What is the differential diagnosis for scleral icterus?

Differential Diagnosis for Scleral Icterus

Scleral icterus indicates hyperbilirubinemia and requires systematic evaluation across hepatocellular, cholestatic, and hemolytic etiologies, with the clinical context determining which pathway to pursue first.

Cholestatic/Obstructive Causes

Biliary Obstruction

• Choledocholithiasis is the most common cause of biliary obstruction, occurring in approximately 18% of adults undergoing cholecystectomy and up to 20% of patients with cholelithiasis 1
• Cholangitis presents with Charcot's triad: fever, rigors, right upper quadrant pain, and obstructive jaundice 1
• Acute cholangitis can markedly elevate CA 19-9 levels (>4,000 U/mL), mimicking malignancy 2

Primary Sclerosing Cholangitis (PSC)

• PSC presents with multifocal strictures creating a characteristic "beading" appearance on cholangiography, strongly associated with inflammatory bowel disease in 60-80% of cases 1, 3
• Consider PSC particularly in young males with ulcerative colitis, who often exhibit pancolitis (87% vs 54% in UC without PSC), reflux ileitis (51% vs 7%), and rectal sparing (52% vs 6%) 3
• Critical pitfall: Up to 47% of pediatric PSC cases may have normal alkaline phosphatase levels, though GGT is typically elevated 1
• PSC carries a 10-15% lifetime risk of cholangiocarcinoma, with 50% diagnosed within the first year after PSC diagnosis 3

IgG4-Related Sclerosing Cholangitis

• IgG4-associated cholangitis mimics PSC but shows long biliary strictures with prestenotic dilatations and low common bile duct strictures, whereas PSC demonstrates beading, peripheral duct pruning, and pseudodiverticula 1
• Serum IgG4 >4× upper limit of normal is highly specific, though 9-15% of PSC patients also have elevated IgG4 levels 4, 3
• Key distinguishing feature: IgG4-SC responds dramatically to corticosteroids (prednisolone 0.6 mg/kg/day), while PSC does not respond to steroids in a sustained manner 4, 3
• IgG4-SC has lower IBD prevalence (5.6% vs ~70% in PSC) 3

Secondary Sclerosing Cholangitis

• Causes include: previous biliary surgery, surgical trauma from cholecystectomy, intraductal stone disease, intra-arterial chemotherapy, recurrent pancreatitis, ischemic cholangitis, and AIDS cholangiopathy 5, 1
• Parasitic infections including liver flukes can cause biliary obstruction 1

Malignant Obstruction

• Cholangiocarcinoma should be considered, particularly in PSC patients with annual incidence of 0.5-1.5% after the first year of diagnosis 1, 3
• Pancreatic head mass is a common cause of distal common bile duct obstruction 1
• Periampullary neoplasms require EUS for local staging 1
• Gallbladder carcinoma occurs in up to 2% of PSC patients 1

Other Biliary Causes

• Lemmel's syndrome (juxtapapillary diverticulum causing biliary obstruction) can present with right upper quadrant pain, fever, and scleral icterus 6
• Sphincter of Oddi dysfunction may cause recurrent symptoms mimicking chronic cholecystitis 1
• Caroli syndrome and biliary hamartomas represent ductal plate malformations causing obstruction 1

Hepatocellular Causes

Infectious Hepatitis

• Hepatitis A can present with scleral icterus, fever, vomiting, and hepatosplenomegaly, occasionally with extra-hepatic manifestations 7
• Syphilitic hepatitis presents with jaundice, right upper quadrant tenderness, hepatomegaly, hyperbilirubinemia, and elevated transaminases; diagnosis confirmed by positive syphilis serology and response to penicillin 8

Autoimmune Liver Disease

• PSC/AIH overlap syndrome occurs in 1.4-17% of adults with PSC, presenting with younger age, higher transaminases, elevated immunoglobulins, positive ANA/SMA, and interface hepatitis on biopsy 5
• Critical diagnostic threshold: Liver biopsy recommended when ALT >5× ULN, IgG >2× ULN, or positive autoimmune antibodies (ANA, SMA, liver/kidney microsomal antibodies) 5
• Important prognostic distinction: AIH/PSC overlap responds to steroids with better prognosis than classic PSC but worse than non-overlap AIH 5
• PSC/PBC overlap syndrome has been reported only in small case series 5

Hemolytic Causes

Infection-Mediated Hemolysis

• Plasmodium ovale infection can cause warm autoimmune hemolytic anemia presenting with fever, scleral icterus, splenomegaly, and positive direct antiglobulin test for IgG and C3d 9

Diagnostic Approach Algorithm

Step 1: Determine pattern of liver injury

• Obtain ALT, AST, alkaline phosphatase, GGT, total/direct bilirubin
• Cholestatic pattern (elevated ALP/GGT) → pursue biliary imaging
• Hepatocellular pattern (elevated transaminases) → pursue hepatitis workup
• Mixed pattern → consider overlap syndromes

Step 2: Initial imaging for cholestatic pattern

• MRCP is cornerstone for identifying biliary obstruction and characteristic patterns 4
• Look for biliary dilation, strictures, stones, masses
• Critical pitfall: Absence of biliary dilation does not exclude obstruction in acute presentations 1

Step 3: Serologic evaluation

• If PSC suspected: Check for IBD association, consider colonoscopy
• If elevated transaminases disproportionate to cholestasis: Check ANA, SMA, IgG, IgG4 levels
• IgG4/IgG1 ratio >0.24 improves specificity for distinguishing IgG4-SC from PSC 4

Step 4: Tissue diagnosis when indicated

• Small duct PSC: Requires liver biopsy when cholangiography is normal 5
• Suspected overlap syndromes: Biopsy when ALT >5× ULN or IgG >2× ULN 5
• IgG4-RD: Tissue showing >10 IgG4-positive plasma cells per high-power field with IgG4+/IgG+ ratio >40% 4

Step 5: Consider therapeutic trial

• If IgG4-SC suspected: Dramatic response to corticosteroids confirms diagnosis 4, 3
• If PSC confirmed: No effective medical therapy; focus on surveillance for cholangiocarcinoma and colon cancer 3