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Increased serum concentrations of intestinal alkaline phosphatase in peritoneal dialysis.

To the Editor:

Patients suffering from chronic renal dysfunction are monitored by measurement of biochemical markers such as serum total alkaline phosphatase (ALP) to detect increased bone remodeling before the development of advanced renal osteodystrophy. There are at least five different isoforms/isoenzymes of ALP: hepatic, skeletal, intestinal, placental, and tumor-associated (1). These can be separated by electrophoresis and differ in their resistance to heat inactivation, with placental and tumorassociated ALP being the most resistant. Approximately 95% of the total ALP activity in serum is derived from bone and liver sources; these isoforms occur in an ~1:1 ratio in healthy adults (2).

Bone remodeling leads to release of skeletal ALP from osteoblasts and, hence, to increased total ALP activity in serum (1). However, one report has indicated that peritoneal dialysis per se may stimulate the intestine to secrete more intestinal ALP and intestinal variant ALP, leading to increased ALP activity in serum (3). I wish to report on two patients who were on long-term peritoneal dialysis and had moderately increased serum total ALP activity (2.4 and 4.4 [mu]kat/L, respectively; cutoff value <1.8 [mu]kat/L) without any biochemical signs of liver disease. Serum agarose gel electrophoresis followed by incubation of the gel with a chromogenic ALP substrate revealed a dominant band with electrophoresic mobility identical to that of intestinal ALP (Fig. 1). The band was unaltered by ficin-induced immunoglobulin fragmentation and disappeared after heat inactivation, excluding that it might represent immunoglobulinbound macro-ALP or placental or tumor-associated ALP.


The two cases support the possibility of an association between peritoneal dialysis and increased serum concentrations of intestinal ALP and caution against interpreting increased total ALP activity in peritoneal dialysis patients as a sign of increased bone remodeling before further investigation by electrophoresis and/or determination of "bone-specific" ALP, for which immunochemical methods are available. It should in this context be noted that macro-ALP interferes with immunochemical tests for skeletal ALP (4). Thus, the presence of macro-ALP should be excluded by electrophoresis or an equivalent method in patients with increased serum concentrations of skeletal ALP.

The molecular mechanism behind the increase in intestinal ALP in peritoneal dialysis is unknown. There may be a direct association between increased production of intestinal ALP and the peritoneal dialysis technique, but because the presence of intestinal ALP has also been reported in hemodialysis patients and in patients with advanced liver cirrhosis, there may be other explanations as well. For example, competition for clearance by the asialoglycoprotein receptor of the liver between asialylated intestinal ALP and asialoglycoproteins can lead to increased serum concentrations of intestinal ALP (5). Whether this is the case in peritoneal dialysis patients remains to be investigated.


(1.) Urena P, De Vernejoul MC. Circulating biochemical markers of bone remodeling in uremic patients. Kidney Int 1999;55:2141-56.

(2.) Magnusson P, Degerblad M, Saaf M, Larsson L, Thoren M. Different responses of bone alkaline phosphatase isoforms during recombinant insulin-like growth factor-I (IGF-I) and during growth hormone therapy in adults with growth hormone deficiency. J Bone Miner Res 1997;12:210-20.

(3.) Oktay G, Fadiloglu M, Onvural B, Camsari T, Celik A. Evaluation of alkaline phosphatase isoenrymes in sera of hemodialysis and periton dialysis patients by agarose gel electrophoresis. Biochem Soc Trans 1995;23:310S.

(4.) Van Hoof V0, Martin M, Blockx P, Prove A, Van Oosterom A, Couttenye MM, et al. Immunoradiometric method and electrophoeesic system compared for quantifying bone alkaline phosphatase in serum. Clin Chem 1995;41:853-7.

(5.) Van Hoof V0, De Broe ME. Interpretation and clinical significance of alkaline phosphatase isoenzyme patterns. Crit Rev Clin Lab Sci 1994; 31:197-293.

(6.) Kuwana T, Rosalki SB. Intestinal variant alkaline phosphatase in plasma in disease. Clin Chem 1990;36:1918-21.

Henrik Zetterberg Institute of Laboratory Medicine Department of Clinical Chemistry and Transfusion Medicine and Institute of Clinical Neuroscience Department of Experimental Neuroscience Sahlgrenska University Hospital Gdteborg University Gdteborg, Sweden

Address for correspondence: Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Harvard Institutes of Medicine, HIM-610, 77 Avenue Louis Pasteur, Boston, MA 02115. Fax 617-525-5305; e-mail
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Title Annotation:Letters
Author:Zetterberg, Henrik
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Mar 1, 2005
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