What could be causing fatigue in a teenager with potentially high alkaline phosphatase (ALP) levels?

High Alkaline Phosphatase in a Teenager with Fatigue

Critical First Step: Determine if ALP is Truly Elevated

In teenagers, ALP levels are physiologically elevated (often 2-4 times adult reference ranges) due to active bone growth, so you must use age-appropriate reference ranges before pursuing any workup. 1 What appears "high" on an adult reference range may be completely normal for an adolescent.

Initial Diagnostic Approach

Confirm the Source of Elevated ALP

• Measure gamma-glutamyl transferase (GGT) immediately to distinguish hepatobiliary from bone origin—elevated GGT confirms liver source, while normal GGT suggests bone or other non-hepatic causes. 1, 2
• If GGT is equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone. 1

Consider Physiologic vs Pathologic Elevation

• Adolescent growth spurts are the most common cause of elevated ALP in teenagers, particularly during peak growth velocity (ages 12-15 in girls, 13-16 in boys). 1
• Fatigue in this context is more likely unrelated to the ALP elevation and requires separate evaluation for common adolescent causes (sleep disorders, anemia, hypothyroidism, depression, infectious mononucleosis). 3

If GGT is Elevated (Hepatobiliary Origin)

Immediate Laboratory Workup

• Obtain complete liver panel: ALT, AST, total and direct bilirubin, albumin. 1, 2
• Calculate R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5). 1
• Review all medications for drug-induced cholestasis (particularly in adolescents taking oral contraceptives, anabolic steroids, or certain antibiotics). 1

First-Line Imaging

• Perform abdominal ultrasound as initial imaging to assess for biliary ductal dilatation, gallstones, or infiltrative liver lesions. 1, 2
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities and early primary sclerosing cholangitis. 1, 2

Consider Specific Hepatobiliary Conditions

• In adolescents with inflammatory bowel disease symptoms, suspect primary sclerosing cholangitis and obtain high-quality MRCP. 1
• Autoimmune hepatitis should be considered—check ANA, ASMA, and IgG levels. 1
• Viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present. 1, 2

If GGT is Normal (Bone or Other Non-Hepatic Origin)

Bone-Related Causes in Adolescents

• Physiologic bone growth is the most likely explanation—no further workup needed if ALP is <5× upper limit of normal for age and patient is asymptomatic aside from fatigue. 1
• If bone pain, fractures, or localized symptoms are present, obtain targeted imaging (X-rays of symptomatic areas or bone scan). 1, 2

Metabolic Bone Disorders to Consider

• X-linked hypophosphatemia (XLH) presents with elevated ALP, hypophosphatemia, elevated FGF23, and can cause fatigue, bone pain, and dental problems. 3, 1
  • Check serum phosphate, calcium, PTH, 25(OH)D, and consider FGF23 if phosphate is low. 3, 2
  • XLH requires treatment with phosphate supplements (20-60 mg/kg/day elemental phosphorus) and active vitamin D (calcitriol or alfacalcidol). 3
  • Healing of rickets is evidenced by normalization of ALP levels—this is a key treatment endpoint. 3

Rare Consideration: Hypophosphatasia (Low ALP Masquerading as Normal)

• Although this question asks about high ALP, be aware that some teenagers with fatigue may have inappropriately low or low-normal ALP for their age, which could indicate hypophosphatasia. 4, 5, 6, 7
• Hypophosphatasia presents with fatigue, muscle weakness, premature tooth loss, and bone pain despite low ALP. 4, 5
• If ALP is unexpectedly low for an adolescent (<30 IU/L or low-normal with concerning symptoms), check bone-specific ALP and consider ALPL gene testing. 5, 6

Addressing the Fatigue

Fatigue Requires Independent Evaluation

• Fatigue in adolescents with 22q11.2 deletion syndrome has multiple potential causes including obstructive sleep apnea, metabolic/mitochondrial/cardiac etiologies, and anxiety disorders. 3
• This principle applies broadly: fatigue can have somatic (sleep disorders, anemia, thyroid dysfunction, cardiac issues) or psychiatric causes (anxiety, depression) that require systematic investigation. 3
• Obtain complete blood count, thyroid function tests, iron studies, and consider polysomnography if sleep disturbance is suspected. 3

Severity-Based Approach

• Mild elevation (<5× ULN): Repeat in 1-3 months if asymptomatic; likely physiologic in adolescents. 1
• Moderate elevation (5-10× ULN): Expedite workup with imaging and comprehensive laboratory evaluation. 1
• Severe elevation (>10× ULN): Requires urgent workup given high association with serious pathology (malignancy, severe cholestasis, infiltrative disease). 1

Common Pitfalls to Avoid

• Do not use adult reference ranges for adolescent ALP—this leads to unnecessary workups for physiologic elevations. 1
• Do not assume fatigue is caused by elevated ALP—these are often separate issues requiring independent evaluation. 3
• Do not overlook medication review—drug-induced cholestasis is common and reversible. 1
• Do not skip GGT measurement—this single test prevents extensive unnecessary workups by immediately distinguishing liver from bone sources. 1, 2