Protein-losing enteropathy (PLE) is characterized by excessive loss of protein through the gastrointestinal (GI) tract, either because of systemic or GI disorders.1 The protein loss in PLE is nonselective but is usually detected as hypoalbuminemia because of the slow turnover rate of albumin. In cases of severe hypoproteinemia, the clinical picture may be complicated by ascites, pleural and/or pericardial effusion and edema and may also be associated with increased risk of infections.
Giardia lamblia, a protozoan parasite, is one of the most common causes of diarrheal disease and is relatively prevalent in developing countries where sanitary conditions are poor.2 Giardiasis may present with a wide spectrum of clinical manifestations. However, selective PLE has rarely been documented in children with chronic Giardia infection.3–5 This study reports 3 children who presented with severe hypoalbuminemia and intestinal protein loss in association with endoscopic and histopathologic evidence of giardiasis, with resolution after treatment.
PRESENTATION OF 3 CASES
Case 1 involved a previously healthy, 13-month-old boy with watery diarrhea and intermittent vomiting for 3 weeks and swelling of the face and abdomen for 1 week. Case 2 involved a 14-month-old girl who was referred to our hospital with suspected nephrotic syndrome. She had diarrhea, facial swelling and a distended abdomen for 2 weeks. Case 3 involved a 19-month-old boy with vomiting, diarrhea and swelling of the abdomen for 10 days before admission. Height-for-age and weight-for-height Z scores in case 1 were −0.6 and 0.95, respectively. Mild acute malnutrition was identified in cases 2 and 3 based on weight-for-height Z scores of −1.1 and −1.4, respectively. Physical examination of all 3 patients revealed pale skin, generalized edema and a distended abdomen without ascites or organomegaly. Laboratory results were similar, and all 3 patients had anemia, hypoproteinemia and hypoalbuminemia (Table 1). Biochemical examinations and repeated urine analysis excluded proteinuria and hepatic dysfunction, but serum vitamin B12, vitamin D and ferritin levels were lower than normal in all patients. Serum immunoglobulin levels were within normal limits, and sweat chloride tests and serology for celiac disease did not show any abnormality. Stool cultures failed to reveal pathogenic organisms in all patients. Although Giardia cysts and trophozoites were only detected on microscopic examination of the stool in case 3, stool analyses for Giardia antigen were repeatedly positive in all 3 patients. Fecal α-1 antitrypsin testing of stool samples was consistent with PLE in cases 2 and 3, but this test could not be performed in case 1. Upper GI endoscopy was performed in all patients to evaluate the intestinal mucosa. In case 1, multiple small erosions were observed in the duodenum, and duodenal biopsies showed villous flattening and significant inflammatory cell infiltration, mostly composed of lymphocyte and plasmocytes in the lamina propria (Figure 1A). Giardia trophozoites were detected by direct microscopic examination of duodenal aspirate. In case 2, examination of the upper GI tract revealed no mucosal abnormality, but histopathologic examination of duodenal biopsies identified villous clubbing and patchy lymphoplasmacytic and eosinophilic inflammation. Upper GI endoscopy showed edematous duodenal mucosa in case 3, with subtotal villous atrophy and lymphoplasmocytic inflammation on duodenal biopsy.
Treatment and Follow-Up
On admission, intravenous albumin infusions were administered because of symptomatic severe hypoalbuminemia in all 3 patients. Metronidazole 20 mg/kg/day for 15 days was commenced in all patients. Dietary modification with high protein content was recommended, and vitamin B12, vitamin D and iron were also supplemented. After metronidazole treatment, signs, symptoms and laboratory findings were found to be dramatically improved. The first and second cases were reevaluated with upper GI endoscopy 3 months after cessation of treatment, and histopathologic examination demonstrated resolution of previous findings (Figure 1B). All patients have been asymptomatic, and their laboratory examinations have been normal for the last 12 months of follow-up (Table 1).
PLE is characterized by severe loss of serum protein into the intestinal lumen; therefore, hypoproteinemia is the most prominent clinical finding.1 The differential diagnosis of hypoproteinemia also includes inadequate dietary intake, impaired synthetic capacity of the liver, proteinuria, lymphatic obstruction and widespread inflammation of vasculature, as in sepsis. Two of our patients had mild malnutrition, but this finding could not account for severe hypoalbuminemia. Fecal α-1 antitrypsin is a noninvasive test for the diagnosis of PLE6 and was found to be higher than normal in 2 of our 3 patients. Thus, PLE was suspected because of concomitant GI signs and symptoms in the absence of proteinuria or liver dysfunction.
Various causes of PLE are mostly secondary to enteric lymphatic obstruction, cardiac disorders associated with increased systemic venous pressure and mucosal inflammation, in association with defective enterocyte barrier function.6 Several GI pathogens (Strongyloides stercoralis, Salmonella, Shigella, rotavirus) including G. lamblia can damage the intestinal mucosa and impair the enterocyte barrier function by disrupting the epithelial brush border and tight junctions. Giardiasis usually presents with mild symptoms such as abdominal pain and chronic diarrhea in immunocompetent individuals. However, children who are repeatedly exposed to contaminated water sources or those who are immunocompromised may present with a variety of symptoms, ranging from malabsorption to severe villous atrophy. Diarrhea was the predominant complaint in our patients. Abdominal distention and edema were other findings compatible with malabsorption. Anemia, vitamin deficiencies and low serum ferritin level may be associated with inadequate dietary intake or malabsorption, or both. Iron deficiency is a known complication of giardiasis; consistent with the literature, severe anemia was observed in all 3 cases.7
Examination of concentrated, iodine-stained wet stool preparations and modified trichrome-stained permanent smears has been the conventional approach to the diagnosis of Giardia infection. However, intermittent excretion of cysts and trophozoites in feces might hinder the detection of parasites despite multiple stool examinations. Therefore, molecular tests based on enzyme-linked immunosorbent assay for detection of Giardia antigens have high sensitivity and specificity and should be considered for initial diagnostic testing. One study compared microscopic examination of stool samples for parasites with stool antigen tests, and the sensitivity of the tests was reported as 83% and 95%, respectively.8 Repeated stool examination for Giardia antigen was positive in all of our cases, and trophozoites were recognized on microscopic examination of feces in case 3. The reported sensitivity of stool examination is 85%, and repeated examinations contributed to the accuracy, while the microscopic analysis of duodenal aspirate for Giardia trophozoites had a sensitivity of 44%.9 As a routine endoscopic procedure in our unit, duodenal aspirates are collected for microscopic analysis for Giardia trophozoites, which were detected in case 1. Identification of trophozoites within small intestinal biopsy specimens may require careful examination of multiple microscope fields, while direct sampling of duodenal aspirate in the same patient may improve sensitivity.10
Giardiasis is a known cause of non-celiac villous atrophy.2,3 Consistent with the literature, duodenal biopsies of all cases in our study demonstrated villous abnormalities such as total or subtotal atrophy of intestinal villi and lymphoplasmocytic inflammation in the lamina propria of the intestinal epithelium. After treatment, follow-up endoscopies performed in 2 of the 3 patients demonstrated complete resolution of histopathologic findings. Thus, we clearly identified a causal association between PLE and giardiasis based on symptom resolution, in addition to laboratory and histopathologic findings. To our knowledge, this is the second published report demonstrating histopathologic recovery after treatment of Giardia infection.3
In conclusion, Giardia is a common cause of diarrhea, particularly in developing countries. It may rarely be complicated by PLE in association with common GI symptoms. Giardiasis is a treatable cause of PLE, which can be associated with severe comorbidities. Early recognition and treatment of Giardia infection presenting with PLE results in rapid clinical, laboratory and histopathologic recovery, thus, preventing malnutrition, particularly in growing children.
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