Tropical Sprue

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] Studies 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: No evidence has been 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, but studies have proposed bacterial and viral infections as the cause.

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: 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 for weeks. The virus has not been successfully isolated from tropical sprue patients so far. Although evidence supports the claim that viral illness is the causative agent, techniques must be developed 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, not all the countries within this geographical area are 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 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 lamina propria inflammatory cells, and lipid accumulation underneath the basement membrane.[19]

History and Physical

Tropical sprue can present with a wide range of clinical features. The patient typically resides in an endemic area or has 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 has steatorrhea. There is a history of anorexia and weight loss. The patient presents signs and symptoms of anemia: fatigue, pallor, or dyspnea on exertion secondary to B12 and folate deficiency due to malabsorption. The physical examination is significant for glossitis, cheilitis, stomatitis, pedal edema, or protuberant abdomen findings. 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 complete blood count is significant for megaloblastic anemia and low vitamin B12 and folate levels. Additional studies would show elevated homocysteine levels. Elevated methylmalonic acid levels can be seen specifically in people with 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]

Studies should be performed to assess the malabsorption of different substances, including fat and D-xylose. Stool studies may show increased fat content. The fat content of 6 g in 24 hrs is abnormal and indicates fat malabsorption. The d-xylose study involves the oral intake of 25 g of D-xylose. A positive test has a 1-hour serum level of less than 20 mg/dl and 5-hour urine levels of less than 4g.[3] Barium studies show increased caliber and thickening of mucosal folds.[25] The endoscopic evaluation shows 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 2 substances (D-xylose, fat) and biopsy findings of villous atrophy, are adequate to diagnose.[17] Some studies have shown that the response to treatment is conclusive in confirming 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 correcting the underlying etiology. There are only a few patients that present to the ED with dehydration and weight loss. These patients need urgent evaluation and initiation of fluid and electrolyte replacement.[26] The patients need hospitalization in complicated cases, including:

• Severe dehydration
• Electrolyte imbalance
• Symptomatic anemia

The treatment includes antibiotics, parenteral vitamin supplementation (vitamin B12 and folate), fluid therapy, electrolyte replacement, and blood transfusion in a few cases. Combination therapy of Tetracycline 250 mg PO 4 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. The treatment duration may be extended to a year in endemic areas and patients with a relapsing course.[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.(B3)

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 of 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 to 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. 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]