What are the possible causes of concurrent elevation of alkaline phosphatase and gamma‑glutamyl transferase in a 66‑year‑old woman?

Causes of Elevated ALP and GGT in a 66-Year-Old Woman

Concurrent elevation of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) confirms a hepatobiliary origin of cholestasis and requires immediate evaluation with abdominal ultrasound to assess for biliary obstruction, followed by systematic workup for cholestatic liver diseases, drug-induced injury, and infiltrative processes. 1

Confirming Hepatobiliary Origin

• Elevated GGT alongside elevated ALP definitively establishes that the ALP originates from liver rather than bone or other tissues, because GGT is present in hepatobiliary tissue but absent in bone. 1, 2
• This cholestatic pattern (both ALP and GGT elevated) indicates either impaired bile secretion, obstruction to bile flow, or a defect in bile synthesis. 3

Primary Differential Diagnoses

Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are major causes of chronic ALP and GGT elevation, with PBC typically showing ALP levels 2–10× the upper limit of normal (ULN) and PSC showing ALP ≥1.5× ULN. 4
• PBC is diagnosed when two criteria are met: elevated ALP plus positive antimitochondrial antibody (AMA), or in AMA-negative cases, positive ANA with sp100/gp210 subtypes. 4
• PSC is strongly associated with inflammatory bowel disease (present in 50–80% of cases) and requires high-quality MRCP for diagnosis, showing characteristic "beading" of bile ducts. 4

Biliary Obstruction

• Extrahepatic biliary obstruction from choledocholithiasis, malignant obstruction, biliary strictures, or infections commonly causes concurrent ALP and GGT elevation. 4
• Approximately 18% of adults undergoing cholecystectomy have choledocholithiasis, which can significantly elevate both enzymes. 4

Drug-Induced Cholestatic Liver Injury

• In patients ≥60 years, drug-induced cholestatic liver injury accounts for up to 61% of cholestatic cases, making thorough medication review essential. 4, 1
• Common culprits include interferon, antipsychotics, beta-blockers, bile acid resins, estrogens, protease inhibitors, steroids, tamoxifen, and thiazides. 1
• Phenytoin specifically can cause increased serum levels of both ALP and GGT. 5
• Marked GGT elevation (>2× ULN) may indicate drug-induced liver injury even when ALP remains below conventional diagnostic thresholds, and such cases warrant drug discontinuation and close monitoring. 6

Infiltrative Liver Disease

• Hepatic metastases account for 57% of unexplained isolated ALP elevations in large cohorts, with infiltrative diseases including amyloidosis, sarcoidosis, and malignancy causing concurrent ALP and GGT elevation. 4
• Approximately 30% of patients with liver metastases have ALP ≥2× ULN. 4

Alcohol-Related Liver Disease

• Alcohol intake >20 g/day in women increases risk of alcoholic fatty liver disease or alcoholic steatohepatitis, with GGT being elevated in approximately 75% of habitual drinkers. 7, 1
• In alcoholic liver disease, AST is typically 2–6× ULN and the AST/ALT ratio exceeds 2 in about 70% of patients. 4
• Even in patients with known hypophosphatasia (genetically low ALP), alcohol-induced hepatitis can transiently elevate ALP levels, illustrating that liver disease can override baseline enzyme patterns. 8

Other Hepatic Causes

• Chronic hepatitis (viral or autoimmune), cirrhosis, congestive heart failure, and partial bile duct obstruction can all cause concurrent ALP and GGT elevation. 4
• Liver adenomas can produce both hepatic and biliary-type ALP, occasionally causing marked elevations (>2500 U/L) that normalize after surgical removal. 9

Diagnostic Algorithm

Step 1: Initial Laboratory Workup

• Obtain a complete liver panel including total and direct bilirubin, ALT, AST, and albumin to assess injury pattern and synthetic function. 1
• Calculate the R value: (ALT/ULN)/(ALP/ULN) to classify the pattern as cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5). 7, 1
• With elevated ALP and GGT, expect a cholestatic or mixed pattern. 1
• Fractionate total bilirubin to determine the percentage of direct (conjugated) bilirubin, as elevation confirms cholestasis and more advanced biliary obstruction. 4, 1

Step 2: Comprehensive Medication and Alcohol History

• Review all prescribed, over-the-counter, and supplement medications systematically, as drug-induced cholestasis is the leading cause in older adults. 4, 1
• Screen for alcohol use with validated tools (e.g., AUDIT score ≥8) and document consumption >40 g/day for women, as this is the most common cause of elevated GGT. 4, 1

Step 3: First-Line Imaging

• Proceed immediately to transabdominal ultrasound to evaluate for:
  • Dilated intra- or extrahepatic bile ducts (suggesting obstruction)
  • Gallstones or choledocholithiasis
  • Infiltrative liver lesions or masses
  • Signs of chronic liver disease 1, 2
• Ultrasound demonstrates 84.8% sensitivity and 93.6% specificity for detecting moderate-to-severe steatosis and reliably identifies biliary obstruction. 4

Step 4: Advanced Imaging if Ultrasound is Negative

• If ultrasound shows dilated ducts but no clear stone, proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, PSC, small-duct disease, and partial bile duct obstruction. 4, 1
• If ultrasound shows common bile duct stones, proceed directly to ERCP for both diagnosis and therapeutic intervention. 4, 1
• MRCP demonstrates 86% sensitivity and 94% specificity for diagnosing PSC, reliably visualizing multifocal strictures, dilatations, and ductal thickening. 4

Step 5: Serologic Evaluation

• Check viral hepatitis serologies (HAV, HBV, HCV) if risk factors are present. 4, 1
• Obtain autoimmune markers including AMA, ANA (with sp100/gp210 subtypes), ASMA, and quantitative IgG to evaluate for PBC, autoimmune hepatitis, or overlap syndromes. 4, 1
• Positive AMA with elevated ALP essentially confirms PBC. 4

Step 6: Consider Liver Biopsy

• If diagnosis remains unclear after comprehensive imaging and serologic workup, liver biopsy should be performed for definitive histologic diagnosis. 4
• In patients with inflammatory bowel disease and suspected small-duct PSC but normal MRCP, liver biopsy is recommended. 4

Severity-Based Urgency

• ALP >10× ULN requires expedited workup due to high association with serious pathology including malignancy and complete biliary obstruction. 4, 1
• Total bilirubin >2× ULN combined with elevated ALP/GGT suggests significant cholestasis requiring urgent evaluation. 1
• Mild elevation (ALP <5× ULN) requires systematic but not emergent workup unless accompanied by other concerning features. 1

Monitoring Strategy

• Repeat ALP, GGT, and complete liver panel in 1–3 months if initial workup is unrevealing. 1
• For suspected cholestatic patterns, repeat testing within 7–10 days to confirm reproducibility and direction of change. 4, 1
• Progressive elevation on repeat testing warrants accelerated investigation. 1

Critical Pitfalls to Avoid

• Do not assume all ALP elevations are liver-related without confirming with GGT or isoenzyme fractionation, though in this case concurrent GGT elevation already confirms hepatobiliary origin. 2
• Do not overlook malignancy, as hepatic metastases are the leading cause of isolated ALP elevation (57% of cases). 4
• Do not underestimate the importance of medication review in older adults, as drug-induced cholestasis comprises the majority of cases in this age group. 4, 1
• Recognize that GGT has limited utility in predicting specific ALP isoform elevations (AUC 0.68 for hepatic isoform), but concurrent elevation definitively confirms hepatobiliary origin. 10
• Normal ultrasound does not exclude intrahepatic cholestasis, PSC, or small-duct disease; MRCP is mandatory if ALP remains elevated. 4