What is the most likely etiology and appropriate evaluation for a patient with low alkaline phosphatase, low blood urea nitrogen, and a serum chloride of 109 mmol/L?

Diagnostic Approach to Low Alkaline Phosphatase with Low BUN and Chloride 109 mmol/L

The most likely etiology is malnutrition or a chronic wasting state, and you should immediately measure serum albumin, prealbumin, pyridoxal-5'-phosphate (vitamin B6), and 25-hydroxyvitamin D to confirm nutritional deficiency, while simultaneously screening for hypophosphatasia with ALPL gene sequencing if alkaline phosphatase remains persistently below 40 IU/L. 1, 2, 3

Initial Laboratory Assessment

Confirm persistent hypophosphatasemia by repeating alkaline phosphatase within 7–10 days, as transient low values are common and do not warrant extensive workup. 4 Only patients with persistently low ALP (ideally <40 IU/L on at least two separate occasions) require further investigation. 5, 6

Nutritional and Metabolic Markers

• Measure serum albumin and prealbumin to assess protein-calorie malnutrition, which commonly causes low BUN (<10 mg/dL) due to reduced hepatic urea synthesis. 7
• Check 25-hydroxyvitamin D and parathyroid hormone (PTH) because vitamin D deficiency can lower alkaline phosphatase through reduced bone turnover, and PTH helps differentiate primary bone disease from nutritional causes. 8
• Obtain serum zinc, magnesium, and copper levels since deficiencies of these trace elements—especially zinc—are associated with low alkaline phosphatase and can occur in malnutrition or chronic intestinal failure. 7

Hypophosphatasia-Specific Substrates

• Measure plasma pyridoxal-5'-phosphate (PLP, vitamin B6) and urinary phosphoethanolamine (PEA) if alkaline phosphatase remains below 40 IU/L after excluding secondary causes. 2, 3, 4
• Elevated PLP (above reference range) is found in 100% of patients with ALPL mutations who have enzyme activity low enough to cause substrate accumulation, making it the most sensitive biochemical marker for hypophosphatasia. 2
• PLP levels correlate inversely with serum alkaline phosphatase (r = -0.51, p = 0.001), and elevated PEA (r = -0.49, p = 0.001) further supports tissue-nonspecific alkaline phosphatase deficiency. 2

Genetic Testing for Hypophosphatasia

Order ALPL gene sequencing if PLP or PEA are elevated, or if alkaline phosphatase is persistently <40 IU/L without an alternative explanation. 5, 2, 3, 4

• Approximately 50% of adults with unexplained persistent low alkaline phosphatase carry an ALPL mutation, most commonly heterozygous missense variants with damaging effects on protein activity. 2
• The presence of a mutated allele is associated with tooth loss (48% vs. 12% in non-carriers, p = 0.04), slightly lower serum alkaline phosphatase (p = 0.002), higher PLP (p < 0.0001), higher PEA (p < 0.0001), and mildly elevated serum phosphate (p = 0.03). 2
• Novel mutations are frequently identified, and even a single heterozygous mutation can cause mild adult-onset hypophosphatasia with skeletal pain, chondrocalcinosis, calcific periarthritis, dental abnormalities, and stress fractures. 5, 2, 3

Evaluation for Wilson Disease

Calculate the ratio of total bilirubin to alkaline phosphatase; a ratio >2.0 strongly suggests Wilson disease, particularly in the setting of acute liver failure. 7, 1

• Measure serum ceruloplasmin, 24-hour urinary copper, and serum copper if the bilirubin/ALP ratio is elevated or if there are any signs of liver dysfunction (jaundice, coagulopathy, encephalopathy). 7, 1
• Perform slit-lamp examination for Kayser-Fleischer rings, which are present in approximately 50% of Wilson disease cases presenting with liver failure. 7, 1
• Wilson disease typically presents with markedly subnormal alkaline phosphatase (often <40 IU/L), Coombs-negative hemolytic anemia, modest aminotransferase elevations (<2000 IU/L), and rapid progression to renal failure. 7

Secondary Causes of Low Alkaline Phosphatase

Malnutrition and Chronic Illness

• Low BUN (<10 mg/dL) combined with low alkaline phosphatase suggests inadequate protein intake or chronic wasting, as BUN reflects hepatic urea synthesis from dietary protein. 7
• Chloride of 109 mmol/L is at the upper end of normal (98–107 mmol/L) and may indicate mild metabolic acidosis or dehydration, which can accompany malnutrition. 7
• Review for chronic diarrhea, high stomal output, or fistula losses in patients with short bowel syndrome or chronic intestinal failure, as these conditions cause electrolyte derangements and nutritional deficiencies that lower alkaline phosphatase. 7

Medication Review

• Bisphosphonates, denosumab, and other antiresorptive agents suppress bone turnover and can lower alkaline phosphatase even in the presence of underlying bone disease. 8, 3
• Antiresorptive therapy in a patient with unrecognized hypophosphatasia may worsen bone mineralization defects and increase fracture risk; avoid bisphosphonates if hypophosphatasia is suspected. 6, 3

Endocrine and Metabolic Disorders

• Hypothyroidism, hypogonadism, and glucocorticoid excess reduce bone turnover and can lower alkaline phosphatase; check thyroid-stimulating hormone (TSH), free T4, and morning cortisol if clinically indicated. 3
• Zinc deficiency is a well-recognized cause of low alkaline phosphatase because zinc is a cofactor for the enzyme; measure serum zinc and consider supplementation if levels are low. 7, 3

Clinical Manifestations to Assess

Even in the absence of severe symptoms, inquire specifically about:

• Dental problems: premature tooth loss, severe caries, or early loss of deciduous teeth in childhood. 2, 3
• Musculoskeletal pain: chronic bone or joint pain, stress fractures, or pseudofractures. 2, 3
• Chondrocalcinosis or calcific periarthritis: recurrent joint swelling or calcium pyrophosphate deposition disease. 2, 3
• Childhood history of rickets or delayed walking, which may indicate undiagnosed infantile hypophosphatasia. 5, 4

Diagnostic Algorithm

1. Repeat alkaline phosphatase within 7–10 days to confirm persistence. 4
2. If ALP remains <40 IU/L, measure albumin, prealbumin, 25-hydroxyvitamin D, PTH, zinc, magnesium, copper, and review all medications. 7, 8, 3
3. Calculate bilirubin/ALP ratio; if >2.0, proceed with Wilson disease workup (ceruloplasmin, 24-hour urinary copper, slit-lamp exam). 7, 1
4. Measure plasma pyridoxal-5'-phosphate and urinary phosphoethanolamine if no secondary cause is identified. 2, 3, 4
5. Order ALPL gene sequencing if PLP or PEA are elevated, or if clinical features suggest hypophosphatasia. 5, 2, 3, 4
6. Avoid bisphosphonates or denosumab until hypophosphatasia is excluded, as antiresorptive therapy can worsen bone mineralization defects in these patients. 6, 3

Critical Pitfalls to Avoid

• Do not dismiss low alkaline phosphatase as clinically insignificant; the prevalence of persistent low ALP in hospitalized adults is 0.13%, yet recognition is only 3%, leading to missed diagnoses of hypophosphatasia and inappropriate antiresorptive therapy. 6
• Do not assume transient hypophosphatasemia requires workup; most cases resolve spontaneously, and only persistent values warrant investigation. 4
• Do not overlook nutritional deficiencies as the primary cause of low BUN and low alkaline phosphatase, especially in patients with chronic illness, malabsorption, or inadequate oral intake. 7, 3
• Do not start bisphosphonates in a patient with unexplained low alkaline phosphatase without first excluding hypophosphatasia, as two patients in one series sustained fractures while on bisphosphonate therapy for unrecognized enzyme deficiency. 6