What does an elevation of intestinal isoenzymes (e.g. lactate dehydrogenase (LDH), alkaline phosphatase (ALP)) indicate in a patient?

Elevated Intestinal Alkaline Phosphatase Isoenzymes: Clinical Significance

Elevated intestinal isoenzymes of alkaline phosphatase (I-ALP) most commonly represent a benign biochemical finding in asymptomatic patients, but can occasionally indicate gastrointestinal pathology, cirrhosis, or drug-induced intestinal mucosal injury.

Determining the Source of ALP Elevation

When total alkaline phosphatase is elevated, the first critical step is identifying whether the elevation originates from liver, bone, or intestine 1, 2:

• Measure gamma-glutamyl transferase (GGT) concurrently - elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone or intestinal sources 1, 2
• If GGT is normal or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver, bone, or intestine 1, 3
• Intestinal isoenzyme can be differentiated by electrophoresis after neuraminidase pretreatment or heat stability testing 3, 4

Clinical Significance of Elevated Intestinal ALP

Benign Causes

The most common scenario is benign elevation in asymptomatic individuals, particularly those of blood groups B or O 4, 5:

• Isolated I-ALP elevation with normal liver function tests, normal imaging, and negative serological workup typically represents a benign finding requiring no specific intervention 5
• Small amounts of intestinal isoenzyme are normally present in some individuals of blood groups B or O 3, 4

Pathological Causes

Elevated intestinal isoenzymes warrant investigation when accompanied by symptoms or other abnormalities 6, 3, 4:

• Cirrhosis - intestinal isoenzyme appears in many cases of cirrhosis, particularly in patients with blood groups B or O 3, 4
• Inflammatory bowel disease - intestinal ALP can be elevated in Crohn's disease, though this is less common than liver isoenzyme elevation 7
• Drug-induced intestinal mucosal injury - certain chemotherapeutic agents can cause increased intestinal mucosal leakage or impaired hepatic uptake and breakdown of intestinal isoenzyme 6
• Impaired hepatic clearance - liver dysfunction may reduce uptake and breakdown of intestinal isoenzyme by the liver 6

Diagnostic Approach

Initial Workup

When intestinal isoenzymes are identified as elevated 1, 2, 5:

1. Confirm the elevation is reproducible by repeating ALP and isoenzyme fractionation within 1-3 months 1
2. Obtain complete liver panel including ALT, AST, total and direct bilirubin, albumin, and GGT 1, 2
3. Review medication history for hepatotoxic or gastrointestinal-toxic drugs 1, 6
4. Assess for gastrointestinal symptoms including abdominal pain, diarrhea, weight loss, or gastrointestinal bleeding 8

Imaging and Further Testing

If liver function tests are abnormal or symptoms are present 1, 2:

• Obtain abdominal ultrasound as first-line imaging to evaluate for cirrhosis, portal hypertension, or hepatobiliary abnormalities 1, 2
• Consider MRI with MRCP if ultrasound is unrevealing but clinical suspicion remains high 1, 2
• Evaluate for inflammatory bowel disease if gastrointestinal symptoms are present, particularly in younger patients 8, 7

When to Reassure vs. Investigate Further

In asymptomatic patients with isolated I-ALP elevation 5:

• Normal liver function tests (ALT, AST, bilirubin, albumin)
• Normal GGT
• Normal abdominal imaging
• Negative serological workup for hepatobiliary disease
• This constellation suggests benign elevation requiring only periodic monitoring 5

Proceed with aggressive investigation when 1, 6, 3:

• Symptoms of liver disease (jaundice, ascites, encephalopathy)
• Symptoms of gastrointestinal disease (chronic diarrhea, bleeding, weight loss)
• Abnormal liver function tests beyond isolated ALP elevation
• Known cirrhosis or inflammatory bowel disease
• Recent chemotherapy or hepatotoxic drug exposure

Common Pitfalls to Avoid

• Do not assume all ALP elevations are liver-related - always confirm the source with GGT or isoenzyme fractionation 1, 2
• Do not overlook blood group - intestinal isoenzyme is more commonly elevated in blood groups B and O 3, 4
• Do not dismiss elevated I-ALP in cirrhotic patients - it may indicate disease progression or portal hypertension 3, 4
• Do not attribute I-ALP elevation to fatty liver alone - fatty liver does not typically cause isolated intestinal isoenzyme elevation 5

Monitoring Strategy

For confirmed benign I-ALP elevation 1, 5:

• Repeat ALP and liver function tests in 3-6 months initially
• If stable and asymptomatic, annual monitoring is sufficient
• Reinvestigate if ALP increases significantly or new symptoms develop