I have an alkaline phosphatase of 266 U/L; what are the possible causes and how should I evaluate this elevation?

Evaluation of Alkaline Phosphatase 266 U/L

Initial Diagnostic Step: Confirm Hepatic vs. Bone Origin

Measure gamma-glutamyl transferase (GGT) immediately to determine whether your ALP elevation originates from liver or bone. An elevated GGT confirms hepatobiliary disease, while a normal GGT points toward bone pathology, physiologic causes, or intestinal sources. 1, 2 If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to quantify the percentage derived from liver versus bone. 1, 2

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If GGT is Elevated (Hepatobiliary Origin)

Complete the Liver Panel

• Obtain ALT, AST, total and direct bilirubin, and albumin to assess hepatocellular injury and synthetic function. 1, 2
• Calculate the R value: (ALT/ULN) ÷ (ALP/ULN). A cholestatic pattern (R ≤2) is most consistent with your isolated ALP elevation. 1, 2
• Fractionate total bilirubin to determine the conjugated (direct) fraction; an elevated direct bilirubin confirms cholestasis. 1

Medication Review

Perform a thorough medication review—including all prescriptions, over-the-counter drugs, and supplements—because cholestatic drug-induced liver injury accounts for up to 61% of cases in patients ≥60 years. 1, 2 Older adults are particularly vulnerable to this etiology. 1

First-Line Imaging: Abdominal Ultrasound

• Order transabdominal ultrasound to evaluate for:
  • Dilated intra- or extrahepatic bile ducts 1, 2
  • Gallstones or choledocholithiasis (present in ~18% of cholecystectomy patients) 1
  • Infiltrative liver lesions or masses 1, 2
  • Hepatic steatosis 1

If Ultrasound is Negative but ALP Remains Elevated

Proceed directly to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, small-duct disease, and partial bile duct obstruction. 1, 2 A normal ultrasound does not exclude intrahepatic cholestasis or early PSC. 1

Serologic Workup for Autoimmune and Infiltrative Disease

• Check antimitochondrial antibody (AMA) if primary biliary cholangitis is suspected; a positive AMA plus elevated ALP essentially confirms PBC. 1
• Measure ANA with sp100/gp210 subtyping if AMA is negative, as these subtypes support PBC variants. 1
• If inflammatory bowel disease is present or suspected, high-quality MRCP is mandatory to evaluate for primary sclerosing cholangitis, which is strongly associated with IBD and typically presents with ALP ≥1.5× ULN. 1, 2
• Consider viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors are present. 1

Critical Differential Diagnoses

• Infiltrative malignancy is the most common cause of isolated ALP elevation in hospitalized cohorts, accounting for 57% of cases—with 61 patients having intrahepatic metastases as the sole finding. 3 Even mild ALP elevations warrant consideration of metastatic disease, especially if constitutional symptoms, weight loss, or a history of malignancy are present. 1, 2
• Sepsis can produce extremely high ALP (>1,000 U/L) with a normal bilirubin in 70% of cases; gram-negative, gram-positive, and fungal organisms have all been implicated. 4 Consider this diagnosis if fever, leukocytosis, or signs of systemic infection are present.
• Infiltrative non-malignant diseases such as sarcoidosis and amyloidosis can cause isolated ALP elevation. 1
• Partial bile duct obstruction from strictures, choledocholithiasis, or malignant obstruction may not be visible on ultrasound but is readily detected by MRCP. 1

Follow-Up Strategy

• If initial evaluation is unrevealing, repeat ALP in 1–3 months and monitor closely. 1, 2
• Accelerate evaluation if ALP rises >1.5× baseline without explanation, constitutional symptoms develop, or bilirubin/transaminases become abnormal. 1, 2

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

Assess for Bone Disease

• Inquire about localized bone pain, fractures, or history of malignancy; these symptoms warrant targeted bone imaging (bone scan or plain radiographs). 1, 2
• Bone metastases are a significant source of ALP elevation, particularly in patients with prostate, breast, or lung cancer. 1
• Paget's disease and osteomalacia can produce marked ALP elevations; osteomalacia classically presents with hypocalcemia, hypophosphatemia, elevated PTH, and elevated bone-specific ALP, though calcium and phosphate are often normal. 1

Physiologic Causes

• Postmenopausal women frequently have elevated ALP due to increased bone turnover from estrogen deficiency, not liver disease. 1, 2
• Pregnancy (second and third trimesters) causes physiologic ALP elevation from placental production; this is benign if aminotransferases, bilirubin, and bile acids remain normal. 1, 2
• Childhood and adolescence produce ALP levels 2–3× adult values due to bone growth. 1

Consider Bone-Specific ALP Measurement

• If bone origin is suspected but clinical context is unclear, measure bone-specific ALP (B-ALP) to quantify bone turnover. 1 However, B-ALP is less useful when liver ALP is also elevated. 1

Renal Osteodystrophy in CKD

• If you have chronic kidney disease (GFR <60 mL/min/1.73 m²), elevated ALP most commonly reflects secondary hyperparathyroidism and high-turnover bone disease (osteitis fibrosa). 1
• Measure intact PTH, calcium, and phosphorus concurrently; elevated PTH + elevated ALP strongly suggests high-turnover bone disease, while low-normal PTH + elevated ALP points toward adynamic bone disorder. 1

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Common Pitfalls to Avoid

• Do not assume NASH is the cause if ALP is ≥2× ULN; NASH typically elevates ALT more than ALP. 1
• Do not delay MRCP while awaiting serology results; order both concurrently to expedite diagnosis. 1
• Do not underestimate sepsis as a cause of isolated ALP elevation, even with normal bilirubin. 4
• Do not overlook malignancy; 57% of unexplained isolated ALP elevations are due to cancer, and 47% of patients in one cohort died within an average of 58 months. 3
• Do not assume a normal ultrasound excludes biliary disease; MRCP is mandatory if ALP remains elevated. 1, 2

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Severity-Based Urgency

• Mild elevation (<5× ULN): Systematic outpatient workup as outlined above. 1
• Moderate elevation (5–10× ULN): Expedite imaging and laboratory evaluation. 1
• Severe elevation (>10× ULN): Urgent workup required; high association with sepsis, malignant obstruction, complete biliary blockage, or advanced metastatic disease. 1, 4

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Summary Algorithm

1. Measure GGT (or ALP isoenzymes if GGT unavailable). 1, 2
2. If GGT elevated: Complete liver panel, medication review, abdominal ultrasound → if negative, proceed to MRCP → check AMA, ANA (sp100/gp210), viral serologies. 1, 2
3. If GGT normal: Assess for bone pain, fractures, malignancy history → consider bone imaging if symptomatic; check for physiologic causes (postmenopause, pregnancy, childhood); measure PTH/calcium/phosphorus if CKD present. 1, 2
4. Repeat ALP in 1–3 months if initial workup is negative; accelerate if rising or symptoms develop. 1, 2
5. Consider liver biopsy if diagnosis remains unclear after comprehensive imaging, particularly to diagnose small-duct PSC or infiltrative disease. 1