Protein-losing enteropathy in patients with Fontan circulation: is it triggered by infection?

A girl with situs inversus, a double outlet right ventricle, pulmonary atresia and D-transposition of the great arteries who had previously undergone cardiac surgery at the age of 3 months (Blalock–Taussig shunt) and at the age of 3 years (bidirectional Glenn anastomosis) underwent a Fontan-type operation (total cavopulmonary connection, with intra-atrial tunnel) at the age of 4.5 years. She was discharged 14 days after surgery, prescribed digitoxin, spironolactone, frusemide, acetylsalicylic acid and alprazolam. Six months later the patient's serum protein and albumin levels were within normal limits (Fig. 1a). The laboratory findings are summarised in Table 1 (time range A, before PLE onset).

Eight months later, the patient was admitted to hospital with rotavirus and streptococcal tonsillitis. She subsequently developed oedema, and low serum protein (Fig. 1a) and γ-globulin concentrations. The patient also had an elevated α₁-antitrypsin level in the stool. The leukocyte count was normal but the neutrophils were left-shifted. There was no proteinuria. The laboratory findings at this time are summarised in Table 1 (time range B). The patient recovered and was discharged after 4 weeks.

Three weeks later (i.e. ~10 months after the total cavopulmonary connection procedure), the patient was referred to our Cardiac Centre because she had suspected infection, again accompanied by oedema and markedly reduced exercise tolerance. On admission the patient was febrile and had oedema of the legs, arms and face. The protein level was very low, and the C-reactive protein concentration (normal value < 1 mg/l) (Fig. 1b) and the neutrophil count (normal range, see Table 1) were increased. Serum albumin (Fig. 1a), γ-globulin and IgG concentration (Fig. 2b) was decreased. Although the serum anti-EBV IgG level (Fig. 2b) was increased twofold to threefold, the IgA and IgM concentration was normal. The lymphocyte count was decreased (Table 1). The serum concentration of IL-8 was increased (52.5 pg/ml; normal range, < 5 pg/ml). Finally, complement activation (Fig. 1b), and CD45 (Fig. 2a), CD11a (LFA-1; data not shown) and CD11b (Mac-1; data not shown) expression on neutrophils were elevated.

The patient was at this time treated with protein (human albumin, 4 × 50 ml 20%/day), a single immunglobulin infusion (Sandoglobin^®), C1-esterase-inhibitor (Berinert^®) and prednisolon (3 × 5 mg/day per orally; during the early phase, in addition, 10–20 mg intravenously) for 5 days and with antibiotics (Cefotiam^®) for 6 days. The serum albumin level normalised while the protein level was still at the lower end of the normal range and below pre-PLE levels (Fig. 1a). The serum concentration of C-reactive protein was not increased after 5 days of treatment. Endoscopy and gastric and intestinal biopsies showed no signs of lymphangiectasia. Cardiac catheterisation and angiography revealed minimal stenosis of the right pulmonary artery (pressure gradient, 2 mmHg). Systemic venous and right atrial pressure were moderately increased (mean, 11 mmHg).

The patient was followed up for the next 5 months and continued on prednisolone (5 mg/day), alprazolam, diuretics (furosemide and spironolacton), digitoxin and acetylsalicylic acid. The serum protein, albumin, IgG and γ-globulin levels remained below pre-PLE levels while the neutrophil count, CD45 expression on neutrophils, complement activation and anti-EBV–IgG remained increased (Figs 1 and 2). The lymphocyte count decreased and, on average, was below pre-PLE values (Table 1). Follow-up of the patient ended 480 days after surgery without resolution of PLE. The laboratory findings until final discharge are summarised in Table 1 (time range C). After the infections at the onset of PLE, no further infections were diagnosed until the end of the followup.

The records and investigations of the seven other patients with longstanding PLE were reviewed. The age (mean ± SD) at Fontan-type surgery was 5.5 ± 0.8 years, and PLE developed 48 ± 32 months after surgery. Six out of the seven patients (i.e. not case 3) had an infection at the time of onset of PLE. Lymphangiectasia was not excluded in any of these cases. The stool α₁-antitrypsin level was determined only in cases 5 and 7, and was increased at this time. Protein levels were below the normal range at PLE onset; α₁-globulin, α₂-globulin and β-globulin were elevated in most patients, whereas γ-globulin was below the normal range only in case 3 (Table 1, time range B). The leukocyte count was normal in all patients. The lymphocyte count was determined in four patients and was below the normal range in three of them. C-reactive protein was analysed only in case 3, and was 47 mg/dl.

Cases 2–4, 6 and 7 had a decreased lymphocyte count, elevated α₁-globulin, α₂-globulin and β-globulin in the serum, and elevated α₁-antitrypsin in the stool during longstanding PLE. The γ-globulin level remained in the normal range. Complement fragment C3d was 6.9 ± 2.1 g/l (normal range 2–4 g/l) and IL-8 was 11.1 ± 6.6 pg/ml, both values were only slightly increased. Case 5 had normal values (C3d, 2.2 g/l; IL-8, 5.3 pg/ml). Case 4 had recurrent infections with rotavirus, but no subsequent infections were reported in the other six patients.