Ann Thorac Surg 2007;84:2110-2112. doi:10.1016/j.athoracsur.2007.06.064
© 2007 The Society of Thoracic Surgeons
Case Reports
Resolution of Protein-Losing Enteropathy With Low-Molecular Weight Heparin in an Adult Patient With Fontan Palliation
Kapil M. Bhagirath, MD*,
James W. Tam, MD, FRCPC
Section of Cardiology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Accepted for publication June 22, 2007.
* Address correspondence to Dr Bhagirath, c/o Dr Tam, Y3005–409 Tache Ave, Winnipeg, Manitoba, R2H 2A6, Canada (Email: umbhagir{at}cc.umanitoba.ca).
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Abstract
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Protein-losing enteropathy is a well-known complication after the Fontan procedure, and unfractionated heparin therapy has been tried with some success as a potential therapy. Low-molecular weight heparin is believed to be ineffective. We now describe a case in which an adult patient with protein-losing enteropathy after Fontan palliation was successfully treated with systemic doses of low-molecular weight heparin, with complete resolution in the 24-hour fecal alpha-1 anti-trypsin level and serum albumin. The patient continues to remain in remission with this therapy. In conclusion, these findings are novel and compel us to re-evaluate our pathophysiologic understanding of this difficult condition.
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Introduction
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Protein-losing enteropathy (PLE) is a well-known complication that develops in up to 13.4% of patients after the Fontan procedure and has an associated mortality rate between 56% and 67% [1, 2]. Precise mechanisms underlying the cause of this condition remain uncertain, but circulatory derangements after the procedure seem to have a significant role. According to one hypothesis [3], it is believed that after the Fontan procedure, chronically low cardiac output contributes to increased mesenteric vascular resistance, and the associated mesenteric hypoperfusion in conjunction with venous congestion contributes to a break in the intestinal mucosal integrity. One approach to the medical management of PLE involves diminishing protein loss at the intestinal mucosal level. High-molecular weight or unfractionated heparins (UFH) have been tried with some success in several case reports [4–7], most notably in a landmark case series published in 1997 from the University of Michigan [4]. In addition to showing for the first time the potential usefulness of UFH, Donnelly and colleagues [4] also demonstrated the lack of efficacy of low-molecular weight heparin (LMWH) in their report.
We believe that this report is the first case in the medical literature of an adult patient with complex congenital heart disease whose PLE resolved with the use of LMWH therapy.
We describe a case of a 30-year-old woman who has complex congenital heart disease. She had tricuspid atresia and primum atrial septal defect with cleft mitral valve from birth. She underwent a palliative Waterston shunt at age 4 in a foreign country with subsequent intracardiac Fontan, takedown of the Waterston shunt, and closure of the large atrial septal defect at age 11.
In January 2000, at the age of 23, the patient was admitted to the hospital with increasing peripheral edema and ascites for the preceding few months. Her course was complicated by rapid atrial flutter. Transesophageal and transthoracic echocardiogram showed spontaneous contrast and laminated thrombus within a dilated right atrium. The left ventricle was mildly dilated with mildly impaired global systolic function. A spiral computed tomographic (CT) scan did not show evidence of pulmonary vascular disease or evidence of systemic-to-pulmonary artery collaterals. The patient received systemic anticoagulation with UFH and underwent aggressive diuresis, which was followed by successful electrical cardioversion. Subsequent right heart catheterization did not demonstrate obstruction within the Fontan circulation, and the mean pulmonary artery (PA) pressure was determined to be 8 mm Hg. The pulmonary capillary wedge pressure was 2 mm Hg, suggesting significant volume contraction secondary to aggressive diuresis. Cardiac output was measured at 4.82 L/minute; normal calculated pulmonary vascular resistance (PVR) of 1.24 Wood units. Given the normal to low left-sided filling pressures after diuresis and the very mild impairment of left ventricular systolic function, there was no consideration made for the use of angiotensin-converting enzyme inhibition or left ventricular pacing.
Her serum albumin during this admission was 18 g/L and measurement of the 24-hour fecal alpha-1 antitrypsin level was 1,790 mg/L (reference range <540 mg/L). Treatment options were limited to long-term continuation of systemic doses of UFH (which was not favored by the patient due to the need for multiple daily injections) or warfarin or LMWH (both of the latter two without proven benefit in the literature). After much discussion, she was started empirically on LMWH, initially with enoxaparin (1 mg/kg subcutaneously twice a day) and then subsequently she was switched to dalteparin (200 IU/kg once daily) for more convenient dosing. The prolonged use of systemic doses of LMWH produced complete resolution of her PLE, with repeat 24-hour fecal stool alpha-1 antitrypsin at 470 mg/L and serum albumin increasing to 41 g/L.
The patient remained on dalteparin until October 2001, at which point she had a financial hardship associated with the cost of LMWH and began to question the need for continued daily injections. Oral anticoagulation with warfarin was attempted, with the goal of an international normalized ratio between 2.0 and 3.0 and discontinuation of LMWH. Within 6 months the patient had re-developed evidence of PLE with peripheral edema, elevated 24-hour fecal alpha-1 anti-trypsin (2040 mg/L), and reduction of her serum albumin to 32 g/L. Dalteparin was then re-initiated again at the same dose, whereas the warfarin was discontinued. Within 5 months, there was complete clinical improvement, and her 24-hour fecal alpha-1 antitrypsin level decreased to 23 mg/L. Serum albumin had risen to 40 g/L. Her energy level also returned to baseline. With this dramatic response, she was granted financial subsidy from the government agencies for lifelong coverage of LMWH.
The patient has remained on chronic daily injections of dalteparin to date, with no documented recurrence of PLE by measurement of 24-hour repeat fecal alpha-1 antitrypsin levels for the last 5 years. Furthermore, she has maintained normal sinus rhythm with amiodarone (200 mg once daily), with frequent but asymptomatic isolated atrial ectopy on ambulatory electrocardiographic monitoring.
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Comment
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This case report illustrates several important points. First, the resolution of PLE with LMWH in a patient with Fontan palliation has never been demonstrated until now. In addition, our experience suggests that LMWH may provide sustained long-term protection against the development of PLE. The durability of the response with UFH is unknown, and in fact, some reports suggest that the response is transient or ineffective [2, 8]. Finally, we also showed that warfarin was ineffective, which is consistent with previous findings [4].
There are specific additional features of LMWH that make it a more attractive option than UFH for management of PLE. Long-term UFH may be associated with complications such as decreased bone mineral density, vertebral fractures, and heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis. These potential side-effects are minimized with the use of LMWH. Furthermore, we used systemic doses of LMWH, unlike reports with UFH [4–7], which did not use systemic doses. Therefore, the use of systemic doses of LMWH theoretically protects against thromboembolic complications after the Fontan procedure. The incidence of this event ranges from 3% to 20% [9, 10], and anticoagulation is recommended by guidelines in various situations after the procedure [11]. Furthermore, in our specific case report, ongoing systemic anticoagulation is also protective against this complication due to the documented atrial flutter during the initial hospitalization.
The mechanism behind the efficacy of LMWH is unclear, compelling us to re-evaluate our hypotheses. It has been postulated that UFH works because it is lipophilic and has a strong negative ionic charge, two important properties that make it essential in maintaining intestinal mucosal integrity [3, 4]. The negative charge is crucial in preventing loss of enteric proteins. Furthermore, in an in vitro model, Bode and colleagues [12] hypothesized that in the absence of heparan sulphate, the integrity of intestinal epithelial cells is compromised, and the effect of cytokines such as IFN
and TNF
is amplified. This ultimately leads to protein leakage. Low-molecular weight heparin is not as strongly ionic, nor does it have a strong propensity to incorporate itself into epithelial cells. This calls into question the need for heparan sulphate binding to the intestinal epithelial cells. Chronic microemboli in the mesenteric circulation have been described as a potential causative factor in the development of PLE [4]. Perhaps this mechanism plays a more significant role than previously believed.
In conclusion, our experience is novel in that it represents the first case of LMWH consistently being effective at treating PLE in a patient after Fontan palliation in a challenge, withdrawal and re-challenge situation. Admittedly, the thought of lifelong daily subcutaneous injections can seem quite daunting. However, this is not unlike the insulin requirements of a type I diabetic. Our patient has slowly become accustomed to self-injection. Perhaps in the future with the development of other oral anticoagulants, newer agents may be considered with careful watchful guidance and monitoring of the serum albumin level and stool alpha-1 antitrypsin levels. Further studies and additional experience are clearly required. However, until such time, this case offers hope that systemic doses of LMWH may be beneficial in Fontan-related protein-losing enteropathy.
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References
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- Feldt RH, Driscoll DJ, Offord KP, et al. Protein-losing enteropathy after the Fontan operation J Thorac Cardiovasc Surg 1996;112:672-680.[Abstract/Free Full Text]
- Lin W, Hwang M, Chung H, et al. Protein-losing enteropathy after the Fontan operation: clinical analysis of nine cases Chang Gung Med J 2006;29:505-512.[Medline]
- Rychik J, Spray TL. Strategies to treat protein-losing enteropathy Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:3-11.[Medline]
- Donnelly JP, Rosenthal A, Castle VP, Holmes RD. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation J Pediatr 1997;130:474-478.[Medline]
- Kelly AM, Feldt RH, Driscoll DJ, Danielson GK. Use of heparin in the treatment of protein-losing enteropathy after Fontan operation for complex congenital heart disease Mayo Clin Proc 1998;73:777-779.[Abstract]
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- Monagle P, Cochrane A, McCrindle B, Benson L, Williams W, Andrew M. Editorial: thromboembolic complications after Fontan procedures—the role of prophylactic anticoagulation J Thorac Cardiovasc Surg 1998;115:493-498.[Free Full Text]
- Jahangiri M, Ross DB, Redington AN, Lincoln C, Shinebourne EA. Thromboembolism after the Fontan procedure and its modifications Ann Thorac Surg 1994;58:1409-1414.[Abstract]
- Adult Congenital Heart Disease in the Netherlands, Guidelines 2000. Working group "Congenitale Cardiologie bij Volwassenen": 64–67. Dutch Society of Cardiology, 2000.
- Bode L, Murch S, Freeze H. Heparan sulphate plays a central role in a dynamic in vitro model of protein-losing enteropathy J Biol Chem 2006;281:7809-7815.[Abstract/Free Full Text]
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Abstract
Introduction
