Alkaline phosphatases (ALPs), located on the outer cell membrane, play a crucial role in catalyzing the hydrolysis of organic phosphate esters within the extracellular space. Serum ALP levels in healthy individuals demonstrate variability depending on age and sex. Specifically, serum ALP levels reach their peak during the growth phases of childhood and adolescence, which is attributable to bone development, and subsequently decrease with age. This decline is more pronounced in men than in women between the ages of 15 and 50 [1]. Abnormal elevations in ALP levels primarily raise suspicions of hepatobiliary disorders, such as bile duct obstruction, primary biliary cirrhosis, and primary sclerosing cholangitis. This concern arises because liver-derived ALP constitutes a significant portion of the ALP present in the bloodstream [1, 2]. In addition, ALP from bone sources significantly contributes to serum levels. Mukaiyama et al. [3] reported that fluctuations in serum ALP levels in postmenopausal women with osteoporosis, both before and after treatment, closely mirror changes in bonederived ALP levels. This observation suggests that monitoring serum ALP levels may be a valuable tool in detecting osteoporosis.

In addition to liver and bone ALP, three tissue-specific isozymes of ALP are recognized: placental ALP, germ cell ALP, and intestinal ALP [4]. Intestinal ALP, predominantly located in enterocytes, is integral for maintaining the balance of the intestinal microbiota and the integrity of the barrier function [4]. Elevations in intestinal ALP levels can lead to increased overall serum ALP levels, often without clinical relevance. Such benign biochemical anomalies have been documented in reports from various countries, underscoring the importance of identifying this condition to avoid unnecessary diagnostic procedures [5-7]. Here, we present the inaugural case of a Korean patient exhibiting sustained high levels of intestinal ALP. This study received approval from the Institutional Review Board of Samsung Medical Center, Seoul, Korea (approval number: 2023-06-085), which also granted a waiver for informed consent.

A 56-year-old female patient underwent esophagogastroduodenoscopy in 2015, prompted by complaints of indigestion. The stomach biopsy from this initial procedure revealed no malignancy, identifying only inactive chronic gastritis. Subsequent esophagogastroduodenoscopies, performed periodically from 2016 to the present, have consistently shown results congruent with the initial findings, indicating no significant pathological evolution. A comprehensive chemistry profile and additional laboratory tests were performed in 2018 to further explore the etiology of her radiating back pain. The patient’s laboratory results from the chemistry profile were as follows: aspartate aminotransferase level, 20 U/L, which was within the reference interval of 0–32 U/L; alanine aminotransferase level, 14 U/L, also within the reference interval of 0–33 U/L; and total bilirubin level, 0.4 mg/dL, which was within the reference interval of 0–1.2 mg/dL. The cholesterol level was recorded at 183 mg/dL, which is considered normal based on the reference interval of 0–200 mg/dL. However, ALP levels were significantly elevated at 496 U/L, surpassing the normal reference interval of 35–104 U/L. This elevation in the serum ALP level has been a consistent observation since 2018, with levels fluctuating between 215 U/L and 599 U/L (Fig. 1). Subsequent serum ALP isozyme electrophoresis tests revealed that the intestinal isozyme fraction constituted approximately 82% to 95% of the elevated ALP level (Table 1). Measurements of gamma-glutamyl transferase have remained within normal reference limits, ranging from 12 U/L to 15 U/L, against a reference interval of 6–42 U/L.

Colonoscopy and capsule endoscopy, conducted in 2019 and 2022 respectively, failed to reveal any specific abnormalities. In 2022, detailed imaging of the hepatopancreatic system and kidneys, via ultrasonography and computed tomography, identified clinically insignificant parenchymal calcification within the right hepatic lobe. No abnormalities were detected in the gallbladder, spleen, pancreas, or kidneys.

Additionally, the patient is under gynecological care for chronic cervicitis and has been on thyroxine since thyroid nodule surgery 21 years prior. Currently, she is not on any other medications and presents no symptoms, and her primary concern revolves around the persistently elevated ALP levels. In the context of the absence of any malignant pathological findings, this condition of hyperphosphatasemia was deemed benign.

Santos et al. [4] described the utility of intestinal ALP levels, not only as a biomarker for evaluating intestinal function, but also as a therapeutic approach for intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, and metabolic syndrome. Given that there are no findings suggestive of intestinal abnormalities in this case, the likelihood of any disease appears very low. Other factors may contribute to the elevation of intestinal ALP levels. Our patient has blood type B, and it is well known that individuals with blood types O or B tend to have higher levels of intestinal ALP due to its attachment to ABO antigens via a glycosyl-phosphatidylinositol anchor [8]. ALP levels can also increase after a meal [9].

Whereas Cho et al. [10] investigated the relationship between fasting and postprandial ALP levels across different blood types and found no statistically significant differences. However, a trend was observed indicating a more marked variation in individuals with blood types O and B. This finding, while insightful, does not align with the clinical presentation of our patient, whose ALP levels not only substantially exceed the upper normal limit by a factor of 4 to 5 times, but also continue to rise regardless of fasting status. Such an anomaly suggests that the elevation in ALP levels cannot be exclusively ascribed to the patient’s blood type or the timing of the measurement.

In the absence of any indicative abnormalities in blood tests and imaging studies that may suggest an underlying condition, and given the lack of abnormal serological, pathological, or radiological findings, our preliminary diagnosis leans toward benign familial hyperphosphatasemia (BFH). A literature review on PubMed using the search term “benign familial hyperphosphatasemia” yielded 23 papers. Ten of these centered on case reports of benign hyperphosphatasemia in humans, of which three were specifically related to isolated intestinal hyperphosphatasemia [7, 11-15]. Notably, one outlier case related to a patient exhibiting a temporary increase in serum ALP levels post SARS-CoV-2 infection underscores the potential for viral infections to contribute to transient hyperphosphatasemia [11], suggesting a broader spectrum of causes beyond genetic predisposition.

Hranjec et al. [12] documented an intriguing case where isolated elevation of ALP levels was linked to an enteric infection caused by the Epstein-Barr virus. Notably, among the studies reviewed, three explicitly correlated the observed condition with increased levels of intestinal ALP, emphasizing the potential for specific infections to significantly influence ALP levels. The diagnostic criteria for BFH hinge on identifying hyperphosphatasemia, driven by elevated ALP levels, without any discernible underlying conditions in either the proband or their relatives, rendering it a diagnosis of exclusion.

A pertinent case study highlighted the examination of a proband’s immediate family members, including the mother, siblings, spouse, and children, which uncovered elevated intestinal ALP levels in one sibling and one child. This pattern suggests the potential for autosomal dominant inheritance of the condition [13]. In our case, the inability to conduct familial testing due to practical constraints precluded the definitive assessment of similar ALP elevations in family members. Nonetheless, considering the comprehensive evaluation of the patient and the absence of any pathological findings, the hyperphosphatasemia is presumed to be of a benign familial nature. While the diagnosis was not confirmed through familial testing in our case, it is noteworthy that elevated intestinal ALP levels, among various isoforms of ALP, is particularly rare in Korea, underscoring the uniqueness of our findings.

To the best of our knowledge, this is the first report of BFH in Korea. A confirmatory diagnosis would ideally involve the assessment of ALP levels among the patient’s family members. It is imperative for clinicians to recognize the benign nature of this condition, as such awareness can significantly alleviate patient and family anxieties related to hyperphosphatasemia, thus obviating the need for unwarranted and invasive diagnostic interventions.