Alkaline Phosphatase is Normal in Gilbert Syndrome
Yes, alkaline phosphatase (ALP) is characteristically normal in Gilbert syndrome. This benign hereditary condition affects bilirubin conjugation but does not involve cholestasis or hepatocellular injury, so ALP remains within normal limits 1.
Key Laboratory Pattern in Gilbert Syndrome
Gilbert syndrome presents with a distinctive biochemical profile that helps differentiate it from other liver conditions:
- Isolated unconjugated (indirect) hyperbilirubinemia is the hallmark, with total bilirubin typically mildly elevated but rarely exceeding 4-5 mg/dL 1
- ALP remains normal because there is no biliary obstruction or cholestatic process 1, 2
- Aminotransferases (ALT/AST) are normal, distinguishing it from hepatocellular injury 2
- GGT is normal, further confirming absence of cholestasis 1
- Albumin and INR are normal, indicating preserved hepatic synthetic function 1
The unconjugated fraction should comprise more than 70-80% of total bilirubin (or direct bilirubin less than 20-30% of total), confirming the conjugation defect rather than cholestatic disease 1.
Clinical Recognition in Practice
When evaluating patients in clinical trials or practice settings, guidelines explicitly recognize Gilbert syndrome as a benign condition that should not trigger exclusion based on bilirubin elevation alone:
- Clinical trial guidelines specifically state that total bilirubin >1.0× ULN should be an exclusion criterion "in the absence of Gilbert's Syndrome or haemolysis" 1
- In PSC trials, patients with baseline bilirubin elevations should be excluded "unless Gilbert's Syndrome or haemolysis is present" 1
This recognition underscores that Gilbert syndrome does not represent true liver disease and should not confound interpretation of liver function tests.
Diagnostic Confirmation
When Gilbert syndrome is suspected based on isolated unconjugated hyperbilirubinemia with normal ALP:
- Fractionate total bilirubin to confirm that conjugated (direct) bilirubin is <20-30% of total 1
- Rule out hemolysis with complete blood count, reticulocyte count, and peripheral smear 1
- Genetic testing for UGT1A1 mutations can be considered if diagnosis remains uncertain, though it is rarely necessary in typical presentations 1
Important Clinical Pitfall
Do not misattribute elevated ALP to Gilbert syndrome. If a patient has known Gilbert syndrome but presents with elevated ALP, this represents a separate pathologic process requiring full evaluation for cholestatic or infiltrative liver disease 1. One case series documented a patient with hypophosphatasia (low ALP at baseline) who developed elevated ALP due to concurrent alcohol-induced hepatitis, illustrating that baseline conditions do not prevent development of separate liver pathology 3.
Rare Exception: Familial Intestinal ALP Variant
One case report described a family with both Gilbert syndrome and a rare inherited elevation of intestinal ALP isoenzyme, but this represented two separate genetic conditions occurring together, not a feature of Gilbert syndrome itself 4. Standard Gilbert syndrome does not cause ALP elevation.