Sustained remission of post-Fontan protein-losing enteropathy achieved by combination therapy with high-dose spironolactone and the somatostatin analogue octreotide: a case report

Abstract

Background

Protein-losing enteropathy (PLE) is a serious complication affecting approximately 5–12% of patients following the Fontan procedure for congenital heart disease and is associated with high mortality. Its pathophysiology is multifactorial, involving elevated central venous pressure, abnormal intestinal lymphatics, and altered mesenteric vascular resistance. No gold-standard therapy has been established, and current management approaches include hemodynamic optimization, nutritional therapy, and medications such as somatostatin analogues and spironolactone. Though spironolactone is frequently used as part of maintenance therapy, reports suggest that high-dose administration may be required in refractory cases. A case of post-Fontan PLE successfully treated with a combination of high-dose spironolactone and the somatostatin analogue octreotide, followed by sustained remission after tapering and discontinuation of octreotide, is described.

Case presentation

A 5-year-old Japanese girl with complex congenital heart disease, including double-outlet right ventricle, pulmonary atresia, and complete atrioventricular septal defect, presented with acute abdominal pain, diarrhea, hypoalbuminemia, and systemic edema four years after undergoing a Fontan procedure. Laboratory evaluation showed marked hypoproteinemia and elevated fecal α1-antitrypsin, and imaging and endoscopy demonstrated intestinal lymphangiectasia. Her central venous pressure was increased to 18 mmHg. She was diagnosed with post-Fontan PLE. Standard-dose spironolactone (1.0 mg/kg/day), octreotide, and nutritional modification produced minimal improvement. Escalation of spironolactone to 6.2 mg/kg/day was followed by progressive resolution of hypoproteinemia. Octreotide was transitioned to intramuscular administration and later tapered. The patient was discharged on hospital day 44. Over long-term follow-up, central venous pressure remained controlled, fecal α1-antitrypsin remained < 40 mg/dL, spironolactone was gradually reduced to 1 mg/kg/day over five years, and octreotide was fully discontinued after eight years. She has maintained remission for more than 1.5 years following octreotide withdrawal.

Conclusions

This case demonstrates that combination therapy with high-dose spironolactone and octreotide can induce remission in post-Fontan PLE unresponsive to standard-dose therapy. Importantly, both medications were successfully tapered, allowing discontinuation of octreotide while maintaining long-term remission. High-dose spironolactone may be an effective therapeutic option, particularly when used alongside somatostatin analogues, and it may help reduce prolonged octreotide exposure in children at risk of endocrine adverse effects. Further studies to evaluate optimal dosing and long-term safety are needed.

Background

Protein-losing enteropathy (PLE) occurs in approximately 5–12% of patients following the Fontan procedure for congenital heart disease, and remains a life-threatening complication with high mortality [1]. Its pathophysiology is incompletely understood and is likely multifactorial; proposed mechanisms include elevated systemic venous pressure, abnormal intestinal lymphatics, and impaired mesenteric vascular resistance [2]. In post-Fontan PLE, lymphatic congestion is thought to lead to leakage of protein-rich lymph into the intestinal lumen, a process exacerbated by chronically elevated central venous pressure (CVP) [2, 3]. A gold-standard therapy has not yet been established, and diverse approaches have been reported, such as hemodynamic modification, anticoagulant, anti-inflammatory, and nutritional therapies, as well as treatment with the somatostatin analogue octreotide and high-dose spironolactone [1, 2]. A case of post-Fontan PLE that achieved remission with combination therapy involving high-dose spironolactone and octreotide, followed by successful tapering to maintenance with standard-dose spironolactone alone, is described.

Case presentation

Patient presentation

A 5-year-old Japanese girl presented with sudden-onset abdominal pain and diarrhea, accompanied by hypoalbuminemia [total protein 3.9 g/dL; albumin (Alb) 2.1 g/dL]. Her medical history consisted of double-outlet right ventricle, pulmonary atresia, and complete atrioventricular septal defect. There was no relevant family history. Despite three months of supportive care, her diarrhea and systemic edema worsened without improvement in Alb levels. She was admitted to our institution after starting spironolactone 1.0 mg/kg/day for further evaluation.

Past cardiac history and surgical interventions

She had a complex congenital heart disease consisting of double-outlet right ventricle, pulmonary atresia, and complete atrioventricular septal defect. She underwent staged palliative surgical interventions, including a central Blalock-Taussig shunt at 1 month of age, followed by a bidirectional Glenn procedure with patent ductus arteriosus closure at 9 months. At 1 year of age, coil embolization of systemic-to-pulmonary collateral vessels was performed. Completion of the Fontan circulation was achieved at 1 year and 5 months using a total cavopulmonary connection with an 18 mm extracardiac conduit.

Physical examination

Her height and weight were 107.3 cm (-0.6 standard deviation) and 17.4 kg (-0.9 standard deviation), respectively, indicating preserved growth. On physical examination, eyelid and lower extremity edema, abdominal distension, and a grade 1 systolic heart murmur were found.

Laboratory findings

Laboratory tests demonstrated marked hypoproteinemia (total protein 3.4 g/dL; Alb 1.7 g/dL; immunoglobulin G (IgG) 156 mg/dL) without elevation of B-type natriuretic peptide (BNP 12.2 pg/mL) or liver enzymes (aspartate aminotransferase 27 U/L, alanine aminotransferase 15 U/L, gamma-glutamyl transpeptidase 21 U/L). Urinalysis showed no proteinuria. Fecal α1-antitrypsin (fα1-AT) was markedly elevated at 246 mg/dL (normal 33–54 mg/dL).

Imaging data

Chest and abdominal X-rays showed mild cardiomegaly (cardiothoracic ratio 58%), bilateral pleural effusions, increased pulmonary vascular markings, and small intestinal gas (Fig. 1). Intestinal ultrasonography demonstrated moderate-to-large ascites, diffuse small intestinal wall thickening, and decreased peristalsis (Fig. 1). Transthoracic echocardiography performed at the time of presentation showed preserved ventricular systolic function, no significant atrioventricular valve regurgitation, and no evidence of Fontan pathway obstruction or newly developed structural abnormalities. Esophagogastroduodenoscopy on hospital day 2 showed duodenal mucosal edema with multiple white spots (Fig. 2). Cardiac catheterization at presentation demonstrated an elevated CVP of 18 mmHg prior to initiation of high-dose spironolactone therapy. Subsequent detailed hemodynamic assessments were performed at 13.5, 49.5, 73.5, and 115 months after treatment initiation to evaluate pulmonary vascular resistance and Fontan pathway patency. No hemodynamically significant stenotic lesions were identified, and the indexed pulmonary vascular resistance remained within the normal range during follow-up.

Fig. 1.

Chest and abdominal X-rays and intestinal ultrasonographic findings of the patient. a Chest X-ray shows mild cardiomegaly (cardiothoracic ratio 58%), bilateral pleural effusions, and increased pulmonary vascular markings; b Abdominal X-ray shows small intestinal gas; c Intestinal ultrasonography demonstrates moderate-to-large ascites (arrow); d Diffuse small intestinal wall thickening and decreased peristalsis are found

Fig. 2.

Findings of esophagogastroduodenoscopy on hospital day 2. a Normal esophageal findings; b Normal findings of the gastric body; c, d Normal findings of the gastric antrum; e, f Duodenal mucosal edema with multiple white spots (arrow)

Pathological examination

Histopathology showed villous atrophy and dilated lymphatic channels consistent with lymphangiectasia (Fig. 3); cytomegalovirus staining was negative.

Fig. 3.

Histopathological findings of the duodenal mucosal biopsy. a Duodenal mucosa shows villous atrophy (HE stain ⋅40); b Dilated lymphatic channels are identified within the interstitial tissue of the duodenal mucosa (arrow) (HE stain ⋅100)

Genetic screening

No mutations were detected in the genes associated with early-onset primary lymphangiectasia such as CD55, PLVAP, TSC2, and CCBE1 by direct sequencing.

Diagnosis, treatment, and follow-up

Based on these findings, she was diagnosed with post-Fontan protein-losing enteropathy. Remission was defined as sustained normalization of serum Alb levels without replacement therapy, together with clinical resolution of gastrointestinal symptoms and peripheral edema. Low-fat meals (25 g/day) were also started on day 6. Alb and IgG replacement (total 1.5 g/kg and 0.45 g/kg) and subcutaneous octreotide were started at 10 µg/kg/day and titrated to 24 µg/kg/day by day 14. However, Alb (1.9 g/dL) and IgG (204 mg/dL) showed minimal improvement by day 16; thus, spironolactone was increased to 3.0 mg/kg/day on day 18, but substantial biochemical improvement was not observed until escalation to 6.0 mg/kg/day on day 24, resulting in improvement of hypoproteinemia. The daily subcutaneous regimen was replaced with a once-monthly long-acting intramuscular formulation of octreotide, with no recurrence thereafter. She was discharged on day 44. Over follow-up, CVP remained controlled (12–14 mmHg), BNP remained low (8–12 pg/mL), and fα1-AT remained < 40 mg/dL. Spironolactone was tapered by approximately 1 mg/kg/day per year to 1 mg/kg/day after 5 years. Octreotide was tapered by 1.5 µg/kg/day every 6 months and discontinued after 8 years. She has remained in remission for over 1.5 years following octreotide discontinuation (Fig. 4). A follow-up intestinal biopsy performed 120 months after treatment initiation demonstrated disappearance of dilation of lymphatic channels.

Fig. 4.

Time-course changes in serum albumin, IgG, fecal α1-antitrypsin, and medication dosing following high-dose spironolactone initiation. Rapid biochemical improvement was observed after dose escalation from 3.0 to 6.0 mg/kg/day. Serial cardiac catheterizations were performed to reassess central venous pressure and Fontan hemodynamics. The monthly dose of long-acting octreotide represents the daily dose multiplied by 30 days. Alb, albumin; IgG, immunoglobulin G; BNP, B-type natriuretic peptide; fα1-AT, fecal α1-antitrypsin; CVP, central venous pressure; BW, body weight

Discussion and conclusions

Despite thorough hemodynamic and anatomical evaluation, including repeated cardiac catheterizations and serial echocardiographic assessments, no potentially correctable cardiac or Fontan-related abnormalities were identified in the present case. In the present case, genetic screening for early-onset primary lymphangiectasia, targeting known disease-associated genes such as CD55, PLVAP, TSC2, and CCBE1, did not identify pathogenic variants [4–7]. Though this finding does not entirely exclude the possibility of an underlying genetic contribution, it supports the interpretation that the patient’s lymphatic dysfunction was more likely secondary to the Fontan circulation rather than attributable to a currently recognized monogenic disorder.

Current treatment strategies remain largely symptomatic, including diuretics, nutritional modification, and repeated Alb infusion, although long-term efficacy is limited [8]. The benefit of spironolactone, which is widely used as part of maintenance therapy, may derive from its natriuretic and anti-inflammatory effects [9]. Notably, several reports have described cases in which standard doses were ineffective, but high doses resulted in clinical improvement [10, 11]. Octreotide, a somatostatin analogue, has also shown benefit in some cases of intestinal lymphangiectasia, possibly through reducing intestinal lymph flow, inhibiting triglyceride absorption, and decreasing gastrointestinal motility [12, 13]. Corticosteroids, including budesonide, have also been reported as a therapeutic option for Fontan-associated protein-losing enteropathy [1, 2]. However, steroid therapy was not initiated in the present case. At our institution, approximately 10 patients with primary intestinal lymphangiectasia or Fontan-associated PLE have been treated, and corticosteroids, including budesonide, were ineffective in achieving sustained clinical or biochemical remission in all cases. In addition, concerns regarding potential growth impairment and long-term adverse effects in pediatric patients influenced our decision to avoid steroid therapy as first-line treatment. The octreotide dose in this case was titrated up to 24 µg/kg/day, which lies within the reported upper therapeutic range for refractory intestinal lymphangiectasia in children, with previous reports describing escalation up to 30–50 µg/kg/day in severe cases [12, 14]. However, further escalation was avoided due to concerns regarding adverse effects in young children. The absence of adverse events and subsequent successful tapering highlights its clinical feasibility when closely monitored.

In the present case, remission was not achieved with standard-dose spironolactone combined with octreotide, but marked improvement occurred after escalation to high-dose spironolactone. To the best of our knowledge, no previous reports have described successful remission of post-Fontan PLE using a combination of high-dose spironolactone and octreotide, nor have they demonstrated sustained long-term remission after tapering both therapies. The observed clinical response may reflect synergistic effects: octreotide may reduce intestinal lymphatic pressure, and spironolactone may decrease mesenteric vascular resistance and protect the intestinal epithelial barrier [15]. In well-compensated Fontan circulation, clinical reports suggest that a resting CVP around 12–15 mmHg may represent a desirable hemodynamic target. Higher levels (≥ 14 mmHg) have been associated with increased late morbidity and mortality [16]. In the present case, reduction from 18 to 12–14 mmHg may have contributed to improved lymphatic drainage and remission of PLE. Furthermore, follow-up histology demonstrated resolution of the previously dilated lymphatic channels, providing morphological evidence that both hemodynamic stabilization and medical therapy contributed to recovery of intestinal lymphatic function.

An additional notable aspect is that both octreotide and spironolactone could be safely tapered, with octreotide discontinued entirely, and remission has been maintained for over 1.5 years. This is clinically relevant because prolonged octreotide therapy in children may impair glucose tolerance, growth, and endocrine function, making discontinuation desirable whenever feasible [14]. However, there are currently no established recommendations regarding tapering or discontinuation of octreotide in post-Fontan PLE. In our case, dose reduction was therefore performed cautiously with close monitoring of clinical symptoms, serum Alb, IgG levels, and fα1-AT. Although height velocity was relatively slow during the early treatment phase, growth gradually normalized over time and no significant endocrine or metabolic adverse effects were observed. These observations allowed gradual tapering and eventual discontinuation. Nevertheless, risk-benefit assessment requires data from larger cohorts, and generalization from a single case should be made with caution.

However, this is only a single case report, and caution is required when generalizing these findings. Moreover, the relative contribution of each therapy to remission could not be determined, highlighting the need for studies that clarify treatment sequence. Objective assessment of intestinal lymphatic flow was not available, which limits mechanistic interpretation. Large studies are needed to clarify the optimal dosage, duration, and safety of high-dose spironolactone, alone or in combination with somatostatin analogues, in the management of post-Fontan PLE.

In conclusion, this case not only suggests potential efficacy of combination therapy with high-dose spironolactone but also provides rare documentation that long-term octreotide can be cautiously tapered and discontinued without relapse, which may offer practical insight for clinicians managing refractory post-Fontan PLE. Importantly, both medications were successfully tapered, with octreotide ultimately discontinued while maintaining long-term remission on standard-dose spironolactone. These findings suggest that high-dose spironolactone may provide an important therapeutic option, particularly when used alongside octreotide, and it may help facilitate withdrawal of prolonged octreotide therapy in children at risk of adverse endocrine effects. Although only a single case report, it highlights the potential value of high-dose spironolactone-based combination therapy and underscores the need for further studies to determine optimal dosing strategies, treatment duration, and long-term safety in post-Fontan PLE.

Abbreviations

PLE

protein-losing enteropathy

BNP

B-type natriuretic peptide

Alb

albumin

IgG

immunoglobulin G

fα1-AT

fecal α1-antitrypsin

CVP

central venous pressure

Authors’ contributions

All authors were associated with the care of this patient. SE, FH, and JK wrote the initial draft of the manuscript. JK, NM, KK, AK, AN, ME, SM, KT, and SH critically approved and revised the overall content of the manuscript. All authors read and approved the final manuscript.

Funding

The authors had no funding sources for this study.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

This case report was prepared in accordance with the CARE guidelines.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written, informed consent was obtained from the parents of the patient for publication of this case report and any accompanying images.

Competing interests

The authors declare no competing interests.