Protein-losing enteropathy in Fontan circulation: Pathophysiology, outcome and treatment options of a complex condition

Abstract

Protein-losing enteropathy (PLE) represents a rare but severe and potentially life-threatening complication following Fontan operation in patients with a functional single ventricle. PLE is characterized by enteric protein loss, leading to devastating multiorgan involvement with increased morbidity and mortality. In spite of remarkable advances in the care of congenital heart disease in recent years, treatment of PLE is still one of the most challenging tasks due to limited understanding of the underlying mechanisms and lack of high-quality evidence from large scale, controlled studies to test the real efficacy of the several treatment strategies, which have been proposed. For this reason, we herewith aim to discuss the pathogenesis and diagnosis of PLE in Fontan patients as well as provide a comprehensive overview on potential advantages and disadvantages of the currently available therapeutic strategies, in order to propose a stepwise approach for the management of this unique condition.

1. Introduction

The Fontan operation was introduced in 1968 to palliate patients with single ventricle physiology. The procedure is based on the premise that a subpulmonary ventricle functioning as a pump is not mandatory for venous return to cross the pulmonary vascular bed. Rather, pulmonary blood flow, and thus the single ventricle preload, can be driven by the pressure gradient between elevated central venous pressure and a pulmonary vascular resistance low enough to permit an adequate forward flow under these hemodynamic circumstances [[1], [2], [3]].

Protein-losing enteropathy (PLE), is a condition characterized by abnormal loss of serum proteins into the intestinal lumen and represents one of the most challenging complications encountered by persons living with the Fontan circulation. It occurs in 5%–12% of Fontan patients and is associated with increased morbidity and mortality [4]. The incidence of PLE may become even higher as these patients continue to age and more patients with less severe or even transient forms of PLE are recognized. Although an earlier diagnosis and recent advances in treatment strategies allowed quality of life improvements, mortality remains still high [5]. In this review, we aim to discuss the pathogenesis and current available treatment strategies for Fontan patients with PLE.

1.1. Clinical presentation and long-term complications

PLE severity and its clinical implications vary widely, ranging from a mild and transient form, especially when associated to a correctable hemodynamic abnormality or following an infection, to a permanent condition with heterogeneous course characterized by alternating phases of relapse and remission. Subclinical PLE has also been described as low levels of enteric protein loss that may not manifest as tissue oedema, but may nonetheless affect somatic growth in young patients presenting with failure to thrive. Symptoms onset varies from a few weeks to years after the Fontan operation. Classical clinical manifestations include weight gain, peripheral oedema, ascites, pleural and pericardial effusion and are related to a significant drop in the intravascular oncotic pressure with subsequent fluid storage in the interstitium. However, most symptoms experienced by patients with PLE are secondary to the consequences of intestinal protein loss and nutrient malabsorption: PLE patients often complaint of chronic or intermittent diarrhea/streatorrhea associated with abdominal bloating and pain. When sustained PLE is present, long-term complications caused by chronic protein loss lead to multiorgan involvement: patients may become severely malnourished due to intestinal malabsorption, with devastating systemic consequences [6,7](Fig. 1). Chronically diffused oedema may undermine tissue integrity with difficult wound healing; abnormalities in the coagulation cascade may raise both the thrombotic and hemorrhagic risk, chronic hypoalbuminemia may lead to hypocalcaemia with subsequent reduction in bone density, occurring in about 58% of patients. Furthermore, low immunoglobulin levels and lymphopenia may develop, increasing the risk of infections and sepsis [8,9].

Fig. 1.

Main systemic complications in PLE.

1.2. PLE-related mortality and impact on quality of life

PLE is a major complication of Fontan circulation associated with poor outcome. Survival after a diagnosis of PLE has initially been reported around 50% at 5-year of follow-up [4,10] and has been recently showed to be improved at 88% at 5-year from diagnosis [5]. It could be speculated that earlier detection and enhanced medical/surgical management could have had a role in improving the prognosis. Factors associated with adverse outcome in PLE patients are increased circuit pressure, impaired ventricular function, atrial arrhythmia and New York Heart Association functional class at diagnosis [5]. Patients with PLE may require frequent and prolonged hospital admissions for therapy optimization as well as monitoring response to treatment during follow-up, leading a significant extra cost for the Public Health System. Those factors may have a tremendous impact on the patients’ social life, psychological status, professional activity, and physical performance. Accordingly, PLE was showed to predict worse perceived quality of life, independently from other associated cardiac and non-cardiac medical conditions [11].

2. Pathophysiology

Several mechanisms may be involved at the same time, with variable contributions of each one of them in every single case.

• •The Fontan circulation is based on increased systemic venous pressure (SVP). Early postoperative SVP>12 ​mmHg was demonstrated to predict PLE [12]. All the factors that cause a further increase in SVP, such as Fontan pathway obstruction, atrio-ventricular (AV) valve regurgitation, pulmonary artery branch stenosis, increased pulmonary vascular resistance, and diastolic dysfunction, may contribute to the pathogenesis of PLE in up to 80% of cases [13]. Those lesions may represent potentially reversible causes of PLE and therefore should be accurately researched and recognized to ensure adequate treatment. Nevertheless, it is worth to point out that, despite SVP is universally raised in Fontan circulation, only a small proportion of patients develop PLE, suggesting a multifactorial pathogenesis of this complex condition.
• •Chronic low cardiac output may lead to decreased intestinal perfusion [14] and promote a proinflammatory state, also demonstrated by increased levels of fecal calprotectin [15], with consequent altered enterocyte membrane permeability, predisposing to PLE [16].
• •Patients with PLE may have diminished levels of heparan sulfate proteoglycans, normally present in the enterocyte membrane, whose absence can result in increased intestinal permeability and protein leakage [17].
• •Lymphatic circulation has recently emerged as a potential determinant factor in the pathogenesis of PLE. Raised SVP contributes to increased lymph production from both liver and extrahepatic portal system, leading to lymphatic congestion, and formation of lymphangiectasia [[18], [19],19] resulting in a chronic spillage of protein-rich lymphatic material. Variability in the anatomic configuration of the lymphatic system may predispose to intestinal lymphatic leakage [20,21].
• •Finally, in some patients none of the above causes can be recognized and even patients with excellent Fontan hemodynamic may develop PLE, through unclear mechanisms. Viral infections may cause transient increase in the enterocyte membranes permeability [22]. Moreover, individual susceptibility may also be due to a genetic predisposition [23].

2.1. Diagnostic work up

A comprehensive diagnostic pathway accounting also for extracardiac conditions, which may exacerbate PLE symptoms is proposed in Fig. 2. PLE is initially suspected based on suggestive symptoms and signs and is confirmed by the evidence of hypoalbuminemia (serum albumin levels <30 ​g/L with no other identifiable causes of protein loss) and elevated alpha-1 antitrypsin in spot stool sample or increased alpha-1-antitrypsin clearance (>24 ml/24 ​h,>56 ml/24 ​h in those with diarrhea) [7]. Alpha-1-antitrypsin is a sensitive marker of intestinal protein loss and could also be useful to monitor response to treatment [24]. Both clinical features and laboratory results showing hypoalbuminemia and increased fecal alpha-1-antitrypsin are required to fulfill the criteria for PLE diagnosis. Furthermore, other possible causes of low blood protein levels (i.e. hepatic, renal or intestinal diseases) must be ruled-out. Urinalysis can exclude proteinuria. The laboratory analysis should also include complete blood count, renal and hepatic function, thyroid hormones, electrolytes, and dosage of immunoglobulin levels. Liver function may be affected by chronic increase in SVP and should be tested in cases of suspected PLE. A gastroenterological evaluation is needed to investigate other possible enteric causes of protein loss. Patients with transient hypoproteinemia should also undergo a full diagnostic evaluation and warrant strict surveillance for potential future PLE development [25].

Fig. 2.

Diagnostic work-up in PLE patients.

Once PLE in confirmed, the diagnostic work-up should focus on the research for potentially reversible causes with echocardiogram, cardiovascular magnetic resonance (CMR), CT scan or cardiac catheterization. Cardiac catheterization allows also invasive measurment of Fontan circuit pressure, pulmonary vascular resistance, cardiac output and ventricular end-diastolic pressure. Electrocardiogram and Holter 24-h monitoring can rule-out rhythm disturbances, as supraventricular tachycardia with the loss of atrial contribution may further reduce the cardiac output causing clinical decompensation in patients within PLE. Recent studies have shed light on the role of the lymphatic circulation [20,26,27], which should be assessed using T2-weighted magnetic resonance liver lymphangiography to identify lymphatic abnormalities, especially in PLE patients not responsive to the first-line pharmacologic treatment [28].

2.2. Treatment

Due to the low prevalence of PLE, the literature regarding treatment of this condition is limited to small observational studies. Response to treatment is highly heterogenous among individuals and scarcely predictable. No single treatment is effective in all patients and most treatments for PLE may take several months to show a measurable response. Patients with a new onset PLE, acute worsening or clinically unstable should be admitted in an adult congenital heart disease unit. Therapy should be individualized, aiming to minimize symptoms and the side effects of therapy and improve quality of life. Treatment options include medical, interventional, and surgical approaches and may be classified as supportive care or pathophysiological treatment, which should account for the most plausible cause of PLE in the single individual. Integrated care, also involving nutritionists and gastroenterologists, is crucial to optimize the therapy. A stepwise approach with progressive escalating of drugs combination is proposed in Fig. 3.

Fig. 3.

Proposed stepwise approach to PLE therapy.

2.3. Supportive care

• -Diet: a high-protein (≥2 ​g/kg/day), low-fat diet (≤25% of calories from fat) with medium-chain triglyceride supplementation is generally recommended in PLE. Medium-chain triglycerides are absorbed directly into the bloodstream bypassing the impaired intestinal lymphatic vessels and can improve overall nutrition status in these patients [5]. Supplementation with electrolytes, iron, folate and fat-soluble vitamins are often required in malnourished patients, suffering from chronic diarrhea.
• -Diuretics: furosemide infusion is the most effective therapy to alleviate symptoms and reduce congestion in subjects hospitalized with PLE. Long-term oral furosemide is indicated in patients with PLE and chronic heart failure since it is beneficial in supporting a decompensated circulation [14,21]. High-dose spironolactone up to 5 ​mg/kg/die was showed to improve albumin levels in two small case series [29,30]. Although the exact mechanism of action is unclear, anti-inflammatory and endothelial-protective properties have been postulated.
• -Albumin infusion: provides prompt symptoms relief in patients with severe hypoalbuminemia and congestion due to reduced oncotic pressure. Albumin can be administered as a short-term therapy in patients with acute PLE worsening, awaiting for the effects of other medications, targeting the pathological substrate. In chronic PLE, regular infusions may be scheduled as part of the long-term therapy to maintain a satisfactory clinical balance [20].
• -Intravenous immunoglobulin administration (IVIG): Immunoglobulin G (IgG) administration is indicated in patients with severe deficiency to prevent life-threatening infections. In a small series, immunoglobulin infusion in children with very low IgG levels (<11–12 μmol/L) and hypoalbuminemia caused a sustained increase in serum albumin values with only mild adverse events [31]. Since IgG turnover is accelerated by intestinal loss, higher dosage of IVIG administrated at shorter intervals may be required (1–1.4 ​g/kg up to every two weeks) [31]. Subcutaneous IgG administration (90–120 ​mg/kg/week) in a case of long-standing PLE in a 20-year-old patient was associated to a sustained clinical improvement at 1-year follow-up [32].
• -Loperamide: is an opioid receptor agonist, which can be used for symptoms relief in patients with PLE and untreatable diarrhea, with anecdotal reports of long-term efficacy [33].

2.4. Pathophysiological treatment

• -Angiotensin-converting enzyme inhibitors (Ace-I): there is no clear evidence of beneficial effects of Ace-I in PLE patients. However, their use is frequent in clinical practice to reduce the systemic vascular resistance and improve cardiac output, particularly in those with impaired systolic function of the single ventricle [5].
• -Phosphodiesterase-5 inhibitors (PDE5-i): by increasing nitric oxide availability and reducing pulmonary arteriolar resistance, PDE5-i may potentially induce beneficial effects on the global hemodynamic in Fontan patients [34]. PDE5-I may also reduce systemic ventricular afterload and contribute to mesenteric vasodilation, thus improving intestinal perfusion and lymphatic drainage [35].
• -Budesonide: is an oral corticosteroid with high first-pass metabolism, resulting in relatively weak systemic activity, which is largely used in the long-term treatment of inflammatory bowel diseases. A meta-analysis of 5 retrospective studies including 36 PLE cases demonstrated the efficacy of budesonide in inducing a significant serum albumin raise [36]. Nevertheless, despite the initial benefit, budesonide effects were not shown to be sustained beyond 6 months in some patients [37] and it may lead to systemic side effects in the long-term (i.e. osteoporosis, immunosuppression, Cushingoid features, hyperglycemia, adrenal insufficiency), which may also be exacerbated by concomitant liver dysfunction. Initial dosage is 9 ​mg once daily, which might be tapered down to 3 ​mg once daily and then 3 ​mg every other day in case of response. Long-term therapy should be considered only in responsive patients with no or minimal adverse effects, whereas treatment should be discontinued if no beneficial effects are showed at 6 months follow-up or if side effects are not tolerated [25].
• -Low Molecular Weight Heparin (LMWH): effects in PLE treatment are likely multifactorial: heparin may decrease inflammation by inhibiting the intestinal mast cells, may preserve the integrity of the enterocyte membrane, and prevents microthrombi formation in the mesenteric circulation. Subcutaneous LMWH (enoxaparin 1 ​mg/kg twice a day or dalteparin 200 IU/kg once daily) have been used in PLE [38], with variable results, as some patients experienced only a subjective symptoms improvement [39]. However, therapy with LMWH should be weighed against a potential increased bleeding risk. If no improvement is achieved in the time span of weeks to months, LMWH should be discontinued.
• -Octreotride: is a synthetic somatostatin analogue, potentially useful to treat PLE when mainly due to intestinal lymphangiectasia, as it reduces the intestinal lymphatic production. However, subcutaneous octreotide (4–10 μg/kg/hour [40]) bears the risk of numerous side effects including pain at the injection site, cholelithiasis or biliary sludge (22–33% of cases), alterations in endocrine function, such as hypo-hyperglycemia, hypothyroidism, pancreatitis, neurological symptoms such as dizziness and headache and sinus bradycardia (up to 25% of patients) [41]. Intramuscular injection of long-acting octreotide is associated with a more tolerable profile and better compliance. A single study reported efficacy of 20 ​mg i.m. octreotide once a month in 3 PLE patients within the first 6 months of therapy [42]. Long-acting octreotide should be regarded as a second-line therapy in addition to other medications and a dose reduction to 10 ​mg i.m. monthly can be considered, once symptoms relief has been achieved [42].
• -Midodrine: is an alfa-adrenergic stimulator which use has been advocated in PLE for its potential effects in increasing the lymphatic tone and reducing the intestinal protein leakage. In a single case series, midodrine was administered in 4 PLE patients unresponsive to other therapies including octreotide and budesonide with a starting dose of 1.25–2.5 ​mg three times a day, uptitrated to 5 ​mg in case of lack of response. Midodrine use was associated to a sustained (up to 2 years in 1 case) significant clinical improvement, as demonstrated by other medication discontinuation and heart transplant (HT) deferral in 3 out 4 patients [43]. Based on the limited experience, midodrine is still considered as a rescue therapy for patients with advanced, refractory PLE with simultaneous referral for HT evaluation.
• -Dopamine:Dopamine infusion is likely to vasodilate the lymphatic vessels and has been described as a rescue therapy in PLE patients awaiting HT [44].

PLE specific medication dosages are summarized in Table 1.

Table 1.

Most common medications dosage for PLE.

Therapy	Dosage
Furosemide	Start 1 ​mg/kg/die po Increase according to clinical status iv in decompensated patients
Spironolactone	2–5 ​mg/Kg/die in 2 administrations po,iv in decompensated patients
Albumin	[Target albumin (g/L)-serum albumin (g/L)]x plasmatic volume 0.04 ​L/Kg) x2
Immunoglobulin	1–1.4 ​g/Kg/month iv, up to every 2 weeks in severe cases 90–120 ​mg/kg/week sc
Loperamide	2–4 ​mg po in case of acute diarrhea, 2 ​mg po after each episode
Budesonide	6–9 mg/die up to 6 months Tapered down to 3 mg/die or 3 ​mg every other day
LMWH	Enoxaparin 1 ​mg/kg twice a day sc Dalteparin 200 IU/kg once daily sc
Octreotide	4-10 mcg/kg/hour sc Long-acting octreotide 20 ​mg/month im Tapered down to 10 ​mg/month if responsive
Midodrine	1.25–2.5 ​mg three times daily po Uptitrated to 5 ​mg three time daily po
Dopamine	5 mcg/Kg/min iv

2.5. Interventional strategies

• -Fontan fenestration: transcatheter Fontan circuit fenestration may be used to reduce the circuit pressure and improve the single ventricle preload with consequent PLE symptoms relief, at expense of right-to-left shunt causing cyanosis [45]. However, spontaneous closure of the fenestration may occur over time, leading to PLE relapses.
• -Catheter angioplasty/stenting of Fontan conduit and pulmonary arteries can improve Fontan hemodynamic and PLE manifestations.
• -Cardiac pacing/trans catheter ablation: rhythm normalization and atrio-ventricular synchrony can improve the overall hemodynamics.
• -Surgery: In spite of very high surgical risk, relief of systemic outflow with subsequent afterload reduction as well as AV valve repair and Fontan conduit revision may have some beneficial effects on PLE syndrome [21]. Rerouting of the innominate vein [46] or the thoracic duct into the atrium [47] as well as surgical [48]/percutaneous [49] Fontan takedown to Glenn anastomosis or aorto-pulmonary shunt can be considered as the last option in patients with advanced disease to decompress the circuit and reduce venous congestion at the expense of mild desaturation.
• -Heart transplant: HT is the ultimate resolutive strategy for PLE. Unfortunately, patients with long-standing PLE are often too sick to enter the transplant list due to malnutrition, multiorgan failure, immune system deficiency or may not pass the HT screening due to high antibody levels. Furthermore, the procedure is technically challenging due to the underlying anatomical complexity and previous interventions. HT receiver Fontan patients show a high 1-year mortality, estimated at 20%, regardless of the history of PLE [50]. Implant of mechanical assist device with creation of a subpulmonary pumping chamber (Petre modification of right ventricular assist device) has been described as a bridge to HT in PLE cases, even in the presence of preserved ejection fraction, aiming to SVP drop with improvement of peripheral congestion and end-organ damage [51,52].
• -Lymphatic system percutaneous treatment: liver lymphangiography followed by percutaneous embolization with injection of ethiodized oil/glue either at the proximal intrahepatic lymphatic ducts or distally close to the leakage site within the duodenum is a fairly novel technique. Two case series including 8 patients each [7,53] and a case report [54] showed promising results. Nevertheless, most patients required repeated procedures to achieve complete embolization or due to development of new lymphatic fistulas. Adverse events included duodenal bleeding and embolization of hepatic veins with subsequent systemic paradoxical embolization. It is likely that improvements in the interventional technique with more distal embolization will allow better outcome. Lymphatic embolization is still a third-line therapy in cases of refractory PLE who are not deemed suitable for HT with lymphatic leakage demonstrated at magnetic resonance lymphangiography and should only be performed in centers with specific expertise.

3. Conclusion

PLE is a complex condition with devastating systemic effects and negative impact on Fontan patients’ quality of life. Therapeutical options are limited due to lack of high quality evidence. However, improved understanding of the pathophysiology of this disorder along with a stepwise, patient-tailored, multidisciplinary optimized management in tertiary adult congenital heart disease centers have improved survival in recent years. Multicentre studies with international collaborations including larger and more homogenous populations are paramount to provide essential data to test the real efficacy of the available treatment strategies.

Funding

This research did not receive any specific grant from funding agencies in the public or commercial sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.