EXPLANATION


The Fontan physiology creates a state of chronic venous hypertension that can lead to multi-system organ dysfunction, characterized by protein-losing enteropathy (PLE), plastic bronchitis, and Fontan-associated liver disease. PLE and plastic bronchitis are associated with lymphatic dysfunction and the leakage of protein-rich lymph fluid into luminal spaces adjacent to lymphatic vessels. The leakage of proteinaceous fluid into the intestinal lumen results in enteric protein loss, also known as PLE. Leakage of proteinaceous material into the bronchial tree causes plastic bronchitis with the formation of bronchial casts. Symptoms of plastic bronchitis include dyspnea, cough, wheezing, and, in severe cases, respiratory failure due to airway obstruction from the casts. The diagnosis is confirmed by bronchoscopy.


Signs and symptoms of PLE include progressive central and peripheral edema, ascites, and often diarrhea. PLE affects up to 13% of Fontan patients, typically within ten years of the Fontan procedure. Factors predisposing to PLE include altered intestinal mucosal perfusion, low cardiac output, a selective increase in mesenteric vascular resistance, a proinflammatory state altering gut membrane permeability, and low heparan sulfate proteoglycans in the enterocyte membrane resulting in reduced enteral protein transport and increased luminal protein loss. Protein loss results in severe hypoalbuminemia and low serum oncotic pressure, leading to edema. The gold standard for PLE diagnosis is an elevated 24-hour stool alpha-1 antitrypsin clearance. PLE may also be diagnosed with a single stool sample with an elevated alpha-1 antitrypsin level concurrent with serum hypoalbuminemia and generalized edema with no other cause. Chronic protein loss is associated with a multitude of clinical sequelae, such as poor tissue integrity and impaired wound healing, coagulation factor deficiency resulting in coagulopathy and thromboembolic complications, hypoalbuminemia leading to secondary hypocalcemia, and low immunoglobulin levels resulting in immunodeficiency.


PLE management focuses on reducing chronic venous hypertension by optimizing Fontan hemodynamics and improving nutritional intake. Medical management includes diuretics to reduce fluid overload, albumin to restore oncotic pressure, steroids to reduce inflammation, aldosterone antagonists and/or heparin to stabilize the proteoglycan layer of the gut, and pulmonary vasodilators to reduce chronic venous congestion. Lymphatic interventions may reroute the lymphatic flow to provide a measure of symptomatic relief and improvement in quality of life. Heart transplantation is the last resort and appears to be effective for symptom relief. However, patients with PLE are often poor candidates due to chronic protein wasting and poor nutritional status and may not survive the waiting period or the transplantation procedure. The prognosis is grim, with 50% mortality within the first five years after diagnosis.


The patient in the stem has elevated stool alpha-antitrypsin, hypoalbuminemia, and ascites, which are diagnostic for PLE. Therefore, PLE is the most likely cause of the clinical presentation described in the stem. Plastic bronchitis is not the correct answer, as it is characterized by respiratory symptoms and the presence of airway casts. Although hypoalbuminemia and ascites are both signs of hepatic dysfunction in Fontan-associated liver disease (FALD), the MRI demonstrates fibrosis rather than cirrhosis, a classic finding in FALD. Additionally, FALD is not usually associated with significant hepatic synthetic impairment.


REFERENCES


Rychik J, Atz AM, Celermajer DS, et al. Evaluation and management of the child and adult with Fontan circulation: A scientific statement from the American Heart Association. Circulation. 2019;140(6):e234-e284.


Mackie AS, Veldtman GR, Thorup L, Hjortdal VE, Dori Y. Plastic bronchitis and protein-losing enteropathy in the Fontan patient: Evolving understanding and emerging therapies. Can J Cardiol. 2022;38(7):988-1001. doi:10.1016/j.cjca.2022.03.011


John AS, Johnson JA, Khan M, Driscoll DJ, Warnes CA, Cetta F. Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol. 2014;64(1):54-62. doi: 10.1016/j.jacc.2014.04.025. PMID: 24998129.


Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines [published correction appears in J Am Coll Cardiol. 2019.14;73(18):2361]. J Am Coll Cardiol. 2019;73(12):1494-1563. doi:10.1016/j.jacc.2018.08.1028