In a patient on lithium therapy with a serum lithium level of approximately 0.6 mmol/L, what is the significance of a high serum albumin and low alkaline phosphatase?

High Albumin and Low Alkaline Phosphatase in a Patient on Lithium

In a patient on lithium with a therapeutic level of 0.6 mmol/L, high albumin combined with low alkaline phosphatase most likely reflects either a laboratory artifact related to the inverse relationship between these markers, medication effects from lithium itself, or—if the alkaline phosphatase is markedly low (<40 IU/L)—should prompt urgent evaluation for Wilson disease, particularly in younger patients with any signs of liver dysfunction or hemolysis.

Understanding the Biochemical Pattern

High Albumin Interpretation

• High albumin (>5.0 g/dL) in HIV-negative patients commonly reflects B-cell hyperplasia and increased immunoglobulin production, which can occur in chronic inflammatory states or untreated conditions affecting immune regulation 1
• In the context of lithium therapy, elevated total protein/albumin may indicate dehydration or hemoconcentration, which is clinically significant because lithium clearance is highly dependent on stable kidney function and fluid status 2
• Normal or high albumin indicates preserved liver synthetic function and argues against significant hepatocellular dysfunction 1

Low Alkaline Phosphatase: Critical Diagnostic Considerations

The interpretation of low alkaline phosphatase depends critically on the degree of reduction:

Markedly Low ALP (<40 IU/L): Wilson Disease Must Be Excluded

• In acute liver failure presentations, markedly subnormal serum alkaline phosphatase (typically <40 IU/L) is characteristic of Wilson disease, which occurs alongside Coombs-negative hemolytic anemia, coagulopathy, and relatively modest aminotransferase elevations (typically <2000 IU/L) 1, 3, 4
• A ratio of alkaline phosphatase to total bilirubin of <2 strongly suggests Wilson disease in the setting of acute liver dysfunction 1, 3, 4
• The American Association for the Study of Liver Diseases recommends considering Wilson disease in young patients with acute liver failure, given this combination is pathognomonic 4
• Wilson disease requires urgent liver transplant evaluation, as the fulminant presentation is considered uniformly fatal without transplantation 1

Mildly to Moderately Low ALP: Common Causes

• Antiresorptive medications, particularly bisphosphonates, can lower ALP levels and represent a critical iatrogenic cause, making medication history review essential 3, 4
• Lithium itself has been associated with alterations in alkaline phosphatase; one study found that chronic lithium administration can affect both total ALP and its bone isoenzyme, though typically this manifests as increased rather than decreased levels 5
• In conditions with low albumin (such as inflammation), plasma ALP measurements may be unreliable, but your patient has high albumin, making this less relevant 3, 4
• Malnutrition, vitamin and mineral deficiencies (particularly zinc, magnesium), hypothyroidism, and severe anemia are all associated with low ALP activity 6, 7
• Hypophosphatasia, due to pathogenic variants of the ALPL gene, is the most common genetic cause of persistently low serum ALP, though it typically presents with skeletal pain, stress fractures, dental problems, and chondrocalcinosis in adults 6

Lithium-Specific Considerations

Therapeutic Monitoring Context

• Your patient's lithium level of 0.6 mmol/L is at the lower end of the therapeutic range (0.30-1.30 mmol/L for the 12-hour standardized level) 2
• For once-daily lithium dosing, trough levels should be measured at 24 hours post-dose, not 12 hours; 12-hour levels can be 1.3 times higher than true trough levels 8
• If this level was drawn at 12 hours in a patient taking once-daily lithium, the true trough may be closer to 0.46 mmol/L, which is subtherapeutic 8

Lithium and Bone Metabolism

• Lithium has complex effects on bone metabolism; one study found increased bone isoenzyme of alkaline phosphatase in 27 of 41 patients on chronic lithium therapy 5
• However, conflicting data exist, and the relationship between lithium and ALP is not fully characterized 5

Recommended Diagnostic Approach

Immediate Assessment (Within 1 Week)

1. Obtain a complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess for any hepatic dysfunction 1, 9
2. If alkaline phosphatase is <40 IU/L and the patient is <40 years old, urgently check:
   • Ceruloplasmin level (typically low in Wilson disease, though may be normal in 15% of cases) 1, 4
   • 24-hour urinary copper (greatly elevated in Wilson disease) 4
   • Serum copper (usually >200 μg/dL in Wilson disease) 4
   • Complete blood count to assess for hemolytic anemia 1, 4
   • Slit-lamp examination for Kayser-Fleischer rings (present in only 50% of acute presentations) 1, 4
3. Review all medications for antiresorptive agents (bisphosphonates, denosumab) that can lower ALP 3, 4
4. Verify lithium level timing: If drawn at 12 hours in a patient on once-daily dosing, repeat at 24 hours post-dose for accurate trough level 8

Secondary Evaluation (If Wilson Disease Excluded)

1. Check thyroid function tests (TSH, free T4) to exclude hypothyroidism 7
2. Assess nutritional status including:
   • Serum magnesium and zinc levels 6, 7
   • Vitamin B6 (pyridoxal phosphate) if available 3
   • Complete blood count to assess for severe anemia 7
3. Measure creatinine and calculate eGFR to assess kidney function, which is critical for lithium clearance 2
4. If ALP remains persistently low without identified cause, consider measuring ALP substrates (pyrophosphate, pyridoxal phosphate, phosphoethanolamine) and genetic testing for ALPL variants to evaluate for hypophosphatasia 6

Critical Pitfalls to Avoid

• Do not dismiss markedly low alkaline phosphatase (<40 IU/L) as benign, especially in younger patients; Wilson disease is a medical emergency requiring immediate transplant evaluation 1, 4
• Do not assume the lithium level is therapeutic without confirming the timing of the blood draw relative to the dosing schedule 8
• Do not overlook dehydration as a cause of elevated albumin in a patient on lithium, as this can precipitate lithium toxicity even at "therapeutic" levels 2
• Do not forget that normal ALP does not exclude significant bone disease in patients on chronic lithium, as bone isoenzyme may be affected independently of total ALP 5
• In predominantly adult male populations, low ALP is rare (0.19% of measurements) and most commonly associated with cardiac surgery, malnutrition, magnesium deficiency, hypothyroidism, or severe anemia 7