What is the likely diagnosis and recommended work‑up for a patient with dizziness, visual impairment and nausea who has low alkaline phosphatase, low alanine aminotransferase, low aspartate aminotransferase, a reduced anion gap, and an elevated red‑cell distribution width?

Wilson Disease: The Most Likely Diagnosis

This clinical presentation—dizziness, visual impairment, nausea, low alkaline phosphatase (ALP), low ALT/AST, reduced anion gap, and elevated red cell distribution width (RDW)—strongly suggests Wilson disease, particularly if the patient is under 40 years old. The combination of low ALP with neurological symptoms is highly characteristic of this treatable but potentially fatal copper metabolism disorder.

Key Diagnostic Features Supporting Wilson Disease

Laboratory Pattern Highly Specific for Wilson Disease

• Low alkaline phosphatase is a hallmark finding in Wilson disease, particularly when presenting with acute or subacute liver failure, where the ratio of alkaline phosphatase (IU/L) to total bilirubin (mg/dL) is typically <2 1
• Modest elevations or even low-normal transaminases (ALT/AST) are characteristic of Wilson disease presenting with acute liver failure, in contrast to other causes of acute hepatic injury where transaminases are typically markedly elevated 1
• The AST may be higher than ALT in Wilson disease with acute liver failure, potentially reflecting mitochondrial damage, though this finding is not sufficiently consistent to be diagnostic 1

Neurological and Visual Symptoms

• Dizziness and visual impairment align with the neuropsychiatric manifestations of Wilson disease, which can include movement disorders, tremor, dysarthria, and psychiatric symptoms 1
• Visual impairment may relate to Kayser-Fleischer rings (copper deposition in the cornea), though these are absent in 50% of patients presenting with acute liver failure 1
• Neurological symptoms typically occur in patients who already have some degree of liver disease, even if not clinically apparent 1

Elevated RDW as a Supportive Finding

• Elevated RDW is commonly seen in liver disease and correlates with disease severity, MELD grade, and poor prognosis 2, 3
• In Wilson disease specifically, Coombs-negative hemolytic anemia is a frequent finding, which would elevate RDW due to increased reticulocyte production 1, 4
• RDW above 15.15% is independently associated with poor hospital outcomes in liver disease patients 3

Reduced Anion Gap

• A reduced anion gap can occur in severe liver disease due to hypoalbuminemia, though this is not specific to Wilson disease 1

Immediate Diagnostic Work-Up

First-Line Laboratory Tests (Obtain Urgently)

• Serum ceruloplasmin level (usually decreased in Wilson disease, though predictive value is poor in acute liver failure) 1
• 24-hour urinary copper excretion (greatly elevated in Wilson disease, typically >100 μg/24h, often >200 μg/dL or 31.5 μmol/L in acute presentations) 1
• Serum copper level (usually >200 μg/dL or 31.5 μmol/L in acute Wilson disease) 1
• Complete blood count with reticulocyte count to assess for Coombs-negative hemolytic anemia 1
• Direct Coombs test (should be negative in Wilson disease-associated hemolysis) 1
• Complete liver panel including AST, ALT, alkaline phosphatase, total and direct bilirubin, albumin, PT/INR to assess synthetic function 1
• Calculate the ratio of alkaline phosphatase to total bilirubin; a ratio <2 strongly suggests Wilson disease in the setting of acute liver failure 1, 5

Essential Physical Examination

• Slit-lamp ophthalmologic examination to identify Kayser-Fleischer rings (present in 50% of acute liver failure cases, higher percentage in neurological presentations) 1
• Look for lunulae ceruleae (bluish discoloration of nail beds), though rarely detected 1
• Assess for signs of chronic liver disease (spider angiomata, palmar erythema, ascites, splenomegaly) 1

Imaging

• Abdominal ultrasound to assess liver parenchyma, exclude other structural causes, and evaluate for cirrhosis 1
• Brain MRI if neurological symptoms are prominent, as Wilson disease causes characteristic basal ganglia changes 1

Genetic Testing (When Available)

• ATP7B gene mutation analysis can confirm diagnosis but results may not be available quickly enough for acute management 1
• Molecular testing should be obtained for family screening once diagnosis is established 1

Critical Management Considerations

Urgent Liver Transplantation Evaluation

• Wilson disease presenting with acute liver failure requires urgent liver transplantation evaluation, as these patients are afforded the highest category of priority by UNOS 1
• Without transplantation, acute liver failure due to Wilson disease carries approximately 95% mortality 1
• Expeditious diagnosis is critically important because medical therapy alone is insufficient in acute presentations 1

Medical Therapy Initiation

• While awaiting transplant evaluation or in less severe presentations, chelation therapy should be initiated under hepatology guidance 1
• Treatment should be started for all individuals >3 years old identified through family screening 1

Common Diagnostic Pitfalls to Avoid

• Do not dismiss Wilson disease based on normal or only modestly elevated transaminases—this is characteristic of the disease, particularly in acute presentations 1
• Do not wait for ceruloplasmin results to initiate work-up, as this test has poor predictive value in acute liver failure and results may be delayed 1
• Do not assume absence of Kayser-Fleischer rings excludes Wilson disease—they are absent in 50% of acute liver failure presentations 1
• Do not overlook Wilson disease in adults—while pediatric patients with autoimmune hepatitis should always be investigated for Wilson disease, adults with atypical presentations or poor response to standard therapy also require evaluation 1

Alternative Diagnoses to Consider

If Wilson Disease is Excluded

• Autoimmune hepatitis (typically shows higher transaminases, elevated immunoglobulins, positive autoantibodies) 1
• Nonalcoholic fatty liver disease (usually shows AST:ALT ratio <1, not the low ALP pattern) 1
• Hemochromatosis (elevated ferritin and transferrin saturation) 1
• Alpha-1 antitrypsin deficiency (low alpha-1 antitrypsin level) 1

Non-Hepatic Causes of Low Transaminases

• Hypothyroidism can cause low transaminases and should be excluded with TSH testing 6
• Severe malnutrition or vitamin B6 deficiency (rare in developed countries) 6

Family Screening Protocol

If Wilson disease is confirmed, first-degree relatives must be screened immediately 1:

• Brief history for jaundice, liver disease, subtle neurological symptoms 1
• Physical examination including slit-lamp examination 1
• Serum copper, ceruloplasmin, liver function tests 1
• 24-hour urinary copper 1
• ATP7B mutation analysis if available in index patient (most efficient screening strategy) 1