What is the differential diagnosis for an adult patient with muscle pain, weakness, fatigue, brain fog, elevated iron levels, and normal ferritin levels?

Differential Diagnosis for Muscle Pain, Weakness, Fatigue, Brain Fog with Elevated Iron and Normal Ferritin

The combination of elevated iron with normal ferritin most likely represents functional iron deficiency in the setting of chronic inflammation, metabolic syndrome, or an early iron overload disorder—but you must immediately measure transferrin saturation to distinguish true iron overload from secondary causes, as this single test determines the entire diagnostic pathway. 1, 2

Critical First Step: Measure Transferrin Saturation

• Order fasting transferrin saturation (TS) immediately, as ferritin alone cannot distinguish between iron overload and inflammatory conditions 3, 1, 2
• If TS ≥45%, suspect primary iron overload and proceed to HFE genetic testing for C282Y and H63D mutations 3, 1, 2
• If TS <45%, iron overload is excluded with >90% probability, and the presentation represents secondary hyperferritinemia or functional iron deficiency 1, 2

Most Likely Diagnoses Based on Clinical Pattern

Primary Considerations (TS <45% scenario)

Metabolic Syndrome/NAFLD

• Accounts for >90% of outpatient hyperferritinemia cases when combined with inflammatory markers 1, 2
• Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 1
• Check fasting glucose, HbA1c, lipid panel, liver enzymes (ALT, AST) 2

Chronic Inflammatory Conditions

• Ferritin rises as an acute-phase reactant during inflammation independent of iron stores 3, 1
• In inflammatory states, hepcidin blocks iron release from storage sites, creating functional iron deficiency despite adequate stores 1
• Check CRP, ESR to detect occult inflammation 2

Hypothyroidism

• Can cause fatigue, weakness, brain fog, and muscle pain 2
• Check TSH and free T4 2

Restless Leg Syndrome (RLS)

• Presents with muscle discomfort, urge to move legs, worse at rest and evening 3
• Impaired dopamine transport due to reduced intracellular iron plays a critical role 3
• Serum ferritin <50 ng/mL is consistent with RLS diagnosis and suggests need for iron supplementation 3
• However, your patient has normal ferritin, making this less likely unless there is functional iron deficiency 3

Secondary Considerations (TS ≥45% scenario)

Hereditary Hemochromatosis

• C282Y homozygosity or C282Y/H63D compound heterozygosity 3, 1
• Classic symptoms include fatigue, arthralgias (especially 2nd/3rd metacarpophalangeal joints), right upper quadrant pain, impotence, decreased libido 3
• Currently, most patients identified by screening are asymptomatic (75%) 3
• Proceed with HFE genetic testing if TS ≥45% 3, 1, 2

Non-HFE Hemochromatosis

• Mutations in TFR2, SLC40A1, HAMP, or HJV genes 1
• Consider if iron overload confirmed but C282Y homozygosity excluded 1

Complete Differential Diagnosis List

Iron-Related Disorders

• HFE hemochromatosis (C282Y homozygosity, C282Y/H63D compound heterozygosity) 3, 1
• Non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations) 1
• Functional iron deficiency in setting of chronic inflammation 1

Metabolic/Liver Disease

• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 1, 2
• Chronic alcohol consumption 1
• Viral hepatitis B or C 1

Inflammatory/Rheumatologic

• Adult-onset Still's disease (ferritin typically 4,000-30,000 ng/mL with glycosylated fraction <20%) 1
• Chronic rheumatologic diseases 1
• Systemic inflammatory response syndrome 1

Endocrine

• Hypothyroidism 2
• Diabetes mellitus 1

Neurologic

• Restless leg syndrome (typically with ferritin <50 ng/mL) 3

Hematologic

• Anemia of chronic disease 1
• Chronic kidney disease with functional iron deficiency 1

Malignancy

• Solid tumors 1
• Lymphomas 1
• Hepatocellular carcinoma 1

Other

• Chronic kidney disease 1
• Cell necrosis (muscle injury, hepatocellular necrosis) 1
• Infections 1

Essential Diagnostic Workup

Immediate Laboratory Tests:

• Fasting transferrin saturation (TS) - most critical test 1, 2
• Complete metabolic panel (ALT, AST, creatinine) 2
• TSH and free T4 2
• Complete blood count with differential 2
• Fasting glucose, HbA1c, lipid panel 2
• CRP, ESR 2
• Creatine kinase (CK) to evaluate muscle necrosis 1

If TS ≥45%:

• HFE genetic testing for C282Y and H63D mutations 3, 1, 2
• Consider liver MRI to quantify hepatic iron concentration 1

If TS <45%:

• Focus on identifying secondary causes (inflammation, metabolic syndrome, liver disease) 1, 2
• Consider soluble transferrin receptor (sTfR) testing to distinguish true iron deficiency from inflammatory iron block 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on iron levels alone without confirming TS ≥45% 1, 2
• Do not initiate phlebotomy therapy when TS <45%, as this indicates the presentation is not from iron overload 2
• Do not overlook functional iron deficiency in inflammatory states, where ferritin can be normal or elevated while patients remain functionally iron deficient 1
• Recognize that ferritin is an acute-phase reactant elevated in inflammation, infection, and liver disease independent of iron stores 1, 4
• Do not assume normal ferritin excludes all iron-related pathology—functional iron deficiency can occur with normal ferritin in chronic inflammatory states 1

Management Algorithm

If TS <45% (most likely scenario):

• Treat underlying inflammatory or metabolic condition, not the iron levels 2
• Address metabolic syndrome components: weight loss, glycemic control, lipid management, blood pressure control 2
• Monitor ferritin every 6-12 months if remains <1,000 ng/mL 2

If TS ≥45%:

• Proceed with HFE genetic testing 3, 1, 2
• If C282Y homozygote confirmed, initiate therapeutic phlebotomy with target ferritin 50-100 μg/L 5
• Screen first-degree relatives 1

Referral Indications:

• Ferritin >1,000 μg/L regardless of TS → refer to gastroenterology/hematology 5
• Evidence of organ damage → specialist referral 5
• Ferritin continues to rise despite management of underlying conditions → hepatology referral 2