What is the most likely diagnosis in a patient with severe anemia, generalized edema (anasarca), normal left‑ventricular ejection fraction on two‑dimensional echocardiography without pulmonary hypertension, normal liver on ultrasound, chest X‑ray showing active pulmonary tuberculosis with a small right pleural effusion, and impaired renal function (serum creatinine 2.08 mg/dL)?

Most Likely Diagnosis: Tuberculosis-Associated Anemia with Renal Dysfunction and Hypoalbuminemia

The most likely diagnosis is severe anemia of inflammation secondary to active pulmonary tuberculosis, complicated by tuberculosis-related renal impairment and hypoalbuminemia causing anasarca, rather than primary cardiac or hepatic disease.

Primary Pathophysiology

The clinical picture is dominated by tuberculosis-driven systemic inflammation causing multiple organ effects:

• Anemia of inflammation (AI) is the predominant anemia type at tuberculosis diagnosis, present in approximately 36% of untreated cases and representing 72.3% of moderate-to-severe anemia in tuberculosis patients 1, 2
• Active tuberculosis triggers massive cytokine release, particularly tumor necrosis factor-alpha (TNF-α), which directly suppresses erythropoietin production and causes inappropriately low erythropoietin levels relative to the degree of anemia 3
• The normal ejection fraction excludes heart failure as the primary cause of anasarca, and the normal liver ultrasound excludes cirrhotic causes 4

Mechanism of Anasarca Despite Normal Cardiac Function

The generalized edema in this patient reflects tuberculosis-induced hypoalbuminemia and salt-water retention, not cardiac failure:

• Chronic severe anemia itself causes neurohormonal activation (15-fold increase in renin activity, 3.2-fold increase in aldosterone, 12-fold increase in atrial natriuretic peptide) leading to sodium and water retention with expansion of extracellular volume by +32% and total body exchangeable sodium by +30% 5
• This occurs despite high cardiac output and low systemic vascular resistance, distinguishing it from heart failure where cardiac output is reduced 5
• Tuberculosis causes chronic inflammation that reduces albumin synthesis and increases capillary permeability, promoting fluid extravasation into interstitial spaces 1, 2
• The elevated creatinine (2.08 mg/dL) indicates venous congestion-mediated renal dysfunction rather than low cardiac output, as kidney venous pressure elevation is the major determinant of worsening kidney function across all ejection fraction ranges 4

Renal Dysfunction Considerations

The impaired renal function requires careful interpretation:

• Venous congestion, not reduced cardiac output, drives renal dysfunction in this clinical context, as increased right atrial pressure is associated with worsening kidney function independent of cardiac output 4
• The modest creatinine elevation likely reflects both tuberculosis-related interstitial nephritis and volume overload-induced venous congestion 4
• Renal blood flow is typically reduced by approximately 46% in chronic severe anemia with edema, with glomerular filtration rate reduced by approximately 24% 5
• The disproportionate elevation of blood urea nitrogen relative to creatinine would suggest prerenal azotemia, but this patient's presentation is more consistent with intrinsic renal involvement from tuberculosis and congestion 4

Tuberculosis-Specific Anemia Characteristics

The anemia pattern in tuberculosis has distinct features:

• Normocytic normochromic anemia is the most common hematological abnormality, present in 56.9% of tuberculosis patients with anemia 6
• Approximately 60% of tuberculosis-associated anemia is classified as mild, though severe anemia occurs particularly with extensive disease 6
• Multiple etiologies frequently coexist: 57.5% of tuberculosis patients with anemia have two or more causes, including iron deficiency (26.5%), folate deficiency (6.1%), and vitamin B12 deficiency (2.5%) 2
• Patients with severe anemia are three times more likely to have tuberculosis (OR = 3.1,95% CI = 1.5-6.5) 2

Diagnostic Workup Required

To confirm and characterize the anemia:

• Complete blood count with peripheral smear to assess red cell morphology and rule out hemolysis or bone marrow infiltration 1, 2
• Iron studies (serum iron, ferritin, transferrin saturation, soluble transferrin receptor) to distinguish anemia of inflammation from iron deficiency anemia or multifactorial anemia 1, 2
• Serum albumin and total protein to quantify hypoalbuminemia as the cause of anasarca 5
• Urinalysis with microscopy and 24-hour urine protein to assess for tuberculosis-related renal involvement 4
• Hepcidin levels if available, as hepcidin is markedly elevated at tuberculosis diagnosis (median 84.0 ng/mL) and decreases dramatically after 2 months of treatment (9.7 ng/mL), serving as a marker of inflammation resolution 1

Critical Pitfall to Avoid

Do not attribute the anasarca to heart failure based solely on the presence of edema and pleural effusion. The normal ejection fraction, absence of pulmonary hypertension, and presence of active tuberculosis point away from primary cardiac disease 4. The minimal pleural effusion is likely tuberculosis-related rather than cardiogenic 4.

Management Priorities

Immediate therapeutic focus should be:

• Initiate standard tuberculosis treatment (rifampin, isoniazid, pyrazinamide, ethambutol) as the primary intervention, which will address the underlying cause of both anemia and systemic inflammation 4, 1
• Diuretic therapy for symptomatic relief of anasarca, with careful monitoring of renal function and electrolytes 4, 7
• Defer iron supplementation until at least 2 months into tuberculosis treatment, as anemia of inflammation predominates initially and hepcidin levels remain elevated, blocking iron absorption and redistribution 1
• Monitor hemoglobin response: AI typically declines from 36% to 8% after 6 months of tuberculosis treatment, but iron-responsive components (IDA, IDA+AI) may persist and require targeted intervention 1
• Serial creatinine monitoring during diuresis, recognizing that modest rises (≈0.3 mg/dL) reflect hemoconcentration rather than true renal injury, and continued decongestion is appropriate unless creatinine increases >0.5 mg/dL or oliguria develops 4

Expected Clinical Course

With appropriate tuberculosis treatment:

• Anemia of inflammation should improve significantly by 2 months, with hepcidin levels dropping from 84.0 to 9.7 ng/mL 1
• Anasarca should resolve as albumin synthesis recovers and neurohormonal activation subsides 5
• Renal function may improve as venous congestion resolves and tuberculosis-related inflammation decreases 4
• If anemia persists beyond 2-6 months of tuberculosis treatment, reassess for iron, folate, or vitamin B12 deficiency requiring specific supplementation 1, 2