Case Presentation: A healthy 21 year-old man presented with progressive headaches and altered mentation. He had severe hemolytic anemia, hemoglobin 3.2 g/dL, indirect hyperbilirubinemia, elevated LDH, undetectable haptoglobin, and a direct antiglobulin test positive for IgG. He developed encephalopathy requiring intubation and CRRT for acute kidney injury. Broad malignancy, infectious, and autoimmune evaluations were unrevealing; bone marrow showed erythroid predominance without blasts. Flow cytometry detected CD4/8 double negative T cells at levels that warranted consideration for autoimmune lymphoproliferative syndrome (ALPS); however, comprehensive gene testing was negative. Serum zinc and copper levels were within normal range.
Discussion: At its core, this is a case of warm autoimmune hemolysis; evident by hemoglobin 3.2 g/dL, elevated LDH, undetectable haptoglobin, marked indirect hyperbilirubinemia, positive IgG DAT, and peripheral smear showing spherocytes and nucleated RBCs. The sudden, catastrophic hemolytic crisis is not representative of the insidious, progressive multi-lineage onset of cytopenias in ALPS. The single lineage involvement is demonstrated by a mildly hypercellular bone marrow with erythroid predominance, normal megakaryocytes, no blast expansion, clonal lymphoid process, or morphological evidence of lymphoproliferative or leukemic process. The exposure to supra-physiologic doses of Zinc ~30x the daily recommended intake, stemed from energy drinks and supplements use. Chronic daily exposure of this magnitude is relatively common in veterinary medicine. Zinc has been shown to cause hemolytic anemia through both oxidative damage and hapten effect on the red cell surface. The IgG-positive DAT and the presence of spherocytes support a hapten-like mechanism. The rise in DNT cells is a key trigger for evaluating ALPS. However, gene panel testing was negative for known associated mutation. Although not ruled out, it makes a primary, lifelong apoptotic disorder much less likely. Supra-physiologic doses of zinc interfere with caspase activity and Fas-mediated apoptosis, increasing the likelihood of non-standard subsets of T-cells, including DNTs, to survive. Therefore, It is more plausible for the DNT rise to reflect zinc-induced functional blockade of apoptosis than gene negative ALPS. The normal serum zinc level is a logical and seemingly significant objection. However, due to its critical biochemical functions, zinc homeostasis is tightly regulated. Zinc is stored mainly in muscle, bone, and liver. In serum, nearly all of the free zinc is albumin or macroglobulin-bound. Thus, serum zinc levels can not be used to determine total body zinc and an isolated value obtained after days in the ICU, on CRRT, and off supplements is not reliable in predicting zinc burden in the weeks preceding presentation.
Conclusions: Acute zinc exposure driven warm autoimmune hemolysis, features of which mimic ALPS (which has yet to be described in humans), is the most plausible cause of this presentation. Evidence supporting such pathophysiology stems from clinical and experimental studies from Immunology, oncology, critical care, hematology, toxicology, and veterinary medicine. Experimental data in immunology and oncology show the apoptosis-suppressing property of high-dose zinc, leading to a higher likelihood of DNT survival; combined with hematologic, veterinary, and toxicological data demonstrating the ability of zinc to induce warm IgG-positive AIHA.
