently reduced orabnormal sense of taste) has been on theincrease.1,2) It has been estimated that about140,000 new patients with such complaints areregistered annually,2) and that about 30% ofthese patients have dietary zinc deficiency.1,2)

Zinc Deficiency and Clinical PracticeJMAJ 47(8): 359–364, 2004

Hiroyuki YANAGISAWA

Associate Professor, Department of Hygiene and Preventive Medicine,Saitama Medical School

Abstract: In recent years, the number of patients visiting outpatient clinics withcomplaints of abnormal sense of taste or olfaction has been on the increase. It hasbeen estimated that about 30% of these patients may have dietary zinc deficiency.This deficiency is more likely to develop among children whose daily requirementsof zinc are greater, among elderly people whose dietary consumption of nutrientsis poor, and among young women who are often on diets for weight reduction. Zincdeficiency may be associated with features such as hypogeusia, hyposmia, growthretardation, dermatitis, alopecia, compromised gonadal function, susceptibility toinfections, and delayed wound healing. At present, measurement of the serum zinclevel is considered to be the most reliable means of diagnosing zinc deficiency. Ithas been proposed that if the serum copper level were also measured, then theratio of the serum copper to zinc level (serum copper/zinc ratio) can be used asreference information for diagnosing zinc deficiency. For the treatment of zincdeficiency, zinc replacement therapy at a daily zinc dose of about 30mg is con-sidered to be relatively safe. However, further study of the safety and adverseeffects of zinc replacement therapy is necessary.

Key words: Zinc; Essential trace elements; Deficiency

Zinc is known to serve as the active center ofabout 300 enzymes, and is an essential traceelement in humans (Table 1).1)

It has been reported that the amount ofzinc ingested per day may be insufficient rela-tive to the daily requirement in some groupsof individuals (children, elderly people, youngwomen on weight-reducing diets, and someother groups). These individuals may developquasi-deficiency or true deficiency of zinc.1,2) In

�Trace Elements


are induced by post-natal factors (Table 2).1)

Acquired zinc deficiency is often attributableto extreme deficiency of nutrients includingzinc, or extremely unbalanced diets (insuffi-cient ingestion of animal proteins rich in zinc).

The most frequent causes of zinc deficiencyare prolonged high-calorie parenteral therapyand enteral nutrition. Long-term high-calorieparenteral therapy inevitably induces zincdeficiency. To avoid its occurrence, IV solutionadditives containing 5 trace elements (iron,

H. YANAGISAWA

this paper, we shall briefly discuss the etiology,clinical symptoms, and the methods of diagno-sis and treatment of zinc deficiency, a conditionthat has recently drawn much attention.

Etiology

Zinc deficiency can be divided into congenitaland acquired types of zinc deficiency. Acro-dermatitis enteropathica, an inherited abnor-mality of zinc absorption, is rare. Most cases

Table 2 Major Causes of Zinc Deficiency

1. Inadequate intake 3. Excessive loss1) Low-zinc-containing diets: 1) Loss into digestive fluid:

Foods poor in animal protein (vegetarians) Child intractable diarrhea, intestinal fistula,2) Loss of zinc during food processing gastrointestinal disease associated with diarrhea

(desalting during production of artificial milk) 2) Increased urinary elimination:3) Prolonged intravenous alimentation, Liver cirrhosis, diabetes mellitus, renal disease,

enteral alimentation hemolytic anemia, intravenous alimentation,4) Shortage of nutrient intake enhanced catabolism (surgery, trauma, infection, etc.),

2. Malabsorptiondiuretics, sodium polyphosphate

1) Congenital: Acrodermatitis enteropathica (very rare)3) Others: Burns, hemodialysis

2) Acquired 4. Increased demand(1) Ingestion of absorption inhibitors: Pregnancy, neonates (premature babies),

Phytic acid, edible fibers enhanced anabolism (during intravenous alimentation, etc.)(2) Malabsorption syndrome:

Liver dysfunction, pancreatic dysfunction,5. Unexplained

inflammatory bowel disease, short bowel syndromeCongenital thymus defect, Mongolism

(3) Drugs, chelating agents: EDTA, penicillamine

*Underlined�particularly importantSource: Yanagisawa, H.: Clinical aspects of zinc deficiency. The Journal of the Japan Medical Association 2002; 127(2): 261–268.

Yanagisawa, H. et al.: Zinc—Extensive blood and urine biochemistry and immunological tests (2). Japanese Journal ofClinical Medicine 1999; 57 (extra issue): 282–286.

Table 1 Zinc and Its Functions

Essentialtrace element Target Function

Carbonic anhydrase, peptidase, alcohol dehydrogenase,alkaline phosphatase, polymerase, superoxide dismutase (SOD),angiotensin-converting enzyme, collagenase,

Cell division,Zinc

�-aminolevulinic acid anhydrase, protein kinase C,nucleic acid metabolism,

phospholipase C, aspartate transcarbamylase,co-enzymes

nucleotide phosphorylase (5’-nucleotidase), RNase, etc.

Source: Yanagisawa, H.: Clinical aspects of zinc deficiency. The Journal of the Japan Medical Association2002; 127(2): 261–268.


ZINC DEFICIENCY

zinc, copper, manganese, and iodine), thathave recently become available commercially(including Elemenmic® (Ajinomoto Pharma Co.,Ltd.) and Mineralin® (Nihon PharmaceuticalCo., Ltd. and Takeda Chemical Industrials,Ltd.), may be used. The use of these additiveshas reduced the apparent incidence of zincdeficiency. Although these 5 trace elements arealso contained in preparations used for enteralnutrition, zinc deficiency can develop if theamount of zinc in the diet is insufficient rela-tive to the requirement, or if the patients havesuch conditions as malabsorption, diarrhea, orintestinal fistula. Furthermore, zinc deficiencycan be induced by continued use of low-mineral purified foods (minerals are lost duringpurification), foods containing additives withchelating activity (sodium polyphosphate, phyticacid, or EDTA [which is also used as a drug]),and drugs which can disturb the sense of taste(about 170 such drugs are known, and many ofthem have chelating activity2)).1,2)

Regarding the relationship of zinc deficiencywith age, the deficiency is more likely to developduring childhood, when the daily requirementof zinc is higher, in adult women (especiallyyoung women on weight-reducing diets), andin elderly people whose dietary consumption ofnutrients is poor. In a survey in the UnitedStates, a reduced serum level of zinc was seen

in 2–3% of the population.1)

Clinical Symptoms

While the symptoms of zinc deficiency arecommon irrespective of the causative factors(Table 3),1) they may vary depending on theseverity of zinc deficiency.

Mild cases of zinc deficiency may presentwith such features as a reduced sense of taste,reduced sperm counts, reduced serum testos-terone level, and non-fat weight loss. Moderatecases of zinc deficiency, which may developin association with deficient nutrient intake,unbalanced nutrition, chronic liver disease,chronic renal disease, malabsorption syn-dromes, may present with growth retardation,delayed gonadal development, skin abnormal-ities, anorexia, somnolence, reduced dark adap-tation, delayed wound healing, hypogeusia,and hyposmia. In severe zinc deficiency, whichmay be associated with acrodermatitis enter-opathica, prolonged high-calorie parenteraltherapy, or penicillamine therapy, features suchas bullous or pustular dermatitis, diarrhea,balding, mental abnormalities (depression, etc.),and recurrent infections due to compromisedimmune function may be seen.

Of the aforementioned symptoms, subjectswith hypogeusia, in particular, and hyposmia

Table 3 Symptoms and Diseases Caused by Zinc Deficiency

Anorexia Hypogeusia/HyposmiaGrowth retardation PicaSkin symptoms Depression/Emotional instability� Extension from mucocutaneous junctions Ataxia� (mouth, eyes, anus, etc.) to the periphery Dementia (hypothesis)� Bullous or pustular dermatitis, erosive eczema, Reduced glucose tolerance� hyperkeratosis, skin atrophy Increased incidence of cataractsAlopecia/baldness Disturbed dark adaptation (night blindness)Gonadal hypofunction Increased incidence of ischemic heart diseaseDelayed wound healing Increased carcinogenesisSusceptibility to infections (compromised immune function) Abnormal pregnancy

Source: Yanagisawa, H.: Clinical aspects of zinc deficiency. The Journal of the Japan Medical Association 2002;127(2): 261–268.


are often encountered at outpatient clinics. Inhospitals for elderly patients, erosive eczemaspreading from mucocutaneous junctions (e.g.,mouth, eye, anus, etc.) towards the periphery,as well as bullous or pustular dermatitis, areoften noted as the first symptoms of zinc defi-ciency. In recent years, it has been suggestedthat zinc deficiency may be associated withcarcinogenesis, senility, and the onset or progres-sion of some lifestyle-related diseases (Table 3).1)

The authors recently reported that zinc defi-ciency may lead to exacerbation or progressionof renal disease (especially diseases of theglomeruli) through inducing the expression ofendothelin-1 (a potent vasoconstrictor) whichstimulates the renin-angiotensin system,4–6) andalso to exacerbation of hypertension throughincreasing the oxidative stress associated withthe production of superoxides.4,7)

Diagnosis

Many methods of diagnosis of zinc deficiency

have been attempted.3) At present, measure-ment of the serum (plasma) zinc level (Table4), and confirmation of a deficient state byadministering a zinc load are considered to bethe most reliable methods of diagnosing zincdeficiency.1–3) However, since the intracellularlevel of zinc is higher than its serum level, it isquite plausible that the serum zinc level maynot faithfully reflect the nutritional state of anindividual. It must be borne in mind that theserum zinc level may fall at the lower end ofthe normal range even in the presence of zincdeficiency. The serum zinc level may also showcircadian variations (high level in the morningand low level in the afternoon) and changesrelated to the contents of meal. It can also beaffected by some drugs (Table 5). Therefore,when checking for zinc deficiency on the basisof the serum zinc levels, in addition to consid-eration of the clinical symptoms, it would beessential to take these aforementioned factorsalso into account.

Zinc is absorbed primarily from the small

H. YANAGISAWA

Table 4 Possible Conditions Suggested by Serum Zinc Levels and Countermeasures

Serum zinc level(�g/dl) Possible conditions Countermeasures

300–700 Acute intoxication (reported) First aid

Intoxication or secondary elevation due to Cause identified and removed160–299

excessive intake or hemodialysis Follow-up

84–159 Normal range

Zinc deficiency (Table 2) Cause identified and removed as needed60–83 Physiological fluctuation (Table 5) Dietary therapy (ingestion of zinc rich food)

Variation caused by drugs, etc. (Table 5) Zinc replacement as needed

Deficiency (Table 2) Cause identified and removedBelow 59 Dietary therapy (ingestion of zinc rich food)

Zinc replacement

Below 30Definite deficiency (acrodermatitis enteropathica, Zinc replacementprolonged high-calorie parenteral therapy) (Table 2)

Reproduced with modifications from:Yanagisawa, H.: Clinical aspects of zinc deficiency. The Journal of the Japan Medical Association 2002;127(2): 261–268.Yanagisawa, H. et al.: Zinc—Extensive blood and urine biochemistry and immunological tests (2).Japanese Journal of Clinical Medicine 1999; 57 (extra issue): 282–286.


ZINC DEFICIENCY

intestine. In the presence of zinc deficiency,absorption of copper is enhanced.1) As a result,a reduced serum zinc level, elevated serumcopper level, and an elevated serum copper/zinc ratio are noted in the presence of zincdeficiency.1,2) Thus, measurement of the serumcopper level may be a helpful auxiliary testin the diagnosis of zinc deficiency.1,2) Like theauthors, Tomita et al. proposed that diet ther-apy and oral zinc replacement therapy must bestarted in individuals who satisfy all of thefollowing criteria of zinc deficiency: (1) serumzinc level lower than the quasi-deficiency level(Table 4) and (2) serum copper level over120�g/dl as a reference value, i.e., a serumcopper/zinc ratio of 1.5 or higher.2) Confirma-tion of the diagnosis using a zinc load is advis-able in suspected cases of zinc deficiency inwhom the serum zinc level is normal.1–3)

Treatment1,2) (Table 4)

In cases of zinc deficiency associated withhigh-calorie parenteral therapy, Elemenmic®

or Mineralin® (trace element preparations)may be added to parenteral nutritional for-mulas. If zinc deficiency is seen during enteralnutrition, zinc compounds such as zinc sul-phate, zinc gluconate, or zinc picolinate may beadded to the enteral preparations. If oral inges-tion is possible, these zinc compounds may beadministered orally mixed with juices, or in theform of enterosoluble capsules.

In adults, a daily zinc dose of 150–200 mg(as the zinc compound) is usually sufficient.In Japan, the anti-ulcer agent polaprezinc(Promac®, ZERIA Pharmaceutical Co., Ltd.) iscommercially available as a zinc preparation.The daily dose of polaprezinc includes 34 mg ofzinc load, which is sufficient for the treatmentof zinc deficiency, although only its use in thetreatment of gastric ulcer is covered by theNational Health Insurance in Japan.

Recently, health promotion foods and OTCdrugs containing zinc have been marketed inJapan. The amounts of these foods or drugstaken per day often contain 20–30 mg of zinc.Therefore, it is possible to use these foodsor OTC drugs for zinc replacement therapy.Usually, zinc replacement therapy is continuedfor 3–4 months. If initiated within 6 monthsafter the onset of zinc deficiency, the responserate to this therapy (the percentage of caseswhere the therapy is effective or markedlyeffective) is 70% or higher. The response ratedecreases, especially in elderly people, if thetherapy is started later than 6 months after theonset of zinc deficiency. In cases respondingto therapy, the zinc replacement therapy maysometimes have to be continued for about6 months.

Conclusion

The etiology, clinical symptoms, and methodsof diagnosis and treatment of zinc deficiency

Table 5 Changes in Serum Zinc Levels

Condition Change

Fasting Increase

Food ingestion Decrease (2–3 hours later)

Stress Increase

Ingestion of marine products Increase (oyster, etc.)

Neonates and infants Decrease

Pregnancy Decrease (gradually)

DrugsGlucocorticoids DecreaseThiazides IncreaseLoop diuretics IncreaseDisulfirams IncreaseClofibrates DecreaseOral contraceptive pills Decrease

Source: Yanagisawa, H.: Clinical aspects of zinc deficiency.The Journal of the Japan Medical Association2002; 127(2): 261–268.Yanagisawa, H. et al.: Zinc—Extensive blood andurine biochemistry and immunological tests(2).Japanese Journal of Clinical Medicine 1999;57(extra issue): 282–286.


H. YANAGISAWA

are described in this paper. Although no opti-mum dose level for zinc replacement therapyhas been established, daily doses of about30 mg zinc seem to be relatively safe. It wouldbe desirable for additional studies on the safetyand adverse effects of zinc therapy to be con-ducted, and for new zinc preparations for thetreatment of zinc deficiency to be developed.

REFERENCES

1) Yanagisawa, H.: Clinical aspects of zinc defi-ciency. The Journal of the Japan Medical Asso-ciation 2002; 127(2): 261–268. (in Japanese)

2) Tomita, H.: Taste Disorder and Diet. KodanshaLtd., Tokyo, 2002; pp.3–140. (in Japanese)

3) Yanagisawa, H., Kurihara, N. and Wada, O.:Zinc—Extensive blood and urine biochemistryand immunological tests (2). Japanese Journal

of Clinical Medicine 1999; 57(extra issue):282–286. (in Japanese)

4) Yanagisawa, H. and Wada, O.: New aspects ofzinc deficiency—Special reference to vasoac-tive substances. Biomedical Research on TraceElements 2002; 13(2): 106–113. (in Japanese)

5) Yanagisawa, H., Nodera, M. and Wada, O.:Zinc deficiency aggravates tubulointerstitialnephropathy caused by ureteral obstruction.Biol Trace Elem Res 1998; 65: 1–6.

6) Yanagisawa, H., Moridaira, K. and Wada, O.:Zinc deficiency further increases the enhancedexpression of endothelin-1 in glomeruli of theobstructed kidney. Kidney Int 2000; 58: 575–586.

7) Sato, M., Yanagisawa, H., Nojima, Y. et al.:Zinc deficiency aggravates hypertension inspontaneously hypertensive rats: Possible roleof Cu/Zn-superoxide dismutase. Clin ExpHypertens 2002; 24(5): 355–370.



Copper Deficiency and the Clinical PracticeJMAJ 47(8): 365–370, 2004

Tsugutoshi AOKI

President, Toho University

Abstract: In 1993, the candidate genes for Menkes disease and Wilson diseasewere cloned, and remarkable progress has been made in the study of coppermetabolism during the past 10 years. The proteins induced by the ATP7A andATP7B genes are highly homologous. Both are P-type ATP-related copper-transporter membrane proteins, and control cellular copper transport. Recently,three chaperones supplying copper to the intracellular copper-requiring enzymeswere discovered, and the physiology of intracellular copper metabolism is becom-ing more and more clear. Numerous copper-requiring enzymes are present in thebody, therefore, copper deficiency may lead to various disorders. Menkes diseaseis well-known as an inherited disorder of copper transport from the intestine result-ing in copper deficiency. In regard to acquired copper deficiency, nutritionaldeficiency is probably the most common cause, and may be seen in malnourishedlow-birth-weight infants, newborns, and small infants. Copper deficiency has alsobeen reported to develop after gastrointestinal surgery, intractable diarrhea, andprolonged parenteral or enteral nutrition. In this article, I present a review of copperdeficiency and its treatment.

Key words: Copper deficiency; Copper metabolism; Menkes disease

resulting in copper accumulation.1,2) Acquiredcopper deficiency is mainly attributable tonutritional deficiency, and may be seen in mal-nourished low-birth-weight infants, newborns,and small infants.1) Copper deficiency has alsobeen reported to develop after gastrointestinalsurgery, intractable diarrhea, and prolongedparenteral or enteral nutrition.1,3) However,since copper supplementation of intravenousand enteral nutritional formulas was mademandatory, the incidence of copper deficiency

Introduction

Copper is one of the essential trace elementsin humans, and disorders associated with itsdeficiency and excess have been reported.1)

Menkes (kinky-hair) disease is well-known tobe associated with copper deficiency due to aninherited disorder of copper transport fromthe intestine metabolism, and Wilson disease(hepatolenticular degeneration) is a well-knowninherited disorder of cellular copper transport

�Trace Elements


T. AOKI

Table 1 Major Copper-requiring Enzymes and Their Actions

Name of major enzymes Major action

Ceruloplasmin Oxidase activity, Fe?�Fe÷

Lysyl oxidase Elastin cross-linkage, collagen formation (cross linking)Superoxide dismutase (SOD) Superoxide radical metabolism

(O2��O2

��2H��O2�H2O2)�Tyrosinase Melanin synthesisMonoamine oxidase Oxidative deaminationDopamine �-hydroxylase Epinephrine synthesisCytochrome c oxidase Complex of cytochrome a and a3,

respiratory chain terminal enzyme (mitochondria)Ascorbate oxidase Oxidation of vitamin C, etc.

Nucleus

IL-6 TNF

Mitochondria

Cytochrome coxidase(Cco)

Cox17

HAH1

Ccs

Ctr Cu-histidineCu-albumin

Metallothionein (MT)

HepaticSinusoidCapillary vessel

Cu/Zn

Superoxidedismutase (SOD)

WilsonATPase

Apo-ceruloplasmin

ER

GolgiTGN

lysosome

Bilecanaliculus

endosome

Holo-ceruloplasmin

Secretion

To plasmaHolo-ceruloplasmin

Fig. 1 Physiological copper transport system in hepatic cells (image)Intracellular copper-transport proteins (Wilson ATPase: ATP7B) and ceruloplasmin are expressed via an intracellular copper-importing protein (Ctr), intracellular copper-storing protein (Metallothionein: MT), intracellular copper-transporting proteinchaperones (Cu or metallo-chaperones: (1) HAH1, (2) Ccs, (3) Cox17) and TGN (trans-Golgi network). ER: endoplasmicreticulum, Golgi: Golgi body, ●: Cu,

➡

� : Wilson ATP7B.Copper is taken up from capillary blood across the hepatic cell membrane via Ctr. It is then taken transported to the cellularorganelles by three chaperones, consisting of recently discovered intracellular copper-transport proteins, with specificfunctions. The first is the HAH1-chaperone, which carries copper to the Golgi bodies; the second is the Ccs-chaperone, whichcarries copper to the Cu/Zn superoxide dismutase (SOD) enzyme; the third is the Cox17-chaperone, which carries copperto cytochrome oxidase (Cco). Metallothionein (MT) works against the stored copper. Holo-ceruloplasmin is secreted fromthe hepatic cells into the capillary blood. The excess copper in the Golgi body is transported to the intracellular vesicularcompartments (lysosomes, endsomes, etc.). After assisting in copper excretion into the biliary canaliculi and executing itsrole, ATP7B returns to the Golgi body (this is called the trans-Golgi network).(Quoted with Harris, Z.L., Gitlin, J.D.: Genetic and molecular basis for copper toxicity. Am J Clin Nutr 1996; 63 (5): 836s–841s with modification by the author.)


COPPER DEFICIENCY AND THE CLINICAL PRACTICE

has decreased dramatically.1,4) An acquiredcopper excess state has been described incases of Indian childhood cirrhosis, non-Indianchildhood cirrhosis, excessive copper intake,and parenteral bolus administration of copperfor the treatment of copper deficiency.1,2)

Many aspects regarding the physiologicalroles of copper in the body remain unknown.However, remarkable progress in the under-standing of copper metabolism has been madesince the cloning of the candidate genes forMenkes disease (ATP7A)5,6) and Wilson dis-ease (ATP7B).7,8) It has been revealed thatthe proteins induced by these genes (ATP7Aand ATP7B) are highly homologous, and thatboth are P-type ATP-related copper-transportermembrane proteins that control cellular coppertransport.5–8) Furthermore, the mechanism bywhich copper is transported into cells and thechaperones (three kinds) supplying copper tothe copper-requiring enzymes have been dis-covered, and the physiology of cellular coppermetabolism is being gradually elucidated.2,9)

For lack of space, the physiological roles ofcopper in humans are not discussed here. Table1 lists the major copper-requiring enzymes inthe body,1,2) and Fig. 1 shows a chart of the vari-ous steps in copper metabolism in hepatocytes.See cited references for further details.2)

The discussion in this article is mainly focusedon copper deficiency in humans.

General Symptoms ofCopper Deficiency

The clinical symptoms associated with copperdeficiency are extremely diverse. The most com-mon features include anemia, leucopenia, bonelesions (scorbutic-like bone changes and occipitalhorn), and vesical diverticula.1) In children,some commonly noted findings are hypotonia,psychomotor retardation, and hypothermia.1)

1. Hematological abnormalities1,2,11)

(1) Microcytic hypochromic anemia:This is attributable to a decrease in the

ferroxidase activity of ceruloplasmin (Cp) andreduced iron oxidation. When anemia isnoted in low-birth-weight infants, patients withchronic diarrhea, and patients receiving pro-longed enteral or parenteral nutrition, copperdeficiency must be suspected in addition to irondeficiency.(2) Neutropenia:

Granulocyte maturation disorder in the bonemarrow and vacuolation in neutrophils areobserved.

2. Bone lesions incopper deficiency states1,2,10,11)

Rachitic-like or scorbutic-like changes (en-largement of the epiphyseal area and changesin the margin) are observed in the bones ofextremities. They may be accompanied by osteo-porosis and occipital horn formation after ado-lescence. These are attributable to functionalimpairment of copper-requiring enzymes, suchas ascorbate oxidase and lysyl oxidase, associ-ated with copper deficiency.

3. Vascular lesions1,2,10)

Menkes disease is characterized by tortuosityand winding of arteries and increased capillaryfragility. Caution must be exercised to avoidprolonged copper deficiency in humans, sincethis may lead to abnormal vascular tortuosityand increased capillary fragility.

4. Central nervous system disorder andconvulsion1,2,10)

Reports of central nervous system disorderand convulsion associated with secondarycopper deficiency are rare, but they are charac-teristic features of Menkes disease. ProgressiveMenkes disease can be fatal. Prolonged copperdeficiency may cause degeneration of thecerebrum and cerebellum (numerous copper-requiring enzymes are present in the brain,such as dopamine �-hydroxylase and cyto-chrome c oxidase), associated with slowing ofmentation and muscular rigidity, as well as hem-orrhagic changes due to increased capillary


fragility.In children, hypotonia is often observed.

5. Hair abnormalities1,2,10)

Change of hair texture, namely, kinky-hair,may be observed in children with Menkesdisease. Hair changes are, however, consideredrare in cases with secondary copper deficiency.On the other hand, the possibility of changesin the hair should be borne in mind in casesof prolonged copper deficiency. The coppercontent of the hair and nail is decreased incases of copper deficiency.

6. OthersAttention should be paid to the develop-

ment of hypothermia, achromoderma, spleno-hepatomegaly, and susceptibility to infectionsin copper deficiency states.1,2,11)

Diagnosis and Evaluation of CopperDeficiency States and Indicators1)

The above-described clinical findings areimportant pointers for the diagnosis of copperdeficiency. In addition, when copper deficiencyis suspected, the following tests must be con-ducted. The most important indicators of thestatus of copper deficiency are the serum cerulo-plasmin (Cp) level and the serum copper level.Caution must be exercised in interpreting theirvalues, because newborns and low-birth-weightinfants often have physiological hypocerulo-plasminemia and hypocupremia, which makethe diagnosis and assessment of copper defi-

ciency difficult in these cases.

1. Serum Cp levelExcept in newborns, low-birth-weight in-

fants, and small infants, serum Cp levels maybe interpreted as follows: 10 to 20 mg/dl, milddecrease; 5 to 10 mg/dl, moderate decrease;5 mg/dl or less, marked decrease.

2. Serum copper levelExcept in newborns, low-birth-weight in-

fants, and small infants, serum copper levelsmay be interpreted as follows: 60 to 80�g/dl,mild decrease; 40 to 60�g/dl, moderate de-crease; 40�g/dl or less, marked decrease.

In addition, information regarding the cop-per content of the hair and nails, and a study ofthe urinary copper excretion and copper bal-ance would be useful.

Treatment of Copper Deficiency1)

1. Treatment of copper deficiency in low-birth-weight infants and newborns

When copper is administered intravenously,the amount of copper accumulating is propor-tional to the amount administered, and a largeamount of non-Cp copper in the blood mayinduce toxicity. Therefore, oral administrationis recommended, where possible. Intravenousadministration may become necessary if noimprovement in the clinical condition is ob-served after oral administration for about aweek. However, this should be avoided asfar as possible during the first 3 weeks after

T. AOKI

Table 2 Copper Treatment for Copper Deficiency (personal proposal)

Segment Oral dose Parenteral/intravenous dose

Low-birth-weight infants100–200�g/kg/day 20–30�g/kg/day

Newborns

Infants/children 2.5–5.0mg/day 20–35�g/kg/day

Adolescents and adults 5.0–10.0mg/day15–20�g/kg/day900–1,500�g/day

¸˝˛


birth, when copper supplementation should beconducted gradually.

2. Treatment of copper deficiency ininfants and children

As a general rule, oral administration shouldbe employed. When oral administration isimpossible, treatment should be provided byeither intravenous or subcutaneous injection.

3. Treatment of copper deficiency inadolescence and adulthood

The doses are shown in Table 2. The route ofadministration is the same as that for infantsand children.

Menkes Disease2,10)

Menkes disease is a genetic disorder ofcopper transport in the body, and disorder ofcopper absorption and excretion is noted inthe intestinal tract and uriniferous tubules. TheMenkes disease gene is located on the long armof the X chromosome (Xq 13.3). The proteininduced by this gene is an intracellular copper-transport membrane protein called ATP7A.The Menkes disease gene is predominantlyexpressed in the duodenum, upper part of thesmall intestine, and renal proximal tubules,while no expression is noted in hepatocytes(the Wilson disease gene is strongly expressedin the hepatocytes). Therefore, this disease istransmitted by X-linked recessive inheritanceand develops in boys, at an estimated incidenceof about 1 in 100,000–200,000. In this disease,copper absorption from the intestine is impaired,resulting in a copper deficiency state. Centralnervous system disorder, collagen metabolismdisorder, bone lesions, vascular lesions, hairabnormalities, abnormality of pigmentation,vesical diverticula, and decreased skin elas-ticity may be noted. However, hematologicalabnormalities, which are commonly seen incases of nutritional copper deficiency are rare.Hypothermia and weak breast-feeding may benoted during the neonatal period in some cases,

COPPER DEFICIENCY AND THE CLINICAL PRACTICE

but many of the infants grow normally until 3or 4 months of age, when the disease oftenmanifests by features such as convulsion, etc.The central nervous symptoms are progressive,may become serious even during the earlystages, and then regress. Typically, kinky hair(nodules, trichorrhexis, and kinky) is noted andthe hair is rough, brittle and breaks easily.However, this may not be evident in somecases. Hypoceruloplasminemia and hypocupre-mia are seen on blood biochemical tests. Cop-per absorption is noted to be poor in the oralcopper sulfate tolerance test, with no increasein the serum Cp level or serum copper level.

The typical form of this disease is calledclassic Menkes disease, which is a seriouscondition. In addition, mild Menkes diseaseand extremely mild Menkes disease (occipitalhorn syndrome and Ehlers-Danlos syndrome,type IX) may also be seen, and abnormalityof the Menkes disease gene has been confirmedin both cases. The mild type develops between6 and 24 months after birth, and the extremelymild type is often discovered from the age of5 or 6 years through adolescence.

There is no radical cure for this disease.Parenteral copper administration (intravenousor subcutaneous injection) may be adminis-tered, but it is ineffective against advancedcerebral disorder. Parenteral copper adminis-tration is believed to resolve the systemiccondition, bone and hair changes, and thesusceptibility to infection, and to prolongpatients’ lives. It is considered effective againstmild and extremely mild cases.

Conclusion

The clinical aspects of copper deficiency inhumans are discussed in this article, includingthe characteristic clinical features, methods ofdiagnosis and evaluation, and treatment. Inaddition, Menkes disease has been reviewedbriefly.


T. AOKI

REFERENCES

1) Aoki, T., Yamaguchi, Y., Shimizu, N. et al.:Copper deficiency and its treatment from thepoint of view of copper metabolism in thebody. Pediatrics of Japan 1996; 37: 317–329. (inJapanese)

2) Culotta, V.C. and Gitlin, J.D.: Disorders ofcopper transport. In The Metabolic andMolecular Bases of Inherited Disease, (ed.Scriver et al.) 8th ed., vol II, McGraw Hill,New York, 2000; pp.3105–3126.

3) Nezu, R., Takagi, Y., Okada, A. et al.: Intra-venous nutrition, enteral nutrition and traceelements. The Pediatric Quarterly 1992; 25(2):283–298. (in Japanese)

4) Yamaguchi, Y., Yamaguchi, K., Aoki, T. et al.:Long-term intravenous and enteral nutritionand trace element abnormality. Pediatrics ofJapan 2002; 43: 625–632. (in Japanese)

5) Vulpe, C., Levinson, B., Packman, S. et al.:Isolation of a candidate gene for Menkes dis-ease and evidence that it encodes a copper-transporting. Nat Genet 1993; 3: 7–13.

6) Mercer, J.F.B., Livingston, J., Hall, B. et al.:Isolation of a partial candidate gene forMenkes disease by positional cloning. NatGenet 1993; 3: 20–25.

7) Yamaguchi, Y., Heiny, M.E. and Gitlin, J.D.:Isolation and characterization of a humanliver cDNA as a candidate gene for Wilsondisease. Biochem Biophys Res Commun 1993;197: 271–277.

8) Bull, P.C., Thomas, G.R., Rommens, J.M. et al.:The Wilson disease gene is a putative coppertransporting P-type ATPase similar to theMenkes gene. Nat Genet 1993; 5: 327–337.

9) Aoki, T., Shimizu, K. and Takeshita, Y.: Pheno-type, genotype and treatment for patients withWilson Disease. The Cell 2002; 34(14): 583–586. (in Japanese)

10) Aoki, T., Yamaguchi, Y., Gitlin, J.D. et al.:Clinical disease type and gene type of Menkesdisease and Occipital horn syndrome—Phe-notype and genotype. Pediatrics of Japan 1997;38: 247–258. (in Japanese)

11) Matsuda, I.: Trace elements and nutrition. ThePediatric Quarterly 1992; 25(2): 203–223. (inJapanese)



Introduction

Chemically, iodine is a halogen. It has anatomic number of 53 and is an amphoteric ele-ment with an atomic mass of approximately127. Iodine possesses both positive and nega-tive valences. At ordinary temperatures itexists in the form of purplish-black scale-likecrystals with a metallic sheen, and it is volatile

Iodine Deficiency Disorder andClinical PracticeJMAJ 47(8): 371–375, 2004

Makoto IITAKA

Associate Professor, Fourth Department of Internal Medicine, Saitama Medical School

Abstract: Most iodine is present in marine sediment, and large amounts arecontained in marine algae and saltwater fish. Thus, there is a risk of iodine defi-ciency in the interior of continents and in countries where marine products are notconsumed. Because of the large amounts of algae consumption, iodine deficiencynever develops in Japan. According to the World Health Organization, however, theiodine deficiency disorders (IDD) are observed in 130 countries throughout theworld, and 2.2 billion people live in iodine-deficient regions. The minimum dailyrequirement for iodine is 100–150�g, and almost all of it is used to synthesizethyroid hormone. In iodine-deficiency states, the decrease in thyroid hormoneleads to an increase in thyroid-stimulating hormone (TSH) resulting in the devel-opment of goiter. Goiter due to iodine deficiency affects 740 million people world-wide, accounting for 13% of the world’s total population. Severe neurological dis-orders and developmental delay due to cretinism are observed in newborn infantsin severely iodine-deficient regions. Cretinism is classified into a myxedematoustype, a neurological type, and a mixed type based on the clinical manifestations.Although intensive efforts have been made by many countries to eliminate IDD, itstill remains the most common endemic disease in the world.

Key words: Iodine deficiency disorder; Hypothyroidism; Endemic goiter;Cretinism

and has a characteristic odor. Iodine is anessential trace element and iodine deficiencycauses serious metabolic disorders.

Distribution of Iodine inthe Natural World

Most of the iodine in nature exists in theform of iodine salts. Since many iodine salts are

�Trace Elements


normally excreted in the urine is 100–200�g/l.However, because Japanese people consumelarge amounts of kelp and other marine algae,their daily intake is 1–3 mg, and their urinaryiodine excretion is much greater than that ofpeople in other countries.

Iodine and Thyroid HormoneSynthesis

The follicular epithelial cells of the thyroidgland convert iodine into organic iodine com-pounds and synthesize thyroid hormone. Iodineis taken up by the follicular epithelial cells viathe Na/I symporter (NIS) on their basementmembrane. When a mutation is present in theNIS, iodine uptake is impaired, and hypo-thyroidism develops. The iodine that has beentaken up is excreted into the follicular lumenby Pendrin, an I�/Cl� transporter present inthe apical membrane facing the follicular lumen.Abnormalities of the Pendrin gene (PDS) areobserved in Pendred syndrome patients, andthey develop hypothyroidism or sensory deaf-ness as a result of impaired conversion of iodineinto organic iodine compounds.

Conversion of iodine into organic iodinecompounds is performed on thyroglobulin (Tg)in the follicles. Tg is a large molecule with amolecular mass of 66�104. Each molecule con-tains 120–130 tyrosine residues, and about 25%of them function as iodine acceptors.

Tg synthesis is modulated by TSH (thyroid-stimulating hormone). The iodine taken up isoxidized in the follicular lumen by H2O2 andthyroid peroxidase (TPO), and it binds to Tg’styrosine residues. 3-monoiodotyrosine residues(MITs) and 3,5-diiodotyrosine residues (DITs)are synthesized as a result. MITs and DITs arethen coupled to form T3 residues on Tg, andpairs of DITs are coupled to form T4 residues.Tg in the follicular lumen is taken up by theepithelial cells in the form of colloid droplets,and Tg is hydrolyzed by proteases to form T3

(triiodothyronine) and T4 (thyroxine). T3 andT4 are then secreted into the blood.

M. IITAKA

water-soluble, they are flushed out by rain-water and rivers to the sea.

There are various opinions as to the totalamount of iodine present in the earth’s crust,which covers the surface of the globe, but thetotal amount is estimated to be 8.7 trillion tons,with the majority present in marine sedimentand sedimentary rock, and approximately 0.8%,70 billion tons, is presumed to be present inseawater.1) The iodine content of soil is approxi-mately 0.2–12 mg/l, but because iodine salts arewater-soluble, clayish soil contains relativelylarge amounts, and sandy soil contains little.Moreover, the soil in mountainous regions pre-viously covered by glaciers contains hardly anyiodine after the glaciers melted, and there isalso little iodine in soil around rivers that haverepeatedly flooded. Since natural water con-tains very small amounts of iodine, there is ex-tremely little iodine in regions far from the sea.

In the biological world, marine algae containlarge amounts of iodine, and a wide range ofsea-dwelling animals also contain iodine, butfreshwater fish and land animals contain little.Expressed as amounts of their dry weight, kelpcontains 200–300 mg/100 g, wakame seaweedcontains 7–24 mg/100g, hijiki seaweed (Hizikiafusiforme) contains 20–60 mg/100 g, and salt-water fish contain 0.1–0.3 mg/100 g. The iodinecontent of cereals and vegetables is about 2–40�g/100 g.

Because of the iodine distribution describedabove, there is a risk of iodine deficiency occur-ring in the interior of continents and in countrieswhere few sea products are consumed. Accord-ing to World Health Organization (WHO) sta-tistics, iodine deficiency occurs in 130 countriesaround the world, and 2.2 billion people, orapproximately 38% of the world’s population,live in iodine-deficient areas.2)

The bodies of healthy persons contain 15–20 mg of iodine. The minimum daily require-ment is 100–150�g, and almost all of it is takenup by the thyroid gland and used to synthesizethyroid hormone. The remaining iodine is ex-creted in the urine, and the amount of iodine


IODINE DEFICIENCY DISORDERS

mild, 49–20�g/l as moderate, and less than20�g/l as severe.

Goiter due to iodine insufficiency was ob-served in ancient times in China and India, andin the Greek and Roman era. The oldest de-scription is a statement in China around 2700BC that marine algae are an effective treat-ment for goiter,1) and in the 4th to 5th centuriesAD, the thyroid glands of animals were shownto be useful in treating goiter. The obviousgoiter of a person in a Buddhist frieze inGandhara Pakistan in the 2nd–3rd century isthought to be the first goiter ever depictedgraphically.1)

Goiter was commonly seen in the Alpineregion of Switzerland. Even today 97 millionpeople in Europe are reported to have goiterdue to iodine insufficiency,3) and huge goiterscaused by iodine deficiency are seen in the moun-tainous zones of the Himalayan and Andeanregions and deep in the African continent.

Several times more people with latent hypo-thyroidism who have elevated serum TSH val-ues but normal T4 values are presumed to existin iodine-deficient regions than those who haveovert hypothyroidism with T4 levels below thereference range.

Table 1 Epidemiological Statistics for the Iodine Deficiency Disorders (1999)

Number of Population affectedProportion of the

Percentage ofRegion IDD-affected by goiter

total population (%)households with access

countries (in millions) to iodized salt

Africa 44 124 20 63

The Americas 19 39 5 90

South-East Asia 9 172 12 70

Europe 32 130 15 27

Eastern Mediterranean 17 152 32 66

Western Pacific 9 124 8 76

Total 130 741 13 68

Source: WHO, UNICEF, ICCIDD: Assessment of iodine deficiency disorders and monitoring their elimination.A Guide for Programme Managers, 2nd ed, World Health Organization, Geneva, 2001; pp. 7–40. (modified)

Endemic Goiter

Iodine insufficiency induces an increase inthyroid-stimulating hormone (TSH) in responseto decreased production of thyroid hormone,and goiter develops as a result of the stimulat-ing action of TSH. Because of the high intakeof seaweed, iodine deficiency never developsin Japan. The WHO, however, estimates that500–850 million people worldwide have goitercaused by iodine deficiency. According to thestatistics for 1999, a survey of WHO memberstates revealed that 130 countries were iniodine-deficient regions and that 740 millionpeople had goiter secondary to iodine defi-ciency, amounting to 13% of the total popula-tion (Table 1).2) If the incidence of goiter inschoolchildren age 6–12 years is 5% or more,the region is considered to be an iodine-deficient region. The WHO defines regionswith a goiter incidence of 5–19.9% as a mildiodine-deficiency regions, an incidence of 20–29.9% as moderate iodine-deficiency regions,and an incidence of 30% or more as severeiodine-deficiency regions.

Iodine excretion in the urine is also used asan index of the severity of iodine deficiency,with median values of 50–99�g/l classified as


Endemic Cretinism

Many of the cases of cretinism in newborninfants in Japan are attributable to thyroidgland anomalies (aplasia, hypoplasia, ectopicthyroid). However, in regions where iodinedeficiency is severe, pregnant women often ex-perience spontaneous abortion and stillbirthsbecause of placental hypofunction, and chil-dren manifest irreversible physical and intel-lectual developmental delay due to the effectsof hypothyroidism beginning in the fetal period.Reduced thyroid hormone levels caused byiodine deficiency lead to brain damage in thefetal and neonatal period, when sensitivity tothyroid hormone is particularly high. More-over, because their resistance is weak, mor-tality in the neonatal period and in childhoodis also high.

Based on its clinical manifestations, cretin-ism due to iodine deficiency is classified into amyxedematous type (myxedematous cretin-ism), a neurological type (neurological cretin-ism), and a mixed type, in which the two aremingled in various degrees. Manifestations ofmyxedema due to hypothyroidism predomi-nate in myxedematous cretinism, and there aremarked delays or decreases in growth, mentaldevelopment, and secondary sex characteris-tics, but there are few neurological manifesta-tions, such as paralysis. Patients have no goiter,and the serum T4 values are reduced. In neuro-logical cretinism, neuropsychiatric manifesta-tions are prominent, and patients exhibit de-creased intelligence, deaf-mutism, strabismus,and spastic quadriplegia, but there are fewmanifestations of hypothyroidism. In the neuro-logical type, patients have a goiter, and theserum T4 values are sometimes normal.

The neurological type is more common inChina although the myxedematous type is alsoseen. The distribution of endemic cretinism inChina is characterized by the neurological typebeing more common in the southeastern partand the myxedematous type being more com-mon in the northwestern part. The thyroid

gland is atrophied in the myxedematous type.Although an autoimmune mechanism has alsobeen proposed,4) developmental disorders ofthe nervous system due to the decrease in thy-roid hormone beginning in the fetal period arethe main cause of both types. The differencebetween them seems to be related to the de-gree and period of hypothyroidism after birth.5)

Prevention and Treatment ofIodine Deficiency

In response to calls by the WHO, UNICEF,and the International Council for Control ofIodine Deficiency Disorders (ICCIDD) overthe past 20 years, iodine salts have been addedto the table salt in countries where iodine defi-ciency exists, and iodine deficiency is now beingprevented. There are also countries where io-dine has been added to drinking water, bread,etc. The WHO is verifying a daily iodine intakeof 90�g for preschool children, 120�g forschoolchildren, 150�g for adults, and 200�g forpregnant and breast-feeding women. As shownin Table 1, it has now become possible to useiodized salt in an average of 68% of householdsworldwide. However, no measures have yetbeen adopted in 30 of the 130 countries whereiodine deficiency exists. Moreover, withoutquality control of the iodized salt or propercontrol of intake, there is the risk of inability toconsume a sufficient amount of iodine, as wellas the opposite, that is, inducing hyperthyroid-ism by taking excessive amounts of iodine, andthese issues represent a future task.

Japan accounts for approximately 40% ofthe world’s iodine production.1) In addition tobeing used as a radiographic contrast medium,6.2% (1,140 tons) of the total iodine producedworldwide is used in the form of iodized salt.

Use of iodine to treat cretinism induced byiodine deficiency is often effective in restoringthyroid function in children up to 4 years ofage, but the prospects for normal functiondecrease with age.6) Neuropsychiatric improve-ment cannot be expected in response to treat-

M. IITAKA


ment with thyroid hormone, and thyroid func-tion fails to recover in children after pubertyand in adults even when given iodine. To avoiddamage to the cranial nervous system, hypo-thyroidism needs to be prevented in the fetus,and pregnant women must not be allowed todevelop iodine deficiency. In other words, pre-vention of iodine deficiency is the most impor-tant means of eliminating endemic cretinism.

Since thyroid hormone supplementation isimmediately started whenever cretinism isdiagnosed on the basis of neonatal screeningtests in Japan, there are very few cases of seri-ous sequelae.

Conclusion

In Japan there is a tendency toward excessiveiodine intake instead of iodine deficiency. How-ever, iodine deficiency disorders are the mostcommon endemic disease in the world. Iodinedeficiency causes goiter and serious neuro-logical damage as a result of hypothyroidism.The WHO, UNICEF, and the ICCIDD areactively attempting to eradicate it. Since iodinedeficiency can be prevented by iodine supple-mentation, sustained government commitmentand motivation are essential to eliminate IDD.

IODINE DEFICIENCY DISORDERS

REFERENCES

1) Irie, M.: Assessment of the role of ODA foriodine deficiency. 2000 Report of the GuestMembers and Investigators of the Japan Inter-national Cooperation Agency (JICA). JICA,Tokyo, 2001; pp.9–24. (in Japanese)

2) WHO, UNICEF, ICCIDD: Assessment ofiodine deficiency disorders and monitoringtheir elimination. A Guide for ProgrammeManagers, 2nd ed, World Health Organiza-tion, Geneva, 2001; pp.7–40.

3) Vitti, P., Rago, T., Aghini-Lombardi, F. et al.:Iodine deficiency disorders in Europe. PublicHealth Nutrition 2001; 4: 529–535.

4) Boyages, S.C., Halpern, J.P., Maberly, G.F.et al.: Endemic cretinism: Possible role forthyroid autoimmunity. Lancet 1989; 2: 529–532.

5) Boyages, S.C., Halpern, J.P., Maberly, G.F.et al.: A comparative study of neurological andmyxedematous endemic cretinism in westernChina. J Clin Endocrinol Metab 1988; 67:1262–1271.

6) Vanderpas, J.B., Rivera-Vanderpas, M.T.,Bourdoux, P. et al.: Reversibility of severehypothyroidism with supplementary iodinein patients with endemic cretinism. New EnglJ Med 1986; 315: 791–795.



Trace Element Deficiency inInfants and Children—Clinical practice—JMAJ 47(8): 376–381, 2004

Hiroko KODAMA

Associate Professor, Department of Pediatrics, Teikyo University, School of Medicine

Abstract: Trace element deficiencies commonly encountered in Japanese infantsand children are discussed. Premature birth infants have a high likelihood ofdeveloping deficiency of trace elements such as iron, zinc, and selenium, duringthe period of rapid growth from 2 months to 6 months of age. Breast-fed infants, inparticular, are prone to develop trace element deficiency, and alopecia anddermatitis attributable to zinc deficiency have been reported. Furthermore, “follow-up milk” formulas (milk-substitute nutritional supplement for infants) in Japan con-tain practically no zinc or copper. Dependence on follow-up milk formulas as themain source of nutrition is associated with a high risk of zinc and copper deficiency.In one study, 60% of short-statured children without any endocrine disease werefound to have zinc deficiency, and zinc administration was associated with anincrease of body height. About 20 to 30% of adolescent and young women exhibitiron and zinc deficiency due to dieting. Excessive iodine intake by mothers duringpregnancy has been suggested to be the cause of hyper-TSH-emia detectedduring the mass screening of neonates. Many enteral formulas in Japan do notcontain selenium and iodine, and long-term administration of such formulas hasbeen reported to be associated with deficiency of these elements.

Key words: Premature birth infants; Short-statured children;Infantile iron deficiency; Infantile zinc deficiency

ment deficiency status in the population is par-ticularly serious in Southeast Asia and Africa,and 41 to 99% of children in these regions havebeen reported to be suffering from deficiencyof vitamin A, iodine, iron, or zinc.1) In Japan,trace element deficiency is seldom encountered

Introduction

Deficiency of trace nutrients is more likelyto be encountered in children and pregnantwomen, who have a larger demand per unitbody weight. On a global level, the trace ele-

�Trace Elements


of age, and adolescent women. In these agegroups, the iron demand is particularly highdue to the rapid growth of body height. Table 1shows the symptoms of iron deficiency anemiain children, the diagnostic criteria, and thetreatment strategies.2,3) When a decrease in thehemoglobin level is noted, iron deficiency canbe confirmed on the basis of a decreased serumiron level, increased serum total iron-bindingcapacity, decreased serum ferritin level, anddecreased mean corpuscular volume (MCV).

2. Premature infantsThe amount of iron delivered from the

maternal body to the fetus via the placentaincreases during the late gestation period,therefore, iron deficiency is more likely to beencountered in premature infants. Anemia inpremature birth infants can be divided into

in healthy infants and children. However, itposes a problem in premature birth infants andchildren with poor nutritional intake, patientsreceiving enteral formulas for prolonged periods,and patients with various chronic diseases.

In this article, we discuss trace element defi-ciency of the type most commonly encounteredin Japanese infants and children. “Trace ele-ments,” in general, do not include iron. How-ever, since iron is a trace element and iron defi-ciency is a particularly important problem inchildren, iron deficiency is also discussed here.

Iron Deficiency Anemia

1. Diagnosis and treatment of iron deficiencyIron deficiency anemia occurs more com-

monly in premature infants (premature birthinfants), infants between 6 months and 2 years

Table 1 Symptoms, Diagnosis, and Treatment of Major Iron Deficiency in Infants

Major symptoms Diagnostic criteria Treatment

Premature birth infants Facial pallor, Iron supplementation (2mg/kg/day)Late anemia inanimate, dysphoria, continued until normalization of(16 months or anorexia, the serum iron and ferritin levelslater after birth) poor weight gain Hb¯10g/dl 3–4mg/kg/day if the birth weight is

1,000g or lessGuidance on weaning, follow-up examination

(one year after completion of treatment)

Delayed weaning, Facial pallor, A. 10g/dl�Hb¯11g/dl: Guidance on diet,between 6 months to inanimate, dysphoria, follow-up examination2 years after birth anorexia, (once a month, every 6 months)(Milk anemia) poor weight gain Hb¯11g/dl B. Hb¯10g/dl: Iron supplementation

(3–6mg/kg/day, 12–14 weeks)Guidance on diet, follow-up for one yearafter completion of treatment

Adolescent women Indefinite complaints A. 11g/dl�Hb¯12g/dl: Guidance on diet,(malaise, fatigability, follow-up examinationpalpitation, (once a month, every 6 months)shortness of breath), Hb¯12g/dl B. Hb¯11g/dl: Iron supplementationfacial pallor, (iron 4–6mg/kg/day, 12–14 weeks)decreased attentiveness, Guidance on diet, follow-up for one yearasthenia after completion of treatment

Athletes Same as in adolescent(Sports anemia) anemia, failure to achieve Hb¯12g/dl Same as for adolescent anemia,

better records, inability to decrease in the exercise levelmuster the last spurt

Note 1) Administer ferric pyrophosphate (Incremin syrup®) to infants and small children, and ferrous sulfate (Ferro-Gradumet®),ferrous fumarate (Ferrum®) or ferrous citrate (Ferromia®) to older children.

(Quoted and modified from Yokoyama, M.: The Journal of Pediatric Practice 1999; 10: 1437–1444)

TRACE ELEMENT DEFICIENCY IN CHILDREN


H. KODAMA

early anemia developing around 8 weeks afterbirth, and late anemia developing 16 weeks orlater after birth. Since early anemia is attribut-able to a decline in hemopoiesis in neonates,iron supplements are not effective, while bloodtransfusion and erythropoietin injection areeffective. The late anemia represents iron defi-ciency anemia due to depletion of iron stores.Its incidence is high among breast-fed infantsand iron supplements are effective in the treat-ment of this condition.

3. Milk anemiaAnemia occurring between late infancy and

early childhood in children with delayed wean-ing who drink a lot of milk is well known asmilk anemia. This has been attributed to insuf-ficient iron intake. It may be associated withprotein-losing enteropathy and gastrointestinalbleeding.

4. Adolescent womenAnemia in adolescent women is caused by iron

loss due to menstruation, unbalanced diets, anddieting for weight loss. It occurs at a high inci-dence, and about 8 to 10% of adolescentwomen are reported to have iron deficiencyanemia. When taking iron deficiency withoutanemia also into account, one out of about fouradolescent patients with indefinite complaintsis thought to have iron deficiency.2,3)

5. AthletesIron deficiency anemia in athletes is con-

sidered to be caused by insufficient iron intake,

iron loss, intestinal bleeding, and erythroclasis.This type of anemia is particularly important tobe borne in mind when adolescent women, whoare already susceptible to anemia, engage inintensive sports activities.4,5)

Zinc Deficiency (Table 2)

1. Diagnosis and treatment of zinc deficiencyZinc deficiency in children is characterized

mainly by dermatitis and alopecia during in-fancy, and by short stature during childhood.Zinc deficiency in children is not rare in Japan.Evaluation of age-related variations of serumzinc levels shows that the levels are low becauseof physiological factors between 2 months to 6months after birth.6,7) However, there are as yetno diagnostic criteria specifically established forzinc deficiency in children. Perhaps the samecriteria as for adults are applicable (serum zinclevel under 65�g/dl).

For the treatment of zinc deficiency, zinc sul-fate is administered at the dose of 5 mg/kg/day(1 mg/kg/day of zinc) b.i.d or t.i.d after meals.However, zinc sulfate is not yet approved foruse as a drug. Polaprezinc (Promac®) is a zinc-containing preparation that can be taken orally,however, only treatment of gastric ulcer withthis drug is covered by the National HealthInsurance in Japan.

2. Premature infantsInfants born prematurely and/or breast-fed

are particularly prone to develop zinc defi-ciency between 2 months to 6 months after

Table 2 Symptoms of Infantile Zinc Deficiency and Predisposition

Symptoms of deficiency Factors related to the onset of zinc deficiency

• Symptoms of acute deficiency Between 2 months and 6 months of age inEruptions around the mouth, on the pubis, premature birth infants (especially breast-fed infants),and extremities, skin erosion, alopecia, unbalanced diets, short stature, young women,susceptibility to infections, poor weight gain long-term administration of large amounts of iron,

• Symptoms of chronic deficiency chronic diarrhea, diabetes mellitus, nephrotic syndrome,Stagnation of growth of body height, anemia, cirrhosis, Crohn’s disease, Down’s syndromedysgeusia, susceptibility to infections


birth.6,7) Since premature infants have onlysmall stores of trace nutrients in the body, theytend to develop trace element deficiency dur-ing the period of rapid growth when the demandfor these elements increases. Moreover, sincethe zinc concentration in breast milk is lowerthan that in milk formulas, breast-fed infantsare more likely to develop zinc deficiency.

Fortified human milk products are availablecommercially for premature infants fed onbreast milk. The appearance of symptoms ofacute zinc deficiency, such as alopecia and der-matitis, has been reported even in infants receiv-ing fortified human milk products between 2months and 6 months of age, when markedincrease in the body weight is observed;8) this isbecause even though fortified human milkproducts contain zinc, they are not present insufficient amounts to satisfy the requirementsassociated with the rapid increase of bodyweight.

3. Infants depending on “Follow-up milk”formulas as the main source of nutrition

“Follow-up milk” formulas (milk-substitutenutritional supplement for infants), which are

used from 9 months after birth, contain practi-cally no zinc or copper. Although there havebeen no reports yet, dependence on follow-upmilk formulas as the main source of nutritioncan lead to zinc and/or copper deficiency.

4. Short-statured childrenOut of 30 short-statured Japanese children

who did not have any endocrine disease, 18(60%) had latent zinc deficiency and 11 (37%)showed serum zinc levels below the standardlevel (under 70�g/dl). Zinc administration isassociated with an increase of body height inmany cases. The increase is particularly markedin boys receiving zinc supplementation; (Fig.1).9) Children with short stature due to zincdeficiency usually do not exhibit other symp-toms of zinc deficiency, such as alopecia anddermatitis.

Therefore, when children of short stature areinvestigated as to the cause, examination forzinc deficiency is essential, and zinc administra-tion may be attempted to improve the height ofthe children.

5. Young womenAbout a half of female college students are

reported to show serum zinc levels below thestandard, and extremely poor nutritional in-take of zinc due to dieting and intake of unbal-anced diets has been suggested to be the cause.

6. Other patient groups susceptible tozinc deficiency

Children with Down’s syndrome, seriouspsychosomatic disorders, diabetes mellitus, ornephrotic syndrome have a relatively higherlikelihood of developing zinc deficiency. Acro-dermatitis enteropathica is a congenital zincabsorption disorder, and symptoms of zincdeficiency are typically observed during infancy.

Copper Deficiency

Copper deficiency, like zinc deficiency, is alsomore likely to develop in premature infants,

Gro

wth

rat

e of

bod

y he

ight

12

10

8

6

4

2

0Before treatment After treatment with zinc

Boys Girls

(cm/year)

Fig 1 Changes in the growth rate after administrationof zinc in children of short stature

(Quoted and modified from Kaji, M. et al.: J AmericanCollege Nutrition 1998; 17: 388)



but it usually does not cause any clinical prob-lems and copper supplementation is unnec-essary. Menkes disease is a congenital abnor-mality of copper metabolism characterized bysevere copper deficiency, but the incidence ofthis condition is extremely low, and it is rarelyencountered in ordinary pediatric practice.

Selenium Deficiency

Selenium deficiency, like iron and zinc defi-ciency, is also more likely to occur in prematurebirth infants between 2 months to 6 months ofage when they show rapid growth, but it is notassociated with any clinical abnormalities. Chil-dren taking enteral formulas with little sele-nium content exhibit marked selenium defi-ciency. Also, children with conditions such asserious psychosomatic disorders who have lowerdaily caloric intake than the caloric require-ment for age are more prone to develop defi-ciency of selenium and other trace elements.

Iodine Deficiency

Since Japanese people consume marine prod-ucts in relatively large quantities, iodine excessmay be more of a problem than iodine defi-ciency. However, some enteral formulas haveextremely low iodine content (Ensure Liquid®,Twinline®, Racol®, etc.). Dependence on suchenteral formulas as the only source of nutritionis associated with the risk of iodine deficiency.10)

Iodine deficiency may cause goiter and/orhypothyroidism.

Conclusion

This article discusses trace element deficien-cies that are relatively commonly encounteredin Japanese infants and children. Particularly inthe following cases, aggressive examinationand treatment are necessary (see the respectivesections for treatment).1) Premature birth infants have a greater like-

lihood of developing deficiency of trace ele-

ments such as iron, zinc, and selenium dur-ing the period of rapid growth between 2months and 6 months of age. Breast-fedinfants are particularly susceptible to traceelement deficiency.

2) The incidence of latent zinc deficiency ishigh among children of short stature with-out endocrine disease, and zinc administra-tion is often associated with an increase inthe body height.

3) Deficiency of iron and zinc is often noted inadolescent and young women.

4) Prolonged use of enteral formulas in chil-dren is associated with the risk of traceelement deficiency, such as selenium andiodine deficiency. Children with serious psy-chosomatic disorders are particularly likelycandidates to develop trace element defi-ciency. One of the countermeasures is toavoid usage of the same type of enteral for-mula over prolonged periods of time.

REFERENCES

1) Ramakrishnan, U.: Prevalence of micronutrientmalnutrition worldwide. Nutr Rev 2002; 60:S46–S52.

2) Kitajima, H.: Iron deficiency anemia in child-hood. Japanese Journal of Pediatric Hematol-ogy 2000; 14: 51–59. (in Japanese)

3) Yokoyama, M.: Iron deficiency in childhood.The Journal of Pediatric Practice 1999; 62(10):1437–1444. (in Japanese)

4) Tatara, M.: Sports anemia in children. Pediat-rics 2001; 42: 383–388. (in Japanese)

5) Nishiyama, S.: Zinc administration improvessport anemia with hemolysis. Biomedical Re-search Trace Elements 2002; 13(2): 120–125.(in Japanese)

6) Iwama, A. and Hasegawa, H.: Zinc metabo-lism in premature infants. Japanese Journal ofNutritional Assessment 2000; 17: 277–282. (inJapanese)

7) Okuyama, H. and Uetani, Y.: Trace elementdeficiency. Neonatal Care 1996; 9(special fallnumber): 232–235. (in Japanese)

8) Saikawa, N., Ichihashi, I., Takeuchi, T. et al.:Three cases of zinc deficiency in very low birth

H. KODAMA


weight infants with fortified human milk.Journal of Japanese Society of ReconstructiveMicrosurgery 2001; 13: 51–57. (in Japanese)

9) Kaji, M., Gotoh, M., Takagi, Y. et al.: Studies todetermine the usefulness of the zinc clearancetest to diagnose marginal zinc deficiency andthe effects of oral zinc supplementation for

short children. J Am Coll Nutr 1998; 17: 388–391.

10) Shiga, K., Kodama, H., Nakamoto, N. et al.:Iodine metabolism during long-term enteralnutrition management. Japanese Journal ofPediatric Gastroenterology, Hematology, andNutrition 2002; 16(suppl): 45. (in Japanese)




Introduction

Various physiological changes related tonutrition take place in old age.

First, the deterioration in the capacity fordigestion and absorption results in a need for

Deficiencies of Trace Elements amongthe Aged and Clinical AspectsJMAJ 47(8): 382–386, 2004

Yoshinori ITOKAWA

Dean, Graduate School of Nursing and Social Welfare Sciences,Fukui Prefectural University

Abstract: A survey was conducted on the aged individuals at health care facilityfor the elderly to investigate problems associated with the intake of minerals andtrace elements among the aged Japanese. In addition, the literature was reviewedto the effects of trace elements that are involved in diseases common among theaged. The results indicated that although aged individuals consume the sameamount as young people, the plasma concentration of calcium of the former waslower, indicating that their capacity to utilize this metal (e.g., intestinal absorptivecapacity) has been compromised. Furthermore, consumption of magnesium andzinc is very low among the aged and their plasma concentrations of these elementsare frequently far below the normal threshold. These facts indicate that agedindividuals suffer from a very poor nutritional state. A review of the literaturerevealed that magnesium and selenium are involved in circulatory diseases; andnot only iron but also copper and zinc play a role in the development of anemia. Ironand zinc are related to the pathogenesis of decubitus ulcers; zinc and lithium inpsychiatric disorders; and chromium and vanadium related to the cause of dia-betes mellitus. Generally speaking, aged individuals consume less than optimumamounts of trace elements and their capacity to utilize them is limited. Thus it ispossible that the lack of an adequate supply of these trace elements may explainwhy many of the diseases normally attributed to old age develop.

Key words: Trace elements; The aged; Nutritional status; Mineral

intake of nutrients in excess of what an averageadult requires per unit weight. In the aged, thecapacity to retain nutrients in the body appearsalso to be reduced. Because the intracellularfluid volume is reduced, a large quantity ofnutrients (e.g., potassium and magnesium) that

�Trace Elements


widely among individuals regardless of theirage but the mean did not differ significantlybetween the two groups. However, the plasmacalcium concentration of the aged individualswas significantly lower than that of the youngersubjects, proving that although calcium con-sumption is similar in these two groups, itsutilization is far less efficient among the elderly.

In Fig. 1, the relationship between magne-sium intake and its concentration in the plasmais shown. The amount of magnesium consumedis evidently low and so is its plasma concen-

have been dissolved in this fluid also tend to belower. The gustatory sensation is compromisedand the sensation for sweet or salty flavorsbecomes exaggerated in comparison with thatthey had when they were younger. The deterio-ration in the masticatory function results ina preference for softer food; and a reducedintake of dietary fibers may lead to the devel-opment of constipation.

The present study was conducted to investi-gate how the physiological changes and thestatus of mineral and trace element nutrition inthe aged — such as that described above — arerelated to their health and affect the develop-ment of diseases.

Status of Mineral Nutrition inthe Aged

First, a study was conducted to discover thestatus of mineral nutrition among the aged.1)

For the subjects, 10 male and 10 female in-patients were selected (average age, 77.4 years).The prerequisites used for the selection werethat they were suffering from conditions suchas arteriosclerosis and osteoporosis (commonamong the aged) but were at a relatively mildstage of the disease; and they still retained acertain level of independence in their dailyactivities. For the controls, 10 male and 10 femalestudents or hospital employees (average age,24.6 years) were selected. The participantswere asked to fill out a dietary survey sheet on3 consecutive days. The amounts of calcium,magnesium, zinc, and copper consumed werecomputed by using a nutrient computing pro-gram prepared for use on a personal computerand which was based on a table of componentsof standard Japanese foods and several refer-ences. Blood specimens were collected fromboth patients and controls following fastingand their plasma mineral contents were com-puted. It was found that each of the 4 mineralscited exhibits a different pattern of consump-tion and absorption.

The amount of calcium consumed varied

Pla

sma

mag

nesi

um c

once

ntra

tion

3002001000

30

20

10

Magnesium consumption (mg/day)

(�g/ml)

Lower threshold ofthe normal level

The aged

Young adults

y�18.2�0.025x

r �0.4414

t �2.9915

p�0.01

Fig. 1 The relationship between the intake and plasmacontent of magnesium in aged inpatients andyoung adults(Itokawa, Y.: Food Chemicals 1995)

Fig. 2 Relationship between uptake and plasmaconcentration of zinc(Itokawa, Y.: Food Chemicals 1995)

Pla

sma

zin

c co

nce

ntr

ati

on

40302010

1.5

1.0

0.5

0

Zinc intake (mg/day)

(�g/ml)y�0.720�0.00828x r �0.4250

t �2.8559 p�0.01

The aged Young adults

DEFICIENCIES OF TRACE ELEMENTS AMONG THE AGED AND CLINICAL ASPECTS


tration in the older population. Although theplasma magnesium concentration is not a sen-sitive indicator of magnesium balance in thebody, the concentrations for 3 of the olderindividuals were below the normal level, sug-gesting that their state of magnesium deficiencywas advanced.

Figure 2 shows the relationship betweenzinc intake and plasma zinc concentration.Zinc intake was generally low among the aged;the plasma zinc concentration was below thelower threshold of the normal level in many;and a correlation was noted between the intakeof magnesium and zinc and their plasmaconcentrations.

Copper intake by the aged was very low, withan evident difference between the young andthe aged. However, there was no difference inthe plasma copper concentrations betweenthese groups; neither was there any correlationbetween the intake and their plasma concen-trations. It appears that there is a need todevelop better evaluation indices for copper.

The study described above has a certainlimitation — i.e., it was conducted on a uniquegroup of aged individuals (e.g., inpatients). How-ever, it is sufficient to suggest that among theseolder subjects, their intake of minerals andtrace elements is reduced and their capacityto utilize them (e.g., their rate of intestinalabsorption) has been compromised; thus theirnutritional state vis-à-vis trace elements dete-riorates as they grow older.

Diseases of the Aged andTrace Elements

1. Circulatory diseasesAlthough not included in the category of

trace elements, magnesium is closely related tocirculatory diseases. The antagonist-like actionof magnesium prevents calcium from flowinginto the vascular smooth muscle cells. Becauseof this action, magnesium has an effect toprevent myocardial and cerebral infarctions.As described above, its intake by the aged is

low: special caution must be exercised in thisarea.

According to a report from China, Keshandisease, a heart disease prevalent there, iscaused by a selenium deficiency. Starting around1974, a special nutritional program was imple-mented to add selenium to the diet of inhabit-ants in those areas where this disease wasendemic, which resulted in dramatic reductionsin its mortality and prevalence.2) Selenium isincorporated in the form of a seleno-aminoacid into glutathione-peroxidases, which playsan important role in preventing oxidation dis-orders. A selenium deficiency and a resultantincrease in the lipid peroxide level invite thedevelopment of circulatory diseases such asarteriosclerosis. Known food sources of sele-nium include fish and grains, which are oftenfavored by the aged. However, the overallintake of food decreases as one grows olderand it is quite possible that some may sufferfrom a deficiency of this element.

2. AnemiaFigure 3 shows the frequency of the inci-

dences of anemia at each age level, accordingto the National Nutrition Survey in Japan.Among women, peaks are noted in those intheir 30s and 40s, which can be explained byheightened iron requirements due to menstru-ation. As men and women become older, theincidence of anemia also rises. However, agedindividuals consume a greater amount of ironthan their younger counterparts. One mustlook into other areas — e.g., a reduced capacityto utilize this element — to explain the causesfor iron deficiency anemia.

In the relationship with trace elements,copper plays a role in supplying iron to varioustissues in the body. Thus even when the ironintake is adequate, a copper deficiency maycause anemia. Furthermore, it was foundrecently that anemia may also be caused by azinc deficiency.3) As stated earlier, copper andzinc intake is low among the aged and it ispossible that a deficiency of either of these

Y. ITOKAWA


elements is involved in the development ofanemia among the aged population.

3. Decubitus ulcerA decubitus ulcer causes extreme pain to the

bed-ridden elderly and markedly deterioratestheir QOL. Tanaka et al.4) divided bed-riddeninpatients over 65-years of age into those witha decubitus ulcer and those without (the con-trols) and studied their nutrient intake. Therewas no significant difference between the twogroups in the intake of iron and zinc; but it wasslightly higher for the group with decubitusulcers. Yet the iron and zinc concentrationsin the serum were significantly lower in thisgroup, suggesting a reduced rate of utilizationof these trace elements. It is probable that forthese aged bed-ridden patients, supplementa-tion with trace elements — such as zinc, whichrestores the immune and tissue repair capac-ities and iron, which prevents the developmentof anemia — will lead to prevent decubitusulcers.

4. Psychiatric disordersAmong autopsy cases, Kimura et al.5)

selected 10 patients with hebephrenia (schizo-phrenia) and 10 who succumbed from otherdiseases and measured the zinc content in theirbrains. It was found that the zinc concentrationin the brain of the former was significantly

DEFICIENCIES OF TRACE ELEMENTS AMONG THE AGED AND CLINICAL ASPECTS

lower. Nishigori et al.,6) in another study,reported that when health foods containingzinc were given to patients with hebephrenia(schizophrenia) their psychiatric symptomsameliorated.

Schrauzer et al.7) reported that there is aninverse relationship between the lithium con-centration in drinking water and the incidenceof suicides and violent crimes, such as homi-cide, robbery, and rape; and they proposed thatlithium probably has a sedative effect.

There is a possibility that these trace ele-ments have an effect on the psychiatric condi-tion of the aged. This subject will be investi-gated further.

5. Diabetes mellitusThere are many reports on diabetes mellitus

and trace elements, among which chromiumand vanadium are particularly worthy of atten-tion. It has been reported that chromium re-stored glucose tolerance in young children whohad been rendered glucose intolerant due to anutritional disorder. In another report, glucosetolerance was reduced in patients who hadbeen fed intravenously with an infusion fluidwithout the addition of chromium: the condi-tion was refractory to insulin treatment andimproved only when chromium was addedto the infusion fluid. There are a number ofreports on the beneficial effects of chromium

Fig. 3 Incidence of anemia stratified by age

(years)20

�29

30�

39

40�

49

50�

59

60�

6970

�

25

20

15

10

5

0

(%)Erythrocyte count

MaleFemale

(years)20

�29

30�

39

40�

49

50�

59

60�

6970

�

60

50

40

30

20

10

0

(%)Hemoglobin content

MaleFemale

(From the 2000 National Nutrition Survey)

Male: Less than 4,100,000/mm3

Female: Less than 3,800,000/mm3Male: Less than 14g/dl Female: Less than 12g/dl


on diabetes mellitus. Vanadium has frequentlybeen cited for its contribution to improvingglucose tolerance in rats with experimental dia-betes mellitus. However, no detailed mecha-nisms by which these two elements act incombating diabetes mellitus have been given.

When these mechanisms are thoroughlyexplained and the safety and efficacy of thesetrace elements are established, it is possiblethat they will be used increasingly for the pre-vention and treatment of diabetes mellitus.

Conclusion

There are few studies that elucidate themetabolic state of trace elements in the aged;and only a limited number have been intro-duced to explain the effects of these elementson diseases. The present study was conductedon these limited data but one can be readilyconvinced that aged individuals take in reducedamounts of trace elements and their capacityto utilize them are also compromised. Theaged suffer from diverse forms of illnesses,some of which are most likely to be caused byinadequate intake of these trace elements.

One hopes that progress will be made instudying this area so that many trace elements

may be used to prevent and treat the diseasesthat afflict aged patients.

REFERENCES

1) Itokawa, Y.: Dietary allowance and nutritionalassessment of minerals and trace elements.Food Chemicals 1995; 19–25. (in Japanese)

2) Chen, X.S.: Selenium deficiency related tohuman endemic disease in China. Proc 5thAsian Congr Nutrition 1987; 369–372.

3) Nishiyama, S., Azuma, A., Imoto, T. et al.: Dif-ferentiation between iron- and zinc-deficiencyanemias in female athletes. J Clin Sports Med1996; 13: 921–923. (in Japanese)

4) Tanaka, Y., Okuda, T., Fukuda, M. et al.: Nutri-tional assessment of elderly people with pres-sure ulcer. Proc 16th Symp Trace Nutrients Res1999; 16: 165–170. (in Japanese)

5) Kimura, K.: Neuro-psychiatric disease andtrace metals. Proc Third Symp Trace NutrientsRes 1986; 3: 89–96. (in Japanese)

6) Nishigori, T., Kimura, K., Itokawa, Y. et al.:Clinical effect of oyster extract on hebephre-nic schizophrenia and Zn and Cu metabolismin it. Proc Third Symp Trace Nutrients Res1986; 3: 79–87. (in Japanese)

7) Schrauzer, G.N. and Shrestha, K.P.: Lithum indrinking water and the incidences of crimes,suicides, and arrests related to drug addictions.Biolog Trace Elem Res 1990; 25: 105–113.

Y. ITOKAWA



Introduction

Among the trace elements essential tohuman nutrition, zinc is typical, the deficiencyof which is known to cause sensory dysfunc-tions. Located at the center of a number ofmetalloenzymes, it is involved in many types of

Sensory Dysfunctions due to Trace ElementDeficiencies and the Clinical Aspects—Taste and olfactory disorders—JMAJ 47(8): 387–390, 2004

Minoru IKEDA

Associate Professor, Department of Otolaryngology,Nihon University School of Medicine

Abstract: Among the trace elements known to be essential to human nutrition,zinc is typical in that the lack of it can cause sensory dysfunctions in human. It isknown that a deficiency of zinc results in a wide variety of diseases with sensory(gustatory, olfactory, and visual) dysfunctions being only one type of them. In thepresent study, the focus is placed on the taste disorders as an example of asensory dysfunction caused by trace element deficiencies; and on the etiologicalmechanism of the disorders that are associated with zinc deficiency. A reducedserum zinc level (below 70�g/dl) seen in cases of taste disorders has also beennoted frequently in similar conditions that are putatively provoked by other causes(e.g., those caused by systemic or drug-induced dysfunctions). These findingssuggest that zinc is likely to play a role in the development of many types of tastedisorders. Supplementation by oral zinc preparations has been found to beeffective in a number of double-blind tests on clinical cases with idiopathic orzinc deficiency-induced taste disorders, which substantiated the aforementionedpossibility.

Key words: Zinc; Taste disorder; Olfactory disorder; Essential trace elements

essential metabolic processes, thus consideredto be a very important trace element for thebody. It is known that a deficiency of zinc isresponsible for a variety of disorders, sensorydysfunctions being one type.

For the sensory dysfunctions, gustatory,olfactory, and visual dysfunctions are known.1)

�Trace Elements


deficient feed, a taste disorder developed in30% of the young animals and 70% of theirolder counterparts. These zinc deficient ratsexhibited a decrease of microvilli at the ends oftheir taste cells where the receptors are locatedor breakage of these cells with their ends tornoff. Many other abnormal features — e.g., a lossof electron dense substance, a reduction in thenumber of Golgi-originated dark granules thatare distributed in the taste cells, and vacuoliza-tion of these cells — were also noted.5) Theseabnormalities involving the taste bud cells thatwere confirmed in animal experiments werealso observed in human subjects who sufferedfrom taste disorders caused by zinc deficiency.6)

The taste cells of normal rats continuouslyundergo a fast turnover (requiring about 10days) through generation followed by replace-ment of their epithelial cells to maintain thefunction as taste receptors. In zinc-deficientrats, however, this turnover time is prolonged:it is known that if the zinc is replaced, this delayin the turnover is corrected, while improvingalso the symptoms of taste disorder.7)

2. Zinc deficiency-induced taste disorderin human

The low serum zinc level (below 70�g/dl)seen in cases of a taste disorder is also fre-quently observed in those patients sufferingfrom a similar affliction that is caused by asystemic disease or incurred by drug actions.8)

It is suspected that in many instances of taste

M. IKEDA

The current study focuses on the first two,which come under the heading of sensorydisorders in the field of otorhinolaryngology.

Zinc Deficiency and Taste Disorders

Table 1 lists diverse causes for taste disor-ders.2) Some develop as a direct consequenceof the dysfunctions of the peripheral or cen-tral nervous system related to taste sensation;but many are considered to be caused bydysfunctions at the peripheral receptor level.Taste disorder caused by zinc deficiency belongsto the category of peripheral receptor leveldysfunctions.

1. Taste disorder in animal experimentsIn the living body, zinc is abundantly dis-

tributed in epithelial tissues and their append-ages (about 20% in organs, such as the skin,hair, and nails).1) The lingual epithelium is alsoknown for its rich zinc content. In particular,zinc is localized in many sites at the base ofthe filiform papillae and the epithelium section,including the taste buds of the vallate papillae.Furthermore, the area within the taste buds(in particular, around the taste pores) is richlyendowed with zinc enzymes (e.g., alkaline phos-phatase, acid phosphatase, ATPase, adenylatecyclase, and cyclic AMP phosphodiesterase),3)

which suggests a significant correlation betweenthe taste organ and zinc.

Of the rats that have been raised on zinc-

Table 1 Causes and Incidences of 2,278 Cases of Taste Disorders

Primary taste disorders Secondary taste disorders

1. Hereditary 0% 1. Caused by oral diseases 6.4%2. Peripheral nerve disorder 2.6% 2. Systemic diseases 7.4%3. Central nervous dysfunction 1.7% 3. Zinc deficiency 14.5%4. Idiopathic 15.0% 4. Drug-induced 21.7%

5. Flavor disorders 7.5%6. Psychogenic origin 10.7%7. Others 9.9%

(Quoted and modified from Hamada, N. et al.: Acta Otolaryngol 2002; Suppl 546: 7–15)


SENSORY DYSFUNCTION DUE TO TRACE ELEMENTS

disorders ostensibly from other causes, zincdeficiency is also involved in their etiology.Even those cases of an idiopathic taste disorderthat yield normal results in clinical tests (in-cluding analysis of serum zinc level), oral zincadministration has been found to be as effec-tive as in those suffering from zinc deficiency.It is suspected that in these cases of idiopathictaste disorders, a latent zinc deficiency thatcannot be detected by ordinary serum chemicalanalyses exists and participates in the develop-ment of taste disorder.

For the pathogenesis of zinc deficiency inhuman, various causes have been put forth;but no organized studies have been conductedon what causes this deficit in patients whoultimately develop a taste disorder. Tomita9)

suggested the low zinc content of the typicalJapanese diet and the high intake of processedfood that may contain a high content of foodadditives as the possible causes for the lowblood zinc levels among Japanese.

Treatment of Zinc Deficiency-InducedTaste Disorder

1. Zinc preparations used for treatmentZinc sulfate has been used for a zinc prepara-

tion. In most instances, each capsule contains100 mg of zinc sulfate (equal to 23 mg of zinc)and is administered 3 times a day (300 mg/day). This method is cumbersome because eachcapsule must be prepared by placing the rightamount of zinc sulfate. The only zinc-containingpharmaceutical preparation that can be pre-scribed is polaprezinc (Promac®), a productused to treat peptic ulcers. Its dosage is set at150 mg/day, which is given twice a day (aftermorning and evening meals). If the serum zinclevel does not rise sufficiently, it may be admin-istered before meal.

2. Therapeutic effect of zinc preparations ontaste disorders

If stratified by the causes of taste disorders,the efficacy of zinc sulfate is 73.7% for a condi-

tion caused by zinc deficiency and 75.8% forthat of an idiopathic nature. Thus the efficacyrate was about the same in the two disordersof different etiologies. For a taste disordercaused by systemic diseases or drug actions,the efficacy rate is slightly lower (65 to 67%),with an overall efficacy of 67%.9) Double-blindtests were conducted on the efficacy of zincpreparations on taste disorders by using zincgluconate10) and zinc picolinate.11) Significantefficacy has been reported for those cases withzinc deficiency-induced and idiopathic tastedisorders.

Olfactory Disorders

In rats with a zinc deficiency such as thatdescribed above, the zinc content in the olfac-tory epithelium also decreases markedly.12)

The ultrastructure of the olfactory epitheliumalso undergoes changes: the entire epitheliumbecomes squamatized, intercellular space mark-edly increases, and most outstandingly, theolfactory cells undergo extreme degeneration.However, it has been reported that adminis-tration of zinc corrects these deformation andinduces neurons to regenerate.13)

Reports such as these suggest that zinc defi-ciency may be one cause for olfactory disor-ders. At the moment, however, there have notbeen sufficient studies to prove the extent ofinvolvement of a zinc deficiency in clinicalcases of olfactory disorders. Future studies areawaited.

Conclusion

For an example of disorders of sensoryorgans caused by zinc deficiency, a taste dis-order was described in detail with special ref-erence to its relationship with a deficit of thistrace element. As a cause of the taste disorder,zinc deficiency is clinically significant. Treat-ment with zinc preparations has been found tobe highly effective in cases with idiopathic orzinc deficiency-induced taste disorders.


REFERENCES

1) Kuwayama, H.: Clinical significance of zinc.Clinics in Gastroenterology 1999; 2: 15–19. (inJapanese)

2) Hamada, N. et al.: Characteristics of 2278patients visiting the Nihon University Hos-pital Taste Clinic over a 10-year period withspecial reference to age and sex distributions.Acta Otolaryngol 2002; Suppl 546: 7–15.

3) Kishi, T.: Histochemical evaluation of the tastebuds of zinc deficient rats. J Nihon Univ Medi-cal Association 1984; 43: 15–31. (in Japanese)

4) Hasegawa, H. and Tomita, H.: Assessment oftaste disorders in rats by simultaneous studyof the two-bottle preference test and abnor-mal ingestive behavior. Auris Nasus Larynx1986; 13 (Suppl 1): 33–41.

5) Kobayashi, T.: Electron microscopic observa-tion of the region around the olfactory poresof the glossal circumvallate papillae of ratswith a zinc deficiency-induced taste disorder.J Nihon University Medical Association 1983;42: 557–565. (in Japanese)

6) Yasuda, M. and Tomita, H.: Electron micro-scopic observations of glossal circumvallatepapillae in dysgeusic patients. Acta Oto-laryngol 2002; Suppl 546: 122–128.

7) Oki, M.: On taste bud cell turnover in rats

M. IKEDA

with a zinc deficiency-induced taste disorder.J Nihon University Medical Association 1990;49: 215–225. (in Japanese)

8) Sakagami, M. et al.: Clinical statistics on tastedisorders. Journal of Otolaryngology, Head andNeck Surgery 2002; 18: 949–952. (in Japanese)

9) Tomita, H.: Physiopathology of taste sensa-tion. Clinical Description of the Otorhino-laryngological Field in the 21st Century(CLIENT 21) No. 10, Sensory Organs (Ed.by Honjo, I.), Nakayama-Shoten Co., Ltd.,Tokyo, 2000; pp.422–434. (in Japanese)

10) Yoshida, S. et al.: A double-blind study of thetherapeutic efficacy of zinc gluconate on tastedisorder. Auris Nasus Larynx 1991; 18: 153–161.

11) Sakai, F. et al.: Double-blind, placebo-controlled trial of zinc picolinade for tastedisorders. Acta Otolaryngol 2002; Suppl 546:129–133.

12) Mikoshiba, H. et al.: A quantitative study ofzinc concentrations in the olfactory epithe-lium of nasal cavity and the central nervoussystem in zinc deficient rats. Trace MetalMetabolism 1983; 11: 27–31. (in Japanese)

13) Shigihara, S. and Tomita, H.: Electron micro-scopy of the olfactory epithelium in zinc defi-cient rats. Nihon Univ J Med 1986; 28: 263–280.



Introduction

Arsenic, chromium, and nickel are said tocontribute to the development of cancer basedon the epidemiologic evidence, and beryllium,cadmium, chromium, cobalt, lead, nickel, zinc,and iron have been found to be carcinogenic inexperimental animals. In this paper, we willdescribe the carcinogenicity of a variety ofmetals.

Trace Elements and CancerJMAJ 47(8): 391–395, 2004

Hiroyuki FUKUDA*1†, Masaaki EBARA*2†, Hiroyuki YAMADA†,Manaka ARIMOTO†, Shinichiro OKABE†, Masamichi OBU†,Masaharu YOSHIKAWA*1†, Nobuyuki SUGIURA*3† and Hiromitsu SAISHO*4†

*1†Research Associate, *2†Assistant Professor, *3†Lecturer, *4†Professor,†Department of Medicine and Clinical Oncology, Graduate School of Medicine,Chiba University

Abstract: In regard to iron, malignant neoplasms are often seen in various organsin idiopathic hemochromatosis, and complication by lung cancer is especiallycommon. In regard to the carcinogenicity of copper, large amounts of copper andiron have been reported to accumulate in the liver and spleen of patients withcancer of the respiratory tract, urinary tract, and thorax. Increases in skin andpulmonary epithelial cancer, and the precancerous condition cutaneous keratosis(Bowen’s disease) are seen as a result of chronic oral or airway exposure toarsenic. In addition, there is a report that leukemia has been observed in aplasticanemia and a report that arsenic causes cancer of the bladder, kidney, digestivetract, and liver, etc. Lung cancer is cited in associations between chromium andcarcinogenesis. Nickel has been reported to be associated with lung cancer andnasal cavity cancer. High mortality from lung cancer in factories handling berylliumand increased tumors of the central nervous system have also been suggested.

Key words: Trace element; Cancer; Metal carcinogenicity

Carcinogenicity of Metals

1. IronSarcomas and skin cancers have been reported

to have developed when animals were intra-muscularly injected with iron dextran.1) Boydet al.2) reported an association between ironore miners and the incidence of lung cancer,but it also appeared that they may have beenexposed to radon, which was also present, and

�Trace Elements


gel-filtration method, the increased copper inhepatocellular carcinoma also appears to existin the form of Cu-MT and hydroxyl radicals aregenerated by a Fenton-like reaction, and simi-larities to LEC rats have been found. Hydroxylradicals form the DNA damage marker 8-OHdG (hydroxydeoxyguanosine), and tissue8-OHdG levels have been shown to be high inchronic hepatitis, liver cirrhosis, and hepato-cellular carcinoma.9)

3. ZincZinc deficiency causes dermatitis, alopecia,

and taste disorders, and excessive intake cancause acute poisoning. In experimental models,development of teratomas and cancers wereobserved when zinc chloride was injected intothe testes of chicks and rats.10)

No epidemiologic evidence of any type ofincreased cancer incidence has yet been obtainedin zinc factory workers or ordinary popula-tions. Zinc is a component of SOD (superoxidedismutase), an enzyme that removes free radi-cals, and since it is also necessary for activationof DNA repair enzymes, zinc has the oppositeeffect and protects against carcinogenesis.

4. ArsenicIn a study in which carcinogenesis was

observed when animals were exposed to arsenic,Yamamoto11) et al. reported that bladder, kidney,liver, and thyroid tumors were induced whenrats were given another initiator at the sametime as a dimethylarsinic acid solution, and thedevelopment of skin, lung, and bladder tumorswas later reported in mice and rats. Increasesin skin and pulmonary epithelial cancer,12) andthe development of precancerous cutaneouskeratosis (Bowen’s disease) are seen whenchronically exposed orally or via the airway.

In addition, there have been reports ofleukemia in aplastic anemia and of arseniccausing cancer of the bladder, kidney, digestivetract, liver, etc. The carcinogenetic mechanismis unknown, but there have been reports thatarsenic compounds inhibit methyl thymidine

H. FUKUDA et al.

smoking.Various malignant neoplasms of different

organs are often seen in idiopathic hemo-chromatosis, but liver cancer is an especiallycommon complication.3) The mechanisms ofthe hepatocarcinogenesis are thought to bethat iron bound to low-molecular protein inthe liver generates hydroxyl radicals via theFenton reaction that damage DNA, and adirect action of iron on the replication processof the DNA. In a study of iron deposits in thesurrounding liver parenchyma in a group ofHCV-positive liver cirrhosis patients with livercancer and a group without liver cancer, theiron deposits were reported to be clearly morecommon in the group with liver cancer.4)

2. CopperAccumulation of large amounts of copper

and iron has been reported in the liver andspleen of patients with cancer of the respira-tory tract, urinary tract, and thorax,5) and thecopper content of benign tumors of the esoph-agus, bronchi, and intestine is said to be lowerthan in cancers.

LEC rats (Long-Evans rats with cinnamon-like color) are animal models of Wilson disease,in which copper accumulates in liver tissue. Theanimals develop hepatitis at 4 months of ageand approximately 40% die, and at approxi-mately 1 year of age those that survive developliver cancer via cirrhotic change. Gel-filtrationanalyses have shown that the majority of theincreased copper exists in the form of Cu-MT(copper-metallothionein),6) and it is thoughtthat hydroxyl radicals are generated in thepresence of hydrogen peroxide as a result of aFenton-like reaction and cause hepatitis andhepatocarcinogenesis.

Liver tissue copper content increases inhuman chronic hepatitis C and liver cirrhosisas the liver disease progresses,7) and the coppercontent of well differentiated hepatocellularcarcinoma becomes significantly greater thanthat of moderately or poorly differentiatedhepatocellular carcinoma.8) According to the


METAL CARCINOGENICITY

uptake by human skin cells in vitro and inhibitDNA synthesis. Chromosome abnormalitieshave been observed when human leukocytes orcutaneous fibroblasts were exposed, and thereis a report that it is due to DNA binding becom-ing weaker as a result of substitution for phos-phorus in DNA.

5. ChromiumAn association between chromium and car-

cinogenesis has been pointed out in regard tolung cancer. A high incidence of lung cancerhas been demonstrated as an occupationaldisease among workers engaged in the chro-mate production process in Germany and theUnited States.13) The risk of lung cancer amongchromium workers compared to an ordinarypopulation is very high, with a lung cancerprevalence rate 100,000 versus 578, and therelative risk from the standpoint of lung cancerdeaths has reached from 3.6 to 29.1. Histo-pathologically, the most common chromium-related lung cancers are squamous cell carcino-mas and small cell cancers.

6. NickelIn experiments on rats, induction of rhabdo-

myosarcoma was reported as a result of intra-muscular injection of nickel subsulfate, anddevelopment of sarcoma in various organs hasbeen reported as a result of intravenous injec-tion of nickel carbon. Lung cancer developedwhen cats were allowed to inhale nickel dust,and high rates of lung cancer and cancer ofthe nasal cavity have been found in nickelrefinery workers.14) The principal carcinogensare thought to be inhaled nickel particles andnickel oxide.

7. VanadiumVanadium has been negative in many bacte-

rial tests for mutagenicity. It is not recognizedas possessing carcinogenic activity, and no asso-ciation has been found with cancer in humansor animals. Nevertheless, vanadium promotescell mutation in some cells, causes tyrosine

kinase phosphorylation, and is said to possiblyexert an effect on oncogenes. Since it also inter-feres with proper chromosome arrangementduring cell division, the risk of carcinogenicitycannot be ruled out. An association is also saidto exist between the vanadium concentration inair and lung cancer, but no clear causality hasbeen established.15)

8. BerylliumLung tumors have been observed in carcino-

genesis experiments in response to intratra-cheal administration, inhalation exposure, andintraperitoneal administration, and develop-ment of osteosarcoma has been reported afterintravenous administration. Carcinogenicity inhumans has been suggested by high mortalityfrom lung cancer in factories handling beryl-lium16) and by increases in tumors of the centralnervous system.

The carcinogenetic mechanism is thought tobe inhibition of the enzymes required for DNAsynthesis, such as thymidine kinase, thymidinesynthase, and DNA polymerase.

9. LeadRenal cancer has been reported in rats and

mice subcutaneously injected with lead phos-phate.17) There are also reports of lung cancerin hamsters after simultaneous intratrachealadministration of lead oxide and benzpyrene,and of development of brain tumors when leadacetate was orally administered to rats. A slightassociation with the development of lung can-cer, stomach cancer, and brain tumors has beenreported in workers in a lead smelter, and inlead poisoning,18) but lead has not been defi-nitely concluded to be carcinogenic in humans.

The carcinogenetic mechanism is assumed tobe interference with the DNA repair process,but the details are currently unknown.

10. CadmiumDNA fragmentation and chromosome muta-

tions have been reported in cultured humancells, sarcoma and testicular interstitial cell


tumors have been reported as a result of injec-tions in rats, and an association with prostatecancer has been reported in humans, but ques-tions about the carcinogenicity of cadmiumhave arisen based on recent epidemiologicresearch.19)

11. CobaltThe mechanism of gene mutations by cobalt

is known to be DNA breaks and inhibition ofDNA repair by cobalt, and gene mutationsand carcinogenicity have been reported in cellsand in experimental animals. However, no evi-dence is yet available in humans.20)

Conclusion

Metal carcinogenesis has recently beenattracting attention not only in terms of occu-pational diseases but in ordinary environments.In humans, iron is said to cause liver cancer inhemochromatosis, copper to cause liver cancer,respiratory tract cancer, urinary tract cancer,and thoracic cancer, arsenic to cause skincancer, liver cancer, respiratory tract cancer,and urinary tract cancer, chromium to causelung cancer, nickel to cause lung cancer andcancer of the nasal cavity, beryllium to causelung cancer and central nervous system tumors,lead to cause lung cancer, stomach cancer, andcentral nervous system tumors, and cadmiumto cause prostate cancer, but many aspects oftheir carcinogenetic mechanisms are unknown.

REFERENCES

1) Rezazadeh, H., Nayebi, A.R. and Athar, M.:Role of iron-dextran on 7, 12-dimethylbenz(a)anthracene-initiated and croton oil-promotedcutaneous tumorigenesis in normal and preg-nant mice. Hum Exp Toxicol 2001; 20: 471–476.

2) Boyd, J.T., Doll, R., Faulds, J.S. et al.: Cancer ofthe lung in iron ore (haematite) miners. Brit JInd Med 1970; 27: 97–105.

3) Finch, S.C. and Finch, C.A.: Idiopathic hemo-chromatosis, an iron storage disease. A. Iron

H. FUKUDA et al.

metabolism in hemochromatosis. Medicine(Baltimore) 1955; 34: 381–430.

4) Chapoutot, C., Esslimani, M., Joomaye, Z. etal.: Liver iron excess in patients with hepato-cellular carcinoma developed on viral C cir-rhosis. Gut 2000; 46: 711–714.

5) Sandberg, M., Gross, H. and Holly, O.M.:Changes in retention of copper and iron inliver and spleen in chronic diseases accom-panied by secondary anemia. Arch Path 1942;33: 834–844.

6) Sakurai, H., Nakajima, K., Kamada, H. et al.:Coppermetallothionein distribution in the liverof Long-Evans Cinnamon rats: Studies onimmunohistochemical staining, metal deter-mination, gel filtration and electron spinresonance spectroscopy. Biochem BiophysRes Commun 1993; 192: 893–898.

7) Hatano, R., Ebara, M., Fukuda, H. et al.:Accumulation of copper in the liver andhepatic injury in chronic hepatitis C. J Gastro-enterol Hepatol 2000; 1: 786–791.

8) Tashiro-Itoh, T., Ichida, T., Matsuda, Y. et al.:Metallothionein expression and concentra-tions of copper and zinc are associated withtumor differentiation in hepatocellular carci-noma. Liver 1997; 17: 300–306.

9) Shimoda, R., Nagashima, M., Sakamoto, M.et al.: Increased formation of oxidative DNAdamage, 8-hydroxydeoxyguanosine, in humanlivers with chronic hepatitis. Cancer Res 1994;54: 3171–3172.

10) Platz, E.A., Helzlsouer, K.J., Hoffmann, S.C.et al.: Prediagnostic toenail cadmium and zincand subsequent prostate cancer risk. Prostate2002; 52: 288–296.

11) Yamamoto, S., Konishi, Y., Matsuda, T. et al.:Cancer induction by an organic arsenic com-pound, dimethylarsenic acid (cacodylic acid)in F344/DuCrj rats after pretreatment withfive carcinogens. Cancer Res 1995; 55: 1271–1276.

12) Ott, M., Holder, B.B., Gordon, H.L. et al.:Respiratory cancer and occupational expo-sure to arsenicals. Arch Environ Health 1974;29: 250–255.

13) Pfeil, E.: Lungentumoren als Berufserkrankungin Chromatbetrieben. Dtsch Med Wochenshr1935; 61: 1197–1200.

14) Heuper, W.C.: Occupational and environ-mental cancers of the respiratory system.


METAL CARCINOGENICITY

Recent Results. Cancer Res 1966; 3: 85–93.15) Leonard, A. and Gerber, G.B.: Mutagenicity,

carcinogenicity and teratogenicity of vana-dium compounds. Mutat Res 1994; 317: 81–88.

16) Mancuso, T.F.: Relation of duration employ-ment and prior respiratory illness to respi-ratory cancer among beryllium workers.Environ Res 1970; 3: 251–275.

17) Silbergeld, E.K., Waalkes, M. and Rice, J.M.:Lead as a carcinogen: experimental evidenceand mechanisms of action. Am J Ind Med

2000; 38: 316–323.18) Steenland, K. and Boffetta, P.: Lead and

cancer in humans: where are we now? Am JInd Med 2000; 38: 295–299.

19) Collins, J.F. and Boffetta, P.: On the carcino-genicity of cadmium by the Oral route. RegulToxicol Pharmacol 1992; 16: 57–72.

20) Lison, D., De Boeck, M., Verougstraete, V. etal.: Update on the genotoxicity and carcino-genicity of cobalt compounds. Occup EnvironMed 2001; 58: 619–625.



Introduction

A variety of trace elements have been shownto be involved in nervous and mental diseases.In this article, the etiological associations willbe described between iron (Fe), zinc (Zn), andaluminum (Al) and dementia, especially Alz-

Trace Elements andNervous and Mental DiseasesJMAJ 47(8): 396–401, 2004

Tameko KIHIRA

Assistant Professor, Department of Neurology, Wakayama Medical University

Abstract: Relationships between Al, Fe, and Mn and Alzheimer’s disease (AD),amyotrophic lateral sclerosis (ALS), and parkinsonism are outlined. These diseasesare thought to be multifactorial, and trace element abnormalities are suspected ofbeing risk factors. Al and Fe are suspected of being involved in the formation ofneurofibrillary tangles (NFT) and senile plaque in AD. The Kii Peninsula of Japanhas been the focus of ALS, and an association between environmental factors andits occurrence is suspected. Environmental metal analyses in this area hasrevealed low contents of Ca and Mg and high contents of Al and Mn in the drinkingwater and soil. Al deposition has been observed in the brain tissue of patients fromKii Peninsula. Cell loss has been noted in the spinal cord and cerebrum of animalschronically given a low Ca/Mg high-Al diet, and an etiological association withthese trace elements was suspected in ALS cases from this area. Mn is known toinduce the development of extrapyramidal manifestations. Although the clinicalmanifestations of Mn-exposure parkinsonism and Parkinson’s disease are different,involvement of environmental factors has been speculated in the onset ofParkinson’s disease, and there is concern about air pollution by Mn. In addition,there are cases of Al encephalopathy in which an association with high-calorieinfusion therapy and Al-containing medical materials is suspected.

Key words: Aluminum; Neurotoxicity; Amyotrophic lateral sclerosis foci;Amyotrophic lateral sclerosis; Iron; Manganese

heimer’s disease; calcium (Ca)/magnesium(Mg) deficiencies and excessive trace elements,such as aluminum and manganese (Mn), inamyotrophic lateral sclerosis (ALS), par-kinsonism induced by manganese poisoning;dialysis encephalopathy and aluminum; andaluminum poisoning by medical materials.

�Trace Elements


increase until the late teens. They remainalmost the same in the 30s to 50s, before slowlyrising in the brain again in old age. The iron isspecifically distributed in the oligodendrocytesin the central nervous system and in theSchwann cells in the peripheral nervous sys-tem, and it binds to ferritin. By storing iron inits molecules, ferritin plays a role in the intra-cellular utilization and inactivation of iron. Asan essential element in tyrosine hydroxylase,the action of iron is important in the synthesisof dopamine, norepinephrine, serotonin, andGABA.

In contrast, iron ions cause peroxide-radicaldamage by changing from an oxidized to areduced form. They also reversibly hyperphos-phorylate and insolubilize tau protein and con-tribute to the formation of NFT.2)

It has been reported that there is increasediron content in the brain tissue of Alzheimer’sdisease patients as well as increased ferritin insenile plaques and microglia, increased ironand zinc content, and decreased selenium (Se)content (selenium is speculated to have apreventive effect against the cytotoxicity pro-duced by toxic elements).3) In addition, there isincreased Fe-binding protein P 97 and melano-transferrin in the serum, spinal fluid, and braintissue of Alzheimer’s patients; and glutathionetransferase, which possesses lipid-peroxide-degrading activity, is decreased and there arechanges in metallothionein. Cytotoxicity causedby metal elements, such as iron and aluminum,is suspected, and use of p97, etc., has beenassessed as a serum biomarker for Alzheimer’sdisease.4) It is hard to imagine that these abnor-mal findings of chemical elements are the solecause of Alzheimer’s disease, but they appearto be associated as risk factors.

Superficial siderosis is known as anothercentral nervous system disorder caused byiron, and chronic, repeated bleeding in notablychronic subarachnoid hemorrhages, durallesions, cervical spinal root lesions, vasculartumors, and vascular malformations, resultsin deposition of iron in the dura mater and

Alzheimer’s Disease andTrace Elements

In 1965 Klazo et al.1) reported the develop-ment of abnormal intracellular accumulationsof neurofilaments (NFs) when they admin-istered aluminum phosphate into the brain ofexperimental animals. Since the changes closelyresembled the neurofibrillary tangles (NFTs)of Alzheimer’s disease, attention was focusedon an etiologic association. Epidemiologic sur-veys in the United Kingdom, the United States,Canada, and Norway have shown high preva-lences of Alzheimer’s disease in regions wherethe aluminum concentration in tap water ishigh. Metal analyses have also shown higheraluminum concentrations in the brains ofAlzheimer’s disease patients than in controls,and aluminum deposition has been demon-strated in NFTs and senile plaques.

In contrast, many reports about the associa-tion between aluminum and Alzheimer’s dis-ease have been negative. Since aluminumdisplays an aggregating action in vitro, at leaston cytoskeletal proteins such as NF, the possi-bility that it plays some sort of etiologic rolecannot be ruled out, and further investigationappears to be needed.

Aluminum binds to the phosphate groups ofDNA and cytoskeletal proteins in vitro andinduces aggregation of amyloid protein andexcessive phosphorylation of tau protein. Itcauses irreversible changes in the structure ofthese proteins, and hyperphosphorylated fibersare thought to cause cell death by accumulatingand impairing axonal transport. The cytotoxicmechanism of aluminum is also suspected ofbeing caused by the production of free radicals,such as hydroxyl radicals, as a result of a tran-sition from Al2� to Al3�.

Next, there is the neural cytotoxicity widelyknown to be caused by iron. The globuspallidus, red nucleus, substantia nigra, cere-bellar dentate nucleus, and cerebral motor areacontain large amounts of non-heme iron. Thevalues are low in newborn infants, but rapidly

TRACE ELEMENTS IN CNS


the surface of the central nervous system. Afteran asymptomatic interval of 4 months to 30years, it leads to sensory deafness (95%),cerebellar ataxia (88%), pyramidal disorders(76%), dementia (24%), and urination dis-orders (24%).

Amyotrophic Lateral Sclerosis (ALS)and Calcium, Magnesium,and Aluminum

ALS is a degenerative disease that systemati-cally affects upper and lower motor neuronsand is characterized by severe neuronal loss ofBetz cells in the motor cortex, and motorneurons in the brain stem, and spinal anteriorhorn cells with degeneration of the pyramidaltracts. Its prevalence is almost the same inevery region of the world, and it is said to be0.8–6.4 per 100,000 people, with an annualincidence rate of 0.4–2.6. In the 1960s, theprevalence of ALS in the Kozagawa region andHobara region of the Kii Peninsula and in thesouthern part of Guam Island reached levels of10 to 100 times higher than in other regions.The incidence of new cases began to decline inthe 1970s, and it dramatically decreased in the1980s to only several times the level in otherareas. A recent repeat survey showed that theregional differences in the Kii Peninsula as awhole have tended to disappear due to themovement of the population to other areas,but, the annual incidence of ALS in thesouthern part of the Kii Peninsula is still high.

The cause and pathogenetic mechanism ofALS are still unknown, but attention is beingfocused on the free-radical and excitatory-amino-acid cytotoxicity hypothesis, superoxidedismutase (Cu/Zn SOD) gene abnormalities,and ubiquitin-proteasome system damage.Involvement of environmental factors appearsto be important in ALS foci, in addition tothese factors.

Another area of focus for ALS lies abovethe Mariana volcano zone that runs geologi-cally north to south through the Western

Pacific. There is high annual rainfall, and thesoil is strongly acidic in this region. The soil andthe water used in daily living were character-ized by low calcium and magnesium levels aswell as high levels of toxic elements, includingmanganese and aluminum according to thesurvey findings obtained during the 1960s andthe 1970s. In addition to the ordinary patho-logical findings in ALS, the autopsy brain andspinal cord tissue in Guam ALS/parkinsonism-dementia (PD) and Kii ALS is characterizedby the presence of NFTs. Element analysisrevealed deposition of calcium and aluminumat the sites of degeneration, and in the nucleiand nucleoli of degenerated neurons, Buninabodies, and NFTs. In considering these com-bined findings, the neuronal degeneration ofKii ALS has been speculated to be due to theseelements.5)

When aluminum was injected into the brainsof experimental animals, extensive abnormal

Fig. 1 NFT observed in the hippocampus ofa Kii ALS patient

The NFT in the lower panel (Bodian stain) has beenstained with Morin stain (aluminum fluorescence stain)in the upper panel. �590.

T. KIHIRA


intracellular accumulation of NFs (neurofibril-lary change; NFC) was observed in the cere-brum and spinal cord, and numerous spheroidsbegan to appear in the anterior horns of thespinal cord in the early stages. This abnormalaccumulation of NFs strongly resembled thespheroids/chromatolysis, which are character-istic pathological findings in the early stages ofALS. NFC differs from NFTs at the electron-microscopic level, but tau, ubiquitin, MAP-2,amyloid precursor protein, etc., have beenobserved immunohistochemically, and similar-ities between the two have been pointed out.6)

To explain the occurrence of NFTs in theALS from the focused area, the author andcolleagues investigated the cytotoxicity of alu-minum due to metal ion interactions in theenvironment of the Kii area. More specifically,experimental animals were chronically admin-istered a low-CA/Mg high-Al diet. Neuro-pathological examinations of these animalsshowed a decrease in the spinal cord anteriorhorn cells, and cerebral cortical neurons, anincrease in spheroids, and an appearanceof anti-PHF (abnormal phosphorylated tau)-antibody-positive neurons.7)

Aluminum is a toxic element, and only about1% of the amount ingested is absorbed by thegastrointestinal tract. Approximately 80% ofthe aluminum in the blood binds competitivelywith iron to transferrin, and a portion of theremainder binds to low-molecular-mass mole-cules, such as citric acid, and is transported.Aluminum’s entry into the brain is mediatedby transferrin receptors, and it is bound to glialtransferrin. Aluminum absorption from theintestine is promoted under low-Ca/Mg con-ditions, and when aluminum is administeredchronically, it is thought to accumulate in thebrain and spinal cord and to have cytotoxiceffects. Clinically, anemia, bone damage, anddialysis encephalopathy are known to developin aluminum poisoning. As mentioned above,aluminum has been found to bind irreversiblyto phosphate groups in vitro and to be widelyneurotoxic, e.g., by inhibiting polymerization/

depolymerization of tau and NF, inhibitingCa-binding proteins, such as calmodulin, andCa-dependent enzymes. A mechanism in whichmild damage caused by microamounts of alu-minum incorporated from the environment,food, etc., accumulates. It has been speculatedthat cell death occurs when it exceeds a certainlevel, and abnormalities in interactions betweenelements appear to be important in terms ofassessing the pathogenesis of the ALS occur-ring in foci.

Parkinsonism and Manganese

The first mention of manganese toxicity wasfound in a report on manganese grindingworkers in Glasgow by Couper et al. in 1837,and extrapyramidal symptoms were subse-quently reported in manganese miners in vari-ous areas of Europe.

Manganese is an essential element in thebody, and 2–9 mg/day is ingested in food.Absorption from the intestine increases in iron,calcium, and magnesium deficiency. Approxi-mately 80% of the manganese in the blood isbound to �1-globulin, and the rest is bound totransferrin and unidentified ligands. It is a con-stitutive element of metalloproteins, includingmitochondrial enzymes, Mn-SOD, pyruvatecarboxylase, and glutamine synthetase. Manga-nese is incorporated by endocytosis mediatedby cerebral vascular transferrin receptors, andapproximately 80% is localized in astrocytes.

Convulsions are known to occur as a result ofmanganese deficiency. Decreased manganesecontent in whole blood has been reported in anepilepsy patient group regardless of whetherthey were on medication, and it appeared tohave been due to a decrease in Mn-SOD andglutamine synthetase activity.8) Dermatitis, hairdamage, and hypocholesterolemia have alsobeen shown to occur. Inner ear damage andataxia have been mentioned as a result ofmanganese deficiency during the fetal periodin animals.

Toxicity due to excess manganese, in contrast,



causes irreversible psychological manifestations(locura manganica) and neurological manifes-tations. Pneumonia and bronchitis develop as aresult of airway exposure, and excess manga-nese accumulated in the lungs is said to passinto the brain. Psychological manifestations,such as impaired orientation, memory dis-orders, compulsive and violent behavior, emo-tional hypersensitivity, hallucinations, etc., aresaid to occur in acute poisoning. Progressiveneurological manifestations, i.e., akinesia, dys-tonia, and gait disturbances appear 1–2 monthsafter the onset of mental symptoms, and mask-like facies, articulation disorders, low voice,and monotonous whispering voice develop. Inchronic poisoning, symptoms of a nervousbreakdown and blunted affect appear afterseveral months to several years of exposure,and progressive akinesia, gait disturbances,language disorders, parkinsonism, dystonia,increased deep tendon reflexes in the lowerextremities, excitement, etc., gradually develop.

Neuropathologically, cerebral atrophy, cere-bral ventricle enlargement, and atrophy of thecaudate nucleus, putamen, globus pallidus, andthalamus are observed in manganese poisoningpatients, with the greatest damage occurring inthe globus pallidus. Loss and demyelination oflarge neurons in the internal segment of theglobus pallidus and astrocyte proliferation areseen, but the substantia nigra is said to be nor-mal. Loss of pigmentation, although mild, isseen in the substantia nigra in chronic manga-nese poisoning. At the cellular level, manga-nese accumulation is seen especially at sites inthe brain where there is a high content of non-heme iron, the caudate nucleus, putamen,globus pallidus, substantia nigra, and hypo-thalamic nuclei. Biochemically, there is saidto be an increase in dopamine and nor-epinephrine in the brain in the early stage,and decreases in the late stage. Exogenousmanganese is claimed to promote active oxy-gen production at sites of very active catechol-amine metabolism, such as the substantia nigra,and cause cytotoxicity.

Parkinson’s disease and parkinsonism due tomanganese exposure clearly differ both in termsof their clinical manifestations and patho-logical findings, but it has also been shown thatenvironmental factors may be involved in thedevelopment of Parkinson’s disease. Air pollu-tion by manganese as a result of the use ofmethylcyclopentadienyl manganese tricarbonyl(MMT) as an anti-knock compound has recentlybeen demonstrated, and accumulation in thecorpus striatum, cerebral cortex, and cerebel-lum and the development of extrapyramidalmanifestations have been shown to occur as aresult of administration of MnO2 and MnCl2 viathe airway in animal experiments. There hasbeen apprehension about low-concentrationmanganese content in the air as an environ-mental factor.8,9)

Aluminum and Neurotoxicity

In 1972 Alfrey et al. noted the onset of articu-lation disorders, aphasia, convulsions, myoc-lonus, and dementia symptoms in long-termdialysis patients, and they found high alumi-num concentrations in the patients’ brains.Residual aluminum from the hemodialysisprocess was considered to be the cause, andas a result of removing the aluminum in thedialysis fluid and discontinuing oral admin-istration of aluminum preparations, no newcases have been seen. Although rare, a ten-dency to have lower scores in neurologicdevelopment examinations using the BayleyMental Development Index has been reportedfor premature infants and children who havereceived aluminum-contaminating high-calorieinfusion therapy,10) and aluminum has beenshown to be replaced by amino acids and toleak out in solutions stored in glassware.

Aluminum encephalopathy has been reportedafter oral administration of aluminum prepa-rations to chronic renal failure patients. Theserum aluminum concentration has been shownto increase to twice the normal upper limit as aresult of intravenous alimentation even when

T. KIHIRA


renal function is normal,11) and there have alsobeen reports of the occurrence of languagedisorders, consciousness disorders, or dementiaafter long-term occupational exposure, such asamong workers in an aluminum refinery, analuminum pot factory, etc. Similar manifesta-tions have been observed as a result of ear-nose-throat (ENT) surgery in which aluminum-containing bone cement (Ionocap®, Ionocem®,Ionos GmbH & Co. KG, Seefeld, Germany)was used. This is thought to represent alumi-num poisoning as a result of aluminum cominginto direct contact with cerebrospinal fluid andeluted because aluminum-containing cementhad been used at bone defect sites or becauseof accidental entry into the spinal fluid com-partment after local CNS fistula formation orsurgery.12)

Conclusion

Associations between aluminum, iron, andmanganese have been primarily outlined,where deficiencies and excesses are thoughtto cause irreversible changes in the nervoussystem as well as neurodegenerative diseases,notably Alzheimer’s disease, amyotrophic lat-eral sclerosis, and parkinsonism. These neuro-degenerative diseases are suspected of having amultifactorial etiology and of being caused byenvironmental factors in addition to geneticfactors. Although these trace element abnor-malities are not thought to exert pathogeneticeffects, the evidence suggests that they areinvolved as risk factors.

REFERENCES

1) Klazo, L., Wisniewski, H. and Stericher, E.:Experimental production of neurofibrillarydegeneration. I. Light microscopic observa-tions. Neuropathol Exp Neurol 1965; 24: 187–199.

2) Yamamoto, A., Shin, R.W., Hasegawa, K. etal.: Iron (III) induces aggregation of hyper-phosphorylated tau and its reduction to iron(II) reverses the aggregation: implications inthe formation of neurofibrillary tangles ofAlzheimer’s disease. J Neurochem 2002; 82:1137–1147.

3) Cornett, C.R., Markesbery, W.R. and Ehmann,W.D.: Imbalances of trace elements related tooxidative damage in Alzheimer’s diseasebrain. Neuro Toxicology 1998; 19: 339–346.

4) Ujiie, M., Dickstein, D.L. and Jefferies, W.A.:p97 as a biomarker for Alzheimer disease.Front Biosci 2002; 7: e42–47.

5) Kihira, T., Yoshida, S., Yasui, M. et al.: Amyo-trophic lateral sclerosis in the Kii Peninsula ofJapan, with special reference to neurofibrillarytangles and aluminum. Neuropathology 1993;13: 125–136.

6) Huang, Y., Herman, M.M., Liu, J. et al.:Neurofibrillary lesions in experimental alumi-num-induced encephalopathy and Alzhei-mer’s disease share immunoreactivity foramyloid precursor protein, Abeta, alpha 1-antichymotrypsin and ubiquitin-protein con-jugates. Brain Res 1977; 771: 213–220.

7) Kihira, T., Yoshida, S., Yase, Y. et al.: Chroniclow-Ca/Mg high-Aluminum diet induces neu-ronal loss. Neuropathology 2002; 22: 171–179.

8) Aschner, M.: Manganese: Brain transport andemerging research needs. Environ HealthPerspect 2000; 108(Suppl 3): 429–432.

9) Carpenter, D.: Effects of metals on the ner-vous system of humans and animals. Int JOccup Med Environ Health 2001; 14: 209–218.

10) Bishop, N.J., Morley, R., Day, J.P. et al.: Alumi-num neurotoxicity in preterm infants receiv-ing intracenous-feeding solutions. N Engl JMed 1997; 336: 1557–1561.

11) Leung, F.Y., Grace, D.M., Aluminumfieri,M.A. et al.: Abnormal trace elements in apatient on total parenteral nutrition withnormal renal function. Clin Biochem 1995; 28:297–302.

12) Hoang-Xuan, K., Perrote, P., Dubas, F.,Philippon, J. and Poisson, F.M.: Myoclonicencephalopathy after exposure to aluminum.Lancet 1996; 347: 910–911.


Documents

CONTENTS · JMAJ, August 2004—Vol. 47, No. 8351 This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129,