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Malabsorption syndromes in the tropics 

Malabsorption syndromes in the tropics

Chapter:
Malabsorption syndromes in the tropics
Author(s):

V.I. Mathan

DOI:
10.1093/med/9780199204854.003.151008
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Essentials

Causes of secondary malabsorption that are mainly prevalent in the tropics include (1) progressive wasting in people infected with HIV, which is known as ‘slim disease’; (2) various infections—protozoal (e.g. Gardia lamblia, Cryptosporidium parvum), helminthic (e.g Capillaria philippinensis, Strongyloides stercoralis), bacterial (Mycobacterium tuberculosis); (3) immunoproliferative small intestinal disease; (4) hypolactasia (see Chapter 15.10.5).

When patients with conditions that can cause secondary malabsorption are excluded, a group remains who have chronic diarrhoea, malabsorption, and its nutritional sequelae. This primary or idiopathic malabsorption syndrome is called ‘tropical sprue’, and it occurs against the background of tropical enteropathy (which describes the fact that the morphology of the mucosa of normal gut is different in tropical preindustrialized countries from that in temperate-zone industrialized countries).

The aetiology of tropical sprue is not known: epidemiological data suggests an infective cause, but no causal agent has been identified. Presentation is typically with loose or watery stools lasting for several weeks or months, and with symptoms and signs of nutritional deficiency. Management involves symptomatic relief from diarrhoea, correction of fluid and electrolyte abnormalities and nutritional deficiencies, and attempts at specific curative measures—vitamin B12, folic acid, and tetracyclines—are usually given for up to 6 months.

Introduction

Patients, in whom the ‘digestive fire is weakened and food is expelled from the body without contributing to growth’ were described in Charaka-Samhita, an ancient Indian treatise on medicine compiled some time between the 6th and 12th centuries bce. The clinical description in the section on ‘Grahani Vyadhi’ or diseases of the organ of assimilation, clearly describes patients gradually wasting with chronic diarrhoea and loud borborygmi. Malabsorption of nutrients with its sequelae has therefore long been recognized as a clinical entity in some tropical regions.

Even in the globalized context of the third millennium, there are defined tropical malabsorption syndromes. All the diseases with malabsorption of nutrients that are prevalent in temperate climates also occur in the tropics, but there are certain conditions, the majority being chronic enteric infections or infestations, that are geographically primarily limited to the tropics. Expatriates from other parts of the world visiting the tropics may have a higher susceptibility to some of these conditions.

Causes of malabsorption primarily prevalent in the tropics

Malabsorption in the tropics, as elsewhere, may have an identifiable underlying aetiology, when it is classified as secondary malabsorption. When no primary cause has yet been identified it is considered primary or idiopathic malabsorption (Table 15.10.8.1).

Table 15.10.8.1 Classification of tropical malabsorption syndromes

Secondary malabsorption

Protozoal infections

  • Giardia lamblia

  • Cryptosporidium parvum

  • Isospora belli

  • Enterocytozoon bieneusi

  • Septata intestinalis

Helminthic infections

  • Capillaria philippinensis

  • Strongyloides stercoralis

Bacterial infections

Mycobacterium tuberculosis

Viral infections

  • Human immunodeficiency virus

  • Tropical (calcific) pancreatitis

  • Immunoproliferative small intestinal disease (IPSID)

  • Late-onset hypolactasia

Primary malabsorption

Tropical sprue (idiopathic tropical malabsorption syndrome)

The importance of a variety of protozoal infections, especially intracellular protozoans, was recognized in temperate-zone countries at the beginning of the AIDS epidemic, these organisms having been identified as opportunistic infections. In tropical countries these protozoa have been identified in symptomatic and asymptomatic immunocompetent subjects.

Capillaria philippinensis infection has been reported in epidemics from the Philippines and as sporadic cases from other tropical countries including India. Hyperinfection with Strongyloides stercoralis can occur rarely. Both these helminths burrow into the mucosa and form tunnels.

Abdominal tuberculosis occurs much less frequently than pulmonary tuberculosis and is often secondary. Malabsorption in abdominal tuberculosis is the result of bacterial colonization of the small intestinal lumen secondary to strictures and extensive ulceration, or due to obstruction of the lymphatic outflow (tabes mesenterica).

Progressive wasting in people infected with HIV is known as ‘slim disease’, especially in Africa. This is usually considered a consequence of malabsorption secondary to enteric opportunistic infections. However there is some evidence to suggest that a primary HIV enteropathy can also contribute to malabsorption.

Calcific pancreatitis affecting young adults, particularly in economically disadvantaged sections of society, is another cause of malabsorption unique to the tropics. The aetiology may be related to malabsorption and dietary ‘toxins’.

Immunoproliferative small intestinal disease (IPSID; see Chapter 15.10.4) is due to the clonal expansion of immunocytes producing altered α‎ heavy-chain immunoglobulin. This is also known as Mediterranean lymphoma and has been reported from several tropical countries. The characteristic histology in the premalignant stage is diagnostic and can be reversed by prolonged antibiotic therapy at this stage, suggesting a trigger that may be related to enteric infection. Once malignant transformation has occurred the treatment is as for other lymphomas, but the prognosis is guarded.

In many tropical regions, particularly south and south-east Asia, the high lactase activity in the intestinal epithelium in neonates declines rapidly after weaning. Since most adults in such countries do not regularly consume milk or lactose in their diets, this abnormality is of relatively small significance. The use of fermented milk and milk products (e.g. yoghurt) can ensure that milk-based nutritional supplementation is still possible in such populations (see Chapter 15.10.5).

Malabsorption, or increased secretion, is an invariable part of all acute diarrhoeal infections. These episodes, most frequent in children, are of short duration, usually a few days. A small proportion of infants and young children have diarrhoea that persists for longer than 2 weeks following an acute episode. This persistent diarrhoea syndrome, seldom if ever seen in adolescents and adults, is not usually considered as one of the malabsorption syndromes.

The concept of a ‘postinfective malabsorption state’ associated with the presence of a mixed bacterial flora in the small intestine has been postulated to explain, in particular, the persistent diarrhoea and malabsorption reported in many European travellers to the Indian subcontinent. By extension, it has been suggested that the syndrome of primary malabsorption in the tropics, tropical sprue, is only another form of postinfective malabsorption. Several facts are against this assumption. Significant bacterial colonization of the small intestine has been found in apparently healthy asymptomatic adults resident in the tropics. Detailed investigation of many overland travellers from Europe to the Indian subcontinent identified several of the infections described earlier as the cause of persistent malabsorption, along with an altered luminal bacterial flora. The epidemiology of tropical sprue is distinctly different from that of acute infectious diarrhoea. Detailed clinical and laboratory investigations of adults and children in more than 20 epidemics of acute diarrhoea, studied in south India, identified no single case of persistent malabsorption, other than the background prevalence of tropical enteropathy. There are also well-documented instances of expatriates from Europe who developed a primary malabsorption syndrome many years after their return to temperate climes. A careful analysis of the available literature therefore suggests that significant persistent and symptomatic malabsorption following acute enteric infectious diarrhoea is a rare event in the tropics.

When patients with conditions that can give rise to secondary malabsorption unique to the tropics or elsewhere are excluded, a group remain who have chronic diarrhoea, malabsorption, and its nutritional sequelae. Such patients are relatively rare in temperate climates, but frequently encountered in regions such as southern India and the Caribbean islands. This primary or idiopathic malabsorption syndrome has been called ‘tropical sprue’. Tropical sprue occurs against the background of tropical enteropathy in the indigenous population of these regions.

Tropical enteropathy

The intestinal mucosal morphology of germ-free rats differs from that of their conventionally reared litter-mates; the latter have shorter villi, higher crypts, and increased mononuclear cells infiltrating the lamina propria and epithelium. These differences are attributed to the modulating effect of the microbial flora in the intestinal lumen of the conventionally reared litter-mates.

Similar morphological differences are found between the jejunal mucosa of apparently healthy asymptomatic individuals living in temperate-zone industrialized countries and those in tropical preindustrialized countries. The morphological features of this tropical enteropathy are characterized by the replacement of finger- and tongue-shaped villi by broader structures in the upper small intestine, reduction in the height of villi with an increase in crypt thickness, and increased infiltration by mononuclear cells of the lamina propria and the epithelium. Similar mucosal morphological changes have also been shown to occur in the large intestine.

The morphology of fetal intestinal mucosa is identical in both geographical regions, the earliest differences appearing shortly after birth. The morphological changes are not apparent in biopsies from residents of Singapore—although this is a tropical country, it has standards of environmental hygiene and nutrition that equal those in temperate-zone industrialized countries. People expatriated from temperate countries to tropical countries develop these mucosal morphological changes over time. Expatriates from tropical countries living in a temperate zone, even if they continue to ingest a diet similar to that in their original home, eventually revert to having temperate-zone morphology. The evidence therefore suggests that the morphological alteration in the small intestine of residents of tropical countries is not a result of climatic differences, but is probably a reflection of an adaptation to environmental factors. In vitro organ culture studies have shown slightly accelerated cell turnover in the jejunal mucosa of people living in the tropics, further supporting an adaptive response as the basis for the change.

Extensive bacterial colonization of the upper small-intestinal lumen and mucosa by aerobes and anaerobes, in apparently healthy adults, has been documented in studies from southern India. Enteric pathogens can be cultivated from the stools of asymptomatic individuals resident in many tropical countries. It is also known that the first dose of oral immunization agents to enteric pathogens usually results in a secondary response, even in children as young as 2 years old living in the tropics. There is no evidence that the macronutrient deficiency widely prevalent in many tropical countries influences intestinal structure or function. All of this suggests that the enteropathy of tropical regions is an adaptation to environmental contamination resulting from poor sanitation practices. Conceptually, it may be useful to categorize ‘specific pathogen-free’ populations (temperate zone) and ‘conventional’ populations (tropical)! Whether these changes in the enteric mucosa, a primary barrier between the internal and external environment, would disappear with improving socio-economic status as a result of industrialization, is an intriguing question.

Minor abnormalities in absorption can also be demonstrated in these healthy subjects, with xylose malabsorption in 40%, mild steatorrhoea in 10%, and vitamin B12 malabsorption in 3%. The overall absorption of calories is reduced by about 5%, while the colonic bacterial mass is increased. Colonic salvage of unabsorbed calories is thereby reduced. There is no evidence that these changes in the lining epithelium of the intestinal tract significantly affect the health of these ‘conventional’ populations. However, the reduction in overall caloric absorption can raise the question as to whether the absence of tropical enteropathy can increase the effective availability of food without an increase in supply.

Tropical sprue

Definition

Tropical sprue is defined as a primary (idiopathic) malabsorption syndrome affecting residents of, or visitors to, certain tropical regions. It is characterized by enterocyte damage, usually associated with chronic diarrhoea and the nutritional sequelae of persisting malabsorption. The underlying aetiology (or aetiologies) is not yet understood. There are differences in the presentation, epidemiology, and clinical course in different geographical regions and between expatriates to endemic regions and indigenous residents affected by the syndrome.

History

William Hillary described a chronic wasting diarrhoea in European expatriates in Barbados in 1759, probably the first description of the syndrome in the English literature. The disease apparently attained epidemic proportions 3 years after he arrived in Barbados. With expanding colonization, the syndrome was well recognized in expatriates by British and Dutch physicians in south and south-east Asia. However, no cases were described from tropical Africa. Tropical sprue assumed epidemic proportions during the Second World War and was a major factor for repatriation from the Assam and Burma theatres of war. Indian troops were also affected. It was only in the postcolonial era, with the work of Baker and colleagues in southern India and of Klipstein in Puerto Rico and Haiti, that the extent of the problem of tropical sprue in indigenous populations was defined.

Epidemiology

Endemic cases in indigenous and expatriate residents in the tropics and epidemics in troops and indigenous populations have been documented. Endemic tropical sprue is apparently geographically restricted to south and south-east Asia and the Caribbean islands other than Jamaica, with a few case reports from Central and South America and sub-Saharan Africa. In fact, much of the literature up to the 1960s is limited to expatriate populations. In India, only two large medical institutions, with well-developed laboratory facilities, have reported detailed studies, suggesting that in marginally nourished indigenous populations many cases may be missed because of the poor availability of diagnostic facilities.

Apart from the reports during the Second World War, large epidemics have only been described from southern India. The first such reported epidemic in 1960–61 affected approximately 100 000 patients, with a 40% case fatality. This was reflected in the unusual death rates in the North and South Arcot Districts of Madras state in the 1961 census of India. The last epidemic was detected in 1978. In all the epidemics, patients initially developed an apparent episode of acute diarrhoea accompanied by vomiting in about 30% and fever in 25% of cases. Significant malabsorption of fat, carbohydrate, and vitamin B12 was present even during the first week of illness and 50% of those affected had diarrhoea for longer than 1 month. The epidemics evolved with new cases occurring over a period of months to years, in contrast to epidemics of acute infectious diarrhoea which are usually over in a few weeks. Adults had a significantly higher attack rate and were affected earlier during the course of the epidemic. The epidemiological data suggested an infective aetiology, but no causal viral, bacterial, or parasitic agent has been identified.

Clinical features

The patient with tropical sprue is usually an adult with a history of loose or watery stools lasting for several weeks or months and with symptoms and signs of nutritional deficiency. There is usually anorexia, a feeling of abdominal distension, and loud, abnormal borborygmi. The signs of nutritional deficiency include pallor due to anaemia, angular stomatitis, glossitis, oedema, and the skin and hair changes of severe hypoproteinaemia. The prevalence of nutritional deficiency, measured by clinical or laboratory parameters, is higher in those patients with a longer duration of symptoms. In the epidemic situation the prevalence of nutritional deficiency in patients during the first month of illness was no different from that in the unaffected people in the same village. However, in patients affected in the epidemics persistent malabsorption begins during the first few days of illness. The diarrhoea can be severe enough to produce life-threatening dehydration. In the epidemics the early deaths were mainly due to fluid and electrolyte imbalance, which can be prevented by maintenance of hydration. As the disease progresses the sequelae of severe malnutrition and consequential acute infections, especially of the respiratory tract, contribute to mortality. The natural history of the illness shows periods of remission, relapses, and spontaneous recovery, which make an evaluation of specific therapy difficult. Although patients have been followed for up to 25 years in southern India, intestinal neoplasms have not developed.

Investigation

Investigation of these patients should confirm the presence of intestinal malabsorption, exclude conditions that can give rise to secondary malabsorption, and evaluate the nutritional sequelae of malabsorption (Table 15.10.8.2).

Table 15.10.8.2 Investigation of a patient with tropical malabsorption syndrome

1. Confirmation of the presence and extent of malabsorption

Steatorrhoea

d-Xylose absorption

Vitamin B12 absorption

Breath hydrogen or CO2 estimation with stable isotopes and other tests of absorption, depending on availability

2. Exclusion of conditions leading to secondary malabsorption

Faecal examination for parasites

Small intestinal luminal fluid cultures to exclude bacterial overgrowth

Careful radiological examination of the small and large bowel including small bowel enema

Duodenal or jejunal mucosal biopsy

Serum protein electrophoresis for heavy-chain abnormality

3. Evaluation of the sequelae of malabsorption

Haemoglobin, haematocrit, reticulocyte count

Bone marrow morphology, when indicated

Serum protein and albumin

Serum electrolytes

Vitamin B12 and folate

Estimation of other micronutrients based on availability

A simple faecal smear stained with a fat stain such as Sudan 3 can often detect fat globules and fatty acid crystals associated with steatorrhoea. The extent of tests for confirming the presence of malabsorption is determined by the availability of facilities, which in many tropical areas is still limited. Tests of xylose absorption should be interpreted in the light of xylose malabsorption as a part of tropical enteropathy in the particular community.

The exclusion of conditions that can give rise to secondary malabsorption is of importance since many of these conditions are amenable to therapy. The diagnosis of the syndrome of primary malabsorption is one of exclusion.

Evaluation of the nutritional sequelae of malabsorption, especially the presence of megaloblastic anaemia, provides useful benchmarks for appropriate nutritional rehabilitation.

Pathology and pathogenesis

The wide availability of peroral mucosal biopsies confirmed the report, as early as 1924, that the primary lesson in tropical sprue was in the small-intestinal mucosa. Electron microscopic examination of jejunal mucosal biopsies confirmed the presence of damage to enterocytes in the crypt (regenerative) and villous (functional) compartments. This damage can be demonstrated in the first weeks of illness in patients affected during epidemics. Accelerated cell turnover in the regenerative compartment and increased loss of enterocytes from the functional compartment was demonstrated by in vitro culture of jejunal mucosal biopsies labelled with tritiated thymidine. In fact these changes in the enterocyte lifecycle explain the observed mucosal architecture, which has often been called partial villous atrophy. In contrast to the situation in coeliac disease, where the initial damage to enterocytes occurs in the functional compartment and the crypts are hypertrophied with morphologically normal enterocytes, in tropical sprue the primary lesion appears to affect the regenerative compartment. These findings have only been confirmed in patients studied in southern India.

The mucosal lesion in tropical sprue is not confined to the small intestine, since functional and structural abnormalities have also been demonstrated in the stomach and the colon. Significant water malabsorption in the colon may contribute to the severity of diarrhoea.

An appreciation of regional differences in the patient profile is essential for understanding the pathology and pathogenesis. All patients have malabsorption, but vitamin B12 malabsorption is only found in about 70% of patients in southern India, while it is almost invariable in expatriates from the temperate zones and in the Caribbean. In Haiti and Puerto Rico the observed seasonal incidence is ascribed to small-intestinal colonization by toxin-producing coliforms, probably secondary to the consumption of rancid pork fat. In southern India, the extent and severity of small-bowel colonization by enterotoxin-producing coliforms is no higher than in matched controls. Identification of one or more ‘agents’ that can damage the mucosal epithelial cells will enable a clearer understanding of these differences.

Treatment

Provision of symptomatic relief from diarrhoea, correction of fluid and electrolyte abnormalities and nutritional deficiencies, and attempts at specific curative measures are the cornerstone of treatment. Diarrhoea and abdominal distension can be helped by the judicious use of loperamide and dimethyl polysiloxane. Increasing the nutrient intake and providing therapeutic supplements such as vitamin B12 and folic acid, as indicated, is beneficial. However, specific therapy to cure the condition awaits understanding of its aetiology.

Empirical evidence from patients in the Caribbean and European expatriate community indicates that folic acid can alleviate symptoms in cases of less than 2 months duration. In patients with a longer duration of symptoms, the addition of oral tetracycline for up to 6 months leads to the restoration of normal intestinal absorption. In southern India, the results of therapy with vitamin B12, folic acid, and tetracyclines were not so clear cut and a few patients were resistant to all therapy. Nevertheless, the recommended management includes the use of all three of these therapeutic agents for up to 6 months.

Further reading

Baker SJ (1973). Geographical variation in the morphology of the small intestinal mucosa in apparently healthy individuals. Pathol Microbiol, 294, 222–37.Find this resource:

    Baker SJ, Mathan VI (1972). Tropical enteropathy and tropical sprue. Am J Clin Nutr, 25, 1047–55.Find this resource:

    Humphrey JH (2009). Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet, 374, 1032–5.Find this resource:

    Manson-Bahr PH (1924). The morbid anatomy and pathology of sprue and their bearing upon aetiology. Lancet, i, 1148–51.Find this resource:

    Mathan M, Mathan VI, Baker SJ (1975). An electron-microscopic study of jejunal mucosal morphology in control subjects and patients with tropical sprue in southern India. Gastroenterology, 68, 17–32.Find this resource:

    Mathan M, Ponniah J, Mathan VI (1986). Epithelial cell renewal and turnover and its relationship to the morphological abnormalities in the jejunal mucosa in tropical sprue. Dig Dis Sci, 31, 586–93.Find this resource:

    Mathan M, et al. (1990). Ultrastructure of the jejunal mucosa in human immuno deficiency virus infection. J Pathol, 16, 119–27.Find this resource:

    Mathan VI (1988). Tropical sprue in southern India. Trans R Soc Trop Med Hyg, 82, 10–14.Find this resource:

    Owens SR, Greenson JK (2007). The pathology of malabsorption: current concepts. Histopathology, 50, 64–82.Find this resource:

    Ramakrishna BS, Mathan VI (1982). Water and electrolyte absorption by the colon in tropical sprue. Gut, 23, 843–6.Find this resource:

    Wellcome Trust (1971). Tropical sprue and megaloblastic anaemia. Churchill Livingstone, London.Find this resource: