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ReviewSynthese

Malnutrition and health in developing countriesOlaf Muller, Mchael KrawinkelAbstract

MALNUTRITION, WITH ITS 2 CONSTITUENTS of protein-energy malnutri-tion and micronutrient deficiencies, continues tobea majorhealth burden indeveloping countries. It is globally the most im-portant risk factor for illness and death, with hundreds of millionsof pregnant women and young children particularly affected.Apart from marasmus and kwashiorkor (the 2 forms of protein-energy malnutrition), deficiencies in iron, iodine, vitamin A andzinc are themain manifestations of malnutrition indevelopingcountries. In these communities, ahigh prevalence of poor dietand infectious disease regularly unites into avicious circle. Al-though treatment protocols forsevere malnutrition have inrecentyears become more efficient, most patients (especially in ruralareas) have little or noaccess toformal health services and arenever seen in such settings. Interventions toprevent protein-energy malnutrition range from promoting breast-feeding tofoodsupplementation schemes, whereas micronutrient deficiencieswould best beaddressed through food-based strategies such asdietary diversification through home gardens and small livestock.The fo rtification of salt with iodine has been aglobal successstory, but other micronutrient supplementation schemes have yetto reach vulnerable populations sufficiently. To beeffective, allsuch interventions require accompanying nutrition-educationcampaigns and health interventions. Toachieve the hunger- andmalnutrition-related Millennium Development Goals, we need toaddress poverty, which is clearly associated with the insecuresupply of food and nutrition,CM/^72005;173{3):279-86M ahiutrition continues to be amajor public healthproblem throughout the developing world, par-ticularly in southern Asia and sub-Saharan Afri-ca.'"' Diets in populations there are frequently deficient inmacronutrients (protein, carbohydrates and fat, leading toprotein-energy malnutrition), micronutrients (electrolytes,minerals and vitamins, leading to specific micronutrient derficiencies) or bo th ,' '^

The high prevalence of bacterial and parasitic diseases indeveloping countries contributes gready to malnutr i t ionthere.' ' '"" Similarly, malnutrition increases one's suscepti-bility to and severity of infections, and is thus amajor com-ponent of illness anddeath from disease.'''^"''' Malnutritionis consequently the most important risk factor for the bur-den of disease in developing countries. '^" It is the directcause of about 300 000 deaths per year and is indirectly re-sponsible for about half of all deaths in youn g children (Fig.1). '""" The risk of death is directly correlated with the de-gree of malnutrition."""

Pover ty is the main underlying cause of malnutr i t ionan d its determinants (Fig. 2),"" The degree and distribu-tion of protein-energy malnutrition andmicronutrient de-ficiencies in a given population depends on many factors:the political and economic situation, the level of educadonand sanitadon, the season and climate condidons, food pro-ducdon, cultural and reHgious food customs, breast-feedinghabits, prevalence of infecdous diseases, the existence andeffecdveness ofnutridon programs and the availability andquality of health services.' '"'"""H e r e we provide an overview on the epidemiology,pathophysiology, clinical features, mana geme nt and controlof protein-energy malnutridon and micronutrient deficien-cies indeveloping coim tries.Protein-energy malnutrit ionEpidemiology

Worldvi^ide, an es t ima ted 852 mill ion people wereunde rnour i shed in 2000-2002, with most (815 mil l ion)living in developing countries. ' The absolute number ofcases has changed lit t le over the last decade. However,

/ 'Perinatal

deaths\ 37%

\\

/ HDeassocmjpcHvith Diarrheamalni^HiQn I 170/ I

^ ^ ~ ^ J H B ^ Malaria /^ ^ ^ k 8% yMeasles

HIV/AIDS 4%3%

Fig. 1: Causes of death among children under 5years of age,2000-2003, worldwide.

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Muller and Krawinkel

while China had major reductions in its number of casesof prote in-energy malnutr i t ion dur ing th is per iod, th iswas balanced by a corresponding increase in the rest ofthe developing world. 'In children, protein-energy malnutrition is defined bymeasurements that fall below 2 standard deviations underthe normal weight for age (underweight) , height for age(stunting) and weight for height (wasting).' Wasting indi-cates recent weight loss, whereas stunting usually resultsfrom chron ic weight loss. Of all children und er the age of 5years in developing countries, about 31 % are underweight,38% have stunted growth and 9% show wasting. ' Protein-energy ma lnutrition usually manifests early, in children b e-tween 6 months and 2 years of age and is associated withear ly wean ing, delayed in t rodu ct ion of co mp lemen taryfoods, a low-protein diet and severe or frequent infec-tions." '* '^* Ta ble 1 shows the geograp hic d istr ibution ofprotein-energy malnutri t ion among young children in de-veloping countries. 'Severe ma lnutrition, typified by wasting, edema or b oth,occurs almost exclusively in children.' Marasmus is definedas severe wasting; marasmic kwashiorkor, as severe wastingin the presence of edema; and kwashiorkor, as malnutritionwith e dem a. '" T he word kwashiorkor originates f i: 'om theGa language in Ghana; i t implies "the disease that the

MalnutritionMarasmus, kwashiorkor,

micronutrient deficiencies

/Insufficient suppl>of protein, energ)or micronutrients

tInsufficienthouseholdfood security>

/Low status andlittle educationof women

\Severe or

frequent infections;diarrhea

V / A_Insufficientch i ld and

maternal careIII health,unhealthy

envi ronment

^ A \ .^ 'i Poverty j \

War ,natural disaster,

civi l disorder

young child developed when displaced fi-om his mother banother child or pregnancy." Early marasmus, occurring ithe first year of Hfe, is frequentiy associated with contaminated bottle-feeding in urban areas.*Pathophysiology and clinical features

After insufficient supply of protein, carbohydrates anfat , the next major cause of protein-e nerg y m alnutri t ion isevere and chronic infections particularly those pr oducing diarrhea, but also other diseases such as helminthiinfections. The underlying mechanisms include decreasefood intake because of anorexia, decreased nutrient absorption, increased metabolic requirements and direct nutrient losses.' '"The t e rm p ro te in - energy malnu t r i t i on desc r ibes thcause ( i .e. , the imbalance between nutrient supplies anrequirements) more than the pathogenesis of starvation.The pathologic changes include immunologic deficiency ithe hu mo ral and cellular subsystem fi-om protein deficiencand lack of immune mediators (e.g., tumour necrosis factor) . Metabolic disturbances also play a role in impaireintercellular degradation of fatty acids because of carbohydrate deficiency. Synthesis of pigments in the hair anskin fails (e.g., hair colour may change and skin become hyperpigmented) because of a lack of substrate (e.g., tyrosinand coenzymes.'^Marasmus is diagnosed when subcutaneous fat and muscle are lost because of endogenous mobilization of all avail

able energy and nutrients. Clinical aspects typically includa triangular face, primary or secondary amenorrhea, extended abdomen (from muscular hypotonia) and anal or rectaprolapse (from loss of perianal fat)."Kwashiorkor usually manifests with edema, changes thair and skin colour, anemia, hepatomegaly, lethargy, severe immune deficiency and early death. Despite decadeof debate, sometimes quite intense, the pathologic featureof kwashiorkor are still not fully understood.' The role oaflatoxins and insufficient protein intake has been stressebecause the presence of edema and ascites seems related treduced osmolarity in the blood, which is thought to bcaused mostly by severe anemia.'"* It is puzzling that totaprotein concentrations in the plasma do not differ betweechi ldren wi th marasmus and those wi th kwashiorkor .

rable 1 : Prevalences of protein-en ergymalnutrition among children under 5 years ofage in developing coun tries, 1995Region Stunting, Underweight, Wasting,

Fig. 2: Direct and indirect causes of malnutrition.

AfricaAsiaLatin Americaand CaribbeanOceania

39411831

28351023

81035

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Malnutrition and health in developing countries

More recently, a role for free radicals in the etiology ofkwashiorkor has heen considered, '^ ' hut the f indings ofinit ial intervention studies have not heen up to expecta-tions. This may possihly he the result of inappropriate ex-perimental design.'"'"On e essential aspect of severe protein -energ y malnu tri-tion is the fatty degeneration of such diverse organs as theliver and heart. This degeneration is not just a sign of se-vere malnutrition; it causes suhclinical or overt cardiac in-sufficiency, especially when mabiutrition is accompaniedhy edema."** If the my ocard ial insufficiency is not co rre c-ted, iatrogenic fluid and sodium overload quickly escalateit into cardiac failure. A second injurious aspect is the lossof suhcutaneous fat , which markedly reduces the hody'scapacity for temperature regulation and water storage.'""^'As a consequence, malnourished children hecome dehy-drated, hypothennic and hypoglycemic more quickly and

severely than others. Finally, severe protein-energy mal-nutrition is associated with atrophy of the mucosa of thesmall howel, leading to a loss of ahsorpdon as well as ofdigestion capacity."".Severe malnu trition is furthermore associated with chro-nic hypovolemia, which leads to secondary hyperaldoster-onism, and further complicates fiuid and electrolyte hal-ance. Because the development of muscular dyst rophymohilizes much of the hody's potassiimi, which is then lostthrough urinary excretion, affected children do not showsigns of hyperkalemia.Most children with severe protein-energy malnutri t ion

have asymptomatic infections hecause their immune systemfails to respond with chemotaxis, opsonizadon and phago-cytosis of hacteria, viruses or fungi. So depressed is the sys-tem that the hody cannot produce even the fever that istypical of inflammadon."Malnutridon is diagnosed hy anthropometric measure-ments and physical examinadon. Where availahle, somelahoratory invesdg adons are helpful (Ta hle 2).

Table 2: Laboratory features of severe malnutrition

Management and controlDespite the manifold dietary approaches to severe mal-nutridon that have heen tr ied/ '" padents with kwashiorkor(including marasmic kwashiorkor) condnue to die muchmore frequently than those with marasmus alone. '" ' ' ' Insuh-Saharan Africa and, increasingly, India, an addidonalconcem is that many padents with severe malnutridon arealso infected with HIV."The high mortality indicates a need for a systemadc ap-proach to the severely malnourished padent that goes he-yond an appropriate diet. To reduce mortality, a complexmanagement scheme is pivotal ." Essendal steps include areduced intake of volume, protein and sodium during thefirst phase while emergency measures are taken to reducethe risk of hypoglycemia, hypothermia and dehydradon."""Oral, enteral and parenteral volume loads must he checked

carefully to avoid imminent heart failure; condnous moni-toring of central venous h lood pressu re is very desirahle. Inthis early phase of rehahihtadon, a protein intake exceeding1 g/kg hody weigh t in comh ination w ith impaired l iverfuncdon (with hreakdown of the urea cycle) and litde urineexcredon (a result of dehydradon) easily exceeds the mal-nourished child's metaholic capacity to rid him- or herselfof excess am mon ia.Although the effecdveness of the World Health Organi-za t ion (W H O ) 10- s t ep scheme ( shown in Ta h le 3 ) isproven, there are sdll pitfalls for certain padents, such asthose with extreme anemia and those who are close to car-

diac failure. The need for transfusions must he weighedagainst the r isk of heart failure; comhining transfusionswith diuresis or applying exchange transfusion can resolvethe dilemma. Th e W H O is currendy revising i ts protocolto address 3 difficuldes: the specific nutridonal prohlems ofTable 3: Elements in the management of severe protein-energy malnutrition'"Problem Management

Blood or plasma variablesHemoglobin, hematocrit,erythrocyte count, meancorpuscular volumeGlucoseElectrolytes and alkalinitySodium

PotassiumChloride, pH, bicarbonate

Total p rotein, transferrin.(pre-)albuminCreatinineC-reactive p rotein.lymphocy te cou nt, serology,thick and thin blood filmsStool examination

The information derivedDegree of dehydration and anemia;type of anemia (iron/folate and vitaminB,2 deficiency, hemolysis, malaria)HypoglycemiaHyponatremia, type of dehydrationHypokalemiaMetabolic alkalosis or acidosisDegree of protein deficiencyRenal functionPresence of bacterial or viral infectionor malariaPresence of parasites

HypothermiaHypoglycemiaDehydrationMicronutrientsInfectionsElectrolytesStarter nutritionTissue-buildingnutritionStimulationPrevention ofrelapse

Warm patient up; maintain and monitor bodytemperatureMonitor blood glucose; provide oral (or intra-venous) glucoseRehydrate carefully with oral solution con tainingless sodium and more potassium than standard mixProvide copper, z inc, iron, folate, multivitaminsAdminister antibiotic and antimalarial therapy, evenin the absence of typical symptomsSupply plenty of potassium and magnesiumKeep protein and volume load lowFurnish a rich diet dense in energy, protein and allessential nutrients that is easy to swallow and digestPrevent permanent psychosocial effects ofstarvation with psychomotor stimulationStart early to identify causes of protein-energymaln utrition in each case; involve the family andthe community in prevention

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children with HIV infection or AIDS; different dietaryregim ens, particularly for infants young er than 6 mo nths ;and the l imited availabili ty of po tassium -mag nesium -zinc-copper preparations.*'T he need to reduce the high sodium content (90 mEq /L)of common oral rehydration solutions for starving chil-dren has led to the production of ReSoMal (a 45-mEq/Lrehydration .foludon for the m /z/nourished). No w that a 75-mEq/L oral rehydration solution has become a standardtreatment for nonsecretory diarrhea,"" there is less needfor a special sodiu m-re duce d rehyd rat ion prepa rat ion.Nevertheless, modification of the standard oral rehydra-don solution is recommended, with diludon to reduce thesodium concentra t ion and enr ichment wi th potassium,magnesium, zinc, copper and selenium.'" '" '" Finally, theseverely malnourished child should always be given aneffecdve broad-spectrum andbiodc, even in the absence of

any signs of infecdon.""^People's diets can benefit fi-om prevendve intervendonsranging f i-om income g eneradon and nutridonal educadonto maternal support, food supplementadon and food prizesubsidies. High immtinizadon coverage and early and cor-rect management of cases of infecdous disease play majorroles in the prevendon and t reatment of prote in-energymalnu t r i t i on . " I n poor communi t i e s , t he t r ea tmen t o fhelminth infecdons 3 dmes per year improved child growthand development."Protein-energy malnutridon and diarrhea typically inter-act in a vicious cycle, but the control of diarrhea depends on

more than medical help.'" Although growth monitoring isconsidered potendally important in child health clinics,there is often a lack of appropriate follow-up acdon.*^'**^ Asmuch as fiincdonal health services may need to be madeavailable, in order to address infecdous diseases as a cause

of protein-energy malnutridon i t is l ikewise important topromote breast-feeding, improve the water supply and sanitadon, and educate people about hygiene. ''" '""" T he mu ldfaceted hor izontal approach of the WHO-suppor ted Integrated Management of Childhood Il lness inidadve harecen dy been shown to be an effecdve strategy."''*Micronutrient deficienciesEpidemiology

Deficiencies in iron, iodine, vitamin A and zinc are sdlmajor public health problems in developing countries, buvitamin C, D and B deficiencies have declined considerablin recen t de ca de s. '" M icro nu trien t deficiencies affect aleast 2 billion people worldwide.^ As there are often no reliable biochemical indices of marginal micronutrient statusrandomized controlled tr ials of supplementadon are thebest method to study the reladon between micronutriendeficiencies and health parameters in human populadons.'"Globally, 740 million people are deficient in iodine, including up to 300 million with goitre and 20 million withbrain damage from maternal iodine deficiency during theifetal development.''""*' About 2 billion people are deficienin zinc; 1 billion have iron-deficiency anetnia. Vitamin Adeficiency affects some 250 million, mainly young childrenand pregnant women in developing countries.'""'^^""'^ Thmain causes worldwide of these 4 major micro nutrien t deficiencies are shown in Table 4.Pathophysiology and clinical features

Not only do protein-energy malnutr idon and micronutrient deficiencies overlap, but a lack of 1 micronutrienTable 4:

NutrientIron

Iodine

VitaminA

Zinc

Causes, manifestations, management and prevention of the major micronutrient deficiencie!Essential fo rthe productionor function of

HemoglobinVarious enzymesMyoglobin

ThyroidhormoneEyesImmune system

Many enzymesImmu ne system

Regular vitamin A supplementation is

Causesof deficiencyPoor dietElevated needs (e.g., while pregnant,in early childhood)Chronic loss from parasite infections(e.g., hookworms, schistosomiasis,whipworm)Except where seafood or salt fortifiedwit h iodine is readily available, mostdiets, worldwide, are deficientDiets poor in vegetables and animalproducts

Diets poor in animal productsDiets based on refined cereals (e.g.,white bread, pasta, polished rice)sometimes a part of immun ization programs.

Manifestations ofisolated deficiencyAnemia and fatigueImpaired cognitive developmentReduced growth and physical strength

Goitre, hypothyroidism, constipationGrowth retardationEndemic cretinismNight blindness, xerophthalmiaImmune deficiencyIncreased childhood illness, early deathContributes to dev elopment of anemiaImmune deficiencyAcrodermatitisIncreased childhood illness, early deathComplications in pregnancy, childbirth

Managementand preventionFoods richer in iron and w itfewer absorption inhibitorsIron-fortified weaning foodsLow-dose supplements inchildhood and pregnancyCooking in iron potsIodine supplementFortified saltSeafoodMore dark green leafyvegetables, animal productsFortification of oils and fatsRegular supplementation*Zinc treatment for diarrheaand severe m alnutritionImproved diet

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is typically associated with deficiencies of o ther micronutri-ents. The pathophysiology and manifestadons of the maindeficiencies are summarized itn Table 4.Iron is an essendal part of hemoglobin, myoglobin andvarious enzymes. Its deficiency thus leads mainly to anem ia,but also to several other adverse effects.'"'"'"Lack of iodine reduces die producdon of thyroid hor-mone and increases that of thj^oid-sdmuladng hormone.As a result, the thyroid gland becomes hyperplasdc andgoitrous, and hypothyroidism d evelops.''Vitamin A deficiency contributes to anemia by immobil-izing iron in the reticuloendothelial system, reducinghemopoiesis and increasing suscepdbility to infecdons.Vitamin A is essendal for the fimcdoning of the eyes aswell as the immune system.*''"" Although diarrhea and re-lated mortality has clearly been shown to be associatedwith vitamin A deficiency, the evidence for associadonswith acute infections of the lower respiratory tract andwith malaria is much weaker.'*'""^'""Zinc is essendal for the fimcdoning of many enzymesand is thus involved in a large number of metabolicprocesses, including RNA and DNA synthesis.'"" Conse-quendy, zinc deficiency interferes with a variety of biologi-cal funcdons, such as gene expression, protein synthesis,skeletal growth, gonad development, appedte and immim-ity. Zinc plays a central role in the funcdon of cells mediat-ing unspecific immimity, such as neutrophils and naturalkiller cells, and is needed for specific immvme processes,such as balancing T helper cellfimcdons.""Zinc deficiencyis a major determinant for diarrhea and pneumonia, butevidence about its role in malaria and growth retardadonis conflicdng.'*'"'^'"'Managem ent and control

Foods with a high content of absorbable micronutrientsare considered the best means for preventing micronutrientdeficiencies.'""'" In communides where supplies of suchfoods are imavailable, specific prevendve and curadve inter-vendons are needed.'^'"''Th ere is growing consensus on the importance of muld-ple micronutrient intervendons in populadons with a highprevalence of malnutridon.'"'"' However, synergisdc andantagonisdc interacdons between micronutrients have tobe taken into consideradon during the development of ap-propriate formuladons.'""'" A special kind of intervendonis the provision of fat-based spreads (e.g., peanut butter)and "sprinkles" containing muldple micronutrients to bemixed with food." A principle limitadon of all these inter-vendons (except dietary diversificadon, of course) is theirorientadon toward single nutrients rather than plant ingre-dients (e.g., phytosterols and fibre), despite the desirabilityof plant ingredients for the prevendon of cancer and car-diovascular diseases.

Micronutrient supplementation is usually providedthrough the exisdng health services and can be taken orally

or (more rarely) by injecdon. Priority shotild be given tovulnerable populadons, such as pregnant women and chil-dren.'" Supplementadon is mandated in cases of a specificdeficiency when other approaches are too slow. Aldioughsome micronutrients must be taken daily or weekly (e.g.,iron and zinc), others can be stored in the body and needonly be taken at intervals of months to years (e.g., vitaminA and iodine).' '" However, modes of delivery, patientcompliance and potendal toxicity all need to be consi-dered.'" Table 4 decribes the principles of managementand prevendon of the 4 most common isolated micro-nutrient deficiencies.Diet-based strategies are probably the most promisingapproach for a sustainable control of micronutrient de-ficiencies. Increasing dietary diversificadon through con-sumpdon of a broad variety of foods, preferably from homegardens and small livestock producdon, is effecdve.""^

Households should be educated and supported to increaseproducdon of dark-green leafy vegetables, yellow and or-ange fruits, poultry, eggs,fishand milk.A possible future strategy to prevent micronutrient de-ficiencies is to breed micronutrient-rich crops, tlirough ei-ther convendonal breeding techniques or genedc modifica-don of existing crops. So far, however, the micronutrientconcentradons achieved are very low. For vitamin A, no-body knows if P-carotenefi-om he new "golden rice" vari-ety is bioavailable and how much rice must be consumed tomeet an individual's needs, and iron concentradons in bio-engineered rice are no higher than those in natural variedessuch as basmad or jasmineConclusions and outlook

Because malnutridon has many causes, only muldpleand synergistic intervendons embedded in true multi-sectoral programs can be effecdve.'" A variety of acdonsare needed, including agriculttiral and micronutrient inter-vendons and the provision of safe drinking water and sani-tadon, educadon about and support for be tter diets, specialattendon to gender issues and vulnerable groups such aspregnant women and young children, and quality healthservices."'"" Nutridon educadon about locally availableprotein- and micronutrient-rich plants is pardcularly effec-dve and sustainable.'"''""During the United Nations Millennium Summit in2000, 147 heads of state adopted 8 development goals.The goal specifically about hunger is to reduce extremepoverty and hunger by the year 2015 by half reladve to1990 figures,'" but progress toward the other 7 goals (tmi-versal primary educadon; empowerment of women; im-proved maternal health; decreased child mortality; advan-ces in the prevendon and management of HIV/AIDS,malaria and other diseases; environmental protecdon; andglobal partnerships for development) would direcdy or in-direcdy contribute to major reducdons of malnutridon indeveloping coimtries.

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This article has been peer reviewed.From the Department of Tropical Hygiene and Public Health, Ruprecht-Karls-University Heidelberg (Muller), and the Institute of Nutritional Sciences and De-partment of Pediatrics, Justus-Liebi g-Universi ty Giessen (Krawinkel), GermanyCompeting interests: None declared.Contributors: Both authors contributed substantially to the study conception anddesign, data collection and analysis, and drafting and revision of the article. Bothapproved the final version to be published.

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Correspondence to: Dr. Olaf Muller, Department of TropicaHygiene and Public Health, INF 324, 69120 Heidelberg,Ruprecht-Karls-University Heidelberg, Germany;olaf.mueller@ urz. uni-heidelberg. de

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