
==== Front
Perm J
tpj
tpj
The Permanente Journal
1552-5767
1552-5775
The Permanente Press

38980790
10.7812/TPP/24.016
TPJ-24-016
Didactic Case Report
Alkaline Phosphatase > 2000 U/L in an Infant With Stool Changes: A Case Report
https://orcid.org/0009-0002-3576-2657
Graber Stephen MD 1
https://orcid.org/0009-0001-6838-1263
Hanna Mary MD, FAAFP, AAHIVS 1
1 Department of Family Medicine, Loma Linda University, Loma Linda, CA, USA
Stephen Graber, MD sgraber@llu.edu
SG and MH contributed equally.

2024
03 6 2024
28 3 172176
© 2024 The Authors.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Published by The Permanente Federation LLC under the terms of the CC BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

Abstract

Transient hyperphosphatasemia (TH) is a benign condition observed among healthy infants and children < 5 years old. It is characterized by an elevation in serum alkaline phosphatase (ALP) in the absence of other signs of organ disease. Prognosis is excellent, and ALP levels stabalize within 4 months. The aim of this case report is to promote broader awareness of TH so further unnecessary workup is avoided.

The patient was a 12-month-old girl who presented with pale stools, a single episode of bloody stool, and elevation (incidentally found) in her ALP of 2379 IU/L. A small anal fissure was present, and the remainder of her physical examination was typical. The differential diagnosis included biliary atresia, liver disease, bone disease, and TH.

Further testing was typical and included complete blood count (CBC, consisting of hemoglobin, hematocrit, white blood cell count, and platelet count), comprehensive metabolic panel (CMP, consisting of glucose, creatinine, BUN, electrolytes, and liver function markers), calcium, phosphate, parathyroid hormone, gamma-glutamyl transferase, and 25-hydroxy vitamin D. Liver ultrasound was also typical without evidence of biliary atresia. The diagnosis of TH was made. The patient was monitored clinically. Repeat blood work was completed 2 months later, with ALP levels returning to the typical range.

Overall, TH is a benign self-limiting condition that can be managed by observation and serial measurement of ALP without further unnecessary investigations.

Keywords:

family medicine
pediatrics
diagnosis
primary care
==== Body
pmcIntroduction

Alkaline phosphatase (ALP), an enzyme synthesized predominantly in the liver and bone and included in the standard comprehensive metabolic panel (CMP), can be atypically elevated in multiple medical conditions in both adults and children. In children, interpretation of an elevated ALP has additional complexity, as typical physiologic levels change with age and growth.1 In the absence of other signs, symptoms, or atypical serum markers, a condition known as transient benign hyperphosphatasemia (TH) of infants and children is a common diagnosis, which, as its name suggests, is benign and resolves over time without intervention.

However, the differential diagnosis for elevated ALP is broad, and clinicians commonly have concern for undiagnosed cholestatic injury, like biliary atresia; hepatocellular injury, like viral hepatitis; metabolic disorders or drug toxicity; and bone disease, like rickets or renal osteodystrophy.2–6 This can often lead to costly and anxiety-inducing workup for patients and their families.

The aim of this case report was to promote broader awareness of TH with the goal of avoiding this unnecessary workup. The patient’s legal guardian provided informed consent for the publication of their medical information in this case report.

Case Presentation

A 12-month-old girl presented to the emergency department with pale stool for 3 days and a single episode of large volume green stool mixed with blood. She was otherwise at her baseline; she was playing, eating, and alert.

There was no associated abdominal pain, fever, vomiting, or constipation. Review of systems was positive only for increasing irritability over the past few weeks, although the patient was consolable. The patient was both breastfed and formula-fed and had regular bowel movements prior to this episode. Her past medical history was notable for a brain cyst in utero, but she was otherwise growing and developing as typical for her age. She was not taking any medications.

A physical examination was typical for the patient’s age, with the exception of a small anal fissure. Notably, there was no jaundice present and no abdominal tenderness.

Due to concern for biliary atresia, blood work was ordered. This included CBC, CMP, and direct bilirubin. Her laboratory results were typical, with the exception of ALP elevated to 2379 IU/L (reference range 25–350 IU/L). The patient was clinically stable and was discharged from the emergency department without further workup. She presented to the clinic the next day.

Repeat blood work was ordered, including a CMP, ionized calcium, parathyroid hormone (PTH), 25-OH vitamin D, and gamma-glutamyl transferase (GGT). The ALP continued to rise to 2630 IU/L with the remainder of the laboratory results being typical (see Table 1). An abdominal ultrasound was ordered but not obtained until 2 months later; the results were typical for the patient’s age with the exception of borderline hepatomegaly.

Table 1: Laboratory and imaging findings of case presentation

Diagnostic tests	At presentation	After 1 d	After 2 mo	
ALP
(25–350 U/L)	2379	2630	154	
AST
(0–30 U/L)	25	29	33	
ALT
(7–37 U/L)	20	23	31	
Total bilirubin
(0.0–1.0 mg/dL)	0.3	0.5	0.7	
GGT
(0–60 IU/L)		5		
Total calcium
(9.2–11 mg/dL)	10.6	10.8	9.6	
Ionized calcium
(4.5–5.6 mg/dL)		5.6		
Phosphorus
(4.0–6.8 mg/dL)		4.5		
BUN
(7–20 mg/dL)	8	6	13	
Creatinine
(0.7–1.3 mg/dL)	0.3	0.28	0.2	
PTH
(15–65 pg/mL)		11		
Vitamin D 25-hydroxy
(30–100 ng/mL)		39.8		
Abdominal US			Borderline hepatomegaly. No evidence of cholelithiasis or biliary duct dilation.	
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GGT, gamma-glutamyl transferase; PTH, parathyroid hormone; US, ultrasound.

Repeat CMP was obtained again 2 months later. The ALP decreased to 154 IU/L, and the patient remained asymptomatic.

Differential Diagnosis

The only notable laboratory abnormality throughout this case was the elevation in ALP to a peak of 2630 U/L. Coupled with an unremarkable physical examination, typical abdominal ultrasound, otherwise typical blood work, and eventual decrease in ALP after 2 months, this clinical picture was most consistent with a diagnosis of TH in infants and children.

The differential diagnosis for this patient at initial presentation was broad and included numerous must-not-miss diagnoses. The differential could be broadly categorized into cholestatic, hepatocellular, bone, and idiopathic etiologies (Table 2).

Table 2: Differential diagnosis with expected findings2–10

Differential diagnosis	Laboratory, imaging, and examination findings	
Liver disease—hepatocellular injury examples: viral hepatitis, metabolic disorders, drug toxicity	Elevated ALP, AST/ALT

Signs and symptoms of liver disease

	
Liver disease—cholestatic injury examples: biliary aresia, gallstones	Elevated ALP, AST/ALT, GGT, direct bilirubin

Atypical abdominal ultrasound (hepatomegaly, biliary duct dilation, etc)

Signs and symptoms of biliary disease

	
Rickets and/or osteomalacia	Low 25-hydroxy vitamin D, calcium, phosphorus

Elevated ALP, PTH

Typical GGT

Atypical skeletal survey (rachitic rosary, frontal bossing, etc)

Signs and symptoms of bone disease

	
Paget's disease	Elevated ALP

Typical GGT, calcium, phosphate, PTH, 25-OH vitamin D

Signs and symptoms of bone disease

	
Primary hyperparathyroidism	Low phosphate

Elevated ALP, calcium, PTH

Typical 25-OH vitamin D

	
Renal osteodystrophy	Low 1,25-OH vitamin D, calcium

Elevated ALP, creatinine, BUN, phosphorus, PTH

	
Malignancy examples: primary bone tumors, primary hepatic tumors, metastases to bone or liver	Variable laboratory findings—elevated ALP, AST/ALT; possibly elevated calcium

Atypical x-ray imaging—osteoblastic vs osteolytic bone lesions, fractures

	
Benign familial hyperphosphatasemia	Elevated ALP (usually intestinal isoenzyme with most substantial elevation; persisting beyond 4 mo)

Typical AST/ALT, GGT, calcium, phosphate, PTH, 25-OH vitamin D

Family members of all ages with similar laboratory profiles

	
Chronic idiopathic hyperphosphatasemia	Elevated ALP (persistent beyond 4 mo)

Typical AST/ALT, GGT, calcium, phosphate, PTH, 25-OH vitamin D

Family members have typical ALP

	
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GGT, gamma-glutamyl transferase; PTH, parathyroid hormone.

Cholestatic diagnoses to consider include biliary atresia and congenital infections. In addition to an elevated ALP, patients presenting with any of these conditions will often have elevated bilirubin and GGT and will present with examination findings of jaundice and stool changes.2

Hepatocellular diagnoses to consider include viral hepatitis, metabolic disorders, and drug toxicities (such as acetaminophen or various antiepileptic medications). In addition to an elevated ALP, patients presenting with any of these conditions will often have elevated alanine transaminase and aspartate aminotransferase and evidence of atypical liver function such as abnormalities in bilirubin, prothrombin time/partial thromboplastin time, and albumin.3,4,7,8

Bone diagnoses to consider include rickets and renal osteodystrophy. In addition to an elevated ALP, patients presenting with any of these conditions will often have abnormalities in PTH, calcium, and phosphate associated with characteristic physical examination or imaging findings of atypical bone growth (delayed fontanelle closure, frontal bossing, rachitic rosary, and lateral bowing of the femur and tibia, among others).5,6

Idiopathic diagnoses to consider, although rare, are benign familial hyperphosphatasemia and chronic idiopathic hyperphosphatasemia. Both conditions demonstrate an elevated ALP, with otherwise typical serum markers, that persists into adolescence and adulthood. As the names suggest, in the familial variant, family members have similar benign elevations in ALP, whereas in the idiopathic variant, family members do not have similar elevations.9,10

Aside from the atypical stool pattern of unclear significance and the incidentally discovered ALP on blood testing, the patient presented in this case did not have any of the findings that were characteristic of the differential diagnoses listed previously. This allowed for a presumptive diagnosis of TH, which was later confirmed during follow-up visits.

Discussion and Clinical Reasoning

TH is likely the most common cause of major hyperphosphatasemia among healthy infants and children younger than 5 years old, and it is rarely seen in adults. However, it is often not recognized well by clinicians, resulting in unnecessary extensive diagnostic evaluations. Recognition of this benign condition is crucial to avoid unnecessary investigations.

TH is a benign condition characterized by transiently elevated serum ALP in the absence of other organ disease or drug exposure. Age of presentation is nearly always younger than 5 years old, with an estimated most common prevalence (between 5% and 6%) in patients who are between 6 months and 2 years old; less than 1% of reported cases are in children older than 7 years.11 In the absence of other associated illnesses (including liver, bone, kidney, intestine, placenta, or blood disease) or known medication exposures (including to antiepileptic drugs),8 the ALP level should stabilize within weeks to months (usually 4 months) from the initial observation.12,13 Some reviews suggest a median duration of 2.5 months, with elevations lasting > 4 months in 20% of cases and persisting for up to 6 months in some cases.14 Elevations persisting for longer than 6 months should prompt further investigation for another cause. Degree of elevation of ALP does not appear to impact likelihood or speed of resolution with levels commonly exceeding 1000 IU/L, which is roughly 2.5 times the upper limit of what is typical in young children.11

Most published studies have been retrospective chart reviews of patients assessed for specific medical conditions or symptoms. Some authors have suggested risk factors associated with TH, including antecedent viral infection,15,16 antecedent gastrointestinal infection,6 failure to thrive,5 or recent changes in vitamin D status.17 However, these risk factors were identified from retrospective data usually lacking a control group, raising the likelihood that selection bias could have accounted for the findings.15 Authors of other previous case reports have reported no associations with atypical growth parameters or other biochemical markers such as vitamin D, PTH, or electrolytes.15,18,19

The mechanism for elevated ALP in TH is an elevation in the bone isoform of ALP due to rapid growth and impaired clearance in healthy infants and children. In the first 3 months of life, the typical serum level of ALP is slightly higher than typical adult levels. It increases at puberty by 2–3 times and remains above the adult level for 1–2 years.2

To summarize, characteristic features of TH, as defined by Kraut et al, include age of presentation being younger than 5 years old, lack of evidence of presence of liver or bone disease on examination or laboratory findings, and elevation in both bone and liver ALP isoenzymes. Additionally, serum ALP is expected to return to typical levels within 5 months.12,13

A detailed history, an in-depth physical examination, and baseline laboratory tests (liver tests, along with electrolytes, calcium, blood urea nitrogen, creatinine, and PTH tests, as well as tests for 25-hydroxy vitamin D levels) are generally sufficient to exclude possible liver or bone disease. Other tests may include γ-glutamyl transferase, leucine aminopeptidase, and inorganic phosphate. Diagnosis can be based solely on history and examination. As was the case with the patient presented, ALP levels typically stabilize within 4 months regardless of the extent of the elevation.12,13

Treatment Pathway

Upon making a presumed diagnosis of TH, no further intervention or testing should be needed. The patient should be observed over time with repeat ALP testing to confirm stabilization of ALP within 4–6 months. Other serum laboratory markers are not required to be repeated unless new symptoms develop. Some experts suggest ensuring adequate intake of calcium and vitamin D, although it is not standard practice to monitor these values if they are initially typical.

Outcomes

As noted in the case history, repeat CMP was obtained 4 months after initial presentation with stabilization of ALP levels. The patient was asymptomatic and continuing to grow and develop typically.

Key Learning Takeaways

TH is a benign, self-limiting condition that typically resolves within 4–6 months.

Serious conditions such as biliary atresia, congenital infections, and toxic drug exposures should be considered. However, an otherwise typical CMP and benign clinical examination can provide reassurance, establish the diagnosis of TH, and prevent unnecessary further diagnostic workup.

Treatment consists of observation with serial measurement of ALP levels to ensure resolution.

Author Contributions: Stephen Graber, MD, and Mary Hanna, MD, FAAFP, AAHIVS, participated in the study design, data collection, data analysis, and drafting of the final manuscript. All authors have given final approval to the manuscript.

Conflicts of Interest: None declared

Funding: None declared

Relevancy Statement: This case report demonstrated quality of care by decreasing physical and emotional harm to young patients and their families by minimizing unnecessary diagnostic workup and providing appropriate reassurance for a benign condition.
==== Refs
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