Malnutrition and Intestinal Malabsorption R

Chapter 18 Malnutrition and Intestinal Malabsorption R. 0. C. KAscHULA

A. Protein Energy Malnutrition

I. General Aspects Protein energy malnutrition of childhood is the most prevalent form of malnutrition in the tropics and throughout the world. Intercurrent infection, particularly gastroenteritis, measles, pneumonia, malaria and schistosomia• sis are known to precipitate overt disease. Associated subclinical vitamin and trace element deficiencies have been found to have an important additional role in augmenting morbidity and mortality attributed to protein energy mal• nutrition. A state of good health requires an adequate and balanced intake of nutrients. Minimal requirements for essential nutrients are dependent upon diverse physiological and climatic factors such as growth, pregnancy, lactation, illness, exercise, temperature and humidity. In addition individual responses to nutritional deprivation are quite variable. In tropical areas a high proportion of the population subsists on a marginal diet where carbohydrate provides 80%-90% daily energy requirements as compared with 35%-50% of the diet amongst prosperous people in temperate climates. It is widely recommended that dietary protein should approxi• mate 1 g/kg body weight in adults while young children require two to three times this amount. In addition to contributing an average 10% of daily energy requirements, proteins contain essential amino acids that are important in metabolic processes. Tryptophan occurs in very limited quantities in white maize, the staple diet in much of Africa, where pellagra often accompanies protein energy undernutrition. In Asia, where thiamine deficient polished rice is the staple diet, beriberi tends to be associated with protein energy undernutrition. The assessment of nutritional status has for a long time been a subjective matter of clinical appearance. Factors that are taken into account are: the amount of subcutaneous fat, muscle wasting (with associated motor weak• ness, sensory loss and calf tenderness), skin changes (including follicular hyperkeratosis, alterations in pigmentation, dryness and pellagrous dermato• sis) oedema, hair changes (comprising thinness, depigmentation and lack of lustre), stomatitis and hepatomegaly. Concurrently there are changes in behaviour. Older children and adults are unable to laugh heartily, sneeze or blush. They develop muscle cramps, increased tolerance of heat with impair• ed tolerance of cold. They are often self-centred and have transient visual disturbances with loss of libido.

T. G. Ashworth et al, Tropical pathology © Springer-Verlag Berlin Heidelberg 1995 986 R. 0. C. KASCHULA A variety of physical measurements for growth failure have been used to evaluate protein energy malnutrition. International anthropometric standards have been based upon aftluent western norms which are nevertheless appropriate for developing countries (Kow et al. 1991). Frequently the precise age of the child is not known, hence innovative ratios have to be used. Head circumference and height are not usually reduced below 85%-90% of that expected for age, whilst skinfold thickness (triceps and subscapular) and weight are most severely affected (KEET et al. 1970), often being of the order of 50%-60% of that which is expected for age. In practice the most useful indices are weight and height (JANSEN et al. 1985). When there has been a chronic shortage of protein and/or energy over a period of several months significant failure of both weight and height occurs with little change in weight to height ratio. Skinfold thickness and the circumference of the mid upper arm have been found to be accurate indicators of nutritional status when the age of children is known (JELLIFFE and JELLIFFE 1969). A number of biochemical measurements have been used to evaluate nutritional status in respect to protein and energy. Plasma albumin and total protein concentrations and ratios have been found to be useful. Albumin has a half-life of 20 days and is thus a relatively slow indicator of nutritional status. Albumin levels below 25 g/1 are considered to be highly significant in the absence of liver disease. Other proteins that have a shorter half-life, such as pseudocholinesterase, transferrin, retinol and T4 binding proteins, fibronectin and C3 complement are considered to more accurately reflect current nutritional status. However, their blood levels will also be influenced by concurrent infection. Nitrogen loss may be assessed by measuring the urea excretion in urine over a 24 h period but in practice a low blood urea level is considered to be significant. Incipient cases of malnutrition have been identified in field surveys by testing for hydroxyproline excretion (WHITEHEAD 1965) and amino acid imbalances (WHITEHEAD 1964). The most widely accepted classification of protein energy malnutrition amongst children was formulated by an international working party sponsor• ed by the Wellcome Trust and reported in 1970 (WELLCOME TRUST WORKING PARTY 1970). It is based upon the percentage of weight deficit for age and the presence or absence of oedema. Nutritionally growth retarded and kwashiorkor children weigh between 60% and 80% of that which is expect• ed for age. In marasmus and marasmic kwashiorkor the weight is less than 60% of that expected for age. The kwashiorkor and marasmic kwashiorkor children have oedema. In addition to these defined forms of protein energy malnutrition, adults may develop wasting conditions referred to as famine oedema (kwashiorkor equivalent) and cachexia (marasmus equivalent). Marasmus is considered to be due to a predominant lack of dietary energy protein required by a growing infant. A view is also held that in marasmus there is an inherent capacity to metabolically adapt to an inadequate energy intake (COWARD and LUNN 1981). In kwashiorkor the adaptive processes are said to fail. Although marasmus may occur at any age, it is particularly Malnutrition and Intestinal Malabsorption 987 common in early infancy after failure of breast feeding. A mixture of socio• economic and cultural factors contribute. There is a direct relationship be• tween lack of income, size of family, nutritional status and rate of infection (gastroenteritis) (HANSEN et al. 1967). All forms of protein energy malnutri• tion are prevalent during times of famine and sociopolitical disturbance with massive migrations to unhygienic and overcrowded living conditions. Maternal starvation reduces the supply of breast milk. The usual situation is an urbanized mother having frequent pregnancies with early and abrupt weaning followed by contaminated dilute formula feeding. When poor unsophisticated and illiterate people migrate to slum dwellings on the out• skirts of cities, mothers find it necessary to stop breast feeding early in order to gain employment while the infant is placed in the care of a baby minder who provides dilute and unhygienically prepared formula feeds. In these situations marasmus is precipitated by intercurrent infections such as gastroenteritis, pneumonia, tuberculosis and measles. Concurrent congenital anomalies, premature birth, metabolic disorders and chronic renal disease augment the process of maternal deprivation and neglect by causing anorexia, vomiting and excessive tissue catabolism. By way of contrast kwashiorkor generally occurs in a slightly older infant or toddler and tends to be more prevalent in rural communities. The condi• tion was described by WILLIAMS in 1933, who worked amongst the Ga tribe of Gold Coast (now Ghana). Amongst the Ga kwashiorkor referred to the sickness of the weaning child meaning first-second and indicating the child deposed from the breast by the next infant. In a WHO/FAO report the name kwashiorkor was firmly established for the highly prevalent syndrome in Africa (BROCK and AUTRET 1952). Thereafter it was shown that cure could be initiated by administering skimmed milk or a vitamin-free casein-based diet (BROCKet al. 1955). The term protein calorie (energy) malnutrition was pro• posed to cover the spectrum of syndromes from marasmus to kwashiorkor (JELLIFFE 1959). The syndromes of protein energy malnutrition (nutritional growth retardation, kwashiorkor, marasmus and marasmic kwashiorkor) have anum• ber of common clinical features. These include growth retardation, poor socioeconomic conditions, frequent or persistent diarrhoea with or without dehydration, high morbidity and mortality from intercurrent infections, dietary protein and/or energy deficit. They respond to correctional manage• ment of diet and have a spectrum of biochemical and pathological changes that depend upon the severity of dietary depletion (HANSEN and PETTIFOR 1991). For a long time the reason that one child develops marasmus and another kwashiorkor has been attributed to the degree of energy and/or protein deprivation to which the children are exposed. Marasmus is con• sidered to be due to long-standing deprivation of food (protein and energy) as occurs in starvation. Whereas the child with kwashiorkor is said to have been exposed to a high-carbohydrate low-protein diet, this particularly occurs with maize and cassava. The child is less underweight but relatively more protein depleted with lower serum albumin levels and associated 988 R. 0. c. K.ASCffiJLA oedema. The difference is now considered to be more complex as kwashior• kor has only once been convincingly reproduced in experimental animals (CowARD and WHITEHEAD 1972) when baboons were fed the same diets given to Ugandan children with kwashiorkor. A hypothesis that is increasingly gaining acceptance is that kwashiorkor occurs in significantly undernourished infants who develop infection or are exposed to mycotoxins or other noxae that produce increased free radicals. This occurs in a milieu where dietary deprivation has led to inadequate protective pathways (GoLDEN and RAMDATH 1987). As a consequence there is a series of iron-catalysed chain reactions which eventually lead to inade• quate reparative processes including peroxidation of lipids. The lipid hydroperoxides and other products of oxidation are toxic to cell membranes which lose their integrity. This results in interstitial oedema, fatty liver, pig• mentary and other skin lesions, bleached hair and immunoincompetence. The relationship between aflatoxin and kwashiorkor has been reported in Nigeria and southern Africa (LAMPLUGH and HENDRICKSE 1982), Sudan (HENDRICKSE et al. 1982) and South Africa (HousEHAM and HUNDT 1991). Fungal growth is facilitated in granaries where crops are stored in darkness in warm, hU¥lld conditions. Analyses of liver samples, blood and urine indicate the presence of aflatoxin and its metabolites in kwashiorkor children and very rarely in marasmic children (LAMPLUGH and HENDRICKSE 1982; . HENDRICKSE et al. 1982). Superoxide and hydrogen peroxide are powerful oxidants liberated by leukocytes in response to infections such as measles and Gram-negative bacteria. A number of micronutrients have a role in the safe disposal of free radicals. These include selenium, copper, zinc, manganese, cysteine, vitamins A, E, C and b-carotene. In addition glutothione, urate, bilirubin, caeruloplasmin, transferrin and other proteins act as endogenous anti• oxidants. There is much evidence to suggest that in kwashiorkor as distinct from marasmus there is an imbalance between the production of free radicals and their removal (GOLDEN and RAMDATH 1987). It is relevant that the administration of iron to children with kwashiorkor results in a high mortality (McFARLANE et al. 1970) which occurs very shortly after treatment is started. This is attributed to increase in unbound serum iron. Similarly the intravenous administration of protein hydrolysates (GILLMAN and GILLMAN 1951) also causes rapid death in children with kwashiorkor. This is now attributed to an acute imbalance between oxidants and scavengers of free radicals. Observations made in Cape Town in regard to red blood cell anti• oxidant enzyme concentrations in kwashiorkor and marasmus support the view that kwashiorkor results from excessive free radicals due to an imbalance between pro- and antioxidants in malnourished children (SIVE et al. 1993). Kwashiorkor children have depressed levels of reduced gluathione and glutathione peroxidase and increased lipid peroxidation as indicated by elevated levels of thiobarbituric acid-reactive substances. Malnutrition and Intestinal Malabsorption 989 II. Overnutrition in the Tropics Obesity is relatively infrequently encountered in the tropics where oppor• tunities for the excessive consumption of food over a prolonged period are uncommon. However, amongst many tribal cultures obesity is regarded as a desirable sign of affluence. Young children and adult women are often provided with a high-calorie, predominantly carbohydrate diet amongst a class of affluent community leaders. In these situations there are now increasing reports of cardiovascular disease, maturity onset diabetes mellitus and osteoarthritis. Hypertension is a particularly prevalent problem amongst young overweight African women where it frequently becomes malignant. Children who are overnourished have defective T-lymphocyte reactivity with an increased incidence of infections and propensity to diseases of the aged such as atherosclerosis. Type II diabetes mellitus is particularly prevalent amongst affluent Indians and people who are becoming increasingly sedentary in lifestyle. Hypervitaminosis is virtually unknown in the tropics though occasional cases of carotonaemia have been seen when squash and carrots are major components in the diet. Excessive consumption of alcohol is probably as prevalent as it is in western industrialised countries but in many areas the pattern is different. In urban communities heavy drinking with inebriation often occurs over week• ends with more frequent episodes of pancreatitis and Wernicke-Korsakoff syndrome because of associated vitamin deficiencies.

III. Undernutrition (Nutritional Growth Retardation) In the tropics undernutrition in children has come to mean mild protein energy malnutrition with retarded growth. They are short in stature and are underweight for age. In terms of the definition proposed by the Wellcome Trust working party, these children are between 60% and 80% of expected weight and have no oedema (WELCOME TRUST WORKING PARTY 1970). With respect to the view that free radicals have a major role in the causation of oedema and fatty liver of kwashiorkor and marasmic kwashiorkor, it is assumed that in this group ofunderweight and growth-retarded children there is a balance in favour of free radical scavengers. However, the balance can easily be reversed with conversion to kwashiorkor when the diet changes to promote peroxidation or severe infections such as measles, gastroenteritis, pneumonia, malaria and/or infestations by hookworm and schistosomiasis intervene. Chronic malabsorption from repeated or persistent gastroenteritis may have an aetiological role in growth retardation. Tuberculosis and post• measles or postpertussis chronic lung disease may have a similar effect. These underweight children exhibit the classic features of failure to thrive, being short in stature with reduced muscle bulk and subcutaneous fat (Fig. 18.1A). In addition, they often have signs of anaemia and infection. Reserves of iron and folic acid are low and bone marrow hypoplasia is seen. 990 R. 0. C. KASCHULA

Fig. 18.1. A Nutritional growth retardation exhibiting short stature, reduced muscle bulk and subcutaneous fat with abdominal distension. B Marasmic child exhibiting emaciation with considerable loss of muscle bulk and subcutaneous fat, sunken eyes and parotid enlargement

Scalp hair may be slightly sparse while impetigo and scabies may also be found. Wound healing may be retarded as occurs with veld sores. Infections such as otitis media, conjunctivitis, herpes simplex and oral candidiasis are not infrequent.

IV. Marasmus The underlying circumstances that lead to marasmus have been discussed. The children are either irritable or apathetic, ravenously hungry or anorexic and usually have an associated infection. They appear emaciated and wizened with sunken eyes, and have considerably reduced subcutaneous fat and muscle bulk without oedema (Fig. 18.1 B). When starvation is relatively acute, the weight to height ratio is considerably reduced. They have the most marked reduction in skinfold thickness and in mid arm circumference. The morphological changes of atrophy that occur in the organs are similar to those seen in other forms of protein energy malnutrition. It is, however, notable that marasmic infants have little or no subcutaneous fat. Their livers are small and atrophic without fatty change. Skin changes are similar to those seen in undernourished growth-retarded children though the skin may be Malnutrition and Intestinal Malabsorption 991 more scaly and dry. Many children have additional features of associated iron or vitamin deficiency such as anaemia, pellagra, beriberi, rickets, xerophthalmia and follicular hyperkeratosis.

V. Kwashiorkor This condition has an insidious onset. Often medical attention is only sought after failure to thrive, oedema, irritability or apathy, vomiting, diar• rhoea, and hair and skin changes have been present for weeks or months. Assistance is sought when refusal to eat, infection or groass oedema appears. In this condition the baby often appears to be fat and chubby because the diet has provided adequate energy. Reference to growth charts, however, indicate growth retardation although those who are very oedematous may exceed 80% of expected weight for age.

1. Oedema The severity of oedema is very variable and may account for between 5% and 20% of body weight. The fluid predominantly accumulates in the extra• cellular space. In spite of considerable accumulation ofbody water, effusions into serous cavities are uncommon and of a low order. When ascites or pleural effusions are present, other causes such as renal disease, tuberculosis, cirrhosis, anaemia, cardiac failure, beriberi and veno-occlusive disease must be considered. Even though kwashiorkor children have hypoalbuminaemia the oedema usually disappears when electrolyte imbalance (potassium and magnesium depletion with sodium retention) has been corrected and before serum albumin levels are restored (WATERLOW 1984; GoLDEN et al. 1980a). Leaky cell membranes caused by a disturbance of the sodium pump may be responsible for the oedema (PATRICK 1979). It is also notable that in some children gross oedema of the legs coexists with signs of dehydration in the upper part of the body (WATERLOW 1984). In spite of dehydration and muscle wasting an oedematous moon-like face is a common feature. In addition cardiac output is significantly reduced (ALLEYNE 1966) and renal blood flow and glomerular filtration are reduced (ALLEYNE 1967) with a reduced capacity to concentrate urine and deal with a sodium load (KLAHR and ALLEYNE 1973). It has been shown that in adults with famine oedema hypoalbuminaemia is not always present (GOPALAN et al. 1952). Attempts have been made to explain the pathogenesis of nutritional oedema upon the basis of reduced total body protein reserves, which may be modulated by the quantity and quality of protein in the diet or simply on the basis of an individual's capacity to adapt (WATERLOW 1984). The apparent role of free radicals and their scavengers is still to be fully investigated. 992 R. 0. C. KA.SCHULA 2. Skin Changes The skin changes that occur in kwashiorkor consist ofhyperpigmentation and hypopigmentation, desquamation, vesicle formation and ulceration. Often the appearance of a "hot water burn" is shown by vesicle formation, ulceration and much weeping of serous fluid. This dermatosis begins to occur in areas subject to friction or pressure such as the groin, on the buttocks, perineum, lower abdomen, behind the knees and at the elbows but can later be manifest anywhere on the body such as the face and extremities of the limbs. Hyperpigmented patches form which peel or desquamate off like old blistered paint. After flaking off, atrophic, depigmented or raw areas of skin may resemble a healing or second-degree burn. Ulceration often leads to secondary infection. The dry scaling dermatosis is distinct from pellagra and is considered to be pathognomic of kwashiorkor {LATHAM 1991 ). The skin lesions have been attributed to deficient dietary tryptophan and/or nicotinamide (TRUSWELL et al. 1962) and to zinc deficiency (GOLDEN et al. 1980b) but they fully respond to timely treatment with protein (LATHAM 1991). Microscopically there is atrophy of the malpighian layer of the epi• dermis which may be associated with parakeratosis, hyperkeratosis and alterations in pigmentation of the basal layer. Melanin also accumulates in the upper layers including the hyperkeratotic and parakeratotic layers. The dermis is usually oedematous and depending upon the presence or absence of secondary septic lesions an acute or subacute dermatitis with patchy ulceration may be found. Hair follicles and sebaceous glands are often atrophic (CAMPBELL 1956).

3. Mucous Membranes The Mucous membranes of the lips may be cracked with or without angular stomatitis. Herpes ulcers are also frequent on the face (Fig. 18.2 A) or around the genitals. They occur near mucocutaneous junctions and are a cause of blindness when they affect the conjunctiva. Associated vitamin A deficiency causes xerophthalmia or keratomalacia. Candida infection of the oral cavity and vulva may also be seen.

4. Hair Changes Hair changes are classically characterised by a reddish discoloration but in Latin America greyness occurs as alternating streaks of dyspigmentation which is known as a "flag sign". The dyspigmentation represents periods of protein energy depletion 1-3 months earlier (HANSEN and PETIIFOR 1991 ). In addition natural curly hair losses its curl and becomes sparse over the temples and occipital regions (Fig. 18.2 A). Malnutrition and Intestinal Malabsorption 993

Fig. 18.2. A Moon-shaped kwashiorkor facies with sparse thin hair, dermatosis and herpetic ulcers of the lips. Subcutaneous fat is copious. B Emaciated marasmic kwashiorkor with gross peripheral oedema and lower abdominal wall dermatosis

5. Muscle Wasting Muscle wasting is a feature of all forms of protein energy malnutrition but in kwashiorkor may be obscured by oedema. Nevertheless muscle fibres are reduced in size by morphometric analyses when compared with age-matched controls.

6. Mental and Neurological Changes The mental and neurological changes that occur in kwashiorkor overlap with those found in marasmus. Apathy or gross irritability with intermittent crying are features of both forms of protein energy malnutrition. K washior• kor children in addition sometimes develop repetitive tremulous movements of one or more limbs. This syndrome referred to as "kwashi shakes" may also affect eye muscles and the vocal cords and has a good prognosis (HANSEN and PETTIFOR 1991). The long-term prognosis for intellect does not seem to be adversely affected when nutritional deprivation occurs after the age of 10 months (HANSEN et al. 1971). 994 R. 0. C. KASCHULA 7. Renal Function Reduced renal function has been considered to be a cause for generalized oedema (ALLEYNE 1967; KLAHR and ALLEYNE 1973).' In addition it has been shown that overflow aminoaciduria with occasional phosphaturia and ineffi• cient acid excretion occur in kwashiorkor. However, these phenomena seem to have little influence on acid-base balance. Alterations to the gastrointestinal tract, cardiovascular system and haemopoietic system are similar to those found in marasmus and marasmic kwashiorkor except that fatty liver and hepatomegaly are features of kwashiorkor and to a lesser extent of marasmic kwashiorkor.

VI. Marasmic Kwashiorkor As the name implies, this syndrome has the features of both kwashiorkor and marasmus. The children are very emaciated but also have oedema (Fig. 18.2 B), skin changes, hair changes and the propensity to infection that is prominent in kwashiorkor. Often these patients come to hospital as cases of marasmus with gastroenteritis and dehydration. Their oedema becomes manifest after they are rehydrated. Fatty change of the liver occurs but is not as severe as that which is seen in kwashiorkor.

VII. Pathology of Protein Energy Malnutrition 1. Water and Electrolyte Balance In regard to water and electrolyte balance, it has been shown that with cessation or slowing of growth, there is a gradual increase in total body water as a percentage of body weight (HANSEN et al. 1965). This change occurs with a simultaneous reduction in fat stores and wasting of muscle. The extra• cellular compartment shows the greatest rise in water content which is lost to the intracellular space and by diuresis when recovery begins (HANSEN and PETTIFOR 1991 ). Balance studies indicate a deficit of total body potassium (MANN et al. 1972), magnesium, calcium and phosphorus (GARROW et al. 1965). In spite oflow total body potassium and magnesium, serum levels are variable and can become very low during the recovery period. These changes seem to account for sudden cardiac arrest (SMYTHE et al. 1962; SWANEPOEL et al. 1964). The restricted administration of sodium during the recovery phase has significantly reduced the incidence of acute cardiac failure (WHARTON et al. 1967).

2. Skeletal Muscle Atrophy Skeletal muscle atrophy is more advanced than it appears to be particu• larly in cases of kwashiorkor. Muscle mass may be reduced to 30% of expected (MONTGOMERY 1962). The fibres are small and rounded to resemble those seen in the fetus. Fibre numbers are also significantly reduced while Malnutrition and Intestinal Malabsorption 995 subsarcolemmal nuclei are only slightly decreased to give an impression of increased nuclei. This is associated with increased macrophage activity, fibroblasts and collagenisation. Eosinophilic degeneration of fibres may be extensive and widespread in severe malnutrition.

3. Heart The functional and pathological changes in the heart have come under scrutiny (GOPALAN et al. 1955; SMYTHE et al. 1962; SWANEPOEL et al. 1964). The heart participates in the generalised wasting and cardiac function is disturbed to cause reduced cardiac output, bradycardia and reduced circula• tion time (ALLEYNE 1966). Heart weights are variably reduced. In the major• ity of cases no significant microscopic changes are seen. Sometimes there is oedema with separation of myocardial fibres with or without vacuolation and disruption of individual fibres. The endocardium is undisturbed and mural thrombi are not a feature of these hearts.

4. Liver Liver pathology is variable with fatty change being the most characteristic feature of kwashiorkor. This is less prominent in marasmic kwashiorkor and absent or most inconspicuous in marasmus and in nutritionally growth retarded children. In the latter groups any incidental hypoxia or acidosis may cause minor degrees of fatty metamorphosis. The fat first appears as small droplets which coalesce to form larger globules that eventually, in severe kwashiorkor, fill the whole cell to push the nucleus to the cell membrane. The process starts in periportal areas (zone 1) at the periphery ofliver lobules and spreads to zone 3 around the central vein. In severe kwashiorkor the liver may enlarge because of considerable accumulation of fat so that it will float in water or formalin solution, Microscopically the plates of liver cells often resemble adipose tissue (Fig. 18.3 A). Inflammatory cell infiltration is incon• spicuous in the absence of infection and leucocytosis. Ultrastructural ex• amination of biopsy specimens shows no zonal variation in severe cases. The lipid vacuoles considerably distend cells without causing rupture of cell membranes (WEBBER and FREIMAN 1974). Hepatocyte lysosomes tend to increase in size and number and have a tendency to congregate around bile canaliculi. Small amounts of collagen may be found adjacent to hepatocytes and this is not considered to be significant or antecedent to cirrhosis. The cirrhosis that occurs in children that recover from protein energy malnutri• tion is attributed to additional supervening factors such as viral hepatitis, mycotoxins and schistosomiasis (STEIN and ISAACSON 1960; CooK and HuTT 1967; SuCKLING and CAMPBELL 1957). The gross fatty metamorphosis is completely reversible by treatment. Biochemical evidence of altered liver function is evident by slightly raised serum liver enzyme levels (WEBBER and FREIMAN 1974) whereas greatly increased levels are found in children who subsequently die, irrespective of 996 R. 0 . C. KASCHULA

Fig. 18.3. A Liver in kwashiorkor showing extensive and diffuse accumulation of fat in parenchymal cells. H & E, x 32. B Pancreas in kwashiorkor showing advanced atrophy of acinar tissue. Cytoplasm is shrunken and without zymogen granules, and nuclei are pyknotic. H & E, x 63 whether they have marasmus or kwashiorkor (McLEAN 1962). Bilirubin levels are slightly raised in patients who are semiconscious. In severe kwashiorkor with advanced fatty metamorphosis serum beta-lipoprotein, cholesterol and triglycerides are reduced (TRUSWELL et al. 1969).

5. Pancreas The pancreas undergoes severe atrophy with considerable reduction in organ weight (TROWELL et al. 1954) without disorganisation of the normal lobular pattern (OwoR 1970). There are striking and highly consistent microscopic changes in all forms of protein energy malnutrition. There is marked atrophy of acinar tissue. The cells shrink and zymogen granules dis• appear while the nuclei become smaller and more pyknotic (Fig. 18.3B). As a result the pancreatic ducts and islets become more conspicuous. In some cases atrophic acini become distended with pale eosinophilic proteinaceous material (CAMPBELL 1956). In kwashiorkor the interstitial tissues may become conspicuously oedematous. The changes are completely reversible after a few weeks of refeeding and fibrosis is not a consequence. Ultrastructural studies show that there is decreased endoplasmic reticulin and zymogen granules in the atrophic acinar glands. Here the remaining Malnutrition and Intestinal Malabsorption 997 endoplasmic reticulin is disorganised so that cytoplasmic matrix and segments of reticular membrane are sequestrated within the cisternal space. Mitochondria are decreased in number but become enlarged. Lysosomal bodies and lipid are increased (BLACKBURN and VINIJCHAIKUL 1969). The exocrine secretion of the pancreas is depressed in both kwashiorkor and marasmus and parallels lowered serum albumin levels. There is complete and early restoration of function following appropriate refeeding (BARBEZAT and HANSEN 1968). Endocrine function is less severely affected. Glucagon production is reduced in severe kwashiorkor when it is also associated with life-threatening and sometimes fatal hypoglycaemia (BucHANAN et al. 1976). The hypoglycaemia is associated with overwhelming infection and anorexia (WHARTON 1970). Plasma insulin levels are low in protein energy malnutrition and abnormal insulin responses have been found in some children as long as 10 years after recovery from kwashiorkor (CooK 1967). Inconsistent changes may be found in pancreatic islets (BECKER 1983). There may be atrophy and degranulation or hypertrophy but the islets are mostly unchanged.

6. Endocrine System The endocrine system is subjected to alterations in the levels of circulat• ing hormones. In addition there are alterations in secretion rates, clearance rates and binding proteins. There may also be alterations to hormone receptors in tissues. These functional changes are generally associated with little or no morphological changes. Malnourished growth-retarded children have elevated levels of growth hormone in the face of decreased epiphyseal bone growth. The levels of the hormone do not increase further in response to hypoglycaemia (GREEN et al. 1967). Serum somatomedin levels are low and this is attributed to reduced synthesis by the liver (BECKER 1983). In short-term protein energy malnutri• tion thyroid hormonal transport is defective. In long-standing malnutrition extrathyroidal free iodine is increased while the thyroid undergoes involu• tional fibrosis and loses its organified iodine. Hypothyroidism with minimal brain damage occurs in some cases (INGENBLEEK 1986). The adrenal glands become very atrophic and may weigh less than 50% of expected weight for age. The cortex is very thin and depending upon con• current infection may also be depleted of lipid. The morphological changes are associated with increased levels of plasma cortisol with reduced urinary 17-hydroxysteroids and aldosterone. These alterations are attributed to reduced clearance because of a prolonged half-life of plasma cortisol (BECKER 1983) and a higher proportion of free active cortisol. The moon facies of kwashiorkor has been attributed to increased cortisol activity. Cate• cholamine activity is mainly unaltered in malnutrition but antidiuretic hormone levels in plasma and urine are increased. The increase is greater in kwashiorkor than in marasmus and it is deduced that this may contribute to oedema (SRIKANTIA and MOHANRAM 1970). Alterations to the endocrine pancreas are discussed above in the section dealing with the pancreas. 998 R. 0. C. KASCHULA 7. Gastrointestinal Tract

The gastrointestinal tract undergoes significant atrophy. Atrophy of the salivary glands resembles that seen in the pancreas. Clinical enlargement of the parotid glands is seen in some older children with kwashiorkor and the reason for this is still unclear. The squamous epithelium of the mouth and oesophagus is thinned and is more frequently the site of infection, particu• larly candida. The mucosa of the stomach becomes atrophic and chronic atrophic gastritis is common. A mixed inflammatory cell infiltration of neutrophils, lymphocytes and plasma cells occurs into the superficial lamina propria. With increasing severity the process extends deeper towards the muscularis mucosa. The surface epithelium becomes attenuated and increased numbers of mixed bacterial organisms adhere to the surface with decreased production of gastrin and gastric acid (GRACEY et al. 1977). In another study gastric acid secretion, in response to histamine stimulation, was found to be satisfactory or increased in 80% ofboys with kwashiorkor. In the remaining 20% rever• sible achlorhydria appeared to occur in those patients who had concurrent irondeficiency anaemia (WITTMANN et al. 1967). The duodenum and jejunum have been extensively studied in protein energy malnutrition without any particular distinguishable features between kwashiorkor and marasmus being identified (BARBEZAT et al. 1967). Some studies suggest that the jejunum in marasmus is less severely affected (BRUNSER et al. 1976). The dissecting microscope and histological features are in fact very similar to those found in a variety of diseases such as coeliac disease, hookworm infestation and tropical sprue (STANSFIELD et al. 1965). The stereoscopic appearances of mucosal biopsies examined through a dissecting microscope show a range of appearances from fused leaf-like villi forming low ridges to irregular convolutions and total atrophy with a flattened mucosa (STANSFIELD et al. 1965; BARBEZAT et al. 1967). Histological examination shows considerable shortening of villous height with unaltered or elongated crypts. There is loss of villous numbers so that crypts outnumber the villi (Fig. 18.4 A, B). Branching and increased tortuos• ity of crypts may also be seen. The numbers of mitoses seen in the crypts of Lieberkuhn are reduced in kwashiorkor and even more so in marasmus (HANSEN and PETTIFOR 1991). The surface epithelial cells become cuboidal or flattened with the nuclei being placed close to the luminal surface. The brush borders of the enterocytes become thin and irregular with a few inter• spersed lymphocytes. Goblet cells occur in normal numbers and have a normal appearance. Within the lamina propria variable to increased numbers of lymphocytes and plasma cells have been reported (STANSFIELD et al. 1965; BARBEZAT et al. 1967). The number of mononuclear cells is, however, reduced when one compares their numbers with those in healthy children who have severe infection (KAscHULA et al. 1979). The proportion of IgA• producing cells and cells that stain for secretory component is significantly reduced compared to adult values. Histochemical stains for acid phosphatase Malnutrition and Intestinal Malabsorption 999

Fig. 18.4. A Normal duodenal mucosa showing tall slender villi with almost equal num• bers of short crypts. Surface enterocytes are columnar and have brush borders. H&E, x63. B Duodenal biopsy in kwashiorkor showing flattened atrophic mucosa with dis• tended Brunner's glands in submucosa. Lamina propria is mainly composed of crypts in a cellular stroma with flattened or cuboidal surface enterocytes. H&E, x63

show a significant reduction in staining in surface enterocytes and the cells of the lamina propria. Staining for leucine amino peptidase and alkaline phosphatase in brush borders of surface enterocytes and in the depths of gland crypts are variable (KAscHULA et al. 1979). Electron microscopic examination of surface enterocytes and blood vessel endothelium shows decreased endoplasmic reticulum with dilated vesicles and numerous cyto• plasmic vacuoles. In severe kwashiorkor the microvilli of enterocytes are shortened, mitochondria are disrupted and there is an accumulation of poly• ribosomes (SHINER et al. 1973). These microscopic and ultrastructural altera• tions show only minimal evidence of morphological improvement after treat• ment for weeks and months even though clinical recovery takes place. In severe protein energy malnutrition intestinal mucosal atrophy is asso• ciated with impaired absorption of nitrogen, fat and carbohydrates (BOWIE et al. 1967). Prolonged fermentation of unabsorbed carbohydrate seems to contribute to diarrhoea. Malabsorption of lactose is particularly prevalent ( 65% of cases) and may persist for more than I year. Although both lactase and sucrose activities are diminished, sucrose and maltose absorption does not seem to be impaired. The total absorption of d-xylose is probably within normal limits but the absorptive process is delayed. As a result of these enzyme deficiencies, careful regulation of dietary content is required when starting treatment. The colon develops surface epithelial atrophy with congested blood vessels in kwashiorkor. There is infiltration by plasma cells with trans• epithelial migration of leukocytes. These changes are restored to normal on recovery after 3-4 weeks oftreatment (REDMOND et al. 1971). 1000 R. 0. C. KASCHULA 8. Haemopoietic System Alterations to the haemopoietic system are variable but most children with protein energy malnutrition have moderate anaemia (Hb 8-10 g/dl). The anaemia, attributed to deficiency of protein, iron and folate, is usually normocytic and normochromic (ADAMS 1970). Serum erythropoietin production is reduced with low serum levels though red cell synthesis continues. A good reticulocyte response is elicited with enhanced production of haemoglobin following nutritional rehabilitation (VITERI and ALVARADO 1970). Folate deficiency occurs in some areas and becomes evident early in recovery if not noted on admission. Giant metamyelocytes and hyper• segmented neutrophils are more conspicuous than are megaloblastic changes. Serum ferritin levels are increased in severe kwashiorkor with reduced serum transferrin but after 2-4 weeks of dietary rehabilitation iron deficiency anaemia may develop (HANSEN and PETTIFOR 1991 ). Red blood cell survival is shortened in protein energy malnutrition and excessive haemolysis is attributed to abnormalities of red cell membranes (LANZKOWSKY et al. 1967). Anaemia with erythroid hypoplasia and increased iron stores in bone marrow is attributed to supervening infections such as malaria and hookworm. White blood cell responses to infection are impaired in malnutrition. Severe lymphopenia (less than 2500/mm3) occurs in about 25% of fatal cases of protein energy malnutrition (SMYTHE et al. 1971). Reduced numbers of lymphocytes, eosinophils and neutrophils may also occur. In addition leucoerythroblastic reaction with or without defective phagocytosis of bacteria is found (SBARRA et al. 1974). Impaired lymphocyte transformation in response to phytohaemagglutinin is reported (SELLMEYER et al. 1972). Defective cellular immunity in kwashiorkor has been shown to have a signi• ficant humeral component. In vitro transformation of lymphocytes from malnourished children is facilitated when cultured in normal serum (BEATTY and DowDLE 1978). A bleeding tendency occurs in some cases of severe protein energy malnutrition with concurrent infection. This is manifest as purpura but without severe thrombocytopenia. Coagulation factors II, VII and X are commonly reduced but are generally not associated with a bleeding tendency (DORANTES et al. 1964).

9. Lymphoreticular System Morphological changes to the lymphoreticular system are relatively inconspicuous but have a profound functional effect. The thymus always undergoes considerable involution and may be difficult to find at autopsy (WATTS 1969). In malnourished children it is represented by loose fibro• vascular tissue but in kwashiorkor it also becomes oedematous and may have fatty infiltration. The wet weight of the gland is not an accurate index of the extent of involution or atrophy. Microscopic examination of the thymus shows loss of distinction between cortex and medulla with considerable depletion of lymphocytes (MUGERWA 1971) (Fig. 18.5 A). Lymphocytes are generally more numerous in the medullary regions than in the cortex. Cells Malnutrition and Intestinal Malabsorption 1001

Fig. 18.5. A Atrophic and involuted thymus in kwashiorkor. The lobules are shrunken and depleted of cortical lymphocytes. Vessels appear relatively large and tortuous. H&E, x25. B Mesenteric lymph node in kwashiorkor showing depletion of paracortical lymphocytes. Cortical follicles are small and inconspicuous. H&E, x 16

staining for epithelial cell markers are abundant but Hassall 's corpuscles are smaller and less frequent than in controls. Occasionally large cystic, relative• ly acellular Hassan's corpuscles are found. In some cases, associated with measles . infection, the medullary areas may accumulate increased fibro• blastic cells with collagen and pale staining eosinophilic extracellular matrix. The blood vessels of the thymus show increased tortuosity and there is often increased indentation of thymic lobules suggesting that the gland was pre• viously more cellular and larger. The mesenteric lymph nodes of children with protein energy malnutrition are particularly small and inconspicuous when compared to well-nourished children (MuGERWA 1971). In kwashiorkor the nodes are more significantly affected than in marasmus (SMYTHE et al. 1971 ). The paracortical areas of the lymph nodes are depleted of lymphocytes. With increasing severity of malnutrition the germinal centres become smaller and fewer in number (Fig. 18.5 B). Their cuff of small lymphocytes is attenuated. Pyroninophilic cells are very frequent in the sinusoids and occur diffusely in follicles, but become less conspicuous after prolonged and severe malnutrition. In kwashiorkor the peripheral and medullary sinusoids may become consider• ably dilated. 1002 R. 0. C. KASCHULA In the spleen lymphoid aggregates are fewer and smaller than in controls. Reactive germinal centres are seen in occasional cases and this is mainly in marasmic children. The lymphoid aggregates of the ileum (Peyer's patches) and appendix are very much reduced in size and number (SMYTHE et al. 1971 ). The cuff of small lymphocytes that surrounds germinal centres becomes attenuated. Plasma cells seem to occur in increased numbers in the lamina propria of the small intestine. The tonsils of children with protein energy malnutrition are significantly smaller than those of adequately nourished children (SMYTHE et al. 1971 ). The diffuse atrophy ofthe lymphoreticular system together with increased numbers of plasma cells and other pyroninophilic cells is associated with depressed cellular immunity and defective antibody responses to new infec• tions. (SCRIMSHAW et al. 1968). This leads to a significantly increased propensity to severe and prolonged infection particularly by Gram-negative bacteria, fungi and viruses.

VIII. Interaction of Protein Energy Malnutrition with Infection

Malnourished children, particularly those with kwashiorkor, are immun• ologically compromised. They suffer from opportunistic infections and have a severe course in common infectious diseases. It is of interest that mal• nourished children have elevated levels of immunoglobulins. Elevated IgA levels fall after nutritional rehabilitation. Hypergammaglobulinaemia seems to be related to the frequency and continuation of intercurrent infections rather than the degree of protein energy deprivation. The production of antibodies to new antigens varies according to the state of nutrition and diet provided after administering an antigen such as typhoid or paratyphoid A and B vaccines (CHANDRA 1972). A poor response to yellow fever vaccine continues even though proper nutrition is provided after administering the vaccine. Delayed hypersensitivity reactions (such as to tuberculin after BCG vaccination) are lost in a large proportion of malnourished children (CHANDRA 1981). In addition conversion rates following BCG immunization in malnourished children are low while they remain malnourished. However, after 18 months of nutritional rehabilitation adequate responses have been found. This indicates that sensitisation takes place but that recall is dependent upon nutritional status. A long-term prospective study in Central American villages shows that maternal malnutrition and infection during pregnancy leads to a high rate (32%) of term small-for-gestational-age infants, and prematurity (MATA 1975). These infants have abnormal cell-mediated immune responses and are at greater risk of malnutrition and infection. Almost all complement factors, lysozyme production, interferon production, T-lymphocytic functions, intra• cellular bactericidal activity and chemotaxis by leukocytes are depressed (CHANDRA 1979). In addition transient depression of secretory IgA occurs Malnutrition and Intestinal Malabsorption 1003 (SIRISINHA et al. 1975). Chronic and repeated infections predispose to malnutrition by altering many metabolic processes including the causing of anorexia and diarrhoea which in turn leads to reduced food intake, intestinal malabsorption, and impaired synthesis of haemoglobin and other proteins. Infection is prevalent in the lungs, gastrointestinal and urinary tracts and bloodstream. High morbidity and mortality rates are attributed to septicae• mia and bacteraemia (SMYTHE and CAMPBELL 1959) and to supervening pneumonia and diarrhoea. Measles occurs at an earlier age and is particular• ly lethal in severely malnourished children. The increased intensity of measles infection is now attributed to associated vitamin A or retinol deficiency rather than protein energy malnutrition (BECKFORD et al. 1985; CABELLERO and RicE 1992). Incipient zinc deficiency and pre-existing lym• phopenia, associated with malnutrition, may also have a role in enhancing the severity of infection. Disseminated herpes simplex infection, Monilia and Pneumocystis carinii pneumonia are particularly severe infections. In immunosuppressed malnourished children herpes simplex infection is a formidable disease as it tends to disseminate to distant organs. Primary lesions on the lips, tongue (Fig. 18.6 A), pharynx, larynx, oesophagus or genitalia have several vesicles that break down to form large confluent ulcers. Typical intranuclear inclusions are found in adjoining squamous epithelial cells or in giant cells. Disseminated necrotising lesions frequently occur in the liver and adrenal glands and less often in the lungs and brain (McKENZIE et al. 1959). In the fatty liver of kwashiorkor there is a striking picture of numerous focal areas of necrosis. The foci have a grey-white centre surround• ed by a hyperaemic border giving a target-like appearance (Fig. 18.6B). Microscopically the lesions resemble ischaemic infarcts having a haphazard

Fig. 18.6. A Extensive herpetic ulceration of the tongue in kwashiorkor. B Fatty liver in kwashiorkor with disseminated herpes simplex causing innumerable foci of necrosis with surrounding haemorrhage and congestion 1004 R. 0. C. KASCHULA distribution with an abrupt change to surviving liver parenchyma. Adjoining parenchyma is hyperaemic and haemorrhagic but lacks inflammatory cells. The liver cells contain variable numbers of typical intranuclear viral inclusions. Similar macroscopic and microscopic lesions are also found in adrenal glands and less often in the lungs and brain. Occasionally the lungs may be infected through the air passages where a necrotising bronchiolitis and bronchitis cause destruction of epithelium, muscle and elastica. Cancrum oris or noma is closely associated with malnutrition and/or measles. There is rapid extension of a destructive gangrenous process in• volving all adjoining tissues related to the oral or nasal cavity. The organisms that have been cultured from the lesions are anaerobic spirochetes and fusi• form bacilli. It has been considered that they developed invasive properties because of a state of anergy. However, a number of observers have drawn attention to the fact that many cases started as primary herpes simplex infec• tion which subsequently becomes progressive and destructive (MORLEY 1983). Herpesvirus conjunctivitis and keratitis may also extend to destroy the cornea and cause blindness. Whooping cough is a particularly severe condition in malnourished children. Episodes of exhaustive coughing, persistent vomiting with anorexia and malaise aggravate the poor nutritional state and marasmus often super• venes. Malnourished children often become infected with opportunistic fungi Candida may cause extensive lesions in the mouth and oesophagus with associated Candida pneumonia, gastritis or colitis. Endocarditis due to Candida or other fungi occurs with prolonged or frequent administration of intravenous fluids. The lesions in the mouth and oesophagus have a heaped up appearance to produce a pseudomembrane in which yeasts and mycelia are identified. Aspergillus infection usually begins in the lungs from where haematogenous spread to other organs may occur. Pulmonary lesions often undergo cavitation after first forming red to dark purplish nodules of con• solidation. The septate mycelia may proliferate into blood vessels. Zygomycosis (mucormycosis) of the lungs with intravascular proliferation of the fungus has also been found to occur in malnourished children (KASCHULA 1989). Pneumocystis carinii causes severe interstitial plasma cell pneumonia in institutionalised infants with marasmus (DuTZ et al. 1974). Helminthic infestations that are particularly associated with malnutrition are Ascaris, hookworm and Strongyloides sterocoralis. Large numbers of mature Ascaris may form a worm bolus in the intestine which causes intestin• al obstruction and volvulus. Frequently they pass through the ampulla of Vater to cause obstructive ja\mdice or pancreatitis. In the intestine anti• enzymes produced by the worms cause malabsorption which aggravates mal• nutrition. Hookworm infestation is prevalent in tropical areas where mal• nutrition is rife. They cause eosinophilia and anaemia due to blood loss which accentuates the state of malnutrition. Infestation by Strongyloides is also associated with eosinophilia and blood loss anaemia. In addition there is watery diarrhoea and autoinfection accentuates the state of malnutrition. Malnutrition and Intestinal Malabsorption 1005 Giardiasis, due to Giardia Iamblia, has a tendency to affect malnourished children in areas of poor sanitation. Large numbers of organisms inhabit the duodenum, upper jejunum and biliary system. The trophozoites adhere to surface epithelium and may cause villous atrophy and reduced production of secretory IgA. Other intestinal infections that frequently occur in malnour• ished children include Cryptosporidia, Salmonella, Shigella and Campylo• bacter. Protein energy malnourished children have a lower incidence of paralytic poliomyelitis and of fatal meningococcal infection (NEVELING and KAscHULA 1993). In endemic malarial areas malnourished children have lower blood parasite rates than do well-nourished children and cerebral malaria occurs more frequently in well-nourished than in malnourished children (EDINGTON 1967; AHMED et al. 1985). In all ages the severity of amoebiasis is related to the nutritional status of the host. Amongst mal• nourished individuals there is a great tendency for the amoebae to invade tissues that are normally resistant to the Entamoeba such as perianal and perineal skin. Children who are slightly or only moderately undernourished and who have normal zinc stores seem to have enhanced T-celllymphocytic functions and increased resistance to infection. They also have some protection form malignancy. Modulation of the immune system becomes particularly relevant during the recovery period when hospitalised children are to be returned to an inhospitable environment where severe and lethal infections may supervene. Useful tests to evaluate the early restoration of immune function include: rosetting of T lymphocytes, which is restored after 5 -15 days (JACKSON and ZAMAN 1980); activation of null lymphocytes containing terminal deoxynucleotidyl transferase (CHANDRA 1979); complement component C3, intracellular killing of bacteria by neutrophils, which takes a few weeks to be restored, and in vivo tests for delayed cutaneous hypersensitivity (CHANDRA 1981). It is notable that associated alterations in vitamin, mineral and trace element intake have a significant role in immune activity and propensity to infection.

IX. Long-Term Sequelae of Protein Energy Malnutrition

During famine the affected persons undergo prolonged physical and psychological deterioration. For as long as 3 months after nutritional rehabilitation, hunger for food persists and feelings of tiredness and lassitude may continue for 6-9 months. After therapeutic and nutritional rehabilitation most malnourished children are said to recover completely without significant permanent derangements. Advanced fatty change of the liver is completely corrected within weeks but it takes several years for intestinal mucosal morphology to be restored while lactase deficiency may persist for longer periods (CooK 1006 R. 0. C. KASCHULA and LEE 1966). Muscle bulk is generally restored but fibre numbers may be permanently reduced (MONTGOMERY 1962). Nutritional rehabilitation after an episode of severe protein energy malnutrition is said to correct previously delayed bone growth. It is, however, suggested that continuous malnutrition or repeated seasonal episodes of malnutrition will lead to short stature (TRUSWELL and HANSEN 1968; MATA 1975). In these situations sexual maturity may also be delayed. Amongst Australian Aboriginal schoolchildren, who have high rates of endemic streptococcal infection and bowel parasitic infestation, it has been shown that those who were significantly growth retarded during infancy had elevated erythrocyte sedimentation rates and hyperimmunoglobulinaemia. These children also have depressed antibody responses to influenza vaccine with defective cell-mediated immune responses to a variety of antigens. There are, however, enhanced cellular responses to influenza A2 and to streptococcal group A polysaccharide as occurs in acute rheumatic fever (JOSE et al. 1970). It is suggested that nutritional insult during fetal and early postnatal life produces irreversible morphological changes in the thymus and thymic-dependent areas of lymph nodes and spleen with impaired immune responses (CHANDRA 1974, 1975). The possibility that malnutrition during the early critical stages of immune development may have prolonged or permanent adverse effects on defence mechanisms has implications for subsequent propensity to infection, neoplasia, aging, the production of low-birth-weight infants and malabsorption (CHANDRA 1981). In regard to brain growth and intellectual and psychomotor development, studies have shown that there is a high incidence of retardation in lower socioeconomic groups. The degree is said to be directly related to the amount of animal protein consumed and the retardation of cranial and physical growth (MoNCKEBERG et al. 1972). In a prolonged study over 11 years of severely malnourished children aged 10 months to 3 years, significant behavioural, electroencephalographic and scholastic performance alterations were found (STOCH and SMYTHE 1967). It was deduced that marasmic children, where nutri-tional deprivation is more severe and occurs at an earlier stage of brain development, have a greater degree of retardation. The study group of children were all from a highly unfavourable environment at the onset of the study. Hence it is considered that alcoholism, illegitimacy, broken homes and educational and linguistic background could explain the differences and overall low performance. In a study comparing kwashiorkor children with their non-kwashiorkor non-marasmic sibling, no significant differences in children older than 10 months has been demonstrated (HANSEN et al. 1971). It therefore seems that nutritional growth retardation is likely to have its greatest permanent effect on cerebral function when it occurs during the third trimester of pregnancy (NAEYE et al. 1973) or before the age of 6 months and is likely to be more severe in premature and low-birth-weight infants who subsequently develop marasmus. Malnutrition and Intestinal Malabsorption 1007 B. Vitamin and Mineral Malnutrition

I. Vitamins While vitamin-rich fruit and vegetables may easily be produced in trop• ical areas, for many recently urbanised and semi-urbanised slum dwellers the regular diet often is almost entirely composed of refined maize, cassava or rice. Dietary deficiency is also prevalent in rural communities living in semiarid areas and in times of drought or crop failure. Consequently pellagra, scurvy, beriberi, rickets and various forms of vitamin A deficiency are partic• ularly prevalent in tropical areas. It has been shown that vitamin supplements given to children on a borderline diet cause enhanced nonverbal intellectual performance (BENTON and RoBERTS 1988). This has important implica• tions for developing countries where deficient and borderline diets are common.

1. Vitamin A Vitamin A and the provitamin carotenoids come from vegetables but stores in the livers of animals are also readily available to man. Retinol is the active agent released into the bloodstream from the liver combined to retinol• binding protein and carried by transthyretin. Retinol is required for normal function by the photoreceptor system of the eyes, for normal cellular differ• entiation, for retaining the normal differentiated integrity of epithelia and of spermatogonia and for maintaining normal cell membrane structure and function. Deficiency manifests as night blindness, conjunctival or corneal xerosis, Bitot's spot, perifollicular hyperkeratosis of the skin on the thighs and upper arms, corneal ulceration or keratomalacia. Severe deficiency is prevalent in south and east Asia where rice is the staple diet and in most of Africa (McLAREN 1991). Affected epithelial tissues that undergo keratiniz• ing squamous metaplasia include respiratory epithelium, the ducts of exocrine glands, the genitourinary system, mouth and oesophagus. As a con• sequence the epithelial tissues lose their effectiveness as barriers to infection and there is increased binding ofbacteria to epithelial cells (CHANDRA 1988). The morbidity and mortality of measles seems to be directly related to vitamin A reserves (HusSEY and KLEIN 1990; CABALLERO and RicE 1992). In developing countries death rates between 30% and 40% have been reported (CANTRELLE et al. 1960) whereas in industrialised western countries death from measles is a rare event (0.1% in the United States). The differences are not genetic but dietary (ANDERSON 1982). Recent studies in South Africa have shown that urban blacks have approximately half the serum vitamin A levels of their white counterparts (VERMAAK et al. 1994). Attention has been drawn to the propensity for respiratory and alveolar lining cells to undergo squamous metaplasia in fatal measles (BECROFT and OsBORNE 1980; KASCHULA et al. 1983). This phenomenon is now attributed to lack of vitamin A. 1008 R. 0. C. KASCHULA Hypervitaminosis A sometimes occurs from the administration of exces• sive amounts by food faddists. Now that very large doses are being given to children with measles and other infections, it is expected that toxicity will become more prevalent. Acute toxicity is not fatal but causes symptoms of raised intracranial pressure with severe headache and vomiting. Chronic intoxication causes hair loss, desquamative dermatitis, cheilosis, gingivitis, otitis, epistaxis, lymphadenopathy, anaemia, ascites, hepatosplenomegaly, arthralgia, headache, papilloedema, nausea, vomiting, diarrhoea, drowsiness, blurring of vision and dizziness (BHETTAY and BAKST 1988). In addition there is osteoporosis with widened metaphyses, thickening of long bones and premature fusion of epiphyses (PERSSON et al. 1965) as well as distinctive fibrosis around hepatic veins.

2. Vitamin E The tocopherols and tocotrienols that have vitamin E act1v1ty are important antioxidants and act as scavengers of free radicals. Deficiency of the vitamin occurs in the presence of malabsorption syndromes. Deficiency results in haemolytic anaemia and retinopathy of prematurity as well as an increased incidence of periventricular and intraventricular haemorrhage in very preterm babies (SINHA et al. 1987).

3. Vitamin K Vitamin K, the coagulation vitamin, is widespread in vegetables and meat. Deficiency occurs in newly born infants who get hemorrhagic disease of the newborn. In areas where people subsist on a diet predominantly of fruit and cereals and where parenteral vitamin K is not given to babies at birth, haemorrhagic disease of the newborn occurs. The haemorrhages occur at multiple sites as a slow ooze giving an insidious clinical onset. Subcapsular haemorrhages into the liver and spleen are often followed by haemo• peritoneum (CvwEs 1967). Haemorrhages also occur in the adrenals, cranial cavity, kidneys, lungs, gastrointestinal tract, skin and subcutaneous tissues. The water-soluble vitamins B and C occur in leafy vegetables, milk, liver and fruit. Deficiency usually arises amongst premature infants and after weaning when poverty and limited choice of food provide insufficient vita• mins to meet the needs of rapidly growing infants. Riboflavin, pyridoxene, ascorbic acid and folate are particularly susceptible to heat, light and oxida• tion. Hence overcooking may also contribute to deficiency.

4. Thiamine (Vitamin B1)

Thiamine (vitamin B 1) deficiency is prevalent in the rice-eating areas of Asia and the Far East. The disease beriberi occurs when one largely subsists on highly milled (polished) rice. Dietary dependency on undermilled brown rice or parboiled rice is not associated with beriberi (BURGESS 1958). Thia- Malnutrition and Intestinal Malabsorption 1009 mine is required for carbohydrate metabolism and when there is deficiency pyruvate accumulates. Cardiac and nervous functions are disturbed in beriberi. Adults get either wet or dry beriberi according to the presence of absence of oedema. Early symptoms include malaise and muscle weakness and these are followed by symptoms of polyneuritis or cardiac failure. Infan• tile beriberi mainly occurs between 1 and 4 months of age amongst the in• fants of mothers with beriberi or having subnormal thiamine reserves. The infants are anaemic, oedematous and irritable. They have abdominal disten• tion, colic, vomiting and periodic screaming. They develop tachycardia, tachypnoea and dyspnoea with aphonia. Congestive cardiac failure occurs with features of raised intracranial pres• sure with meningism, rigidity, twitching, drowsiness, coma and death (BRAY 1928; THURNHAM 1991). At postmortem there is emaciation with muscle atrophy as occurs in kwashiorkor. However, the right ventricle of the heart is dilated with or without hypertrophy. In wet beriberi there is oedema with hydropic degeneration of muscle fibres. Myocardial fibres focally lose their cross striations and there is fatty degeneration and a lymphocytic infiltration. Pulmonary oedema and effusions occur with congestion of liver and spleen. In dry beriberi oedema is less conspicuous but there is degeneration of nerves with demyelination and fragmentation of axis cylinders. Dry beriberi is accentuated by alcoholism when Wernicke's encephalopathy and/or Korsakoff's psychosis occurs.

5. Riboflavin (Vitamin B 2)

Riboflavin (vitamin B 2) facilitates cellular respiration, being incorporated into flavoprotein enzymes like cytochrome oxidase. Deficiency of riboflavin depresses growth in the young. The richest source of the vitamin is dairy pro• ducts and deficiency is most prevalent in equatorial areas where riboflavin sources are scarce and expensive (BATES 1987). Dietary deficiency especial• ly causes lesions at mucocutaneous junctions. Angular stomatitis and cheilo• sis affect the lips and mouth while the tongue shows glossitis and atrophy of lingual papillae with magenta discoloration. Vascularisation of the cornea followed by conjunctivitis, keratitis and corneal ulceration occurs in the eyes. The skin at the nasolabial folds and genitalia often develops seborrhoeic dermatitis. Deficiency is most often seen in children and adolescent youths (THURNHAM 1991).

6. Niacin (Nicotinic Acid, Vitamin B 5)

Niacin (nicotinic acid, vitamin B 5) is derived from the oxidation of nico• tine and is an essential constituent of nicotinamide adenine dinucleotide (NAD) and its phosphate derivative (NAD), which are involved as proton and electron carriers in many oxidative and reductive reactions. Pyridoxine has a role in synthesising niacin from dietary tryptophan. Pellagra is a multiple vitamin deficiency mainly due to a diet of white maize or sorghum (tryptophan 1010 R. 0 . C. KASCHULA

Fig.18.7. Colon in pellagra showing superficial oedema of mucosa, lymphocytic infiltration, cystic dilation of a mucosal crypt and epithelial atrophy. H & E, x 50 deficiency). Other contributory factors are alcoholism, excessive exposure to sunlight, severe organic disease or infection, achlorhydria with folic acid deficiency and the presence of nicotinic acid antagonists in the diet (e. g. drugs such as isoniazid). Pellagra causes weakness, anorexia, indigestion with dermatitis, diarrhoea and dementia. The dermatitis is most prominent on the exposed parts of the skin, which become roughened, keratotic, scaly and hyperpigmented. Microscopically the epidermis may show intra- and subepithelial vesiculation. The dermal papillae become congested and oedematous with a mild lymphocytic infiltration. The tongue is swollen and red and there may be ulcers with membranes in the mouth. The colon develops a thickened wall due to oedema and lymphocytic infiltration. A membranous enteritis with or without ulceration develops with epithelial atrophy and cystic dilatation of mucosal crypts (Fig. 18. 7). The liver becomes fatty and may have some focal necrosis. The body becomes emaciated with atrophy of most viscera. There is demyelination of the posterior columns of the spinal cord, and degenerative changes in the autonomic ganglia and the intrinsic nervous system of the intestine have been reported (WINCKEL 1951 ). Neuronal cells become intensely stained and have pyknotic nuclei. There is proliferation of the supporting cells in the ganglia and some of these have enlarged pleomorphic nuclei.

7. Pyridoxine (Vitamin B 6)

Pyridoxine (vitamin B 6) consists of six interchangeable pyridoxal com• pounds being in the form of alcohol, aldehyde, amine or phosphate esters. Pyridoxal 5 phosphate is the ester that is mainly released into the blood and which has an important role in amino acid and protein metabolism including Malnutrition and Intestinal Malabsorption 1011 the conversion to tryptophan it niacin. Vitamin B6 is involved in the synthe• sis and catabolism of many neurotransmitters, with glycogen phosphorylase activity in muscle and with the metabolism of polyunsaturated fatty acids and phospholipids (THURNHAM 1991). Deficiency of vitamin B6 is now rare but occurs when antivitamins such as hydrazine, isoniazid, penacillamine and drugs used to treat parkinsonism are administered. Some cases of sickle cell disease and beta-thalassaemia become deficient and require supplementa• tion. In deficiency states there is microcytic anaemia, retarded growth, alopecia, acrodynia, seborrhoea, dermatitis, glossitis, siderosis of bone marrow and liver and central nervous system disorders such as convulsions, irritability and abnormal encephalographic waves.

8. Pantothenic Acid Pantothenic acid is a component of coenzyme A that promotes growth. Subnormal levels are found in beriberi, pellagra and ariboflavinosis. Pure deficiency of pantothenic acid causes malaise, headache, insomnia and nausea. Vitamin B 12 and folic acid both produce macrocytic megaloblastic anaemia and large doses of the one causes a response when the other is deficient. However, the folate response in pernicious anaemia is only temporary and does not improve the neurological deficit.

9. Cobalamin Compounds (Vitamin Bu)

Cobalamin compounds (vitamin B12) act as intracellular coenzymes and deficiency tends to occur in vegetarians or when the diet is predominantly milk. The daily requirement is small but absorption and transport is a complex process that requires intrinsic factor form an acid-secreting stomach, transcobalamin 1 and 2 as binding proteins in the circulation as well as R proteins, synthesised by granulocytes, which bind cobalamin form necro-tic tissues. Pernicious anaemia is relatively infrequent amongst black people in the tropics. A few cases occur in infants and children with inborn errors of absorption, of transport within enterocytes and of transcobalarnin 2 produc• tion. It is mostly a disease of the elderly and advanced disease may go un• recognised for long periods. There is megaloblastic anaemia with disturbed granulocytic function, sore mouth and tongue, failure to thrive, or loss of weight, functional anomalies of the gastrointestinal tract, paraesthesias, sensory disturbances, ataxia and muscle weakness and spasticity. Dementia and psychosis may also occur.

10. Folic Acid Folic acid is a powerful stimulant for growth and multiplication of cells, being involved in synthesis of pyrinidine and purine for the formation of 1012 R. 0. C. KASCHULA nucleic acid. It occurs in green vegetables but is easily lost in cooking. Goat's milk and some milk powders are deficient in folic acid. Deficiency occurs in premature infants being given powdered milk and in some malabsorption syndromes including chronic diarrhoeal disease when absorption is inade• quate. Certain cytotoxic agents (methotrexate), antiprotozoal agents (pyri• methamine, Daraprim) and antibiotics disturb folate metabolism. Amongst black South African women, who do not take vitamin supplements during pregnancy and lactation, up to 90% have evidence of folate deficiency (METZ 1986). Folic acid deficiency during early pregnancy is implicated in the occurrence of neural tube defects (SMITHELLS 1983). In deficiency states there is megaloblastic anaemia followed by enlarge• ment of epithelial cells that line the mouth, respiratory tract and genitourin• ary tract. Thrombocytopenia and a bleeding tendency may cause purpura and bruising. Intercurrent infection accentuates the anaemia. In children growth retardation and severe mucosal lesions occur (THURNHAM 1991).

11. Ascorbic Acid (Vitamin C) Ascorbic acid (vitamin C) affects various oxidative enzyme systems but particularly the hydroxylases. Propyl and lysyl residues are hydroxylated in collagen synthesis. The heat-labile vitamin occurs in abundance in fruit (especially citrus) and vegetables. Deficiency causes scurry, where there is reduced production of collagen, elastin is underhydroxylated and comple• ment C 1q is less reduced making its binding to antigen-antibody complexes less effective. Connective tissue ground substances are weakened and bind tissues less effectively so that wound healing becomes defective. Carnitine levels within cardiac and striated muscle, liver and kidney are reduced. In scurvy the lesions that occur in the body are mainly due to deficiencies in intercellular fibres and cement substance. Scurvy occurs amongst inappro• priately fed infants and in older persons in association with nutritional siderosis or during war, siege, internment and sometimes in prisons or other institutions. Infants become listless, irritable and fail to thrive. The extremi• ties become very tender and painful to touch. The limbs become swollen by subperiosteal haemorrhages while petecchiae and purpura appear on the skin. Erupting teeth become distorted and gums are inflamed and swollen. Haemorrhages also occur into joints, pleura, pericardium, brain and bladder. Distinctive radiographic changes to the diaphysis and epiphyseal cartilages of long bones are seen. At the growth plate of growing bones the cartilage between correctly aligned chondrocytes becomes intensely calcified. Osteo• blasts that resemble young fibroblasts migrate into the zone of provisional calcification but do not deposit normal ground substance. As a consequence oedematous loose connective tissue forms to give a wide zone of rarefaction instead of osteoid. The epiphyses may be disconnected from the metaphyseal shafts by fractures and haemorrhage. Malnutrition and Intestinal Malabsorption 1013 12. Vitamin D, Calcium and Phosphorus Vitamin D, calcium and phosphorus are essential for the mineralisation of bone. The cholecalciferol (vitamin D) content of a normal diet is insufficient for the body's needs and most of the requirements are synthesised from pre• cursors in the skin under the influence of exposure to sunlight (DE LUCA and SCHNOES 1983). Its characteristics and those of its metabolites are more akin to a hormone than a vitamin. Deficient stores of vitamin D cause osteo• malacia in adults and rickets in growing children. The main causes of nutritional rickets are:

Lack of exposure to sunlight which should not be a problem in the tropics but occurs in some cultures Lack of dietary calcium as occurs amongst the very poor or when dairy products are not eaten Inhibition of calcium absorption by phytate in predominantly cereal diets

Vitamin D stimulates intestinal absorption and bony deposition of calcium and phosphate as well as the remodelling of bones. It facilitates renal conservation of minerals, and is involved in sterol metabolism in the skin, in T-lymphocyte lymphokine activity and in the secretion of hormones such as parathyroid hormone, prolactin and insulin.

Fig. 18.8. A Narrow chest in rickets with lateral depression of central ribs (Harrison's sulcus). B Frontal bossing of skull due to nutritional rickets 1014 R. 0. C. KASCHULA The features of rickets are best seen at rib ends and the wrists where the growth plate of the bones becomes widened and cupped. In rural areas of tropical countries the radiological features of metaphyseal cupping and spreading are often not seen. These infants and children often have associat• ed protein energy malnutrition (JAIN et al. 1985). Microscopically there is architectural disarray of bony trabeculae with deficient provisional cal• cification at the epiphysis. Normally narrow and straight physeal columns of chondrocytes become clumped and cartilagenous cores surrounded by mineralised osteroid appear deep in the metaphyses. Secondary hyperpara• thyroidism and osteitis fibrosa may occur. Children rarely die from rickets but they do have increased propensity to infection and to malignancy. Permanent body deformities include: Harrison's sulcus (Fig. 18.8A) where the central ribs are compressed to form a sulcus on the chest wall, com• pressed pelvis, bow legs and bossing of the skull (Fig. 18.8 B). Craniotabes, where the temporal and occipital bones of the skull are excessively soft, and rickety rosary (swollen costochondral junctions) are not usually permanent deformities. Van Jaksch's anaemia is a rare complication where there is retarded differentiation of haemopoietic cells, hepatosplenomegaly, lymph• adeneopathy and a marked leucocytosis. In ostemalacia deformities are uncommon but when they occur the spine, pelvis and legs are affected. Affected persons get muscle weakness with pain in the ribs, sacrum, lumbar vertebrae, pelvis and legs. They develop a wadd• ling gait and tetany with carpopedal spasm, and facial twitching may occur. There may be spontaneous fractures independently of bone rarefaction with radiolucent bands (Looser's zones) (PASSMORE and EASTWOOD 1986). Osteo• malacia more commonly affects women during pregnancy and after the menopause.

II. Minerals and Trace Elements Minerals and trace elements that are of importance in tropical areas are iron, zinc and copper. Selenium and chromium deficiencies are not speci• fically related to a tropical environment.

1. Iron Deficiency Anaemia Iron deficiency anaemia is prevalent amongst the infants in the lower socioeconomic groups of most societies. In the United States as many as 30% of such infants are anaemic and another 25% are iron deficient without anaemia (HADDY et al. 1974). Amongst the peri-urban areas of cities in developing countries, the figures are considerably larger. Infants have low iron stores at birth, and breast milk levels are marginally low. After weaning it is important that they be given food containing much bioavailable iron (OsKI 1985). Children with iron deficiency have reduced mental develop• ment indices and a higher rate of abnormal behaviour (LozoFF and WOLF 1983) with lowered intelligence potential. In iron deficiency the plasma Malnutrition and Intestinal Malabsorption 1015 ferritin levels fall. This is followed by a reduction in serum iron and increased iron-binding capacity, which in turn is followed by morphological changes to erythrocytes and reduced haemoglobin concentrations. There is microcytosis and hypochromia leading to poikilocytosis with some target cells and others having basophilic stippling. The number of platelets may increase while leucocytes often show hypersegmentation. Erythroid hyperplasia of bone marrow is present in the early stages of iron depletion but hypoplasia ensues with increased severity. Erythroblasts are smaller than normal and contain less haemoglobin.

2. Zinc Deficiency Zinc deficiency has been shown to occur in protein energy malnutrition, malabsorption syndromes, sickle cell disease, long-term diuretic usage, penicillamine therapy for Wilson's disease and chronic debilitating disorders including chronic renal failure. Deficiency occurs when diets lack animal protein and are mainly composed of bread and beans. Phytate in heat flour rends zinc unabsorbable. In steatorrhoea zinc and fat form unabsorbable emulsions. Zinc is required for DNA and protein synthesis, cell division, several enzymatic functions, steroid synthesis, chemotaxis and for the for• mation of thymopoietin that modulates T-lymphocyte maturation. It is required for the function of T-helper cells, T-suppressor cells and natural killer cells. The state of anergy that occurs with protein energy malnutrition is associated with low serum zinc levels. Delayed hypersensitivity reactive• ness can be resolved by the local application of zinc (GOLDEN et al. 1978). In protein energy malnutrition the low serum zinc levels remain relatively unchanged for some time after clinical recovery (SUBOTZKY et al. 1992). Zinc supplementation given during nutritional rehabilitation enhances the rate of weight gain (GOLDEN and GOLDEN 1981 ). Lymphopenia occurs in sickle cell disease when zinc deficiency arises. Hypozincaemia during pregnancy has been shown to be associated with an increased incidence of amniotic fluid infection syndrome as well as increased fetal and maternal morbidity and mortality (ScHLIEVERT et al. 1976; WooDs et al. 1988). In acute zinc deficiency a bullous pustular dermatitis and alopecia may develop with diarrhea, weight loss, repeated infections, emotional disorders and hypo• gonadism in males. When zinc deficiency is moderate, there is growth retardation, delayed puberty, rough skin, poor appetite, delayed wound healing, reduced taste acuity, mental lethargy and poor adaptation to dark• ness.

3. Selenium, Copper and Manganese Although pure deficiencies of selenium, copper and manganese are not a particular problem in tropical areas, it has recently been shown that children in the acute stage of kwashiorkor have reduced plasma copper, caerulo• plasmin and selenium together with normal blood and red blood cell 1016 R. 0. C. KASCHULA manganese. The levels of copper and caeruloplasmin return to normal within 30 days but low levels of zinc and selenium are not fully restored (SuBOTZKY et al. 1992). Deficiency of these substances may have a role in increasing the incidence of infection and in enhancing anaemia that occurs with other disorders of nutrition.

C. Nutritional Siderosis

Varying degrees of iron overload occur in the black populations of Africa. It is manifest from late adolescence and reaches its peak after 40 years (BOTHWELL and BRADLOW 1960). Males are more severely involved. In 1950 it was recognised that the condition is due to excessive dietary iron (WALKER and ARvmssoN 1950). The iron comes from iron utensils used to prepare fermented cereal products. The high level of dietary iron overcomes the mucosal barrier that normally prevents excessive absorption. A staple maize diet and heavy consumption of alcohol seem to facilitate iron absorption. In South Africa and other parts of middle Africa, the consumption of beer

Fig. 18.9. A Liver in nutritional siderosis with much deposition of iron in portal tract and small amounts in hepatocytes and Kupffer cells. Perle's Prussian blue stain, x 160. B Spleen showing marked deposition of iron in interfollicular areas. Perle's Prussian blue stain, x25 Malnutrition and Intestinal Malabsorption 1017 brewed in iron pots has very significantly declined during the past 3 decades. Commercially brewed beer and spirits that have a low concentration of iron are now favoured. As a consequence, the incidence and severity of iron over• load is now considerably reduced (IsAACSON 1982a). In nutritional siderosis deposition of haemosiderin begins in the liver parenchyma and spleen. In the liver the deposits are first found in hepato• cytes followed by Kupffer cells and portal tracts (BOTHWELL and BRADLOW 1960) (Fig. 18.9 A, B). In other organs the deposition of iron is initially mainly in the reticuloendothelial system with very little in the parenchymal cells (Fig. 18.9 B). Thus the pancreas, adrenal, pituitary, thyroid, kidney and heart only have small quantities of iron whereas the macrophages of the bone marrow, intestines and synovium have greater quantities. There is deposition in thyroid acinar cells and cardiac myofibres after micronodular cirrhosis or severe portal fibrosis has developed (IsAACSON et al. 1961). There is a signi• ficant correlation between siderosis and micronodular cirrhosis (GILLMAN et al. 1957; IsAACSON et al. 1961). The distribution of the iron in such long• standing cases is distinguished from idiopathic haemochromatosis by a high splenic iron concentration in nutritional siderosis. Very occasionally is the pancreatic concentration higher than that in the liver. Once micronodular cirrhosis develops the percentage of saturation of serum transferrin rises and iron deposition in organs accelerates. The intense accumulation of iron in the liver is considered to have a fibro• genic effect that begins in the portal tracts and progresses into the interior of liver lobules to eventually lead to micronodular cirrhosis (SEFTEL et al. 1960). Other authors dispute this view but it is generally agreed that iron potentiates the effect of some other exotoxin. The source of the latter may also be in alcoholic beverages (ISAACSON 1982b). A proportion of cases of nutritional siderosis with micronodular cirrhosis become diabetic. Episodes ofhypoglycaemia and liver failure are prominent features. The diabetes is more rapidly progressive than that which occurs with genetic haemochromatosis (ISAACSON 1982a). In South Africa it was found that nutritional siderosis with cirrhosis accounted for 7% of diabetes amongst blacks (SEFTEL et al. 1961). It has also been shown that collapse of lumbar vertebrae and femoral head may occur amongst siderotic middle• aged blacks (SEFTEL et al. 1963). It has also been shown that siderosis, osteo• porosis and scurvy are associated in adult Africans. This occurs because excessive ferric iron causes rapid oxidative catabolism of the ascorbic acid that is necessary to form bone matrix. Bone formation is diminished while bone resorption is increased. An association between iron overload and porphyria cutanea tarda has been observed amongst black Africans who drink home-brewed beer and amongst white South Africans who drink wine containing much iron (KEELEY 1963/1964; ISAACSON 1982a). The patients get blistering skin lesions or they may find that it darkens over the face and hands. The liver shows siderosis, focal necrosis, portal fibrosis and cirrhosis (UYS and EALES 1963). It seems that the development of porphyria cutanea tarda may partly 1018 R. 0. C. KASCHULA depend upon iron overload and partly on the presence of a process that reduces ferric to ferrous iron (IsAACSON 1982a). The virulence of a variety of organisms including tuberculosis, Gram• negative bacteria and possibly Staphylococcus are enhanced by iron. Some siderotic patients get fatal Gram-negative bacterial peritonitis without having an identifiable primary focus of infection. These patients get a phlegmonous colitis with oedema of the bowel wall and septic shock often supervenes (BUCHANAN 1970).

Pathology of Nutritional Siderosis The liver of the siderotic patient develops a rusty brown colour and in many cases there is an associated micronodular cirrhosis. Occasionally coincidental macronodular cirrhosis may occur. In the early stages iron is deposited in parenchymal cells near the portal tracts at the biliary pole of the cells (WAINWRIGHT 1957). Siderosis progresses toward the centre of liver lobules (zone 3). After this the pigment appears in Kupffer cells and in portal tracts. Regenerative liver cells that are considered to develop after recovery from alcoholic drinking bouts may be devoid of stainable pigment. Eventual• ly iron is deposited in bile duct epithelium and endothelial cells of portal blood vessels. Massive amounts of iron may be deposited in the liver so that iron may constitute more than 3% of the dry weight (IsAACSON 1982a). In the spleen the concentration of iron is even higher than in the liver. The organ has a rusty brown colour. Iron is deposited in the sinusoidal lining cells and endothelial cells as well as in macrophages caught up in the capsule and trabeculae. In the pancreas and intestines iron deposition is mild and is mainly in the reticuloendothelial system until cirrhosis occurs. In the panc• reas parenchymal deposits are found in both acinar and islet cells. The mucosa of the duodenum and jejunum becomes a deep rusty brown colour and the draining mesenteric lymph nodes also become pigmented. Deposi• tion of iron is particularly heavy in the stroma of the intestinal villi. It is seen within macrophages as well as extracellular deposits. Brunner's glands are not usually involved. The stomach and salivary glands contain much less iron than does the duodenum and upper jejunum. In the kidney scanty granules or iron may be found in the distal convoluted tubules and loops of Henle. The heart is hardly affected with only scanty granules of iron being found in the interstitium and rarely in myofibres. When cirrhosis is present iron deposition in myofibres is accentuated. Osteoporosis causes bony trabeculae to become small while the marrow accumulates much haemosiderin. Scattered siderophages are also found in the thyroid, pituitary, testes, adrenals, choroid plexus, gums and synovium. When cirrhosis is present, epithelial cells of the pituitary, adrenal and thyroid also accumulate iron (ISAACSON 1982a). Malnutrition and Intestinal Malabsorption 1019 D. Tropical Sprue Tropical sprue appeared as a new disease to the western world when tropical areas were colonised. It is endemic in particular areas, mainly in the Caribbean, India, Sri Lanka and South East Asia in regions having a high rainfall, where it affects indigenous as well as expatriate populations. The condition has been defined as a "primary" malabsorption syndrome occurr• ing in people resident in or previously resident in the tropics (BAKER et al. 1962). It is usually associated with defective absorption of fat, carbo• hydrates, vitamins and other nutrients with radiological changes in the intestine (HuTT and SPENCER 1973). The disorder is characterised by chronic diarrhoea followed by anorexia and weight loss. The diarrhoea may be acute or insidious in onset. Subsequently there is emaciation, profound weakness, glossitis and macrocytic anaemia (O'BRIEN 1971). In practice affected pa• tients with overt disease or with subclinical tropical malabsorption have defective absorption of two or more substances (D-xylose, fat and vitamin B 12) (KLIPSTEIN and BAKER 1970). The condition has also been known as white flux, hill diarrhoea, cachectic diarrhoea, diarrhoea alba and psilosis, but tropical sprue is now the most widely used term. It is synonymous with malabsorption of the tropics (CooK 1984). The name sprue was applied by MANSON in 1880 when he anglicised the Dutch term "Indische sprouw" al• though the condition had been described in Barbados by HILLARY 120 years earlier (MANSON 1880; HILLARY 1759 quoted by CooK 1984). Tropical sprue is relatively infrequent and milder in Africa, but has been described in Nigeria, South Africa, Zimbabwe and Angola (FALAIYE 1970; MOSHAL 1970; THOMAS and CLAIN 197 6; CARNEIRO CHAVES 1981 ). It occurs in both endemic and epidemic forms and affects all ages though is uncommonly diagnosed in children (BAKER 1972). There is evidence that persons acquire a measure of immunity that protects them from further attacks during subsequent epidemics (BAKER 1972). The aetiology is not yet understood as intestinal damage can be attributed to toxins, deficiency or infection (BAKER 1972). The concept that the disease is mediated by abnormal bacterial colonisation of the small intestine after a non-specific infection has caused extensive damage to enterocytes, is attractive, but strongly opposed by BoOTH ( 1984). Is is considered that initial mucosal damage to jejunum, ileum and colon leads of defective absorption of fat and folate with increased liberation of entero• glucagon into the plasma. Enteroglucagon slows the transit of intestinal contents which permits overgrowth by intraluminal coliform bacterial organisms. They produce enterotoxins that cause secretion of water into the intestinal lumen (KLIPSTEIN et al. 1978). The organisms are toxic to entero• cytes and/or adhere to intestinal epithelium and damage brush borders. It is deduced that intestinal absorption is thus further aggravated and with increased luminal colonisation folate deficiency accentuates the severity of mucosal damage (CooK 1984). There is no obvious reason that this process should have a predilection to occur in particular regions in the tropics. The long latent period which elapses between a patient leaving the tropics and the 1020 R. 0. C. KASCHULA later onset of symptoms in a temperate climate in some instances in un• explained but suggests a slow infection. The occurrence of the disease in epidemics, sometimes affecting particular households (MATHAN et al. 1966) or particular military barracks (JoNEs et al. 1972), with clinically acute diarrhoea that responds to antibiotics strongly points to an infective agent (CooK 1984). Chronic infection with a comavirus has been suggested as a possible cause (BAKER et al. 1982). Attention has been drawn to the possible role of long-chain fatty acids that depress the normally pre• dominant Gram-positive small bowel flora so enhancing contamination by anaerobic or facultatively anaerobic coliform organisms (KLIPSTEIN 1981). Although associated with raised serum concentrations of IgG, IgE, complement component C4, orosomucoid, gastric parietal cell antibodies, and lymphopenia with reduced T cells, there is no evidence of a primary immunological process to account for tropical sprue (Ross and MATHAN 1981). Amongst expatriates residing in endemic areas for more than 1 year tropical sprue has affected many British and American troops and their families while on duty in India, Burma and the Far East {KEELE and BOUND 1946; AYREY 1948; JONES etal. 1972; O'BRIEN and ENGLAND 1966). In India and the Far East the disease is relatively common with seasonal increases. The incidence of the disease is also higher amongst poor people living under conditions of poor sanitation {KLIPSTEIN 1981 ). Short-term visitors to endemic areas more frequently contract giardiasis, which needs to be distinguished from sprue. Tropical sprue has been divided into three clinical stages (O'BRIEN and ENGLAND 1966). The first is characterised by anorexia, diarrhoea, extreme asthenia, weight loss and nausea for up to 2 months. The next stage occurs when symptoms have persisted for between 2 and 3 112 months. Glossitis and dyspepsia are then added and megaloblastic anaemia occurs in the third stage when symptoms have persisted for more than 4 months. A subclinical stage is also recognised where morphological changes in the intestines are found without associated symptoms (BRUNSER et al. 1970). The disease generally has spontaneous remissions and exacerbations with occasional cases having an acute unremitting course. It is generally found that the severity of intestinal malabsorption parallels the extent of histopathological changes in the mucosa (HuTT and SPENCER 1973). The morphological changes are similar to those that are seen in other causes of malabsorption such as coeliac disease. The ileum is less severely affected than is the jejunum and as with coeliac disease there is increased propensity to develop intestinal lymphoma in long-standing disease (BAKER 1972). Dissecting microscopic examination ofjejunal biopsies shows transforma• tion of normal finger-like villi by swelling and shortening with fusion of adjoining villi to form tongue-like and leaf-like conglomerations (SWANSON and THOMASSEN 1965). As the disease progresses and becomes more severe, the mucosa becomes more flattened and smooth. The villus pattern eventually gives way to low convoluted ridges. The atrophic changes do not have a uniform distribution and focal abnormalities are the rule in early, borderline Malnutrition and Intestinal Malabsorption 1021 and subclinical disease. In intense unremitting disease, there is often oedema and a fairly uniform villus pattern without evidence of villi fusing to form convoluted ridges. A progression of light microscopic changes seen in the mucosa was described in detail by Swanson and Thomassen in 1965. They found that the villus height crypt depth ratio was considerably altered from a normal 4: 1 ratio to 1 : 4 in severe cases. Villi develop broad bases with progressive reduc• tion in the numbers of epithelial cells. The loss of epithelium also affects the crypts as the severity of the disease increases. The number of mitoses in the epithelium of the crypts as well as those occurring on the whole epithelial surface initially increase to reach maximal numbers in mild disease and thereafter are progressively reduced. Paneth cells occur in normal numbers but the argentaffin cells in the crypts are considerably increased in severe disease. Relative to the total cell population, they can represent an eightfold increase (SWANSON and THOMASSEN 1965). The surface epithelium may become predominantly or partly cuboidal and may be infiltrated by chronic inflammatory cells. Lymphocytes preferentially infiltrate the epithelium in the upper crypt and crypt-villus interzones (MARSH et al. 1983). In the sub• epithelial region increased collagen is deposited in cases of overt disease but not in subclinical cases (BRUNSER et al. 1970). Fat stains of frozen tissue sections indicate accumulation of lipid droplets in the surface epithelium and the adjoining lamina propria. The lamina propria becomes infiltrated by plasma cells, granulocytes and lymphocytes. Cells staining for IgA by immunocytochemical techniques are also increased. Electron microscopic examination of mucosal biopsies from jejunum midway along its length indicates variable changes in the surface epithelium. Microvilli may be shortened and cultured into groups while accumulation of fat in smooth endoplasmic reticulin and Golgi occurs. The number of lysosomes and free ribosomes also increases in the enterocytes. Below the basa1laminae ofvillus epithelium there is an accumulation of finely granular or finely fibrillar material in which collagen fibres and lipid droplets are embedded (BRUNSER et al. 1970). These abnormalities are not specific for tropical sprue but lipid accumulation is more prominent in overt tropical sprue than is found in other forms of malabsorption. In tropical sprue the lipid does not appear in the intercellular spaces of epithelial cells as normal• ly occurs during the lipid-absorption phase and has been described to occur in coeliac disease (RUBIN et al. 1966). Decreases in a number of intestinal cell enzymes have been reported (particularly disaccharidases) which correlate with the severity of disease. Persistent deficiency of lactase with symptomatic intolerance of milk is not uncommon amongst cases that have recovered from overt disease (GRAY et al. 1968). The megaloblastic anaemia that is a feature of severe sprue is due to a multiplicity of factors. Gastritis with reduced output of intrinsic factor is reported in 14% of cases (BAKER 1972). Alteration of the intraluminal bacterial flora and malabsorption are additional factors. Malabsorption is 1022 R. 0. C. KASCHULA thought to be the main reason that folic acid reserves are reduced but diminished intake and increased requirements also seem to have a role.

E. Chronic Pancreatic Disease in the Tropics

For the past 3 decades non-alcoholic chronic calcific pancreatitis has been recognised as a distinct entity that occurs in the tropics. It is often fatal before the age of 40 years (SHARPER 1964). It is particularly prevalent along the Malabar coast of India (THOMAS et al. 1990), but also commonly occurs in Uganda (OwoR 1970), Zaire (SONNET et al. 1960), Indonesia (ZUIDEMA 1959), Nigeria (KINNEAR 1963) and Brazil (DANI et al. 1986). The clinical expression of the disease differs somewhat according to geographic location. In Nigeria preceding or concurrent malnutrition is found in 90% of cases (0LURIN and 0LURIN 1969; MABOGUNJE and LAWRIE 1990). The male preponderance is extremely high in Uganda and it is an important cause of malabsorption, diabetes and obstructive jaundice (OwoR 1970, 1972). In India the disease usually manifests as abdominal pain in childhood, or non• ketotic diabetes during adolescence. In India malabsorption is uncommon and the disease in only slightly more frequent in males (THOMAS et al. 1990). Familial clustering of the condition has been reported in India (PITCHUMONI 1984) where some cases have also developed pancreatic carcinoma (THOMAS et al. 1990). In areas of high prevalence it is considered to be the cause of insulin-dependent diabetes in up to 16% of diabetics admitted to hospital (THOMAS et al. 1990). The aetiology of tropical calcific pancreatitis is an enigma that still needs to be resolved. Preceding pancreatic damage by protein energy malnutrition is considered to be an unlikely initiating factor (SARLES et al. 1989). In Ivory Coast the disease is rare but kwashiorkor is common. In Kerala state, India, the disease is very common but kwashiorkor is rarely seen. A diet low in fat and possibly also low in protein is now considered to be a high-risk factor (SARLES et al. 1989). Pancreatic stasis due to prolonged lack of food in the stomach with or without gastroenteritis and dehydration may facilitate the formation of mucus plugs and eventual calculus formation (NWOKOLO and Ou 1980). In addition it has been shown that there are lasting alterations in pancreatic juice protein of the type that predisposes to calcification in rats born to malnourished mothers (SARLES et al. 1987). Manioc (cassava) consumption, deficiency of micronutrients such as selenium, copper and vitamins A and B6, chronic alcoholism, viral infections and immunological factors have been suggested as possible causative factors but convincing supportive evidence is still lacking (THOMAS et al. 1990). In common with other forms of chronic calcific pancreatitis, there is precipitation of protein plugs in pancreatic ducts and acini flowed by calcification. It seems that the stabilising agent in pancreatic juice, pancreatic stone protein, may be deficient and permit the development of calculi (SARLES et al. 1989). Malnutrition and Intestinal Malabsorption 1023 The gross appearance of an affected pancreas depends on the stage of the disease. The organ is generally small, firm, fibrous and gritty with dilated ducts containing calculi (THOMAS et al. 1990). Sometimes the ducts are cystic and there may be metaplasia of epithelium to mucus-producing cells or rarely to a squamous lining (OwoR 1970). Initially the degenerative changes have a patchy lobular distribution but as the condition progresses fibrous replace• ment of lobules becomes more diffuse. Chronic inflammatory cell infiltra• tion around ducts and nerves is generally inconspicuous and may be related to earlier superimposed episodes of acute inflammation. During such episodes, oedema, fat necrosis and haemorrhage may be seen (THOMAS et al. 1990). The islets vary in size and number and often resemble atrophic acinar tissue. Hyaline fibrosis within surviving islets is not a feature of the diabetes that occurs with tropical calcific pancreatitis (OwoR 1970). In Uganda almost two-thirds of cases have fatty livers at autopsy. This has a centri-lobular distribution (zone 3) and is associated with malabsorption syndrome (OwoR 1970). Obstructive jaundice is a significant complication and it is of interest that many cases have dilated bile ducts without demonstrable gallstones or pancreatic calculi in the biliary outflow system. Pseudocysts are very occasionally associated with the disease (OwoR 1972). Although steatorr• hoea occurs in about 40% of cases in Africa, xylose absorption and jejunal morphology are normal. Other complications include growth retardation, extreme wasting and parotid hypertrophy. Peripheral neuropathy and angio• pathy, as a consequence of the diabetes, may also occur (TANNER and LAMA 1991 ). Upper abdominal distension is a fairly constant feature in Kerala state, India (PITCHUMONI 1984).

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