What is the differential diagnosis for a patient with dizziness, low alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), low anion gap, and elevated red‑cell distribution width (RDW)?

Differential Diagnosis: Dizziness with Low Liver Enzymes, Low Anion Gap, and Elevated RDW

The constellation of low ALT, AST, and ALP alongside elevated RDW and low anion gap most strongly suggests a combined picture of nutritional deficiency (particularly B12/folate deficiency causing macrocytic anemia with elevated RDW) and possible hypoalbuminemia (causing low anion gap), with dizziness likely secondary to anemia rather than primary liver pathology.

Primary Diagnostic Considerations

Iron Deficiency Anemia with Nutritional Deficiency

• Elevated RDW (>15%) is a hallmark of iron deficiency anemia, reflecting increased red cell size heterogeneity (anisocytosis), and inversely correlates with hemoglobin levels and transferrin saturation 1
• In inflammatory bowel disease, which commonly causes both iron deficiency and B12/folate deficiency, the minimum anemia workup must include RDW, MCV, reticulocyte count, serum ferritin, transferrin saturation, and CRP 2
• High RDW with normal or low MCV suggests coexisting iron deficiency and macrocytic anemia (B12/folate deficiency), where the two abnormalities neutralize each other's effect on MCV 2
• Dizziness in this context reflects symptomatic anemia from combined nutritional deficiencies 2

Hypoalbuminemia and Low Anion Gap

• A low anion gap (<3 mEq/L by modern ion-selective electrode methodology) most commonly indicates hypoalbuminemia, as albumin is the primary unmeasured anion 3
• Low anion gap can also signal occult neoplasms such as multiple myeloma (producing cationic paraproteins) or lithium/bromide intoxication 3
• The combination of low liver enzymes and low anion gap raises concern for severe malnutrition or chronic liver disease with synthetic dysfunction (low albumin production) 3

Chronic Liver Disease with Portal Hypertension

• Elevated RDW is an inflammatory marker in liver diseases and correlates positively with MELD grade, serum bilirubin, and prothrombin time, while correlating negatively with platelet count and albumin 4, 5
• In liver cirrhosis, RDW increases progressively with worsening Child-Pugh grade and independently predicts poor hospital outcomes (OR 13.29 for RDW >15.15%) 5
• However, low ALT/AST/ALP is atypical for active liver disease—normal or low transaminases can occur in advanced cirrhosis with "burned-out" hepatocytes, but alkaline phosphatase is usually elevated in cholestatic disease 2

Wilson Disease (Critical to Exclude)

• Wilson disease presenting as acute liver failure characteristically shows modest ALT/AST elevations with markedly low alkaline phosphatase (ALP:bilirubin ratio <2) and Coombs-negative hemolytic anemia 2
• Serum copper is typically >200 μg/dL (>31.5 μmol/L), and 24-hour urinary copper is greatly elevated 2
• Kayser-Fleischer rings may be absent in 50% of acute presentations, so their absence does not exclude Wilson disease 2
• Any patient <40 years with unexplained low liver enzymes, hemolysis, and neuropsychiatric symptoms (including dizziness) requires urgent ceruloplasmin and copper studies 2

Diagnostic Algorithm

Immediate Laboratory Evaluation

• Complete blood count with differential, reticulocyte count, and peripheral smear to assess for anemia type, hemolysis, and red cell morphology 2, 6
• Comprehensive metabolic panel to confirm low anion gap, assess renal function (creatinine, urea), and measure albumin 2, 6
• Serum ferritin, transferrin saturation, vitamin B12, and folate levels to identify nutritional deficiencies causing elevated RDW 2, 6
• Serum protein electrophoresis if low anion gap persists with normal albumin, to exclude paraproteinemia from multiple myeloma 3
• Ceruloplasmin, serum copper, and 24-hour urinary copper if patient is <40 years or has hemolytic anemia, to exclude Wilson disease 2

Pattern Recognition by RDW and MCV

• High RDW with low MCV (<80 fL): iron deficiency anemia or thalassemia trait (though thalassemia typically has normal RDW) 1, 7
• High RDW with normal MCV (80-100 fL): combined iron and B12/folate deficiency, early iron deficiency, or chronic disease 2, 1
• High RDW with high MCV (>100 fL): B12/folate deficiency, alcohol abuse, hypothyroidism, or thiopurine therapy 2
• Low or normal reticulocyte count with elevated RDW: inappropriate erythropoiesis from nutritional deficiencies or bone marrow disease 2
• Elevated reticulocyte count with elevated RDW: hemolysis (check haptoglobin, LDH, bilirubin) 2

Liver-Specific Evaluation

• Repeat liver enzymes (ALT, AST, ALP, GGT, bilirubin, albumin, PT/INR) to confirm persistently low values and assess synthetic function 6, 8
• Viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV) to exclude chronic viral hepatitis 6, 8
• Abdominal ultrasound with Doppler to assess liver parenchyma, spleen size (portal hypertension), and vascular patency 6, 8
• If Wilson disease suspected: slit-lamp examination for Kayser-Fleischer rings and liver biopsy for quantitative copper (>250 μg/g dry weight is diagnostic) 2

Critical Pitfalls to Avoid

• Do not dismiss low liver enzymes as "normal"—in advanced cirrhosis, transaminases may be paradoxically low due to hepatocyte depletion, while synthetic dysfunction (low albumin, elevated INR) reveals the true severity 5
• Do not overlook Wilson disease in young patients—acute liver failure from Wilson disease requires urgent liver transplantation and has a characteristic pattern of low ALP, modest transaminases, and hemolysis 2
• Do not assume elevated RDW always indicates iron deficiency—nearly half of thalassemia trait cases also show elevated RDW, and RDW elevation occurs in chronic liver disease independent of iron status 7, 4
• Do not ignore low anion gap—it may be the only clue to hypoalbuminemia, multiple myeloma, or toxic ingestion (lithium, bromide) 3
• Do not attribute dizziness solely to anemia without excluding cardiac, neurologic, or metabolic causes—check orthostatic vital signs, ECG, and glucose 2

Management Priorities

If Anemia Confirmed

• Initiate iron supplementation (oral or IV) if ferritin <30 ng/mL or transferrin saturation <20%, targeting hemoglobin normalization within 8-12 weeks 2
• Administer intramuscular B12 (1000 μg weekly × 4 weeks, then monthly) if B12 <200 pg/mL, and oral folate 1-5 mg daily if folate deficient 2
• Investigate underlying cause of nutritional deficiency: malabsorption (celiac disease, IBD, gastric surgery), dietary insufficiency, or chronic blood loss 2

If Liver Disease Suspected

• Calculate FIB-4 score (age, ALT, AST, platelet count) to stratify fibrosis risk; score >2.67 mandates hepatology referral 6, 8
• Refer urgently to hepatology if evidence of synthetic dysfunction (INR >1.5, albumin <3.5 g/dL, thrombocytopenia <150,000/μL) or if Wilson disease cannot be excluded 2, 8

If Low Anion Gap Persists

• Measure serum albumin and total protein; if albumin <3.0 g/dL, investigate for nephrotic syndrome, protein-losing enteropathy, or severe malnutrition 3
• Perform serum protein electrophoresis and immunofixation if albumin is normal, to detect monoclonal gammopathy 3

2, 6, 8, 1, 7, 4, 5, 3