What is the diagnosis and management for a 47-year-old female with paresthesia, mildly elevated bilirubin, elevated alkaline phosphatase (Alk Phos) and gamma-glutamyl transferase (Gamma GT), and normal liver transaminases?

Cholestatic Liver Disease with Peripheral Neuropathy

Most Likely Diagnosis

This presentation is most consistent with Primary Biliary Cholangitis (PBC), given the cholestatic enzyme pattern (elevated alkaline phosphatase and GGT with normal transaminases) in a middle-aged woman with peripheral neuropathy. 1

The laboratory pattern shows:

• Cholestatic pattern: Alkaline phosphatase 166 U/L (elevated, >1.5× upper limit of normal) and Gamma GT 165 U/L (markedly elevated, >4× upper limit of normal) 2, 3
• Normal hepatocellular markers: ALT 18 U/L and AST 20 U/L are both normal, indicating preserved hepatocellular function 1
• Preserved synthetic function: Normal albumin (45 g/L), protein (66 g/L), and bilirubin (14 umol/L) indicate no cirrhosis or hepatic decompensation 1
• Low globulin gap (21 g/L, below normal range of 22-38 g/L) is unusual but does not exclude PBC 1

Diagnostic Algorithm

Step 1: Confirm Cholestatic Pattern

• The disproportionate elevation of alkaline phosphatase and GGT compared to transaminases confirms a cholestatic rather than hepatocellular pattern 2, 3
• GGT elevation confirms the hepatic origin of alkaline phosphatase elevation (ruling out bone disease) 4, 5

Step 2: Immediate Serologic Testing

• Antimitochondrial antibodies (AMA) are mandatory and diagnostic—present in >90% of PBC patients with >95% specificity 1
• If AMA negative, check anti-Sp100 and anti-gp210 antibodies, which are highly specific for PBC (>95%) though less sensitive 1
• Complete viral hepatitis panel (HBsAg, anti-HCV) to exclude viral causes 1
• Autoimmune markers (ANA, anti-smooth muscle antibody) if AMA negative 1

Step 3: Imaging to Exclude Obstruction

• Abdominal ultrasound is the mandatory first-line imaging to differentiate intrahepatic from extrahepatic cholestasis 1, 6
• Ultrasound will identify biliary ductal dilation, gallstones, masses, or structural abnormalities 6
• MRCP should be performed if ultrasound shows dilated ducts or is inconclusive, or if AMA testing is negative 1

Step 4: Consider Liver Biopsy

• A liver biopsy is not mandatory if AMA is positive with characteristic cholestatic biochemistry 1
• However, biopsy is useful for staging disease (Ludwig stages 1-4) and assessing prognosis 1
• Biopsy should be considered if AMA is negative despite clinical suspicion, or if competing diagnoses need exclusion 1

Peripheral Neuropathy Connection

Peripheral neuropathy (pins and needles) can occur in PBC and other cholestatic liver diseases through several mechanisms:

• Vitamin E deficiency from fat-malabsorption in chronic cholestasis 1
• Symmetric peripheral neuropathy is a recognized extrahepatic manifestation of alcohol-related liver disease, though less likely given the enzyme pattern 1
• The neuropathy may also be unrelated to liver disease and require separate neurologic evaluation 1

Alternative Diagnoses to Consider

Drug-Induced Liver Injury (DILI)

• DILI can present with marked GGT elevation (>2× ULN) even without meeting conventional thresholds 7
• Cholestatic DILI shows GGT positively correlated with alkaline phosphatase 4
• Critical action: Review all medications, supplements, and herbal products against the LiverTox® database 8

Primary Sclerosing Cholangitis (PSC)

• Less likely without inflammatory bowel disease history 1
• Would require MRCP to visualize bile duct strictures and beading 1

Hereditary Cholestatic Syndromes

• Consider ABCB4 genetic testing if AMA negative and biopsy findings compatible with PBC or PSC 1

Hepatic Vascular Malformations (HHT)

• Unlikely given the clinical presentation, but elevated alkaline phosphatase and GGT can occur in the biliary type of hereditary hemorrhagic telangiectasia 1
• Would present with epistaxis, telangiectases, or family history of HHT 1

Management Approach

Immediate Actions

1. Order AMA testing (anti-PDC-E2/anti-AMA-M2 if available) 1
2. Perform abdominal ultrasound to exclude biliary obstruction 1, 6
3. Complete medication review for potential hepatotoxins 8
4. Check vitamin levels (A, D, E, K) given cholestatic pattern 1

If PBC Confirmed (AMA positive)

• Ursodeoxycholic acid (UDCA) is first-line therapy 1
• Monitor liver biochemistry every 3 months initially 1
• Screen for complications: osteoporosis, fat-soluble vitamin deficiencies 1
• Upper endoscopy if evidence of cirrhosis develops (platelets <150,000 and FibroScan >20 kPa) 1

If AMA Negative

• Proceed to MRCP to evaluate biliary tree 1
• Consider liver biopsy for definitive diagnosis 1
• Evaluate for alternative autoimmune markers 1

Critical Pitfalls to Avoid

• Do not assume elevated alkaline phosphatase is from bone disease without checking GGT—the markedly elevated GGT confirms hepatic origin 4, 5
• Do not delay AMA testing—this is the diagnostic hallmark of PBC and should be ordered immediately 1
• Do not perform ERCP diagnostically—MRCP or EUS should be preferred due to ERCP's morbidity and mortality 1
• Do not overlook medication-induced cholestasis—even marked GGT elevation can occur in DILI without meeting conventional thresholds 7
• Do not ignore the peripheral neuropathy—evaluate for vitamin E deficiency and consider neurologic consultation if symptoms persist 1