What is the most likely diagnosis and management for a patient with hypoferremia, elevated ferritin, normal transferrin, low transferrin saturation, and mild direct hyperbilirubinemia?

Diagnostic Assessment: Functional Iron Deficiency with Cholestasis

This laboratory pattern—hypoferremia (iron 22), markedly elevated ferritin (180), normal transferrin, very low transferrin saturation (5%), and elevated direct bilirubin (1.2)—most likely represents functional iron deficiency superimposed on an inflammatory or cholestatic process, requiring immediate investigation for underlying liver disease, chronic inflammation, or malignancy.

Understanding the Paradoxical Iron Profile

The combination of low serum iron with elevated ferritin indicates iron sequestration rather than true iron overload. Ferritin functions as an acute-phase reactant that rises during inflammation, infection, and hepatocellular injury independent of actual iron stores 1. When transferrin saturation falls below 16–20%, this confirms that insufficient iron is available for erythropoiesis despite seemingly adequate ferritin levels 1. Your transferrin saturation of 5% is profoundly low, indicating severe functional iron restriction 1.

• Transferrin saturation <16% is highly sensitive for iron deficiency, though it has relatively low specificity (40–50%) 1
• The pattern of low iron + low TSAT + elevated ferritin characteristically indicates anemia of chronic disease (inflammatory iron block), where hepcidin elevation traps iron in reticuloendothelial macrophages 1
• Normal transferrin (TIBC) argues against severe iron overload, as TIBC typically decreases when true iron excess is present 2

The Cholestatic Component: Direct Hyperbilirubinemia

Direct bilirubin of 1.2 mg/dL (normal <0.3) signals hepatocellular injury or biliary obstruction. This finding transforms your iron abnormalities from an isolated hematologic issue into a potential hepatobiliary emergency 3.

Critical Differential Diagnosis

When elevated ferritin coexists with elevated direct bilirubin, the following conditions must be excluded urgently:

• Acute or chronic liver disease (alcoholic hepatitis, viral hepatitis, NAFLD, cirrhosis) causes ferritin elevation through hepatocellular injury and impaired iron metabolism 3
• Hemolysis with hepatic iron deposition can produce this exact pattern, though indirect bilirubin would typically predominate
• Malignancy (hepatocellular carcinoma, lymphoma, solid tumors with hepatic involvement) elevates ferritin as a tumor marker while causing cholestasis 3
• Adult-onset Still's disease presents with extreme hyperferritinemia (often >4,000 ng/mL) and can cause hepatic dysfunction, though your ferritin of 180 is too low for this diagnosis 3
• Hemophagocytic lymphohistiocytosis causes ferritin >5,000 ng/mL with multiorgan dysfunction, again unlikely at ferritin 180 3

Immediate Diagnostic Algorithm

Step 1: Assess for True Iron Overload (Rule Out First)

Calculate and confirm transferrin saturation:

• TSAT = (Serum iron ÷ TIBC) × 100 1
• If TSAT ≥45%, suspect primary iron overload and order HFE genetic testing for C282Y and H63D mutations 3
• Your TSAT of 5% definitively excludes hereditary hemochromatosis or primary iron overload 3

Step 2: Evaluate Hepatobiliary Disease

Order the following tests immediately:

• Complete metabolic panel including AST, ALT, alkaline phosphatase, total bilirubin, albumin, and prothrombin time to assess hepatocellular function 3
• Hepatitis panel (HBsAg, anti-HBc, anti-HCV) to exclude viral hepatitis 3
• Abdominal ultrasound to evaluate for fatty liver, cirrhosis, biliary obstruction, or hepatic masses 3
• Complete blood count with differential to assess for anemia, thrombocytopenia (suggesting cirrhosis), or hematologic malignancy 3

Step 3: Assess Inflammatory State

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to quantify systemic inflammation 3
• If CRP/ESR are markedly elevated, this confirms anemia of chronic disease (inflammatory iron block) 1
• Soluble transferrin receptor (sTfR) can distinguish true iron deficiency from inflammatory block when ferritin and TSAT are discordant; elevated sTfR confirms real iron deficiency even in the presence of inflammation 1

Step 4: Exclude Hemolysis

• Lactate dehydrogenase (LDH), haptoglobin, reticulocyte count, and peripheral blood smear to rule out hemolytic anemia, which can produce elevated indirect bilirubin but may also cause direct hyperbilirubinemia if hepatic clearance is impaired 1

Management Strategy Based on Findings

If Liver Disease is Confirmed (Most Likely Scenario)

Treat the underlying hepatobiliary condition, not the iron parameters:

• In chronic liver disease, ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 3
• Do NOT administer iron supplementation when TSAT <20% with ferritin >100 ng/mL in the setting of inflammation, as this represents inflammatory iron block where supplementation will not improve anemia and may worsen outcomes 3
• Phlebotomy is contraindicated unless TSAT ≥45% with confirmed iron overload 3

If Inflammatory Iron Block is Confirmed

The pattern of TSAT <20% with ferritin >100 ng/mL indicates anemia of chronic inflammation:

• Hepcidin elevation blocks intestinal iron absorption and traps iron in reticuloendothelial macrophages, making supplementation ineffective 1
• Address the underlying inflammatory condition (e.g., treat infection, control autoimmune disease, manage malignancy) 3
• In chronic kidney disease patients on erythropoiesis-stimulating agents, functional iron deficiency (ferritin 100–700 ng/mL with TSAT <20%) may respond to IV iron therapy despite elevated ferritin 3, 4

If True Iron Deficiency Coexists with Inflammation

When ferritin is 30–100 ng/mL with elevated CRP/ESR, a mixed picture of absolute iron deficiency and anemia of chronic disease is present:

• Initiate oral iron supplementation with ferrous sulfate 65 mg elemental iron daily or alternate-day dosing 1
• Expected hemoglobin rise ≥10 g/L within 2 weeks if iron deficiency is the primary driver 1
• Continue supplementation for 3 months after hemoglobin normalizes to achieve target ferritin >100 ng/mL 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based solely on elevated ferritin without confirming TSAT ≥45% 3
• Do not assume ferritin of 180 ng/mL represents adequate iron stores when TSAT is 5%; this is functional iron deficiency where iron is sequestered and unavailable 1
• Do not overlook liver biopsy if ferritin >1,000 ng/mL with abnormal liver tests, though your ferritin of 180 does not meet this threshold 3
• Do not administer oral or IV iron when TSAT <20% with ferritin >300 ng/mL, as this represents pure inflammatory block that will not respond to supplementation 3
• Recognize that direct hyperbilirubinemia of 1.2 mg/dL is never normal and mandates urgent hepatobiliary evaluation regardless of iron parameters 3

When to Refer to Hepatology

Immediate specialist referral is indicated if:

• Ferritin >1,000 ng/mL with elevated bilirubin (not applicable here) 3
• Clinical evidence of cirrhosis (platelet count <200,000/µL, elevated bilirubin, hepatomegaly) 3
• Direct bilirubin >1.2 mg/dL with abnormal liver enzymes or imaging findings suggesting advanced liver disease 3
• Failure to identify a clear etiology after initial workup 3