What causes elevated alkaline phosphatase (alk phos) levels?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) results from either hepatobiliary disease or bone pathology, with the most common causes being cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis), biliary obstruction (choledocholithiasis, malignancy), infiltrative diseases (hepatic metastases, sarcoidosis), sepsis, and bone disorders (Paget's disease, metastases, fractures). 1, 2

Initial Diagnostic Approach

Measure gamma-glutamyl transferase (GGT) immediately to determine the source of ALP elevation. 1, 2 Elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone disease or other non-hepatic sources. 1 If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone. 1

Severity Classification Guides Urgency

• Mild elevation: <5× upper limit of normal (ULN) 1
• Moderate elevation: 5-10× ULN 1
• Severe elevation: >10× ULN—requires expedited workup due to high association with serious pathology 1, 3

Hepatobiliary Causes (When GGT is Elevated)

Primary Cholestatic Liver Diseases

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic conditions causing persistent ALP elevation. 2

• PBC typically presents with ALP 2-10× ULN and positive antimitochondrial antibody (AMA). 1 Diagnosis requires two of three criteria: elevated ALP, positive AMA, or consistent liver histology. 1

• PSC characteristically shows ALP ≥1.5× ULN and is strongly associated with inflammatory bowel disease (75% of cases). 2 Episodes of cholangitis cause abrupt elevations of ALP, total bilirubin, and aminotransferases from transient obstruction due to inflammation, bacterial cholangitis, sludge, or choledocholithiasis. 2

Critical pitfall: In patients with inflammatory bowel disease and elevated ALP, obtain high-quality MRCP to evaluate for PSC. 1, 2 If MRCP is normal but suspicion remains high, consider liver biopsy to diagnose small-duct PSC. 1

Biliary Obstruction

Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, and biliary strictures are major causes. 2 Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis. 1, 2

• Choledocholithiasis can cause partial or complete biliary obstruction leading to cholestasis. 1 Sustained ALP elevation is significantly correlated with choledocholithiasis on MRCP. 1

• Malignant obstruction from pancreatic cancer, cholangiocarcinoma, or metastatic disease causes progressive ALP elevation. 2, 4

Important consideration: Do not assume elevated transaminases exclude biliary obstruction—in acute choledocholithiasis, ALT can surpass ALP, mimicking acute hepatitis. 1

Infiltrative Liver Diseases

Hepatic metastases are a leading cause of isolated elevated ALP, accounting for 57% of unexplained isolated ALP elevations in one study. 1, 5 Infiltrative intrahepatic malignancy was the most common cause (61 patients), followed by bony metastasis (52 patients), and combined hepatic and bone metastasis (34 patients). 5

Non-malignant infiltrative diseases including amyloidosis and sarcoidosis also cause isolated ALP elevation. 1, 2

Sepsis-Related Cholestasis

Sepsis is a major cause of extremely high ALP elevations (>1,000 U/L). 4 Seven of 10 patients with sepsis had extremely high ALP with normal bilirubin. 4 Gram-negative organisms, gram-positive organisms, and fungal infections can all cause this pattern. 4

Other Hepatobiliary Conditions

• Cirrhosis represents the most frequent condition causing both elevated ALP and hypoalbuminemia simultaneously, as the liver loses synthetic capacity and develops cholestatic features. 2, 3

• Chronic hepatitis progressing to cirrhosis demonstrates ALP elevation from intrahepatic cholestasis. 2, 3

• Drug-induced cholestasis is particularly common in older patients, comprising up to 61% of cases in patients ≥60 years. 1 Review medication history meticulously. 2

Critical pitfall: ALP elevation ≥2× ULN is atypical in nonalcoholic steatohepatitis (NASH), making NASH an unlikely cause of significantly elevated ALP. 1, 2, 3

Overlap Syndromes

Autoimmune hepatitis (AIH) overlap with PBC or PSC should be considered when serum ALP is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment. 6, 1 About 8% of adults with PSC have probable AIH, and 2% have definite AIH. 6 In AIH/PBC overlap, most patients achieve biochemical remission with prednisolone (with or without azathioprine) plus UDCA. 6

Bone-Related Causes (When GGT is Normal)

Primary Bone Disorders

• Paget's disease causes markedly elevated ALP from increased osteoblastic activity. 1
• Bony metastases from prostate, breast, or lung cancer elevate ALP through osteoblastic activity. 1, 5
• Fractures cause transient ALP elevation during healing. 1

Physiologic Causes

• Childhood: ALP levels are physiologically 2-3× adult values due to bone growth. 1
• Pregnancy: Placental production elevates ALP. 1

Diagnostic approach for bone origin: Obtain bone-specific ALP measurement or bone scan if localized bone pain or radiographic findings suggest bone pathology. 1 In postmenopausal women with mild ALP elevation and no symptoms, bone metastases are less likely. 1

Imaging Algorithm for Hepatobiliary Evaluation

1. Abdominal ultrasound as first-line imaging to assess for dilated intra/extrahepatic ducts, gallstones, infiltrative lesions, or masses. 1, 2, 3

2. If ultrasound shows common bile duct stones: Proceed directly to ERCP for both diagnosis and therapeutic intervention. 1

3. If ultrasound is negative but ALP remains elevated: Proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, PSC, small duct disease, and partial bile duct obstruction. 1, 2, 3

4. In PSC patients with abrupt ALP elevation: Evaluate for dominant stricture with MRCP or ERCP to detect cholangiocarcinoma. 2

Additional Laboratory Workup

• Fractionate total bilirubin to determine the percentage of direct bilirubin, which helps differentiate cholestatic patterns. 1, 2, 3
• Check prothrombin time/INR and albumin to assess hepatic synthetic function and disease severity. 3
• Measure ALT and AST to calculate the R value [(ALT/ULN)/(ALP/ULN)]: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5). 1
• Obtain AMA, ANA, ASMA, and IgG levels if autoimmune disease is suspected. 1
• Consider viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present. 1

Rare and Special Causes

• Benign familial hyperphosphatasemia: Markedly increased intestinal ALP (29-44% of total) in all family members, with significantly elevated liver/bone/kidney activity. 7 Early recognition avoids unnecessary diagnostic tests. 7

• X-linked hypophosphatemia (XLH): Presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23. 1

• Common variable immunodeficiency (CVID): Approximately 40% have abnormalities in liver function tests, with increased ALP the most frequent abnormality. 1

• Parenteral nutrition: Can cause ALP elevation through chronic cholestasis, with reported incidence up to 65% in home parenteral nutrition patients, particularly with excessive intravenous lipid administration (>1g/kg/day). 1

Prognostic Significance

Isolated, elevated ALP of unclear etiology carries significant mortality risk. In one study, 47% of patients died within an average of 58 months after identification, with underlying malignancy accounting for 57% of cases. 5 This underscores the importance of thorough evaluation rather than observation, particularly when ALP is severely elevated. 3