What are the implications and treatments for elevated total bilirubin levels?

Management of Elevated Total Bilirubin

For patients with elevated total bilirubin, the first step is to determine whether the hyperbilirubinemia is predominantly conjugated or unconjugated by obtaining fractionated bilirubin levels and complete liver function tests. 1

Initial Diagnostic Evaluation

• Obtain fractionated bilirubin levels to determine if hyperbilirubinemia is predominantly conjugated or unconjugated 1
• Order complete liver function tests including ALT, AST, ALP, GGT, and albumin to assess for liver injury and synthetic function 1
• Measure prothrombin time (PT) and INR to evaluate liver synthetic capacity 1
• Complete blood count with peripheral smear should be checked to assess for hemolysis if unconjugated hyperbilirubinemia is suspected 1, 2

Diagnostic Pathway Based on Bilirubin Type

Unconjugated Hyperbilirubinemia

• Consider Gilbert's syndrome and evaluate for hemolysis with reticulocyte count, haptoglobin, and LDH 1, 3
• In neonates, assess for risk factors of severe hyperbilirubinemia including G6PD deficiency, which may cause sudden increases in total serum bilirubin (TSB) 4
• Evaluate for drug-induced causes, as certain antibiotics (sulfisoxazole, sulfamethoxazole, dicloxacillin, cefoperazone, and ceftriaxone) can displace bilirubin from albumin binding sites 5

Conjugated Hyperbilirubinemia

• Perform ultrasound of the abdomen as the initial imaging study to evaluate for biliary obstruction 1
• If direct bilirubin is 50% or more of the total bilirubin, consultation with an expert in the field is recommended due to limited guidance for therapy 4
• Evaluate for dominant stricture with magnetic resonance cholangiography or endoscopic retrograde cholangiography if abrupt elevations in liver tests occur in patients with PSC 4

Management Considerations

For Adults

• For biliary obstruction, consider preoperative biliary drainage if total bilirubin is >12.8 mg/dL, especially if major hepatic resection is planned 1
• In patients with acute cholecystitis or biliary colic with elevated bilirubin, immediate imaging or procedural intervention is recommended rather than obtaining follow-up bilirubin levels 6

For Neonates

• If TSB is at a level at which exchange transfusion is recommended or if TSB level is 25 mg/dL or higher at any time, it is a medical emergency requiring immediate admission for intensive phototherapy 4
• Exchange transfusions should be performed only by trained personnel in a neonatal intensive care unit with full monitoring and resuscitation capabilities 4
• In isoimmune hemolytic disease, administration of intravenous immunoglobulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy 4
• For all newborns, treatment is recommended at lower TSB levels at younger ages to prevent additional increases in the TSB level 4

Laboratory Tests for Neonatal Hyperbilirubinemia

• TSB and direct bilirubin levels 4
• Blood type (ABO, Rh) and direct antibody test (Coombs') 4
• Serum albumin (important for bilirubin binding capacity) 4
• Complete blood cell count with differential and smear for red cell morphology 4
• Reticulocyte count 4
• G6PD if suggested by ethnic or geographic origin or if poor response to phototherapy 4

Pitfalls to Avoid

• Do not subtract direct (conjugated) bilirubin from total bilirubin when making treatment decisions 4
• Avoid delay in appropriate imaging in patients with conjugated hyperbilirubinemia, as early identification of biliary obstruction is critical 1
• Be aware that standard laboratory tests for hemolysis have poor specificity and sensitivity 4
• Remember that in the presence of hemolysis, G6PD levels can be elevated, which may obscure the diagnosis in the newborn period 4
• Avoid medications with high bilirubin-displacing activity in jaundiced newborns when alternatives are available 5

Special Considerations

• The bilirubin/albumin (B/A) ratio can be used as an additional factor in determining the need for exchange transfusion in neonates, but should not be used in lieu of the TSB level 4
• Phototherapy is effective for neonatal hyperbilirubinemia through the photochemical transformation of bilirubin into water-soluble isomers that can be excreted 7
• Tin-mesoporphyrin, a drug that inhibits the production of heme oxygenase, could be considered for preventing the need for exchange transfusion in infants not responding to phototherapy, though it is not yet FDA approved 4