What causes elevated alkaline phosphatase (all phos) levels, particularly in older adults or individuals with a history of liver or bone disease?

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) most commonly originates from hepatobiliary disease (cholestasis, biliary obstruction, infiltrative liver disease) or bone disorders (Paget's disease, metastases, fractures), with the specific cause determined by measuring GGT to differentiate hepatic from non-hepatic sources. 1

Primary Hepatobiliary Causes

Cholestatic Liver Diseases

• Primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and partial bile duct obstruction are major causes of chronic ALP elevation 1
• Cholestatic liver diseases typically elevate both ALP and GGT together, distinguishing them from bone sources 1
• In primary sclerosing cholangitis, ALP is typically ≥1.5× ULN, particularly in patients with inflammatory bowel disease 1

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, and infections causes chronic ALP elevation 1
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which significantly impacts liver function tests 1
• When gallstones migrate to the common bile duct, they cause partial or complete biliary obstruction leading to cholestasis and elevated ALP 1

Infiltrative Liver Diseases

• Infiltrative diseases including amyloidosis, hepatic metastases, and sarcoidosis cause ALP elevation 1
• In one study of 260 patients with isolated elevated ALP, underlying malignancy was the most common cause (57%), with 61 patients having infiltrative intrahepatic malignancy 2
• Extremely high ALP elevations (>1,000 U/L) are frequently seen in patients with diffuse liver metastases 3

Other Hepatic Conditions

• Cirrhosis, chronic hepatitis, viral hepatitis, and congestive heart failure are associated with ALP elevation 1
• In chronic liver disease, bone alkaline phosphatase is difficult to measure accurately when liver ALP is elevated 4

Primary Bone Causes

Malignant Bone Disease

• Paget's disease, bony metastases, and fractures are significant sources of ALP elevation 1
• In the study of isolated elevated ALP, 52 patients had bony metastasis alone, and 34 had both hepatic and bone metastasis 2
• Raised alkaline phosphatase in prostate cancer patients with bone metastases reflects increased osteoblastic activity 1

Benign Bone Disorders

• Bone disease accounted for 29% of cases in patients with isolated elevated ALP of unclear etiology 2
• Classical biochemical changes in osteomalacia include hypocalcaemia, hypophosphataemia, increased PTH, and elevated bone alkaline phosphatase, though serum calcium and phosphate are often normal 4, 1

Physiologic Causes

Age-Related Elevation

• ALP levels are physiologically 2-3× adult values in childhood due to bone growth 1
• This represents normal bone turnover and does not indicate pathology 1

Pregnancy

• ALP levels increase beginning in the second trimester and continue rising through the third trimester, reaching up to twice the upper limit of normal due to placental production 1, 5
• If ALP is elevated with normal GGT, bilirubin, and aminotransferases, this represents normal pregnancy physiology 5
• The placenta directly produces and secretes alkaline phosphatase into maternal circulation 5

Infectious and Inflammatory Causes

Sepsis

• Sepsis is a major cause of extremely high ALP elevations (>1,000 U/L), including gram-negative organisms, gram-positive organisms, and fungal infections 3
• Seven of 10 patients with sepsis had extremely high ALP with normal bilirubin 3
• In Thai hospitalized patients, sepsis was one of three major groups with high serum ALP levels 6

AIDS-Related Causes

• In patients with AIDS, elevated ALP can result from sepsis, mycobacterium avium intracellulare infection, cytomegalovirus infection, or drug toxicity 3
• Approximately 40% of patients with common variable immunodeficiency have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1

Drug-Induced Causes

• Drug-induced cholestasis is a significant cause, with older patients (≥60 years) particularly prone, comprising up to 61% of cholestatic drug-induced liver injury cases 1
• Glucocorticoids and anticonvulsants can induce increased alkaline phosphatase activity 7
• 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

Rare and Genetic Causes

• Benign familial hyperphosphatasemia presents with markedly increased intestinal alkaline phosphatase levels (29-44% of total) and significantly elevated liver/bone/kidney activity 8
• X-linked hypophosphatemia presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23 1

Diagnostic Approach Algorithm

1. Measure GGT concurrently with ALP to confirm hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources 1
2. If GGT is elevated (hepatic origin): Obtain abdominal ultrasound as first-line imaging to assess for dilated ducts, gallstones, infiltrative lesions, or masses 1
3. If ultrasound is negative but ALP remains elevated: Proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities 1
4. If GGT is normal (non-hepatic origin): Measure bone-specific alkaline phosphatase (B-ALP) and consider bone imaging if symptomatic 1

Critical Clinical Pitfalls

• Do not assume isolated ALP elevation is benign—in one study, 47% of patients with isolated elevated ALP died within an average of 58 months, with malignancy being the most common cause 2
• Extremely high ALP (>1,000 U/L) requires urgent evaluation for sepsis, malignant obstruction, or AIDS-related conditions 3, 6
• In pregnancy, any elevation in aminotransferases, bilirubin, or bile acids is abnormal and requires investigation, even though ALP elevation alone is physiologic 5
• Treatments like bisphosphonates and denosumab can alter ALP levels despite underlying pathology 1