Supplement 2. Overview of published definitions and their building blocks

1. Bejiqi 2014

‘PLE was defined as and with no identifiable mode of loss other than the .’

Building blocks (n = 3): (1), PROTEIN (2), EXCLUSION (5)

2. Day 2006

‘PLE: recurrent or sustained albumin levels less than 3.0 g/dl with no known alternative cause of hypoalbuminemia.’

Building blocks (n = 2): ALBUMIN (1), EXCLUSION (5)

3. Driscoll 1992

‘A patient was considered to have protein-losing enteropathy or hypoproteinemia or hypoalbuminemia when: 1) there was historical information in the Mayo Clinic medical record substantiating that fact, 2) there was a postoperative protein level less than 6.3 g/dl, 3) the postoperative level was less than 3.1 g/dl, or 4) a surviving patient indicated on the medical questionnaire that he or she had hypoproteinemia or protein-losing enteropathy 5 years postoperatively or currently.’

Building blocks (n = 2): ALBUMIN (1), PROTEIN (2)

4. Feldt 1996

‘PLE was considered present when increased enteric loss of α1-antitrypsin was documented OR the clinical syndrome of PLE was present (persistent or intermittent with hypoproteinemia without evidence for deficient protein production or excessive protein loss from systems other than the gastrointestinal tract).’

Building blocks (n = 4): PROTEIN (2), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

5. Griffiths 2009

‘Hypoalbuminemia (≤ 3.0 mg/dL) for 3 months or longer in the absence of or renal disease and accompanying , pleural effusions, edema, diarrhea, or for 3 months or longer.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), EXCLUSION (5)

6. Gursu 2014

‘PLE diagnosis: on the basis of clinical criteria including history, presence of ascites, peripheric edema on physical examination, normal renal and hepatic functions, and

1 persistently (>3 months) low serum albumin levels (< 3.0 g/dL) with or without an elevated stool α1-antitrypsin.’

Building blocks (n = 4): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

7. Jayakumar 2004

‘PLE was defined as persistent hypoalbuminemia with resulting edema, ascites, , or chronic diarrhea.’

Building blocks (n = 2): ALBUMIN (1), CLINICS (3)

8. John 2011

‘The diagnosis of PLE was made through a combination of elevated α1-antitrypsin levels and albumin of less than 3.0 g/dL. The study excluded patients with other primary causes of protein loss, such as or intestinal , and patients with known inflammatory bowel disease such as Crohn disease or .’

Building blocks (n = 3): ALBUMIN (1), ENTERIC LOSS (4), EXCLUSION (5)

9. John 2014

‘The diagnosis of PLE was made through a combination of clinical symptoms (peripheral edema, diarrhea, abdominal pain, or effusions within the pericardial or pleural space), elevated fecal α1-antitrypsin clearance (>50 ml/24h or elevated spot fecal α1-antitrypsin concentration [>100 mg/ml]), and serum albumin < 3.0 g/dl. The presence of 1 clinical feature with both laboratory abnormalities was needed for diagnosis.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4)

10. Kaulitz 2005

‘PLE was diagnosed in patients with clinical symptoms related to hypoproteinemia; when indicated, the α1-antitrypsin clearance was calculated.’

Building blocks (n = 2): CLINICS (3), ENTERIC LOSS (4)

11. Kim 2011

‘PLE was defined as hypoalbuminemia (<3.0 mg/dl) for > 3 months in the absence of liver or renal disease accompanied by ascites, pleural effusion, edema, diarrhea, or abdominal pain for > 3 months.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), EXCLUSION (5)

2 12. Kreutzer 1996

‘PLE was considered to be present with a serum albumin concentration of less than 2 gm/dl on more than three separate determinations and a requirement for albumin replacement therapy at least once every 3 months.’

Building blocks (n = 2): ALBUMIN (1), ALBUMIN RT (7)

13. Lin 2006

‘The diagnosis of PLE was based on clinical symptoms and laboratory studies. The manifestations of hypoproteinemia were effusion and peripheral edema. Laboratory studies included serum albumin and total protein level, urinalysis to exclude renal protein loss, liver function test for normal protein production, fecal α1-antitrypsin excretion to confirm enteric protein loss and intestinal biopsy for pathologic changes.’

Building blocks (n = 6): ALBUMIN (1), PROTEIN (2), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5), BIOPSY (8)

14. Malcic 1992

‘The diagnosis of protein-losing enteropathy was made exclusively on the basis of low serum protein levels in the absence of severe hepatic or renal disorder.’

Building blocks (n = 2): PROTEIN (2), EXCLUSION (5)

15. Meadows 2008

‘PLE was defined as: (1) hypoalbuminemia and hypoproteinemia with no other identifiable mode of protein loss; (2) documented clinical signs or symptoms consistent with PLE, including but not limited to edema, ascites, and pleural effusions; and (3) the clinical diagnosis of PLE as documented by the patient’s primary cardiologist. A positive stool alpha-1-antitrypsin was not required for the diagnosis but was documented in the majority of cases.’

Building blocks (n = 5): ALBUMIN (1), PROTEIN (2), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

16. Meadows 2011

‘PLE was defined as hypoalbuminemia and hypoproteinemia with no other identifiable mode of protein loss other than the gastrointestinal tract, and documented clinical signs or symptoms consistent with PLE, including but not limited to oedema, ascites, and pleural effusions. Documentation of enteric protein loss by nuclear scintigraphy or stool alpha 1-antitrypsin was not required for the diagnosis but was documented in all cases.’

Building blocks (n = 5): ALBUMIN (1), PROTEIN (2), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

3 17. Mertens 1998

‘patient who had had Fontan-type surgery and in whom clinical symptoms of documented hypoproteinemia (edema, effusions) due to PLE developed. Other causes of hypoproteinemia such as and renal protein loss needed to be excluded.’

Building blocks (n = 3): PROTEIN (2), CLINICS (3), EXCLUSION (5)

18. Ozawa 2014

‘The diagnosis of PLE was based on a serum albumin level lower than 3.0 g/dL, a level lower than 5.0 g/dL, and an elevated stool α1-antitrypsin clearance or evidence of an abnormal enteric protein loss on technetium-99m (99mTc)-labeled scintigraphy.

Building blocks (n = 3): ALBUMIN (1), PROTEIN (2), ENTERIC LOSS (4)

19. Powell 2001

‘Two criteria were required for the diagnosis of PLE: (1) hypoalbuminemia (<3.0 mg/dl) for > 3 months in the absence of liver or renal disease, and (2) accompanying ascites, pleural effusions, edema, diarrhea, or abdominal pain for > 3 months.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), EXCLUSION (5)

20. Rychik 1997

‘PLE was diagnosed by serum albumin level <3 g/dL, total protein <5 g/dL, and elevated stool α1-antitrypsin clearance.’

Building blocks (n = 3): ALBUMIN (1), PROTEIN (2), ENTERIC LOSS (4)

21. Rychik 2002

‘PLE was diagnosed by serum albumin level <3.0 g/dL, total protein <5.0 g/dL, and elevated stool α1-antitrypsin clearance (>27 ml/24 hours).’

Building blocks (n = 3): ALBUMIN (1), PROTEIN (2), ENTERIC LOSS (4)

22. Ryerson 2008

‘PLE was defined as the presence of clinical symptoms (diarrhea, abdominal pain, peripheral edema, ascites) and increased fecal α1-antitrypsin (FA1AT; >200 mg/dl) or persistently low serum albumin (<3.0 g/dl). Patients with evidence of deficient protein production or excessive protein loss from organ systems other than the gastrointestinal tract were excluded.’

Building blocks (n = 4): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

4 23. Schumacher 2011

‘The study patients had been previously diagnosed on the basis of clinical criteria including history, physical manifestations of hypoproteinemia including peripheral edema and ascites, and persistently low serum albumin levels with or without an elevated stool α1-antitrypsin.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4)

24. Silvilairat 2008

‘PLE was defined as the presence of: (1) serum albumin <3.5 g/dL; (2) elevated stool alpha-1-antitrypsin concentration or clearance; and (3) accompanying edema, ascites, diarrhea, or pleural effusion.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4)

25. Thacker 2010

‘The diagnosis of PLE was based on the clinical findings of peripheral edema or ascites and confirmation of hypoalbuminemia on multiple samples with serum albumin level less than 3.0 g/dL. Patients were excluded if another cause for hypoproteinemia such as renal losses or severe hepatic dysfunction could be identified, or if they had chronic draining pleural effusions as a possible cause for excessive protein loss.’

Building blocks (n = 3): ALBUMIN (1), CLINICS (3), EXCLUSION (5)

26. Yu 2013

‘Criteria for the diagnosis of PLE were: (1) symptoms of Fontan circulation failure, such as generalized edema, pleural effusion, ascites, diarrhea or abdominal pain for more than 2 months, and (2) abnormal laboratory findings, such as hypoalbuminemia (<3.0 g/dL) lasting longer than 2 months and elevated fecal α1-antitrypsin clearance (>27 ml/day) in the absence of liver or renal disease.’

Building blocks (n = 4): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5)

27. Zaupper 2011

‘PLE was diagnosed from repeatedly low albumin and IgG levels associated with peripheral edema while excluding primary liver disease, , and severe . Stool alpha-1-antitrypsin clearance was not determined routinely.

Building blocks (n = 5): ALBUMIN (1), CLINICS (3), ENTERIC LOSS (4), EXCLUSION (5), IgG (6)

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