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The diagnosis and treatment of tropical sprue
148 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. 62. No. 1. 1968.
SPECIAL ARTICLE THE DIAGNOSIS AND TREATMENT OF TROPICAL SPRUE W. O'BRIEN
Royal Army Medical College Tropical sprue is a syndrome of chronic intestinal malabsorption occurring in people who are resident in, or who have been resident in, the tropics. It is endemic in India, Pakistan, Burma, South-East Asia, Indonesia, the Philippines and Queensland as well as in certain of the Caribbean islands, notably Cuba, Puerto Rico and Haiti. In many of these countries it has been shown that a condition of "subclinical sprue" manifest by intestinal mucosal abnormalities, with varying degrees of intestinal malabsorption, is widespread among the indigenous inhabitants. European and North American adults introduced into this environment may also be affected and, perhaps owing to different dietary habits, tend to develop a progressive illness, the main features of which include intestinal malabsorption, non-specific changes in the small-intestinal mucous membrane and a progressive deficiency of folate and vitamin B12. This article deals with the diagnosis and treatment of this syndrome as seen in the European.
Symptoms Children are rarely if ever affected, and negroes appear to be relatively immune. On the whole, the longer a person remains in an endemic area, the more likely he is to contract this illness. However, symptoms may begin within weeks of arrival in the tropics or may be delayed until several years after return to a temperate climate. The principal symptoms are diarrhoea, loss of appetite, loss of weight, loss of energy, a sore tongue and flatulant dyspepsia. If the condition remains untreated the symptoms of anaemia become superimposed. Diarrhoea is of a characteristic type, patients passing 1-10 loose, pale, bulky, very offensive stools in the 24 hours. It is often preceded by abdominal colic and may be confined to the morning, though in some patients the diarrhoea occurs mainly at night. There may be periods during which the patient suffers from acute watery diarrhoea, when the motions tend to be yellow. Occasionally patients deny having had diarrhoea and may even complain of constipation, but the stools, though formed, are pale and bulky. Loss of appetite often amounting to complete anorexia occurs, but some patients feel hungry until they sit down to a meal, and are then unable to eat. A normal appetite practically excludes the diagnosis of tropical sprue. The loss of appetite is accompanied by rapid and substantial loss of weight, a loss which is measured in stones and not pounds, and which may exceed 5 stones (30 kg.). Another equally characteristic symptom is mental and physical fatigue, which may be severe and crippling, and is often associated with depression and irritability. These symptoms may so overshadow the alimentary upset that the latter is not mentioned by the patient, who may be suspected of a psychiatric disturbance.
W. O'BRIEN
149
Soreness of the tongue has always been recognized as a classical symptom of sprue, indeed the name derives from this, but it is by no means invariably present even in severe tropical sprue. The whole of the inside of the mouth may be affected, and discomfort on swallowing is also common. Upper abdominal discomfort and flatulence after meals, accompanied by abdominal distension, may be the presenting complaint, while nausea and later intractable vomiting add to the patient's discomfort. Other less frequent complaints include amenorrhoea, loss of hair and intolerance of alcohol. Finally, a minority of patients first attend with the symptoms of severe anaemia. This presentation is more frequent among those who develop their symptoms for the first time in a temperate climate months or years after their return from a tropical zone.
Physical examination In early sprue, examination of the patient fails to reveal any abnormal physical sign. Glossitis is usually the first abnormality and is found in approximately twothirds of the patients who have been ill for longer than 2 months. It starts with small vesicles on the edges of the tongue, which rupture to leave small, shallow, painful ulcers. Later the whole tongue becomes red, raw and inflamed and eventually smooth or fissured. A general darkening of the skin is a helpful diagnostic feature, there is usually objective evidence of recent loss of weight and patients may look much older than their actual age. The clinical signs of severe anaemia are more common in females and may be accompanied by fever and enlargement of the spleen. In severe sprue the clinical state may resemble closely that seen during a relapse of Addison's disease, the patient lying still, withdrawn, answering only in monosyllables, and showing irritation if disturbed, so that no adequate history can be obtained. Finally, inspection of the stool is an essential part of the examination, the two important features being the pallor and the bulk.
Investigation of a patient with tropical sprue It would be convenient if a typical history and a few simple laboratory tests would allow of a confident diagnosis, but unfortunately this is not the case. Tropical sprue is only one of the intestinal disorders which may present in a similar way in the tropics, and even in an endemic area it will seldom account for more than two-thirds of such patients. A full and detailed investigation is required and if this is not possible locally the patient should be transferred to a hospital where the facilities are adequate. Intestinal absorption In tropical sprue, however early in the course of the illness the patient is seen, malabsorption of fat, xylose and vitamin B12 can always be demonstrated. Thus, on a diet containing 50-100 g. of fat an average of over 6 g. of fat will be excreted daily. It may be difficult to ensure that the anorexic patient takes this amount of fat, and the severity of the steatorrhoea will be proportional to the fat intake. A 5 g. oral dose of D xylose is better tolerated in sprue than the 25 g. dose, and malabsorption is shown by the failure to excrete 25% of this dose in the urine during the subsequent 5 hours. In order to assess absorption of vitamin B12 by the intestine it is necessary to give it with active intrinsic factor. A convenient test is to give 1 ~g. of vitamin B12 labelled with cobalt 58 by mouth, and measure the faecal excretion over the succeeding week. Malabsorption is shown by faecal excretion of more than 50% of the oral dose. A scintilation count over the liver at the end of the week is useful in confirming the result and guarding against a false result caused by loss of stool specimens. So consistent is
150
TILE D I A G N O S I S A N D T R E A T M E N T O F T R O P I C A L SPRUE
this pattern of malabsorption in tropical sprue that any deviation from it should at once lead to a reconsideration of the diagnosis. The glucose tolerance test gives less reliable results, for not only may flat curves be found in healthy people, but normal curves may be found in patients with tropical sprue. Folic acid absorption tests may also give results within normal limits in early sprue though these almost certainly do not reflect the absorption of dietary folate in these circumstances.
Barium meal examination In early sprue the radiological appearance of the small intestine is normal, The radiological abnormalities which develop later are non-specific. Instead of the normal feathery distribution of barium the primary transverse mucosal folds become apparent and thickened, and are seen as thick transverse bars across the lumen, or as filling defects indenting the barium silhouette. In addition there is dilatation of the lumen of the jejunum. Barium meal examination is also important in excluding anatomical abnormalities of the small intestine.
Intestinal biopsy Intestinal mucosal biopsy is a simple and safe procedure provided that the patient is not severly anaemic. It is of considerable value in the diagnosis of tropical sprue and immediate examination of the specimen with a dissecting microscope gives useful information to the clinician. In early sprue little or no abnormality may be found; the appearance seen with the dissecting microscope is of finger-shaped villi, or tall thin tongues or leaves. On histological examination also the appearance may be normal, though there is often some increase in cellular infiltration. In sprue of longer than 3 months' duration the jejunal biopsy appears abnormal; with the dissecting microscope the leaves are seen to be thickened and oedematous, or more commonly they are replaced by flattened, brancing serpiginous ridges, the "convoluted" pattern. On histological examination there is partial villous atrophy, the mean villous height being reduced to below 300 microns. In addition there is a moderate reduction in columnar cell height and increased infiltration of the epithelium and the lamina propria with plasma cells and lymphocytes. Haematological investigation The haematological abnormality of tropical sprue is progressive, and its development is consistent with almost total malabsorption of dietary folate and vitamin B12. There may also be malabsorption of iron. In the absence of a previous cause of deficiency, such as pregnancy or malnutrition, these patients do not become anaemic until they have been ill for 4 months. Nevertheless, full haematological investigation demonstrates evidence of folate deficiency even in early sprue. Thus the serum folate concentration as measured by Lactobacillus casei is always below normal, and usually below 3 m~g. per ml. (normal 6-21 m~g. per ml.) and bone marrow examination usually reveals some degree of megaloblastic change. The F I G L U excretion test becomes positive after 3 months and the red cell folate concentration falls to subnormal levels at about the same time. In patients who have been ill for 4 months or longer megaloblastic anaemia due to folate deficiency is usually present. In female patients this anaemia may be severe, but in males it is often mild. At this time bone marrow biopsy reveals frank megaloblastic change. In addition to this folate deficiency there is also a progressive fall in serum vitamin B12 concentration so that after 6 months values vary from 50 ~ g . to 145 ~ g . per ml. as measured by Euglena gracilis assay (normal 160-925 ,~g. per ml).
W. O'BRIEN
151
In chronic tropical sprue the serum vitamin B12 concentration falls to the range seen in pernicious anaemia, and vitamin B12 deficiency becomes an important factor in the aetiology of the megaloblastic anaemia. Evidence of iron deficiency may be found in low serum iron levels and the absence of iron from the bone marrow. These signs may, however, be masked by the megaloblastic anaemia and only become obvious during the haematological response to folic acid. It is likely that women are particularly liable to contract tropical sprue in the first few months after childbirth. Under these circumstances the condition appears to run a much more rapid course, with evidence of florid folate deficiency and a severe intestinal lesion, after only one month's illness.
Differential diagnosis Most diseases of the small intestine give rise to malabsorption and such conditions must be excluded before a diagnosis of tropical sprue can be entertained. Patients with coeliac disease may undergo a complete clinical remission in childhood or adolescence, whereas others present for the first time in adult life. Should these patients develop symptoms in the tropics the clinical features are similar to those seen in tropical sprue. A jejunal biopsy, however, reveals a fiat or "mosaic" mucosa and histological examination complete loss of villi (subtotal villous atrophy). Another helpful diagnostic feature is that in this group of patients the absorption of vitamin B12 is often normal, as is the serum vitamin B12 concentration. Other conditions which may give rise to a syndrome clinically indistinguishable from tropical sprue include regional ileitis, intestinal lymphoma, anatomical abnormalities of the intestine, hypogammaglobulinaemia and tuberculous enteritis, which is not uncommon in many tropical countries. In addition intestinal helminth infection may give rise to a maiabsorpfion syndrome closely resembling tropical sprue. Infection with Giarclia intestinalis is a well recognized cause of intestinal realabsorption, but hookworms and Strongyloides stercoralis are probably more important in this respect. Severe steatorrhoea associated with a high eosinophilia may follow early infection with these parasites, but xylose excretion is usually normal and the jejunal mucosal changes are mild. Other causes of malabsorption such as chronic pancreatitis must also be considered. Though it still remains true that the diagnosis of tropical sprue can only be made after exclusion of other disease processes, careful consideration of the nature and degree of the abnormal findings, taken in conjunction with the duration of the illness, affords valuable diagnostic support.
Treatment Though the origin of tropical sprue remains obscure, it is becoming more and more clear that two important factors which maintain the state of chronic intestinal realabsorption are folate or vitamin B12 deficiency superimposed on a blind-intestinalloop-like syndrome. The standard treatment of a patient with tropical sprue is with folic acid supplemented by treatment with antibacterial drugs. It is probably advisable to give folic acid at first in small intramuscular doses of 0- 2 mg. daily. Such a dose is sufficient for most patients, it carries little risk in those with severe vitamin B12 deficiency, and parenteral injection overcomes any malabsorptive defect that may be present. Later, as the position becomes clearer, larger oral doses may be substituted. The course of oral antibacterial drugs commonly used in Britain is constructed so as to give the broadest spectrum of antibacterial action, and is as follows :--succinyl sulphathiazole 10 grammes daily for 5 days, followed by Aureomycin 2 grammes daily for 5 days and then chloramphenicol 2 grammes daily for 5 days. An akernative course is
152
THE DIAGNOSIS AND TREATMENT OF TROPICAL S P R I g
oxytetracycline 2 grammes daily for 4 weeks followed by 0.5 gramme daily for 5 months. The response of tropical sprue to treatment depends upon the duration of the disorder. Patients with early sprue often undergo remission after bed rest and a suitable diet, particularly if they have returned to a temperate climate. Tropical sprue of up to 6 months' duration usually responds to folic acid alone, but in sprue of longer duration antibacterial drugs may also be required. Though it is customary to give folic acid and antibiotics together, it is convenient for descriptive purposes to deal with the response to those two forms of treatment separately. Within 48-72 hours of starting treatment with these small doses of folic acid, there is symptomatic improvement which in severely ill patients is remarkable. The sore mouth is relieved, diarrhoea ceases, energy returns, the appetite becomes insatiable and from being miserable, withdrawn and irritable, they become cheerful and co-operative. It is difficult to keep such patients in bed though they may still be severely anaemic. A steady gain in weight ensues and very soon they come to look years younger. In the absence of associated iron deficiency or severe B12 deficiency most anaemic patients have a full haematological response starting within 5 or 6 days, with a sharp increase in reticulocytes followed by a steady rise in red cell and haemoglobin concentrations. In a small minority of patients with very severe megaloblastic anaemia, a small blood transfusion is required before there is an adequate response to folic acid. Female patients may also require iron. This haematological response to folic acid is sometimes accompanied by evidence of fluid retention with some breathlessness on lying flat, a rise in jugular venous pressure and peripheral oedema. In patients who have been ill for less than 6 months, in addition to the symptomatic and haematological remission, there is also improvement in intestinal absorption. Xylose absorption improves rapidly and though faecal fat excretion may actually rise at first, it then falls usually to reach normal levels within 3 months. At this time, however, absorption of vitamin B12 may still be severely reduced in approximately a quarter of the patients. There is early but incomplete improvement in the histological appearance of the jejunal mucosa, followed by a more gradual improvement over the ensuing months. In some patients with severe folate deficiency this small dose of folic acid appears to be insufficient, and symptomatic, haematological and intestinal improvement does not occur until the dose of folic acid is raised. Treatment with oral antibacterial drugs is also effective, but the manner of response differs from that seen with folic acid. Thus, symptomatic improvement is very slow and the haematological response is delayed. In an anaemic patient the reticulocyte rise may not occur until nearly 2 months after treatment has started, and in non-anaemic patients asthenia associated with evidence of folate deficiency may persist for over 3 months. Nevertheless, there is a steady improvement in intestinal absorption of fat and xylose and a particularly rapid improvement in the absorption of vitamin B12. There is also a gradual return of the jejunal mucosa to normal. Tropical sprue is a serious disorder, which without adequate treatment may end in chronic invalidism or even in death. The therapeutic actions of folic acid and antibiotics are complementary and these remedies should be given together. An early return to full health may then be confidently expected and relapse is rare. After recovery there is no contra-indication to the return of these patients to the tropics. In accordance with editorial policy no references have been included in this paper but those familiar with the literature of tropical sprue will recognize my debt to numerous authors.
SPECIAL ARTICLE THE DIAGNOSIS AND TREATMENT OF TROPICAL SPRUE W. O'BRIEN
Royal Army Medical College Tropical sprue is a syndrome of chronic intestinal malabsorption occurring in people who are resident in, or who have been resident in, the tropics. It is endemic in India, Pakistan, Burma, South-East Asia, Indonesia, the Philippines and Queensland as well as in certain of the Caribbean islands, notably Cuba, Puerto Rico and Haiti. In many of these countries it has been shown that a condition of "subclinical sprue" manifest by intestinal mucosal abnormalities, with varying degrees of intestinal malabsorption, is widespread among the indigenous inhabitants. European and North American adults introduced into this environment may also be affected and, perhaps owing to different dietary habits, tend to develop a progressive illness, the main features of which include intestinal malabsorption, non-specific changes in the small-intestinal mucous membrane and a progressive deficiency of folate and vitamin B12. This article deals with the diagnosis and treatment of this syndrome as seen in the European.
Symptoms Children are rarely if ever affected, and negroes appear to be relatively immune. On the whole, the longer a person remains in an endemic area, the more likely he is to contract this illness. However, symptoms may begin within weeks of arrival in the tropics or may be delayed until several years after return to a temperate climate. The principal symptoms are diarrhoea, loss of appetite, loss of weight, loss of energy, a sore tongue and flatulant dyspepsia. If the condition remains untreated the symptoms of anaemia become superimposed. Diarrhoea is of a characteristic type, patients passing 1-10 loose, pale, bulky, very offensive stools in the 24 hours. It is often preceded by abdominal colic and may be confined to the morning, though in some patients the diarrhoea occurs mainly at night. There may be periods during which the patient suffers from acute watery diarrhoea, when the motions tend to be yellow. Occasionally patients deny having had diarrhoea and may even complain of constipation, but the stools, though formed, are pale and bulky. Loss of appetite often amounting to complete anorexia occurs, but some patients feel hungry until they sit down to a meal, and are then unable to eat. A normal appetite practically excludes the diagnosis of tropical sprue. The loss of appetite is accompanied by rapid and substantial loss of weight, a loss which is measured in stones and not pounds, and which may exceed 5 stones (30 kg.). Another equally characteristic symptom is mental and physical fatigue, which may be severe and crippling, and is often associated with depression and irritability. These symptoms may so overshadow the alimentary upset that the latter is not mentioned by the patient, who may be suspected of a psychiatric disturbance.
W. O'BRIEN
149
Soreness of the tongue has always been recognized as a classical symptom of sprue, indeed the name derives from this, but it is by no means invariably present even in severe tropical sprue. The whole of the inside of the mouth may be affected, and discomfort on swallowing is also common. Upper abdominal discomfort and flatulence after meals, accompanied by abdominal distension, may be the presenting complaint, while nausea and later intractable vomiting add to the patient's discomfort. Other less frequent complaints include amenorrhoea, loss of hair and intolerance of alcohol. Finally, a minority of patients first attend with the symptoms of severe anaemia. This presentation is more frequent among those who develop their symptoms for the first time in a temperate climate months or years after their return from a tropical zone.
Physical examination In early sprue, examination of the patient fails to reveal any abnormal physical sign. Glossitis is usually the first abnormality and is found in approximately twothirds of the patients who have been ill for longer than 2 months. It starts with small vesicles on the edges of the tongue, which rupture to leave small, shallow, painful ulcers. Later the whole tongue becomes red, raw and inflamed and eventually smooth or fissured. A general darkening of the skin is a helpful diagnostic feature, there is usually objective evidence of recent loss of weight and patients may look much older than their actual age. The clinical signs of severe anaemia are more common in females and may be accompanied by fever and enlargement of the spleen. In severe sprue the clinical state may resemble closely that seen during a relapse of Addison's disease, the patient lying still, withdrawn, answering only in monosyllables, and showing irritation if disturbed, so that no adequate history can be obtained. Finally, inspection of the stool is an essential part of the examination, the two important features being the pallor and the bulk.
Investigation of a patient with tropical sprue It would be convenient if a typical history and a few simple laboratory tests would allow of a confident diagnosis, but unfortunately this is not the case. Tropical sprue is only one of the intestinal disorders which may present in a similar way in the tropics, and even in an endemic area it will seldom account for more than two-thirds of such patients. A full and detailed investigation is required and if this is not possible locally the patient should be transferred to a hospital where the facilities are adequate. Intestinal absorption In tropical sprue, however early in the course of the illness the patient is seen, malabsorption of fat, xylose and vitamin B12 can always be demonstrated. Thus, on a diet containing 50-100 g. of fat an average of over 6 g. of fat will be excreted daily. It may be difficult to ensure that the anorexic patient takes this amount of fat, and the severity of the steatorrhoea will be proportional to the fat intake. A 5 g. oral dose of D xylose is better tolerated in sprue than the 25 g. dose, and malabsorption is shown by the failure to excrete 25% of this dose in the urine during the subsequent 5 hours. In order to assess absorption of vitamin B12 by the intestine it is necessary to give it with active intrinsic factor. A convenient test is to give 1 ~g. of vitamin B12 labelled with cobalt 58 by mouth, and measure the faecal excretion over the succeeding week. Malabsorption is shown by faecal excretion of more than 50% of the oral dose. A scintilation count over the liver at the end of the week is useful in confirming the result and guarding against a false result caused by loss of stool specimens. So consistent is
150
TILE D I A G N O S I S A N D T R E A T M E N T O F T R O P I C A L SPRUE
this pattern of malabsorption in tropical sprue that any deviation from it should at once lead to a reconsideration of the diagnosis. The glucose tolerance test gives less reliable results, for not only may flat curves be found in healthy people, but normal curves may be found in patients with tropical sprue. Folic acid absorption tests may also give results within normal limits in early sprue though these almost certainly do not reflect the absorption of dietary folate in these circumstances.
Barium meal examination In early sprue the radiological appearance of the small intestine is normal, The radiological abnormalities which develop later are non-specific. Instead of the normal feathery distribution of barium the primary transverse mucosal folds become apparent and thickened, and are seen as thick transverse bars across the lumen, or as filling defects indenting the barium silhouette. In addition there is dilatation of the lumen of the jejunum. Barium meal examination is also important in excluding anatomical abnormalities of the small intestine.
Intestinal biopsy Intestinal mucosal biopsy is a simple and safe procedure provided that the patient is not severly anaemic. It is of considerable value in the diagnosis of tropical sprue and immediate examination of the specimen with a dissecting microscope gives useful information to the clinician. In early sprue little or no abnormality may be found; the appearance seen with the dissecting microscope is of finger-shaped villi, or tall thin tongues or leaves. On histological examination also the appearance may be normal, though there is often some increase in cellular infiltration. In sprue of longer than 3 months' duration the jejunal biopsy appears abnormal; with the dissecting microscope the leaves are seen to be thickened and oedematous, or more commonly they are replaced by flattened, brancing serpiginous ridges, the "convoluted" pattern. On histological examination there is partial villous atrophy, the mean villous height being reduced to below 300 microns. In addition there is a moderate reduction in columnar cell height and increased infiltration of the epithelium and the lamina propria with plasma cells and lymphocytes. Haematological investigation The haematological abnormality of tropical sprue is progressive, and its development is consistent with almost total malabsorption of dietary folate and vitamin B12. There may also be malabsorption of iron. In the absence of a previous cause of deficiency, such as pregnancy or malnutrition, these patients do not become anaemic until they have been ill for 4 months. Nevertheless, full haematological investigation demonstrates evidence of folate deficiency even in early sprue. Thus the serum folate concentration as measured by Lactobacillus casei is always below normal, and usually below 3 m~g. per ml. (normal 6-21 m~g. per ml.) and bone marrow examination usually reveals some degree of megaloblastic change. The F I G L U excretion test becomes positive after 3 months and the red cell folate concentration falls to subnormal levels at about the same time. In patients who have been ill for 4 months or longer megaloblastic anaemia due to folate deficiency is usually present. In female patients this anaemia may be severe, but in males it is often mild. At this time bone marrow biopsy reveals frank megaloblastic change. In addition to this folate deficiency there is also a progressive fall in serum vitamin B12 concentration so that after 6 months values vary from 50 ~ g . to 145 ~ g . per ml. as measured by Euglena gracilis assay (normal 160-925 ,~g. per ml).
W. O'BRIEN
151
In chronic tropical sprue the serum vitamin B12 concentration falls to the range seen in pernicious anaemia, and vitamin B12 deficiency becomes an important factor in the aetiology of the megaloblastic anaemia. Evidence of iron deficiency may be found in low serum iron levels and the absence of iron from the bone marrow. These signs may, however, be masked by the megaloblastic anaemia and only become obvious during the haematological response to folic acid. It is likely that women are particularly liable to contract tropical sprue in the first few months after childbirth. Under these circumstances the condition appears to run a much more rapid course, with evidence of florid folate deficiency and a severe intestinal lesion, after only one month's illness.
Differential diagnosis Most diseases of the small intestine give rise to malabsorption and such conditions must be excluded before a diagnosis of tropical sprue can be entertained. Patients with coeliac disease may undergo a complete clinical remission in childhood or adolescence, whereas others present for the first time in adult life. Should these patients develop symptoms in the tropics the clinical features are similar to those seen in tropical sprue. A jejunal biopsy, however, reveals a fiat or "mosaic" mucosa and histological examination complete loss of villi (subtotal villous atrophy). Another helpful diagnostic feature is that in this group of patients the absorption of vitamin B12 is often normal, as is the serum vitamin B12 concentration. Other conditions which may give rise to a syndrome clinically indistinguishable from tropical sprue include regional ileitis, intestinal lymphoma, anatomical abnormalities of the intestine, hypogammaglobulinaemia and tuberculous enteritis, which is not uncommon in many tropical countries. In addition intestinal helminth infection may give rise to a maiabsorpfion syndrome closely resembling tropical sprue. Infection with Giarclia intestinalis is a well recognized cause of intestinal realabsorption, but hookworms and Strongyloides stercoralis are probably more important in this respect. Severe steatorrhoea associated with a high eosinophilia may follow early infection with these parasites, but xylose excretion is usually normal and the jejunal mucosal changes are mild. Other causes of malabsorption such as chronic pancreatitis must also be considered. Though it still remains true that the diagnosis of tropical sprue can only be made after exclusion of other disease processes, careful consideration of the nature and degree of the abnormal findings, taken in conjunction with the duration of the illness, affords valuable diagnostic support.
Treatment Though the origin of tropical sprue remains obscure, it is becoming more and more clear that two important factors which maintain the state of chronic intestinal realabsorption are folate or vitamin B12 deficiency superimposed on a blind-intestinalloop-like syndrome. The standard treatment of a patient with tropical sprue is with folic acid supplemented by treatment with antibacterial drugs. It is probably advisable to give folic acid at first in small intramuscular doses of 0- 2 mg. daily. Such a dose is sufficient for most patients, it carries little risk in those with severe vitamin B12 deficiency, and parenteral injection overcomes any malabsorptive defect that may be present. Later, as the position becomes clearer, larger oral doses may be substituted. The course of oral antibacterial drugs commonly used in Britain is constructed so as to give the broadest spectrum of antibacterial action, and is as follows :--succinyl sulphathiazole 10 grammes daily for 5 days, followed by Aureomycin 2 grammes daily for 5 days and then chloramphenicol 2 grammes daily for 5 days. An akernative course is
152
THE DIAGNOSIS AND TREATMENT OF TROPICAL S P R I g
oxytetracycline 2 grammes daily for 4 weeks followed by 0.5 gramme daily for 5 months. The response of tropical sprue to treatment depends upon the duration of the disorder. Patients with early sprue often undergo remission after bed rest and a suitable diet, particularly if they have returned to a temperate climate. Tropical sprue of up to 6 months' duration usually responds to folic acid alone, but in sprue of longer duration antibacterial drugs may also be required. Though it is customary to give folic acid and antibiotics together, it is convenient for descriptive purposes to deal with the response to those two forms of treatment separately. Within 48-72 hours of starting treatment with these small doses of folic acid, there is symptomatic improvement which in severely ill patients is remarkable. The sore mouth is relieved, diarrhoea ceases, energy returns, the appetite becomes insatiable and from being miserable, withdrawn and irritable, they become cheerful and co-operative. It is difficult to keep such patients in bed though they may still be severely anaemic. A steady gain in weight ensues and very soon they come to look years younger. In the absence of associated iron deficiency or severe B12 deficiency most anaemic patients have a full haematological response starting within 5 or 6 days, with a sharp increase in reticulocytes followed by a steady rise in red cell and haemoglobin concentrations. In a small minority of patients with very severe megaloblastic anaemia, a small blood transfusion is required before there is an adequate response to folic acid. Female patients may also require iron. This haematological response to folic acid is sometimes accompanied by evidence of fluid retention with some breathlessness on lying flat, a rise in jugular venous pressure and peripheral oedema. In patients who have been ill for less than 6 months, in addition to the symptomatic and haematological remission, there is also improvement in intestinal absorption. Xylose absorption improves rapidly and though faecal fat excretion may actually rise at first, it then falls usually to reach normal levels within 3 months. At this time, however, absorption of vitamin B12 may still be severely reduced in approximately a quarter of the patients. There is early but incomplete improvement in the histological appearance of the jejunal mucosa, followed by a more gradual improvement over the ensuing months. In some patients with severe folate deficiency this small dose of folic acid appears to be insufficient, and symptomatic, haematological and intestinal improvement does not occur until the dose of folic acid is raised. Treatment with oral antibacterial drugs is also effective, but the manner of response differs from that seen with folic acid. Thus, symptomatic improvement is very slow and the haematological response is delayed. In an anaemic patient the reticulocyte rise may not occur until nearly 2 months after treatment has started, and in non-anaemic patients asthenia associated with evidence of folate deficiency may persist for over 3 months. Nevertheless, there is a steady improvement in intestinal absorption of fat and xylose and a particularly rapid improvement in the absorption of vitamin B12. There is also a gradual return of the jejunal mucosa to normal. Tropical sprue is a serious disorder, which without adequate treatment may end in chronic invalidism or even in death. The therapeutic actions of folic acid and antibiotics are complementary and these remedies should be given together. An early return to full health may then be confidently expected and relapse is rare. After recovery there is no contra-indication to the return of these patients to the tropics. In accordance with editorial policy no references have been included in this paper but those familiar with the literature of tropical sprue will recognize my debt to numerous authors.