How could the patient's borderline‑high hemoglobin, low mean corpuscular hemoglobin (iron‑deficiency anemia), hypercalcemia, mild renal impairment with hyperchloremic non‑anion‑gap metabolic acidosis, and low alkaline phosphatase be linked to a non‑Hodgkin lymphoma diagnosis?

How Laboratory Abnormalities Link to Non-Hodgkin Lymphoma

The constellation of borderline-high hemoglobin, low MCH (iron deficiency), hypercalcemia, renal impairment with hyperchloremic non-anion-gap metabolic acidosis, and low alkaline phosphatase can all be directly explained by non-Hodgkin lymphoma through tumor lysis syndrome, direct tumor effects on calcium metabolism, and bone marrow involvement.

Tumor Lysis Syndrome (TLS) as the Primary Mechanism

The renal impairment with metabolic acidosis is most likely due to spontaneous or treatment-related tumor lysis syndrome, which is well-documented in NHL patients, particularly those with high tumor burden 1.

• Hyperuricemia from tumor lysis causes renal tubular obstruction, leading to acute kidney injury with the metabolic acidosis pattern described 1.
• The risk of developing TLS increases dramatically with elevated uric acid levels (relative risk 11.66 for uric acid ≥8 mg/dL versus <4 mg/dL in NHL patients) 1.
• Patients with high tumor burden and elevated LDH should be assessed for spontaneous TLS, including uric acid measurements, as recommended by NCCN guidelines 1.
• TLS can occur before chemotherapy initiation in 12-72 hours after treatment, explaining why these abnormalities may be present at diagnosis 1.

Hypercalcemia in NHL

Hypercalcemia in NHL can occur through direct tumor production of parathyroid hormone-related protein or cytokine-mediated bone resorption, mimicking the CRAB features typically associated with multiple myeloma 2.

• While hypercalcemia is more commonly associated with multiple myeloma, diffuse large B-cell lymphoma and other NHL subtypes can present with identical CRAB features (hypercalcemia, renal dysfunction, anemia, bone lesions) 2.
• The low alkaline phosphatase is paradoxical but can occur when bone resorption predominates over formation in lymphoma-related bone involvement 2.

Iron Deficiency and Anemia Pattern

The low MCH indicating iron deficiency combined with borderline-high hemoglobin creates an unusual pattern that warrants careful interpretation in the NHL context.

• While anemia of chronic disease is typical in lymphomas (characterized by iron sequestration), true iron deficiency can coexist due to gastrointestinal involvement 3.
• GI tract involvement occurs in 15-30% of NHL cases (particularly mantle cell lymphoma, where microscopic involvement reaches 88-92%) 1.
• The borderline-high hemoglobin may represent hemoconcentration from volume depletion secondary to hypercalcemia and renal dysfunction 1.

Renal Impairment Mechanisms

The hyperchloremic non-anion-gap metabolic acidosis specifically points to renal tubular dysfunction from multiple lymphoma-related mechanisms 1.

• Uric acid crystal deposition in renal tubules is the most common cause of uremia in TLS 1.
• Additional mechanisms include calcium phosphate precipitation, tumor infiltration of kidneys, and obstructive uropathy from lymphadenopathy 1.
• The metabolic acidosis pattern suggests type 4 renal tubular acidosis from tubular damage rather than simple uremia 1.

Clinical Integration and Workup Priorities

The comprehensive metabolic panel abnormalities should trigger immediate assessment for TLS and staging workup per NCCN guidelines 1.

• Essential initial assessments include: CBC with differential, comprehensive metabolic panel, LDH, uric acid, and hepatitis B testing 1.
• Bone marrow biopsy with adequate trephine core (>2 cm) is essential for staging, which may reveal marrow involvement explaining some hematologic abnormalities 1.
• GI endoscopy should be considered given the high frequency of microscopic GI involvement and potential for occult bleeding causing iron deficiency 1.

Common Pitfalls to Avoid

• Do not assume hypercalcemia automatically means multiple myeloma—NHL can present with identical CRAB features, and protein electrophoresis may be negative 2.
• Do not overlook spontaneous TLS—it can occur before any treatment in high-burden NHL and requires immediate intervention 1.
• Do not dismiss the iron deficiency as unrelated—it may indicate significant GI involvement requiring endoscopic evaluation for complete staging 1.
• Monitor for hyperkalemia and hyperphosphatemia as additional TLS components that may develop rapidly and cause life-threatening cardiac arrhythmias 1.