Intermittent Jaundice (Yellowing of Sclera): Differential Diagnosis and Evaluation
Most Likely Causes
Intermittent jaundice suggests either relapsing hepatobiliary disease, intermittent biliary obstruction, or episodic hemolysis rather than progressive liver failure. The pattern of "on and off" yellowing narrows the differential significantly compared to persistent jaundice.
Primary Diagnostic Considerations
Relapsing Hepatitis A is a well-documented cause of intermittent jaundice, occurring in 10-15% of hepatitis A cases with relapses lasting up to 6 months, and approximately 20% of these patients experience multiple relapses 1. Hepatitis A virus can be detected in stool during relapses, and despite the relapsing nature, overall outcomes remain very good 1.
Intermittent biliary obstruction from choledocholithiasis (common bile duct stones) commonly presents with fluctuating jaundice as stones intermittently obstruct then pass or shift position 1. This represents 13-14% of severe jaundice cases and is one of the most common obstructive causes 1.
Cholestatic hepatitis can present with prolonged or intermittent jaundice, particularly in the context of hepatitis A or drug-induced liver injury 1.
Hemolytic episodes can cause intermittent unconjugated hyperbilirubinemia, particularly in Wilson's disease where acute hemolytic episodes may occur as single events or recurrently 1. Hemolysis was a presenting feature in 12% of Wilson's disease cases in one series 1.
Diagnostic Algorithm
Step 1: Initial Laboratory Evaluation
Obtain fractionated bilirubin (conjugated vs unconjugated), complete blood count, AST, ALT, alkaline phosphatase, GGT, albumin, PT/INR 2, 3. This determines whether hyperbilirubinemia is conjugated (suggesting hepatobiliary disease) or unconjugated (suggesting hemolysis or Gilbert syndrome) 1, 2.
- Unconjugated hyperbilirubinemia points toward hemolysis, hematoma resorption, or Gilbert syndrome 4, 5
- Conjugated hyperbilirubinemia indicates hepatocellular disease, biliary obstruction, or cholestatic processes 1, 4
- Elevated alkaline phosphatase suggests biliary obstruction or infiltrative disease 6
- Elevated transaminases indicate hepatocellular injury from viral hepatitis, drug toxicity, or autoimmune disease 6
Step 2: First-Line Imaging
Abdominal ultrasound is mandatory as the initial imaging test for all patients with jaundice 1, 7. Ultrasound is designated by the American College of Radiology as first-line due to its non-invasive nature, lack of radiation, low cost, and rapid availability 7.
Ultrasound will:
- Detect biliary ductal dilatation (sensitivity 32-100%, specificity 71-97%) 1, 7
- Identify gallstones with 96% accuracy 7
- Detect cirrhosis (sensitivity 65-95%, positive predictive value 98%) 1
- Assess for portal hypertension and ascites 7
Critical caveat: Ultrasound has limited sensitivity (22.5-75%) for common bile duct stones because the distal duct may be obscured by bowel gas 1. Normal ultrasound does not exclude choledocholithiasis if clinical suspicion remains high 7.
Step 3: Advanced Imaging When Indicated
If ultrasound shows biliary obstruction or is inconclusive, proceed to MRCP 1, 7. MRCP has pooled sensitivity of 86% and specificity of 94% for diagnosing biliary pathology including primary sclerosing cholangitis 1.
If biliary obstruction is confirmed and therapeutic intervention needed, ERCP is appropriate 1, 7. However, ERCP carries risks including pancreatitis (1.3-1.5% of cases, 70% mild), cholangitis (<1%), and perforation 1.
Step 4: Specific Disease Considerations
For suspected relapsing hepatitis A: Check hepatitis A IgM and IgG serology 1. Patients typically improve within 3-4 weeks but 10-15% have relapsing disease 1. A short course of rapidly tapered corticosteroids can reduce symptoms in cholestatic hepatitis 1.
For suspected choledocholithiasis: The presence of multiple small (<5 mm) gallstones creates 4-fold risk for CBD migration 1. If ultrasound is negative but suspicion high, proceed to MRCP or endoscopic ultrasound 7.
For suspected hemolysis: Check Coombs test, LDH, haptoglobin, and reticulocyte count 1, 4. Consider Wilson's disease in younger patients, particularly if accompanied by neurologic symptoms or Kayser-Fleischer rings 1.
For suspected primary sclerosing cholangitis: Look for concomitant inflammatory bowel disease (present in 50-80% of PSC cases) and persistently elevated alkaline phosphatase 1. MRCP is the preferred diagnostic test showing multifocal strictures and dilatations 1.
Critical Pitfalls to Avoid
Do not assume normal ultrasound excludes significant pathology 7. If clinical suspicion remains high despite negative ultrasound, proceed to MRCP or endoscopic ultrasound, particularly for suspected choledocholithiasis 7.
Do not delay evaluation of new or worsening jaundice in patients with known PSC, as this may indicate cholangiocarcinoma, which has a lifetime risk of up to 20% in PSC patients 1. Rapidly increasing jaundice, weight loss, or elevated CA 19-9 warrant urgent cross-sectional imaging and possible ERCP with tissue sampling 1.
Do not attribute jaundice solely to "hepatic encephalopathy" in cirrhotic patients without excluding acute processes such as sepsis (22% of new-onset jaundice), decompensated cirrhosis (20.5%), or biliary obstruction 1.
Recognize that intermittent jaundice from biliary obstruction may resolve spontaneously as stones pass, but this does not eliminate the need for definitive evaluation and treatment to prevent recurrence and complications like cholangitis 1.