INTRODUCTION — Tropical sprue is a chronic diarrheal disease, possibly of infectious origin, that involves the small intestine and is characterized by malabsorption of nutrients, especially folic acid and vitamin B12. Sprue is an Anglicized form of the Dutch word "sprouw," a term applied in 1669 to a chronic diarrheal disease of unknown etiology accompanied by aphthous ulcers that was prevalent in Belgium [1]. The designation tropical sprue was coined in 1880 by Sir Patrick Manson, an English tropical disease expert working in China [2].
EPIDEMIOLOGY — Tropical sprue occurs in the tropics in a narrow band north and south of the equator to 30° latitude; however, the disease does not occur in all countries within this band [3]. In the Western hemisphere, tropical sprue is particularly prevalent in Haiti, the Dominican Republic, Puerto Rico, and Cuba, but is rare or absent in Jamaica and the Bahamas. Tropical sprue is also common in India, Pakistan, and to a lesser degree in Burma, Indonesia, Borneo, Malaysia, Singapore, and Vietnam, but is uncommon in Africa, China, and the Middle East [4]. Only rare cases of tropical sprue have been reported in the United States.
The disease affects indigenous populations as well as visitors to the tropics who stay for more than a month. Tropical sprue is seldom seen in travelers who visit an endemic area for less than two weeks.
Although data are limited, tropical sprue continues be among the most common causes of malabsorption in India, even though the incidence of tropical sprue appears to be declining [5-8]. This decline in incidence is likely due to improved public hygiene, the widespread use of antibiotics, and more accurate serologic tests for celiac disease, which can mimic tropical sprue in its presentation and pathology.
ETIOLOGY — A number of observations support the hypothesis that tropical sprue is an infectious disease [3,9-11]:
●In some patients, the disease follows an acute diarrheal illness typical of infectious enteritis [12].
●Epidemics of acute diarrhea in households and communities have been documented, particularly in India where the disease is common. The majority of such patients recover, while only some develop tropical sprue.
●Most patients with tropical sprue have overgrowth of toxigenic coliform bacteria (Klebsiella, E. coli, and Enterobacter) in the proximal small intestine, as discussed below.
●Treatment with broad spectrum antibiotics is usually curative (see 'Treatment and prognosis' below).
A role for bacterial overgrowth has been suggested in several reports:
●In one report, coliform bacteria were found in the upper small bowel in two-thirds of patients with tropical sprue, but also in one-half of controls, many of whom had chronic diarrhea without the typical diagnostic features of tropical sprue [13].
Similar results were found in another report in which 13 patients with tropical sprue were compared with 12 patients with irritable bowel syndrome and 12 healthy subjects [14]. Bacterial contamination in the proximal small bowel was observed in 10 of the 13 patients with tropical sprue compared with three with irritable bowel syndrome. The most commonly isolated bacteria in tropical sprue were Gram-negative aerobic bacilli.
●In a bacteriologic study from Puerto Rico, small bowel aspirates from patients with tropical sprue had a higher mean colony count of Klebsiella pneumoniae, Enterobacter cloacae, and Escherichia coli compared to Puerto Rican and American controls [11]. These organisms produced enterotoxins in culture that caused fluid secretion in the rabbit ileal loop model.
●In a small study, fat infusion into the proximal gut of patients with tropical sprue resulted in exaggerated "ileal brake" via increased secretion of the gut hormones peptide YY and neurotensin and slowing of the proximal small intestinal motility with resultant stasis causing bacterial colonization and overgrowth [15].
No specific causative infectious agent has been isolated from patients with tropical sprue. Many of the bacteriologic studies conducted in the tropics are confounded by the presence of significant growth of coliform bacteria in the small bowel of control patients. Furthermore, studies of diarrheal diseases in India and other subtropical resource-limited countries are often difficult to interpret because few individuals pass formed stools, as is the expected norm in Western developed countries.
To further evaluate the role of various microorganisms in the pathogenesis of tropical sprue, further study with polymerase chain reaction-based diagnostic techniques is needed.
PATHOGENESIS — Toxins and fermentation products produced by bacterial overgrowth can cause significant small bowel structural damage. In turn, the intestinal injury results in malabsorption of a variety of nutrients:
●Malabsorption of dietary carbohydrates results from reduced levels of the disaccharidase enzymes – lactase, sucrase, and maltase.
●Impaired fat absorption in the proximal small bowel results from the loss of the normal villous architecture and causes steatorrhea.
●Folate and vitamin B12 malabsorption lead to megaloblastic anemia. Fermentation products such as ethanol diminish folate absorption [3]. It has been suggested that folate deficiency is predominant early in the disease, and that vitamin B12 malabsorption occurs as the structural abnormalities progress distally to involve the terminal ileum. Vitamin D deficiency (leading to hypophosphatemia and hypocalcemia) and hypomagnesemia are also common, and are thought to reflect impaired absorption across the damaged small bowel mucosa.
In contrast with tropical sprue, folate deficiency does not result from chronic small bowel overgrowth or blind loop syndrome in patients from the United States. This may be related to a difference in the bacterial species colonizing the small bowel in the two conditions: facultative anaerobic, toxigenic coliforms in tropical sprue versus anaerobic nontoxigenic flora in small bowel overgrowth or blind loop syndrome [11]. In bacterial overgrowth of the small intestine, the bacteria generate folic acid, and serum folate concentrations are usually increased [16]. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis".)
CLINICAL FEATURES
Symptoms and signs — Tropical sprue should be strongly considered in patients with chronic diarrhea and nutrient malabsorption who have lived for more than one month in an area where tropical sprue exists. Diarrhea can first develop after a patient returns from the tropics.
Most patients have steatorrhea, typically in the range of 10 to 40 g of stool fat per day (normal less than 5 g per day). The chronic diarrhea is sometimes accompanied by cramps, gas, fatigue, and, with time, progressive weight loss. Auscultation of the abdomen may reveal hyperactive bowel sounds, and borborygmi is common.
Signs and symptoms of malabsorption are common, and include glossitis and cheilitis, protuberant abdomen, and pedal edema.
Patients may report fatigue and demonstrate pallor due to megaloblastic anemia. However, subacute combined degeneration of the spinal cord and other neurologic manifestations of vitamin B12 deficiency have not been described in patients with tropical sprue. (See "Treatment of vitamin B12 and folate deficiencies".)
Similarly, tetany and carpopedal spasm, due to hypocalcemia and vitamin D deficiency, are rare.
Laboratory features — Megaloblastic anemia secondary to folate deficiency is maximal three to four months after disease onset, producing a hematocrit less than 30 and an elevated mean corpuscular volume. In the presence of longstanding vitamin B12 deficiency, pancytopenia may be present. Folate deficiency appears to be more common than B12 deficiency in India and Southeast Asia, whereas the reverse is true in the Caribbean [17]. (See "Treatment of vitamin B12 and folate deficiencies".)
Other laboratory abnormalities, including hypoalbuminemia, are present in chronic, severe disease (due to malnutrition and/or protein-losing enteropathy), mild hypocalcemia, and vitamin D deficiency. The D-xylose absorption test, if available, is often abnormal. (See "Approach to the adult patient with suspected malabsorption".)
Radiologic features — Radiologic examinations of the small intestine in tropical sprue reveal nonspecific changes of dilation, thickening and edema of mucosal folds, and retention or secretion of fluid in the lumen which dilutes the barium column during its passage through the small intestine [18,19]. These changes are nonspecific and are also described in celiac disease, olmesartan-associated enteropathy, scleroderma, and hypoalbuminemia and anasarca of any etiology [20].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of tropical sprue includes other infections, celiac disease and other causes of malabsorption.
●The term "tropical enteropathy" has been proposed to describe structural abnormalities of the small intestine observed in residents of the tropics where tropical sprue is common, but without the typical symptoms of classic tropical sprue. The findings include shortened or blunted villi and mild lymphocytic infiltration, which may be accompanied by subclinical malabsorption of carbohydrates, fat, and vitamin B12. These changes are thought to arise from low-grade infection of the small bowel with bacteria acquired from contaminated food and water [5].
●Infections with Entamoeba histolytica, Giardia lamblia, Strongyloides stercoralis, Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanensis may mimic tropical sprue.
●Intestinal lymphoma can mimic tropical sprue and celiac disease, and occasionally coexists with the latter disorder. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
●AIDS, with or without intestinal opportunistic infections, should be considered in patients with known HIV risk factors.
●Malabsorption secondary to intestinal scleroderma, small bowel bacterial overgrowth, and blind loop syndrome should be excluded. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)
●Celiac disease (gluten sensitive enteropathy) and tropical sprue have overlapping clinical, endoscopic, and histological changes and there is no single diagnostic feature for distinguishing celiac disease from tropical sprue except for celiac specific serological tests [21]. Patients with tropical sprue do not have antibodies to tissue transglutaminase or anti-endomysial antibodies that are found in patients with celiac disease. In some cases, overlap between these entities may require genotyping for HLA DQ-2 and DQ-8. HLA-DQ-2 or DQ-8 are present in almost all patients with celiac disease, and thus their absence would exclude celiac disease. (See "Diagnosis of celiac disease in adults".)
●Tropical pancreatitis is a form of idiopathic chronic pancreatitis of the Indian subcontinent and Africa which may produce malabsorption, diarrhea, and wasting that mimic tropical sprue. (See "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Idiopathic'.)
DIAGNOSIS — The diagnostic possibilities in patients with diarrhea acquired in the tropics are quite extensive since a large number of infectious and inflammatory diarrheas can mimic tropical sprue (see 'Differential diagnosis' above). Therefore, exclusion of these causes of diarrhea is necessary to establish a diagnosis in patients with a clinical presentation that is suggestive of tropical sprue. Stool tests and serologic studies can help exclude other causes of diarrhea. If these are negative, upper endoscopy with biopsy of the small bowel should be performed. However, small bowel biopsy findings in sprue are supportive of the diagnosis, but not diagnostic of tropical sprue. The diagnosis of tropical sprue is ultimately confirmed by a response to treatment.
Stool tests and serology — Careful stool and serologic testing may be required to exclude infection with Entamoeba histolytica, Giardia lamblia, Strongyloides stercoralis, Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanensis. (See appropriate topic reviews.)
Serologic tests should be performed to rule out celiac sprue. (See "Diagnosis of celiac disease in adults", section on 'Serum antibody assays'.)
In immunocompromised individuals or with HIV risk factors, HIV and associated opportunistic infections should be ruled out. (See "Screening and diagnostic testing for HIV infection" and "Evaluation of the patient with HIV and diarrhea".)
Endoscopy and mucosal biopsy — Upper endoscopy with biopsy of the small bowel (duodenum) should be performed in patients with a clinical presentation suggestive of tropical sprue in whom stool tests and serology have excluded other causes.
Tropical sprue involves the entire small bowel; in some patients, mild colonic involvement can also be demonstrated [17]. Gross findings at endoscopy include flattening of duodenal folds and "scalloping." The latter finding was originally thought to be pathognomonic of celiac disease (picture 1), but also occurs in tropical sprue and other small bowel infections [22].
The main histologic features are shortened, blunted villi and elongated crypts with increased inflammatory cells including lymphocytes, plasma cells, and eosinophils in the lamina propria, although these features are not specific to tropical sprue [23-26]. Early in the illness, these morphologic changes are most pronounced in the upper small intestine but, with time, the ileum becomes involved, although usually not as severely as the duodenum and jejunum [27].
Histologic features of tropical sprue closely mimic celiac disease but there are a few features which might suggest one diagnosis over the other [21]. In celiac disease, the intraepithelial lymphocytosis occurs in a crescendo pattern (mostly in the upper third of villous mucosa) in contrast with tropical sprue, where intraepithelial lymphocytosis occurs in a decrescendo pattern (basal one third of the villi or mucosal crypts). Loss of tall columnar cell architecture and goblet cells at the villous tip and pseudo-stratification of epithelial cell nuclei are more common in celiac disease. Extent of epithelial damage is more likely to be focal or patchy in tropical sprue as compared with celiac disease. While laminal propria inflammation is very common in both the entities, eosinophilic infiltration is twice as likely in tropical sprue. In addition, blunting of the villi is more severe in celiac disease with complete or nearly complete absence of villi, producing a flat mucosa free of any villous protrusions.
Villous atrophy also occurs in other small bowel diseases, including AIDS enteropathy, parasitic infections with Giardia lamblia or Cryptosporidium parvum, Whipple's disease, small bowel bacterial overgrowth or stasis syndrome, and intestinal lymphoma. Specific histologic diagnosis of these conditions requires identification of infectious microorganisms, malignant lymphocytes, or other specific diagnostic features absent in patients with tropical sprue. (See appropriate topic reviews.)
TREATMENT AND PROGNOSIS — While spontaneous recovery from mild tropical sprue may occur, most authorities recommend treatment with tetracycline (250 mg PO four times daily) or doxycycline (100 mg once or twice daily) plus folic acid (5 mg per day) for three to six months. Even on this regimen, relapses or reinfection occur in up to 20 percent of patients living in the tropics [28].
Oral folic acid replacement alone effectively reverses most of the signs and symptoms of disease [29]. Within several weeks, most patients treated with pharmacologic doses of folic acid (1 to 5 mg per day) show improvement in megaloblastic anemia, weight gain, and an increased sense of well-being. This dramatic symptomatic response to oral folate therapy is observed so frequently in tropical sprue and so rarely (if ever) in other forms of small bowel disease with megaloblastic anemia that it is considered to be diagnostic of the illness. Folate therapy also corrects many of the morphologic abnormalities in the small intestine, suggesting that the etiology of the villous atrophy in tropical sprue is related in part to folate deficiency.
Patients with coexistent vitamin B12 deficiency may require intramuscular injection of 1000 µg of vitamin B12 weekly to achieve complete reversal of megaloblastic anemia [30]. If steatorrhea is present, restriction of long-chain fatty acid in the diet and substitution with medium chain triglycerides can provide extra calories.
Despite the favorable initial response to folate therapy, clinical and morphologic abnormalities of the intestine persist in 50 percent of patients treated with folate alone [3,9]. The administration of tetracycline for three to six months completely reverses the intestinal and hematologic abnormalities of tropical sprue in a majority of patients. The duration of therapy should be based on normalization of hemoglobin levels and improvement in steatorrhea and diarrhea. An alternative to tetracycline for patients who cannot take tetracycline (pregnant women, children, or those with allergy to tetracycline) is one of the poorly absorbable sulfonamide drugs (sulphaguanidine, succinylsulfathiazole, phthalylsulfacetamide or phthalylsulfathiazole) for six months [31].
SUMMARY AND RECOMMENDATIONS
●Tropical sprue is a chronic diarrheal disease, possibly of infectious origin, that involves the small intestine and is characterized by malabsorption of nutrients, especially folic acid and vitamin B12. (See 'Introduction' above.)
●While no single identifiable pathogen has been identified as the cause of tropical sprue, it is likely that persistent overgrowth in the small intestine of coliform bacteria that elaborate toxins and fermentation products like ethanol eventually causes significant small bowel structural damage and chronic diarrhea. (See 'Etiology' above and 'Pathogenesis' above.)
●Tropical sprue should be suspected in patients with chronic diarrhea and nutrient malabsorption who have lived for more than one month in an area where tropical sprue exists. Patients may have associated cramps, gas, and fatigue and, with time, progressive weight loss. Signs of malabsorption are common including glossitis and cheilitis, protuberant abdomen, pallor, and pedal edema. (See 'Clinical features' above.)
●The differential diagnosis of tropical sprue includes infection, celiac disease, intestinal scleroderma, small bowel bacterial overgrowth, blind loop syndrome, lymphoma, and tropical pancreatitis. (See 'Differential diagnosis' above.)
●Careful stool and serologic testing may be required to exclude infection. The key diagnostic test in tropical sprue is upper endoscopy with small intestinal mucosal biopsy of the duodenum. The major histologic findings are shortened, blunted villi and elongated crypts with increased inflammatory cells in the lamina propria, although these findings are not specific to tropical sprue. (See 'Endoscopy and mucosal biopsy' above.)
●We suggest treating patients with tropical sprue with tetracycline (250 mg PO four times daily) plus folic acid (5 mg/day) for three to six months (Grade 2A). Even on this regimen, relapses or reinfection occur in up to 20 percent of patients living in the tropics. (See 'Treatment and prognosis' above.)
