Syndrome of Inappropriate Anti-Diuretic Hormone Secretion Associated with Multiple Myeloma: A Case Report and Literature Review
Hyponatremia, characterized by a serum sodium concentration below 135 mmol/L, is the most prevalent electrolyte imbalance encountered in clinical practice. It often arises secondary to conditions such as heart failure, renal dysfunction, or pulmonary infections. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH), a disorder marked by excessive water retention due to dysregulated anti-diuretic hormone (ADH) release, is a notable cause of euvolemic hyponatremia. While SIADH is frequently linked to malignancies, its association with hematologic malignancies, particularly multiple myeloma (MM), remains rare. This article presents a detailed case of SIADH as the initial manifestation of MM, highlighting diagnostic challenges, therapeutic interventions, and pathophysiological insights.
Clinical Presentation and Initial Evaluation
A 60-year-old Chinese male presented with progressive lower limb weakness, numbness, and tingling sensations over three months, culminating in difficulty walking during the final ten days. Accompanying symptoms included significant weight loss (10 kg over three months) and a history of hypertension. Physical examination revealed normal muscle strength and sensory function in the lower extremities, but the patient exhibited an indifferent facial expression.
Laboratory investigations disclosed severe hyponatremia (serum sodium: 111.9 mmol/L; normal range: 135–145 mmol/L) alongside elevated globulin (45 g/L) and IgG levels (4.13 g/L; normal: 0.87–1.70 g/L). Suppressed IgM (0.013 g/L) and IgA (0.033 g/L) levels, coupled with a monoclonal IgG-kappa spike on serum protein electrophoresis (M-component: 23%), raised suspicion of a plasma cell disorder. Bone marrow aspiration confirmed the diagnosis, revealing 23% clonal plasma cells positive for CD38, CD138, and cytoplasmic IgG-kappa. Fluorescence in situ hybridization (FISH) showed no cytogenetic abnormalities. Skeletal imaging identified lytic lesions in the thoracic and lumbar spine, consistent with MM. The patient was staged as Durie-Salmon III and International Staging System (ISS) I.
Diagnostic Confirmation of SIADH
Further evaluation of hyponatremia revealed hypo-osmolality (plasma osmolality: 228.0 mOsm/kg H₂O; normal: 285–295 mOsm/kg H₂O) and inappropriately elevated urine osmolality (261.9 mOsm/kg H₂O) and urine sodium (400.9 mmol/24h; normal: 40–220 mmol/24h). Thyroid and adrenal functions were normal, excluding alternative endocrine causes. Magnetic resonance imaging (MRI) of the pituitary gland identified a small adenoma (0.3 cm) with reduced post-contrast enhancement. However, the absence of clinical correlation between the adenoma and hyponatremia, coupled with normalization of sodium levels following MM treatment, supported SIADH as paraneoplastic rather than pituitary-driven.
Therapeutic Management and Outcomes
The patient’s management addressed both SIADH and MM. Fluid restriction and oral Samsca (tolvaptan, 15 mg daily), a selective vasopressin V2-receptor antagonist, were initiated to correct hyponatremia. For MM, a bortezomib-based regimen (1.3 mg/m² on days 1, 4, 8, and 11) combined with methylprednisolone (80 mg on the same days) was administered. Within two cycles, IgG levels declined from 4.13 g/L to 1.14 g/L, achieving complete hematologic remission. Sodium levels normalized (135–145 mmol/L), allowing discontinuation of tolvaptan without recurrence of hyponatremia. At two-year follow-up, the patient remained in sustained remission with stable serum sodium.
Pathophysiological Considerations
SIADH in malignancy typically stems from ectopic ADH production by tumor cells or secretion of ADH-like peptides. However, in this case, no direct evidence of ADH synthesis by myeloma cells was identified. Proposed mechanisms include:
- Paraneoplastic Mediators: Myeloma-derived cytokines or inflammatory markers may stimulate hypothalamic ADH release.
- Drug-Induced SIADH: Although bortezomib and cyclophosphamide have been implicated in SIADH, this patient’s hyponatremia predated chemotherapy, suggesting a disease-related etiology.
- Pituitary Interactions: The incidental pituitary adenoma’s role was deemed negligible, as hyponatremia resolved despite its persistence.
Clinical Implications and Literature Context
SIADH as the presenting feature of MM is exceedingly rare, with only sporadic cases reported. Prior studies describe SIADH in MM patients receiving proteasome inhibitors (e.g., bortezomib) or alkylating agents, often reversible upon drug cessation. In contrast, this case underscores SIADH as a paraneoplastic phenomenon, emphasizing the importance of screening for underlying malignancies in unexplained hyponatremia.
The rapid correction of sodium following MM therapy highlights the centrality of targeting the primary disease. While tolvaptan provided symptomatic relief, long-term sodium normalization depended on myeloma remission, reinforcing the interplay between tumor burden and metabolic derangements.
Conclusion
This case illustrates SIADH as a rare but critical initial manifestation of MM. Clinicians should maintain a high index of suspicion for occult malignancies in patients with refractory hyponatremia, even in the absence of typical hematologic symptoms. Comprehensive evaluation, including serum protein electrophoresis and bone marrow biopsy, is essential for early diagnosis. Effective management requires dual focus on electrolyte correction and antimyeloma therapy, with close monitoring for relapse.
doi.org/10.1097/CM9.0000000000000837
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