What is the management and diagnosis for a patient with hyperferritinemia and low alkaline phosphatase (ALP) levels?

Management and Diagnosis of Hyperferritinemia with Low Alkaline Phosphatase

The diagnostic approach for a patient with hyperferritinemia and low alkaline phosphatase should focus on determining the underlying cause through complete iron studies, including transferrin saturation (TSAT), serum iron, and total iron binding capacity (TIBC), followed by appropriate management based on the etiology. 1

Initial Diagnostic Workup

Iron Studies Assessment

• Complete iron studies are essential to differentiate between true iron overload and inflammatory conditions:
  • Transferrin saturation (TSAT)
  • Serum iron
  • Total iron binding capacity (TIBC)
  • Complete blood count
  • Liver function tests (including ALT, AST, bilirubin)

Interpretation Based on TSAT

• TSAT >45%: Suggests true iron overload
• TSAT <20%: Suggests functional iron deficiency with inflammation 1

Additional Testing Based on Clinical Suspicion

• Inflammatory markers (CRP, ESR)
• Hepatitis B and C serology
• Alcohol use assessment
• Screening for metabolic syndrome components
• Genetic testing for hemochromatosis if TSAT is elevated

Differential Diagnosis

Common Causes of Hyperferritinemia

1. Inflammatory conditions (most common cause in adults)

   • Chronic inflammatory disorders
   • Infections
   • Malignancies

2. Iron overload conditions

   • Hereditary hemochromatosis
   • Transfusional iron overload
   • Dysmetabolic Iron Overload Syndrome (DIOS) 2

3. Liver diseases

   • Non-alcoholic fatty liver disease (NAFLD) - present in ~30% of NAFLD patients 3
   • Alcoholic liver disease
   • Viral hepatitis

4. Rare but serious conditions

   • Hemophagocytic lymphohistiocytosis (HLH) - consider when ferritin >10,000 μg/L 4
   • Aceruloplasminemia (ACP) - characterized by absent/low ceruloplasmin, low serum copper and iron 4

Low Alkaline Phosphatase Considerations

• Low ALP may suggest:
  • Zinc deficiency
  • Malnutrition
  • Certain genetic conditions
  • Hypophosphatasia
  • Wilson's disease

Management Approach

For True Iron Overload (TSAT >45%)

• Therapeutic phlebotomy (400-500 mL blood weekly or biweekly) to reduce ferritin levels to 50-100 μg/L 1
• Monitor ferritin and TSAT every 3 months during treatment
• Consider genetic testing for hemochromatosis and non-HFE hemochromatosis 5

For Inflammatory Hyperferritinemia (TSAT <20%)

• Identify and treat the underlying inflammatory condition
• Do not initiate phlebotomy as it is ineffective and potentially harmful 3
• Regular monitoring of ferritin levels every 1-3 months 1

For NAFLD-Associated Hyperferritinemia

• Lifestyle modifications:
  • Weight loss
  • Regular physical activity
  • Reduced red meat consumption
  • Limited alcohol intake
  • Avoidance of iron supplements 1

For Extremely High Ferritin (>10,000 μg/L)

• Consider urgent evaluation for:
  • Hemophagocytic lymphohistiocytosis (HLH)
  • Acute liver failure
  • Malignancy
  • Severe infection 6
• Note that while extreme hyperferritinemia raises suspicion for HLH, most cases are due to chronic transfusion (35%), liver disease (27%), or hematologic malignancy (16%) 6

Referral Criteria

• Refer to gastroenterologist or hematologist when:

  • Ferritin >1000 μg/L
  • Elevated TSAT >45% with suspected iron overload
  • Elevated liver enzymes
  • Unclear cause after initial evaluation 1

• Urgent hematology referral when:

  • Extremely high ferritin (>10,000 μg/L) with cytopenias
  • Suspected hemophagocytic lymphohistiocytosis
  • Suspected hematologic malignancy 4, 1

Monitoring and Follow-up

• For mild-moderate elevation without clear cause: recheck ferritin and iron studies in 1-3 months
• For confirmed iron overload undergoing treatment: monitor every 3 months
• For stable patients without iron overload: annual monitoring 1

Important Caveats

• Low alkaline phosphatase with high ferritin may be seen in rare conditions like Wilson's disease - consider copper studies if clinically indicated
• Hyperferritinemia alone has poor positive predictive value for HLH and more common explanations should be considered first 6
• In patients with aceruloplasminemia, anemia is typically mild and does not require specific treatment 4
• Phlebotomy is only effective with hepatocellular iron overload and should not be used when hyperferritinemia is related to inflammation 3