Continuing Education Activity

Tropical sprue is a malabsorption syndrome characterized by chronic diarrhea, weight loss, and malabsorption of nutrients. It occurs in travelers to the tropical regions or the natives of the tropics. To avoid the complications and morbidity associated with this condition, it must be promptly diagnosed and treated. This activity reviews the evaluation and treatment of tropical sprue and highlights the interprofessional team's role in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of tropical sprue.
• Summarize the epidemiology of tropical sprue.
• Outline the typical physical findings associated with tropical sprue.
• Review some interprofessional strategies that can enhance care delivery and patient outcomes for cases of tropical sprue.

Introduction

Tropical sprue is a malabsorption syndrome characterized by acute or chronic diarrhea. It is seen in the people of the tropical region in the absence of any specific cause of malabsorption.[1] It is thought to be infectious in etiology with a contribution of environmental factors. It affects the small intestine and is characterized by malabsorption and multiple nutritional deficiencies, especially vitamin B12 and folic acid.[2][3] 

The disease was first described by William Hillary in 1759 in a population with chronic diarrhea from Barbados.[4] The term “sprue” was added later by Patrick Manson in 1880 to describe persistent diarrhea seen in the Asian countries.

Etiology

The exact causative agent for tropical sprue is unknown. Although there has been significant research and studies, little is known about the etiology of tropical sprue. It may be an interaction of multiple factors.[5] The most accepted theory is that following an acute intestinal infection episode, there is an injury to the mucosa of the small bowel. This leads to enterocyte damage leading to bacterial overgrowth and retardation of small-intestinal transit.[6] There have been studies that have shown the link between small intestine bacterial overgrowth and tropical sprue.[7]

The factors that seem to be responsible for the pathogenesis include intestinal damage due to a toxic agent, a deficiency, or an infection.

• Toxins: There has been no evidence found in multiple studies on any toxin being the causative agent. There was a hypothesis concerning the rancid fats as a possible cause. However, there is not enough evidence to support this.[8]
• Deficiency: It has been hypothesized that vitamin or mineral deficiency could be causing the disease. However, studies have shown that these are secondary to the disease and not the primary event causing the disease.[9]
• Infection: Studies have suggested infection to be causative for the disease. The factor favoring this is a long latent period between the exposure and the onset. This rules out toxins or a deficiency state.[10]

There has been no definitive evidence on the exact agent causing the disease. Studies have proposed bacterial and viral infections causing the disease.

1. Bacterial infection: The symptomatic resolution with anti-bacterial agents suggests that bacterial infections may be causative. However, contradictory to this, stool cultures from patients to look for bacterial infections have not shown any positive results.[11] The isolation rates of bacteria from stool samples have been comparable with the control groups. Further, the biopsies of the lesions have failed to demonstrate any bacterial growth in the intestinal mucosa.[12]
2. Viral infection: The viral illnesses cause enterocyte injury. They usually cause acute, self-limiting diarrhea but not chronic diarrhea lasting months, as seen in tropical sprue. Viruses like Reovirus, when inoculated into monkeys, caused diarrhea lasting up to weeks. The virus has not been successfully isolated from tropical sprue patients so far. Although evidence supports viral illness to be the causative agent, there is a need to develop techniques to isolate these agents.[13]

Epidemiology

The geographical distribution of tropical sprue is not fully explained. It is seen in the countries lying in the tropical region, predominant between the latitudes of 30°N to 30°S. However, all the countries within this geographical area are not affected.[14] It is prevalent in Puerto Rico, Haiti, and Cuba in the Western Hemisphere, with no rare or no cases in the Bahamas and Jamaica. In the Eastern Hemisphere, it is common in India and Pakistan.[15] 

The disease is rarely seen in the African continent, China, and the Middle East. There have been only a few cases in the USA.[16] The disease usually affects the indigenous population and travelers with a stay greater than 1 month in the endemic areas. It is rarely seen in visitors who stay for less than 2 weeks in these areas. The incidence is declining in India and Pakistan, likely secondary to improved hygiene and rampant use of antibiotics.[17] Males and females have the same prevalence of this condition. Although it is usually seen in adults, cases have been described in children too.

Histopathology

The biopsy findings will show normal mucosa in the early stages of the disease. However, as the disease progresses, there is a decrease in the villous height with eventual villous atrophy.[18] The other findings include increased villous crypt depth, nuclear immaturity, enlarged epithelial cells, intraepithelial lymphocytic infiltrates, increased inflammatory cells in the lamina propria, and accumulation of lipid underneath the basement membrane.[19]

History and Physical

Tropical sprue can present with a wide range of clinical features. The patient will typically be a resident of an endemic area or have a history of travel to an endemic area.[20] It has been seen that in several cases, the disease manifests a couple of years later after traveling to these areas. The initial event is usually traveler’s diarrhea, as seen in gastroenteritis. The bowel function does not return to normal, and the patient continues to have watery and foul-smelling diarrhea. It is associated with bloating, crampy abdominal pain, and loud borborygmi.[21] 

Fever is not a common finding. The patient will have steatorrhea. There will be a history of anorexia and weight loss. The patient will present with signs and symptoms of anemia: fatigue, pallor, or dyspnea on exertion secondary to B12 and folate deficiency due to malabsorption. The physical examination will be significant for the findings of glossitis, cheilitis, stomatitis, pedal edema, or protuberant abdomen. The patient may show signs of malnutrition, including anorexia, inability to concentrate, cold intolerance, fatigue and irritability, poor wound healing, and propensity for frequent infections.[22]

Evaluation

There are many diseases, both infectious and inflammatory, that can present with prolonged diarrhea and mimic tropical sprue. The diagnosis is made after the exclusion of these conditions.[23] The workup includes laboratory and stool tests. The CBC will be significant for megaloblastic anemia and low vitamin B12 and folate levels. Additional studies would show elevated homocysteine levels. The elevated methylmalonic acid levels will be seen specifically in vitamin B12 deficiency. The comprehensive metabolic panel may show electrolyte abnormalities in potassium, chloride, and sodium levels. Infectious studies with stool testing should be done to rule out infection with Giardia, Entamoeba, Strongyloides, and Cryptosporidium. Serological testing should be done to exclude Celiac disease.[24]

The studies to assess for malabsorption of different substances, including fat and D-xylose, should be performed. Stool studies may show increased fat content. The fat content of 6 g in 24 hrs is abnormal and is indicative of fat malabsorption. The d-xylose study will involve the oral intake of 25 g of D-xylose. A positive test will have a 1-hour serum level of less than 20 mg/dl and 5-hour urine levels of less than 4g.[3] 

Barium study will show increased caliber and thickening of mucosal folds.[25] The endoscopic evaluation will show changes in the duodenum and jejunum involving absent duodenal folds and the presence of scalloped folds and mucosal fissures. The findings of steatorrhea, including malabsorption of two substances (D-xylose, fat), and biopsy findings of villous atrophy, are adequate to make a diagnosis.[17] Some studies have shown the response to treatment is conclusive to confirm the diagnosis.

Treatment / Management

The management of tropical sprue is based on a multimodal approach. The treatment is usually done in the outpatient setting. It focuses on treating malnutrition via mineral and vitamin supplementation and correction of the underlying etiology. There are only a few patients that present to the ED with dehydration and weight loss. These patients will need urgent evaluation and initiation of fluid and electrolyte replacement.[26] The patients will need hospitalization in complicated cases, including:

• Severe dehydration,
• Electrolyte imbalance, and
• Symptomatic anemia

The treatment includes antibiotics, parenteral vitamin supplementation (vitamin B12 and folate), fluid therapy, electrolyte replacement, and blood transfusion in few cases. Combination therapy of Tetracycline 250 mg PO four times daily and oral folic acid 5 mg daily is given for 3 to 6 months.[27][28] In cases with no treatment or premature termination of therapy, there can be a relapse of the disease resulting in malabsorption. In endemic areas and patients with a relapsing course, the treatment duration may be extended up to a year.[29]

The patients should be evaluated for response to therapy. They should be regularly assessed for a couple of months after treatment to look for improvement of symptoms, weight gain, and correction of blood counts and electrolyte abnormalities.

Differential Diagnosis

The differential diagnosis is very extensive for patients with tropical sprue. Infectious conditions like Entamoeba histolytica, Giardia lamblia, Strongyloides stercoralis, Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanesis should be ruled out. The other causes for chronic diarrhea that should be looked into include lactose intolerance, short bowel syndrome, and bile salt deficiency. Patients should specifically be evaluated for the diseases causing fat malabsorption, including small intestinal bacterial overgrowth, pancreatic insufficiency, and celiac disease.[30]

Prognosis

The prognosis of tropical sprue is usually good. The response with treatment has been excellent in people who acquired it during travel to endemic regions, with rare or no recurrence. The recurrence rate in residents of endemic regions is reported to be around 20%, with frequent relapses over the years. However, recent studies have shown improvement in the trends.[29]

Complications

The morbidity and mortality associated with tropical sprue are low. The acute diarrheal illness is usually concerning. The severe electrolyte abnormalities and dehydration can be fatal and may lead to adverse outcomes. Complications include worsening anemia, vitamin deficiencies, and malnutrition leading to tissue damage and organ dysfunction. Prolonged illness with severe malnutrition can lead to death in patients with underlying comorbidities.[31]

Deterrence and Patient Education

The people traveling to the endemic areas and the tropical regions should be made aware of this condition. People should take all the appropriate steps to avoid exposure to enteric pathogens. Patients with prolonged diarrhea should not delay treatment and should consult medical personnel immediately.[30]

Enhancing Healthcare Team Outcomes

The most important approach to treating chronic diarrhea is to find a specific diagnosis. The differential should be kept broad. The workup should involve checking for anemia, electrolytes, infectious workup, stool studies, and serological studies to reach a diagnosis.[32] 

If the study results are inconclusive and no definitive diagnosis is reached, the patient should be referred to a gastroenterologist. The patient should undergo endoscopy and biopsies to reach a conclusive diagnosis to initiate appropriate therapy. Regular follow up visits should be scheduled with the primary physician and the gastroenterologist. Patents should be followed closely for monitoring the laboratory workup and assessing the response to treatment. Pharmacists can verify the dosing of pharmaceutical agents and check for interactions. The interprofessional healthcare teams should collaborate to ensure proper care for the patients.[6][33] [Level 5]