Hyperbilirubinemia in Dengue vs Yellow Fever
Yellow fever causes predominantly conjugated (direct) hyperbilirubinemia due to severe hepatocellular necrosis, while dengue typically causes mild mixed hyperbilirubinemia with predominantly hepatocellular injury pattern, though conjugated hyperbilirubinemia can occur in severe dengue hemorrhagic fever.
Yellow Fever: Conjugated Hyperbilirubinemia
Yellow fever characteristically produces conjugated (direct) hyperbilirubinemia as a hallmark feature of the disease:
Hyperbilirubinemia appears as early as the third day of illness but typically peaks toward the end of the first week, distinguishing it from other viral hemorrhagic fevers 1
The jaundice in yellow fever results from severe hepatorenal disease with marked elevations of serum transaminases that may remain elevated for up to 2 months after onset 1
Physical examination reveals scleral and dermal icterus as prominent features, occurring in approximately 15% of infected persons who progress to severe disease 1
Yellow fever with jaundice must be differentiated from viral hepatitis, malaria, leptospirosis, and other causes of conjugated hyperbilirubinemia, as the clinical presentation overlaps significantly 1
Pathophysiology in Yellow Fever
The conjugated hyperbilirubinemia reflects direct hepatocellular damage from yellow fever virus infection of hepatocytes, causing impaired bilirubin excretion rather than hemolysis 1
Hepatic involvement occurs without hepatic enlargement, which is an important distinguishing feature on physical examination 1
Dengue: Mixed Pattern with Variable Conjugation
Dengue infection produces a more variable pattern of hyperbilirubinemia that differs significantly from yellow fever:
Hyperbilirubinemia in dengue is typically mild, with mean total bilirubin of 1.26±1.14 mg/dl in a large series, and occurs in only 27% of patients 2
When present, dengue causes predominantly hepatocellular injury with AST rising significantly more than ALT (mean AST 364.43 U/L vs ALT 240.38 U/L), suggesting myocyte involvement in addition to hepatocyte damage 2
Hyperbilirubinemia was noted in only 12% of dengue hemorrhagic fever (DHF) patients and 8% of classic dengue fever (DF) patients, with mean serum bilirubin higher in DHF [14.2 micromol/l] compared to DF [10.9 micromol/l] 3
Cholestatic Pattern in Severe Dengue
Rare cases of dengue hemorrhagic fever can present with cholestatic jaundice, representing an atypical manifestation:
Two documented cases of DHF presented with cholestatic-type jaundice with elevated alkaline phosphatase and conjugated hyperbilirubinemia, highlighting that dengue should be considered even when cholestatic pattern is present 4
Severe dengue with fulminant hepatitis can produce massive transaminase elevations (ALT: 3,515 U/L, AST: 12,541 U/L) with conjugated hyperbilirubinemia, though this is exceedingly rare 5
In cirrhotic patients with dengue, bilirubin elevation is more pronounced and predicts development of liver failure on multivariate analysis 6
Key Clinical Distinctions
The pattern of hyperbilirubinemia helps differentiate these two flavivirus infections:
Yellow fever: Conjugated hyperbilirubinemia is a defining feature appearing early and prominently, with jaundice being one of the classic triad findings (fever, jaundice, hemorrhage) 1
Dengue: Hyperbilirubinemia is usually absent or mild, and when present, reflects hepatocellular injury rather than the severe hepatic necrosis seen in yellow fever 2, 3
Dengue hemorrhagic fever with spontaneous bleeding shows higher ALT, ALP, and bilirubin levels compared to those without bleeding, but still typically remains below the severe elevations seen in yellow fever 3
Critical Diagnostic Pitfall
Do not exclude dengue based solely on the presence of cholestatic jaundice, as atypical presentations with conjugated hyperbilirubinemia have been documented, particularly in dengue hemorrhagic fever 4. However, prominent early jaundice strongly suggests yellow fever over dengue in the appropriate epidemiological context 1.