What is the differential diagnosis for a patient presenting with pancytopenia and hypoalbuminemia?

Differential Diagnosis for Pancytopenia with Hypoalbuminemia

The combination of pancytopenia with hypoalbuminemia most commonly suggests bone marrow failure syndromes (particularly megaloblastic anemia or aplastic anemia), hypersplenism secondary to chronic liver disease with portal hypertension, hemophagocytic lymphohistiocytosis (HLH), or severe systemic infections. 1, 2, 3

Primary Bone Marrow Disorders

Megaloblastic anemia is the most common reversible cause of pancytopenia and frequently presents with hypoalbuminemia in critically ill patients, accounting for 23-74% of pancytopenia cases depending on the population studied 2, 3, 4. This diagnosis should never be missed as it is rapidly correctable 3.

• Macrocytosis (MCV >100 fL) is present in approximately 90% of cases, with hypersegmented neutrophils visible on peripheral smear in over 92% 5
• Hypoalbuminemia occurs due to ineffective protein synthesis and systemic inflammation 2
• Bone marrow shows hypercellularity with megaloblastic erythropoiesis 2

Aplastic anemia represents 18-41% of pancytopenia cases and commonly presents with hypoalbuminemia 2, 3, 4.

• Bone marrow biopsy (not just aspiration) is essential, as aspiration frequently fails to obtain adequate samples 3
• Hypoalbuminemia correlates with disease severity and systemic inflammation 6

Myelodysplastic syndromes (MDS) affect approximately 10.7% of pancytopenia cases and require cytogenetic analysis for diagnosis and prognostication 1.

• Patients over 60 years with pancytopenia warrant bone marrow examination specifically to evaluate for MDS 1
• Dysplastic changes on peripheral smear and bone marrow are diagnostic 6

Hypersplenism and Portal Hypertension

Chronic liver disease with portal hypertension is the second most common cause (19-63% in various series) and characteristically presents with both pancytopenia and hypoalbuminemia 3, 5.

• Hepatosplenomegaly is a key physical finding 2, 4
• Hypoalbuminemia results from decreased hepatic synthetic function 7
• Macrocytosis may be present in up to 63% of cases, potentially causing diagnostic confusion with megaloblastic anemia 5

Hemophagocytic Lymphohistiocytosis (HLH)

HLH should be strongly considered when pancytopenia and hypoalbuminemia occur with fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin 1.

• This diagnosis requires prompt recognition and immunosuppressive treatment 1
• Bone marrow examination may reveal hemophagocytosis 1

Infectious Causes

Severe systemic infections commonly present with both pancytopenia and hypoalbuminemia 6.

• Ehrlichiosis causes pancytopenia with leukopenia and thrombocytopenia, particularly in immunosuppressed patients 1
• Brucellosis presents with mild transaminitis and pancytopenia, with bone marrow culture having the highest diagnostic sensitivity 1
• HIV and hepatitis C should be tested in all adult patients with pancytopenia 1, 8
• Hypoalbuminemia in infection indicates severe systemic inflammation and is an independent predictor of bacteremia 6

Multisystem Inflammatory Syndrome in Children (MIS-C)

In pediatric patients with fever and SARS-CoV-2 exposure, MIS-C should be considered when pancytopenia occurs with hypoalbuminemia, elevated inflammatory markers (CRP, ESR), and evidence of multisystem involvement 6.

• Hypoalbuminemia is one of the tier 1 screening criteria for MIS-C 6
• Other features include lymphopenia, neutrophilia, thrombocytopenia, and hyponatremia 6

Drug-Induced Causes

Methotrexate can cause pancytopenia even with low-dose weekly therapy, particularly in patients with impaired renal function or concomitant sulfonamide medications 1.

• Onset typically occurs 4-6 weeks after dose increases 1
• Hypoalbuminemia may reflect underlying renal dysfunction predisposing to toxicity 1

Chemotherapy and immunotherapy cause pancytopenia through direct bone marrow suppression 1.

Autoimmune Disorders

Systemic lupus erythematosus and other autoimmune diseases can present with pancytopenia and hypoalbuminemia due to autoimmune destruction and chronic inflammation 8.

• ANA and anti-dsDNA antibodies should be checked when systemic symptoms suggest autoimmune disease 8
• Direct antiglobulin test (Coombs) helps identify Evans syndrome 8

Critical Diagnostic Approach

Immediate laboratory evaluation should include complete blood count with differential, peripheral blood smear, reticulocyte count, vitamin B12, folate, HIV, hepatitis C, liver function tests, and albumin 1, 8.

Bone marrow aspiration AND biopsy should be performed simultaneously in most cases, as aspiration alone is frequently inadequate 8, 3.

• Indicated for patients over 60 years, those with systemic symptoms, abnormal physical findings, or unclear diagnosis after initial testing 1
• Should include morphological assessment, immunophenotyping, cytogenetic analysis, and flow cytometry 8

Common Pitfalls

• Do not miss megaloblastic anemia—it is rapidly reversible and may present acutely in critically ill patients 3
• Do not rely on aspiration alone—bone marrow biopsy is essential when aspiration yields inadequate samples 3
• Do not overlook infection—hypoalbuminemia with pancytopenia strongly suggests sepsis and warrants blood cultures 6
• Do not forget HLH—check ferritin, triglycerides, and fibrinogen if fever and hepatosplenomegaly are present 8