Correspondence *Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Bioinformatics Building, CB#7080, Chapel Hill, NC 27599, USA

Email hherf@med.unc.edu

The case

A 40-year-old male was admitted for evaluation of recurrent gastrointestinal bleeding. He had recently recovered from heart surgery and had been passing tarry stool for several days, but had otherwise been well.

His medical history was remarkable for pentalogy of Fallot (a congenital heart defect with five anatomical components), as a result of which he had been operated on several times in the past 20 years. The last operation, performed 2 weeks before admission, had been reconstruction of the right ventricular outflow tract with a pulmonary homograft and a patch plasty, to correct a pulmonary valve stenosis (pulmonary valve area of 0.9 cm²) that was diagnosed by right heart catheterization and cardiac MRI. His medical history also included Mosaic Down syndrome which manifested with facial abnormalities (flat face, flat nasal bridge, orbital hypertelorism, epicanthal folds, small mouth) and a small stature (163 cm, 58 kg). The patient had also been diagnosed with type 2 diabetes 2 years before admission and had suffered from immunoglobulin deficiency for several years.

On admission the patient's abdomen was soft and tender, and a mild edema of both legs was visible. Rectal examination revealed tarry stool, which was positive for occult blood. For at least 2 months before admission he had been treated with the potassium-sparing diuretic triamterene (100 mg daily), omeprazole (40 mg daily), digoxin (0.1 mg daily), and repaglinide (0.5 mg three times a day before meals) for his type 2 diabetes.

Laboratory test results revealed mild leukopenia with concomitant lymphopenia in addition to reduced hemoglobin and albumin serum concentrations (Table 1). Esophagogastroduodenoscopy revealed multiple polypoid lesions in the duodenum and the mucosal surface was eroded (Figure 1). Histology of duodenal biopsies revealed an inflammatory leukoplasmoid cellular infiltration and, in addition, isolated focal lymphangiectasias on the tips of the villi. Colonoscopy was performed to rule out lower gastrointestinal bleeding, with unremarkable results. The patient was switched to a higher PPI dosage (omeprazole 40 mg twice daily) and, as no further bleeding occurred, he was transferred to a rehabilitation center to facilitate his recovery from heart surgery.

Figure 1 Endoscopic image of a 40-year-old male with intestinal lymphangiectasia, concurrent protein-losing gastroenteropathy and recurrent gastrointestinal bleeding.

The image shows edematous duodenal folds with ulcerations and diffuse bleeding.

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Table 1 Laboratory test results of a 40-year-old male with intestinal lymphangiectasia, concurrent protein-losing gastroenteropathy and recurrent gastrointestinal bleeding.

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He was readmitted to hospital 1 week later with a hemoglobin concentration of 4.9 g/dl. A small-bowel enteroscopy, performed using a pediatric colonoscope, revealed additional focal lymphangiectasias in the proximal jejunum (Figure 2). Findings in the duodenum were identical to those of the previous upper-gastrointestinal endoscopy. A review of all previous biopsies revealed that the mucosa of the small intestine contained an inflammatory infiltrate that consisted mainly of T lymphocytes, and that dilated lymphatic vessels were present. Polymerase chain reaction confirmed that there was no clonal expansion of T lymphocytes in the duodenal mucosa, which ruled out a diagnosis of gluten-sensitive enteropathy, gastrointestinal lymphoma, Crohn's disease, or Whipple's disease. Video-capsule endoscopy revealed that there was fresh blood in the duodenum and jejunum without a visible source. Further laboratory analyses revealed that the patient's coagulation parameters were in the normal range. Levels of serum vitamin B₁₂, IgG, IgA and IgM were reduced (Table 1). Serum IgE concentration was within the normal range (12–240 g/l). Screening for the presence of autoantibodies revealed weak perinuclear antineutrophilic cytoplasmic antibody staining. Other autoantibodies (antinuclear antibody, double-stranded DNA, cytoplasmic antineutrophil cytoplasmic antibody) could not be detected. In consideration of the immunoglobulin deficiency, an extensive screening for viral or bacterial infections was performed. Infection with Yersinia, Salmonella, Giardia lamblia, Mycobacterium tuberculosis or fungal pathogens was excluded, as was infection with cytomegalovirus, herpes simplex virus, Epstein-Barr virus or HIV. Transesophageal and transthoracic echocardiography were performed, to exclude concomitant right heart insufficiency, and revealed a right ventricular hypertrophy and a pulmonary arterial pressure gradient of 23 mmHg. A xylose absorption test was performed, which indicated severe malabsorption. ^99mTechnetium-labeled human serum albumin (^99mTc-HSA) scintigraphy revealed a marked enhancement of the tracer in the region of the terminal ileum after 1.5 and 3 h, which indicated a protein leakage into this region (Figure 3). Lymphoscintigraphy performed using ^99mTc-labeled nanocolloid revealed no migration of this tracer from injection sites between the first and second, and the second and third digits of both feet, indicating severe lymphostasis (Figure 4). A CT scan of the abdomen showed multiple enlarged abdominal lymph nodes and splenomegaly, whereas a CT scan of the thorax was unremarkable. To exclude lymphoma, a bone-marrow biopsy and aspiration were performed, both of which were negative. As there was extensive abdominal lymphadenopathy, laparoscopy was performed and several abdominal lymph nodes were resected. The lymph node histology revealed reactive hypertrophy and severe lymphangiectasia but no signs of lymphoma or Whipple's disease.

Figure 2 Histologic image from a jejunal biopsy from the case patient.

The arrows indicate dilated lymphatic ducts at the tips of the villi (stained with hematoxylin and eosin, magnification 200).

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Figure 3 ^99mTc-labeled human serum albumin scintigraphy images for the case patient: (A) 1 h and 15 min postinjection, (B) 1 h and 30 min postinjection, (C) 1 h and 45 min postinjection and (D) 3 h postinjection.

A loss of albumin into the ileum can be seen starting 1 h and 30 min to 1 h and 45 min (arrow) after injection of the tracer. The loss of albumin is clearly visible after 3 h (arrow). Abbreviations: ^99mTc-HSA, ^99mTechnetium-labeled human serum albumin; p.i., postinjection.

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Figure 4 Lymphoscintigraphic image using ^99mTc-labeled nanocolloid for the case patient.

No migration of the tracer from the point of injection in between the first and second and the second and third digits of both feet can be seen after 3 h. Serial images were obtained with the same result up to 24 h.

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After reviewing all the diagnostic results, the patient was diagnosed with intestinal lymphangiectasia and concomitant protein-losing gastroenteropathy.

Therapy with a high-dose steroid (60 mg prednisolone daily) was initiated and the patient was put on a low-fat diet enriched with medium-chain triglycerides; however, the patient continued to pass tarry stool and approximately 2–3 packed red blood cell transfusions had to be carried out every 2–3 days for 10 days. In addition, the patient developed massive lymphedema of both legs. The serum albumin level remained markedly low (19.3 g/l) despite the replacement of up to 80 mg albumin per day. Another laparotomy and intraoperative enteroscopy were performed: multiple small ulcers were detected throughout the small intestine and sutured. A massive dilatation of the thoracic duct was also found. A lymphovenous anastomosis to decompress the thoracic duct was not surgically possible. Following a period of a few days, during which the patient showed no signs of intestinal bleeding, the intestinal bleeding recurred and the patient developed severe sepsis with renal and pulmonary failure. Despite broad antibiotic and antimycotic therapy the patient died of multiple organ failure. The relatives of the patient declined a postmortem autopsy.

Discussion of diagnosis

Protein-losing gastroenteropathy encompasses a variety of gastrointestinal disorders in which there is an excess loss of serum proteins into the gastrointestinal tract. In most patients, these disorders lead to concomitant hypoproteinemia and hypogammaglobulinemia, which are the laboratory hallmarks of this disease (Box 1). Some protein-losing enteropathies are also associated with fat or carbohydrate malabsorption, which can lead to fat-soluble vitamin deficiencies. Clinically, a lower extremity edema secondary to the diminished colloidal osmotic pressure of the plasma is frequently found.

The gastrointestinal tract does not normally contribute greatly to the catabolism of plasma proteins, accounting for only about 10% of the normal turnover of albumin and gammaglobulins; however, once plasma proteins pass into the gastrointestinal tract they are rapidly degraded to amino acids and partially reabsorbed into the portal circulation. An increase in intestinal leakage of plasma proteins can occur by two mechanisms,¹ one of which is mucosal injury with or without erosions and ulcerations (e.g. in IBD, celiac disease, lupus erythematosus or giant hypertrophic gastritis [Ménétrier's disease]). Such leakage also can occur through increased lymphatic pressure in the gut, either as a result of occlusive diseases of the lymphatic system or after dilatation of the lymph vessels.

Protein-losing gastroenteropathy through increased lymphatic pressure in the gut can occur as a primary cause in congenital intestinal lymphangiectasia, or as a secondary cause in various diseases, including constrictive pericarditis, Whipple's disease, Crohn's disease, lymphoma, or sarcoidosis. In contrast to glomerulopathies, where the protein loss is determined by the molecular weight of the protein, the leakage of individual serum proteins in patients with protein-losing gastroenteropathy is independent of molecular weight.² Other serum components such as iron, lipids, or trace elements, can also be lost into the gut lumen, as was found in this patient. Hypoproteinemia occurs if the extent of the net enteral loss of protein is greater than the capacity of the liver to resynthesize the proteins in question. The serum concentration of proteins such as albumin and IgM, IgA and IgG, which have a slow catabolic rate, is typically decreased. By contrast, there is normally little change in the serum concentrations of proteins that have rapid turnover rates, such as insulin or IgE. In patients with lymphatic obstruction, lymphocytopenia can also be seen in conjunction with the hypoproteinemia described above.

Differential diagnosis

The differential diagnosis in this case is very broad, and includes viral and bacterial infections, autoimmune diseases, right heart failure, gastrointestinal lymphoma, Crohn's disease and Whipple's disease. As described above, the diagnosis and the underlying etiology can only be reached by a stepwise approach that employs upper gastrointestinal endoscopy with duodenal and small-bowel biopsies, imaging studies such as CT of the abdomen, lymphoscintigraphy and ^99mTc HSA-scintigraphy, and a broad laboratory evaluation to exclude infectious and autoimmune diseases.

Treatment and management

Treatment of protein-losing gastroenteropathy should be aimed at correcting the underlying disease.^{9, 10} In congenital intestinal lymphangiectasia, enteric protein loss is usually diminished by a low-fat diet, which reduces the intestinal lymphatic transport of triglycerides and, therefore, reduces the stimulation of the intestinal lymph flow.¹¹ Octreotide, which is a somatostatin analog, could also be administered; however, this treatment is relatively costly. If primary intestinal lymphangiectasias are localized to bowel segments, resection of these segments can improve the clinical symptoms or a lymphovenous anastomosis can be established to divert lymph from the dilated intestinal lymphatic vessels to the venous system.¹² In this case, however, such an anastomosis was not technically possible and a partial resection of the bowel was unfeasible, owing to extensive ulceration of the entire length of the small bowel.

Conclusions

This case describes the clinical features of protein-losing gastroenteropathy, which is caused by a diverse group of diseases that are associated with a loss of serum proteins into the intestine. The observed intestinal lymphangiectasias (the pathophysiology of which is poorly understood) were the cause of the severe protein loss and the gastroenteropathy in this case. The development of a protein-losing gastroenteropathy has been previously described in patients with or without prior heart surgery.^{13, 14} Both types of patient suffered only a mild to moderate pericardial constriction, owing to a tight adherence between the visceral and parietal layers of the pericardium that did not result in discernible pressure abnormalities in the right heart. Owing to the numerous heart operations and the focal nature of the lymphangiectasia in this patient (a focal presentation is often seen in patients with acquired or secondary lymphangiectasia, in contrast to those with congenital disease who typically present with diffuse lymphangiectasia), this might also have been the case in the case patient. In addition, the patient had several signs of Hennekam syndrome, which is normally defined as intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia, and face, as well as facial anomalies and mild growth retardation.¹⁴ Seizures and moderate mental retardation are sometimes also present. Profound lymphangiectasia in the mesenteric lymph nodes and long-standing immunoglobulin deficiency favor a diagnosis of congenital lymphangiectasia. Unfortunately, the relatives of this patient refused a postmortem autopsy, which prevented further verification of the pathophysiology of the protein-losing gastroenteropathy.

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Subject areas under which this article appears: Small intestine | Gastrointestinal bleeding