In a 78‑year‑old man with an isolated elevated alkaline phosphatase, how can I determine whether the abnormality is due to bone disease or liver disease?

Determining Bone vs. Liver Origin of Isolated Elevated Alkaline Phosphatase

Measure Gamma-Glutamyl Transferase (GGT) First

The most direct and efficient approach is to measure GGT concurrently with the elevated ALP: if GGT is elevated, the source is hepatobiliary; if GGT is normal, the source is likely bone or another non-hepatic origin. 1

• GGT is the most sensitive indicator of biliary-tract disease and confirms hepatobiliary origin when elevated alongside ALP 1
• Normal GGT in the setting of isolated ALP elevation strongly suggests bone disease, intestinal ALP, or other non-hepatic sources 1
• This single test provides immediate diagnostic direction and determines the entire subsequent workup pathway 1

Alternative Confirmatory Tests if GGT is Unavailable

If GGT measurement is unavailable or results are equivocal:

• Measure 5'-nucleotidase, which elevates specifically in hepatobiliary disease and remains normal in bone disorders 1
• Order ALP isoenzyme fractionation to determine the percentage derived from liver versus bone, though this is less commonly available 1
• Bone-specific ALP measurement can identify bone origin, with the bone-to-total ALP ratio improving diagnostic accuracy (ratios >0.86 suggest bone disease, while lower ratios suggest liver disease) 2

Hepatobiliary Workup When GGT is Elevated

Once hepatobiliary origin is confirmed:

• Obtain abdominal ultrasound as first-line imaging to evaluate for dilated bile ducts, gallstones, choledocholithiasis, or infiltrative liver lesions 1, 3
• Review all medications carefully, as cholestatic drug-induced liver injury accounts for up to 61% of cases in patients ≥60 years old 1
• Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: R ≤2 indicates cholestatic pattern, R >2 and <5 indicates mixed pattern, R ≥5 indicates hepatocellular pattern 1
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, and small duct disease 1, 3

Key Hepatobiliary Differentials to Consider

• Primary biliary cholangitis: Check antimitochondrial antibody (AMA); diagnosis requires elevated ALP plus positive AMA 1
• Primary sclerosing cholangitis: Particularly suspect if the patient has inflammatory bowel disease; ALP typically ≥1.5× ULN 1
• Choledocholithiasis: Approximately 18% of adults undergoing cholecystectomy have common bile duct stones 1
• Infiltrative diseases: Including hepatic metastases (most common cause at 57% in one cohort), amyloidosis, or sarcoidosis 1, 4

Bone Workup When GGT is Normal

When bone origin is suspected based on normal GGT:

• Assess for localized bone pain, fracture history, or constitutional symptoms that would indicate need for imaging 1, 3
• Order bone scan only if symptomatic (localized bone pain or radiographic findings suggestive of bone pathology); do NOT order bone scan in asymptomatic patients 1
• Consider Paget's disease, bone metastases, or recent fractures as primary differentials 1, 3
• In postmenopausal women, physiologic bone turnover from osteoporosis may cause mild ALP elevation without pathology 1

Critical Bone Disease Considerations

• Bone metastases are a significant cause of isolated ALP elevation, accounting for 52 patients (20%) in one study of unexplained ALP elevation 4
• The positive predictive value of bone-specific ALP for bone metastasis is high and superior to total ALP alone 5
• In the absence of bone pain or symptoms, the likelihood of positive bone scan is very low (<5%) 1

Age-Specific Considerations for a 78-Year-Old Patient

• Malignancy is the most common cause of unexplained isolated ALP elevation (57% in one cohort), with infiltrative intrahepatic malignancy and bony metastases being most frequent 4
• Drug-induced cholestatic injury is particularly common in older adults, comprising up to 61% of cholestatic cases in patients ≥60 years 1
• Carefully review all medications, supplements, and over-the-counter agents for hepatotoxic potential 1
• Consider that 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, underscoring the importance of thorough evaluation 4

Common Pitfalls to Avoid

• Do not assume non-alcoholic steatohepatitis (NASH) as the cause when ALP is ≥2× ULN, as NASH typically causes ALT elevation more than ALP 1
• Do not order bone scan in asymptomatic patients with normal GGT, as the yield is extremely low 1
• Do not delay workup in patients with moderate-to-severe elevation (≥5× ULN), as this is highly associated with serious pathology requiring expedited evaluation 1, 3
• Do not stop at normal ultrasound if ALP remains persistently elevated; proceed to MRI/MRCP for superior detection of intrahepatic pathology 1

Monitoring Strategy

• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months and monitor closely for rising trends 1
• Persistent or rising ALP warrants further investigation even if initial workup was negative 1
• For cholestatic patterns, recognize that normalization occurs more slowly than hepatocellular injury, typically within 6 months after removing the offending agent 1