Author + information
- Gruschen R. Veldtman, MBChB and
- Gary D. Webb, MD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Gary F. Webb, Adolescent and Adult Congenital Heart Program, Cincinnati Children's Hospital Heart Institute, 3333 Burnet Avenue, Cincinnati, Ohio 45229.
Protein-losing enteropathy (PLE) has long been recognized as a potentially devastating complication of a Fontan procedure. Although not very common, affecting perhaps 10% of Fontan patients, a consistently effective management strategy has yet to be developed, and the 5-year mortality rate is believed to be 50%. Accordingly, the paper in this issue of the Journal by John et al. (1) is welcome in that it addresses important questions of whether the historical mortality data of PLE in Fontan patients still holds true in the contemporary era and which treatment strategies are most effective in managing such patients. With the availability of new medical therapies as well as interventional strategies, the reported data represent a welcome extension to our knowledge base. Our best data to this point came from the multicenter study by Mertens et al. (2), suggesting a 50% mortality at 5 years following the diagnosis of PLE.
John et al. (1) conducted a retrospective, cross-sectional, hospital record–based study reviewing the Mayo Clinic experience of 42 Fontan patients. These patients (55% male) were diagnosed with PLE between 1992 and 2010. The diagnosis was based on a combination of clinical symptoms, decreased serum albumin levels, and elevated fecal alpha 1 antitrypsin clearance. Public health records via Accurint also were reviewed to assess mortality. The follow-up period was 8 ± 6 years (range 1 to 22 years).
Survival was 88% at 5 years; 11 patients in this cohort died. The mean age at death was 32 ± 7.7 years (range 22 to 47 years), and time from diagnosis to death was 7.5 ± 5.4 years (range 1 to 18 years). The causes of death included sepsis (n = 7), complications after Fontan revision surgery (n = 1), and unknown (n = 3). The authors identified the following factors, assessed at the time of diagnosis, as being associated with worse survival in this cohort: Fontan pressure >15 mm Hg, New York Heart Association functional class >II, higher pulmonary vascular resistance, lower cardiac index, and lower mixed venous oxygen saturation. Patients with PLE who had Fontan pressures >15 mm Hg had worse survival at 5 years (83% vs. 95%) and 10 years (63% vs. 86%). PLE patients who had ejection fraction (EF) of <55% had 5- and 10-year survival rates of 87% and 62%, whereas those PLE patients with EF of >55% had 5- and 10-year survival rates of 91% and 85%. Serum creatinine levels were higher in the PLE patient cohort that died (1.34 ± 0.4 mg/dl vs. 0.84 ± 0.33 mg/dl). Serum albumin levels, alpha-1 antitrypsin levels, and arrhythmia prevalence were not different between the survivors and nonsurvivors.
Medical therapy alone was used in 15 of 42 patients. Of these, 7 (47%) improved, 5 (33%) did not improve, and 3 (20%) died. Combined medical and surgical/interventional treatment was used in the remaining 27 patients. Of these, 10 (37%) improved, 9 (33%) did not improve, and 8 (30%) died. Surgical treatment was used in 7 patients. Of these, the Fontan was taken down in 2 patients (PLE got better in one and was unchanged in the other); cardiac valve replacement or repair was performed in 4 and cardiac transplantation was performed in 1 patient, with subsequent resolution of PLE.
This study has many strengths. It represents the largest contemporary Fontan PLE series. It successfully demonstrated significantly better outcomes compared with the multicenter trial by Mertens et al. (2) Survival was similar to that of another contemporary series, but this study was smaller and thus less conclusive (3).
Surgical treatment was used more often in the Mertens multicenter study (52 of 114 patients), and 62% died. On the other hand, 46% of their medically treated patients died; therefore, the current results represent a great apparent improvement. That said, the current results were obtained from a relatively shorter follow-up time (8 years vs. 18 years), as compared with the multicenter series. Further confirmation of these promising outcomes is therefore awaited. One cannot assume that these results are generalizable. The commitment and skills of institutions, teams, and individuals vary greatly and will undoubtedly impact outcome.
This report does not present the denominator of Fontan patients from whom this cohort was drawn. Important questions remain, therefore, with respect to whether the epidemiology and epigenetics of the disease have changed over time. For example, have better surgical planning and experience changed the prevalence of PLE and has earlier management of lower cardiac output states altered the disease state and its natural history? Other sources of luminal protein loss, such as plastic bronchitis, were not specifically covered in this report. There is an important and yet underrecognized role that defective lymphatic drainage plays, in addition to inflammation at the level of the intestinal barrier, in mediating abnormal luminal protein loss (4).
Results of medical therapy are difficult to interpret because crossover from the medical to the combined medical/surgical/catheter-interventional group may have occurred. The more recent availability of pulmonary vasodilator therapies (5) and oral budesonide (6–8) have substantially improved the armamentarium available to treat this complex and multifactorial disease process, which may partly explain the improved results.
Fontan hemodynamics at the commencement of the protein-losing state appear to play an important role in late outcomes. Higher venous pressures and pulmonary vascular resistance, lower mixed venous oxygen saturation, and EF <55% were associated in univariate models with a worse late outcome. This is not surprising given that a simple 2.5-mm H2O hydrostatic pressure increment augmented protein flux 9-fold across the intestinal epithelial monolayer in an experimental setting. Indeed, when a 2.5-mm H2O pressure increment was combined with heparin sulfate loss in the same experimental epithelial cell monolayer, a synergistic effect occurred that led to a 15.7-fold augmentation in albumin loss. These effects could be further exaggerated in the presence of inflammatory markers (tumor necrosis factor-alpha and interferon-gamma) (8). It stands to reason, therefore, that therapies primarily targeting inflammation and Fontan hemodynamics are likely to meet with success.
In their discussion, John et al. (1) highlighted a role for the detection and aggressive management of obstructive sleep apnea in the treatment algorithm of PLE. This is a potentially very important avenue for further exploration. Very few data currently exist as to how important this issue might be in this cohort. There are, however, some signals that treatment of sleep apnea may benefit some Fontan patients (9). Clearly, further work is needed to define the extent and nature of this problem.
Sepsis was the dominant cause of mortality in patients with PLE in this series (7 of 11). Acquired immune deficiency has previously been documented (10). Both cellular and humoral immune compromise may be present (11). This immune deficiency should be a key focus of any therapeutic strategy. Looking for and actively treating opportunistic infections, particularly in the gut and respiratory tract may limit inflammatory signaling known to promote albumin loss via the intestinal epithelium. The mechanisms of how immune deficiency develops needs further exploration and may yield new therapeutic targets.
The researchers bring together their collective experience with the management of PLE in presenting general treatment principles, as well as a useful therapeutic algorithm. It should not be forgotten that these patients may have profound nutritional deficits, not dissimilar to kwashiorkor and consisting not only of hypoproteinemia (including clotting factors) but also involving trace elements, fat soluble vitamins, iron, magnesium, and calcium, to name a few. These deficiencies in turn may adversely affect intestinal barrier function through altering transcellular and paracellular transport mechanisms and therefore should be considered an important component of supportive therapy.
It has long been recognized that intestinal function may be altered under certain pathological states. For instance, the colon plays a greater absorptive role in the presence of small-bowel dysfunction and has been demonstrated to “rescue” malabsorbed carbohydrate. This phenomenon may be used in the setting of PLE by prolonging gut transfer time, and this was recently demonstrated to be useful (12).
In conclusion, this paper summarized the contemporary outcomes following a diagnosis of PLE in Fontan patients and discussed potential therapeutic approaches. The data, although reassuring that progress has been made, clearly call for further experimental and observational endeavors to improve management of this chronic, debilitating, and frequently lethal disease.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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