Copper deficiency anemia due to zinc supplementation in a chronic hemodialysis patient

Abstract

Zinc deficiency causes dysgeusia and dermatitis as well as anemia. As approximately half of dialysis patients have zinc deficiency, zinc supplementation should be considered in case of erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia. We report a case of a chronic dialysis patient with copper deficiency anemia caused by standard-dose zinc supplementation. The patient was a 70-year-old woman who had received maintenance hemodialysis for 8 years due to diabetic nephropathy. She had been treated with weekly administration of darbepoetin 30 μg for renal anemia, which resulted in Hb 12 to 14 g/dL. She had no dysgeusia. When zinc deficiency (44 μg/dL) had been identified 4 months earlier, 50 mg daily zinc acetate hydrate (Nobelzin®), which is the standard dose, was started. Unexpectedly, her anemia progressed slowly with macrocytosis together with granulocytopenia. Her platelet count did not decrease at that time. Laboratory tests revealed a marked decrease of serum copper (< 4 μg/dL) and ceruloplasmin (< 2 mg/dL), although serum zinc was within the normal limit (125 μg/dL). We discontinued zinc acetate and started copper supplementation including cocoa for 1 month. Her anemia and granulocytopenia were dramatically restored coincident with the increase in both serum copper and ceruloplasmin. Copper supplementation also improved her iron status as assessed by transferrin saturation and ferritin. Clinicians should monitor both zinc and copper status in anemic dialysis patients during zinc supplementation, as both are important to drive normal hematopoiesis.

Background

Zinc is one of the essential trace elements that is required for the structural stability and activity of various proteins and enzymes [1]. A systematic review and meta-analysis of studies demonstrated lower serum zinc levels in hemodialysis patients. Another report showed zinc deficiency in approximately half of maintenance dialysis patients [2–4]. Zinc acetate hydrate (Nobelzin®) was developed to treat patients with zinc deficiency, and is widely used in hemodialysis patients with erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia in Japan [3, 5]. The standard prescribed dose of zinc acetate hydrate is 50 mg–100 mg daily for zinc deficiency. Oral supplementation of zinc acetate hydrate is effective to correct hypozincemia; however, excessive zinc supplementation may induce copper deficiency [6, 7]. Thus, copper monitoring is necessary during zinc supplementation.

Here, we report a hemodialysis patient who had copper deficiency while receiving the standard dose of zinc supplementation. We also discuss the absorption, utilization, and interaction of iron, copper, and zinc in hematopoiesis.

Case presentation

A 70-year-old female presented with general fatigue with anemia and granulocytopenia. She had been receiving maintenance hemodialysis for 8 years due to end-stage renal failure as a result of diabetic nephropathy. She had a history of multiple cerebral infarctions and lumbar compression fractures. Her rehabilitation was not progressing due to lumbago, leading into bedridden status for most of the day. Her height was 152 cm, dry weight was 48.0 kg, and temperature was 36.1 °C. Her blood pressure was 110/71 mmHg and pulse rate was 58 bpm. She had pale palpebral conjunctiva, but no edema, petechiae, or purpura was observed in her extremities. She had no dysgeusia, although she had repeated aspiration pneumonia. She had been treated with weekly administration of darbepoetin 30 μg for renal anemia, which resulted in Hb 12 to 14 g/dL. Zinc deficiency (44 μg/dL) had been found in a blood test 4 months earlier, and daily supplementation of zinc acetate hydrate (Nobelzin® 50 mg tablet) was started. Unexpectedly, her anemia progressed to Hb 5.9 g/dL with macrocytosis despite an increase in darbepoetin and another ESA epoetin-β for 2 months, as shown in Fig. 1. Moreover, she developed fever with positive C-reactive protein (CRP), possibly associated with leukopenia. Her platelet count was not changed at that time. We proceeded with a differential diagnosis of macrocytic anemia, hyporesponsive to ESA therapy and granulocytopenia. Laboratory findings indicated that she did not have deficiencies of iron, vitamin B12, or folate. She did not have any paraproteinemia. However, her serum copper (< 4 μg/dL; normal range: 64–132 μg/dL) and ceruloplasmin (< 2 mg/dL; normal range: 21.0–37.0 mg/dL) were markedly decreased to an undetectable level, although serum zinc was within normal range (125 μg/dL; normal range: 80–130 µg/dL). We determined that copper deficiency might also explain her leukopenia without thrombocytopenia. The patient refused a bone marrow aspiration test. Therefore, we stopped her zinc supplementation and started her on 30 to 45 g of pure cocoa (copper content: 1.1–1.6 mg/day) and a commercially available copper-containing supplement (copper content: 2 mg/day). Her anemia and granulocytopenia were dramatically improved without additional ESA and granulocyte colony-stimulating factor after starting copper supplementation (Fig. 1). We did not use iron supplementation after the switch. She regained her vitality along with the increase in her Hb level, and her fever spontaneously disappeared after normalization of the white blood cell count. Copper supplementation was discontinued 2 months after serum copper levels returned to normal range. Thereafter, both serum copper and zinc remained at 70–80 μg/dL.

Fig. 1.

Clinical course. ESA erythropoiesis-stimulating agent, DPA darbepoetin, EPO epoetin-β

Discussion and conclusions

Copper deficiency has been reported in a variety of cases, such as long-term parenteral nutrition or tube nutrition [8]. Excessive zinc intake also causes copper deficiency [9]. Copper deficiency presents as both neurological and hematological disorders. Spastic gait and sensory ataxia have been previously reported as typical neuropathy, and anemia with granulocytopenia as hematopoietic abnormality [10, 11]. The neurological symptoms in our case were not obvious because the patient had been bed bound most of the time before the onset. However, she became weaker due to the progression of anemia, and susceptible to infections due to granulocytopenia. In copper deficiency, most anemia has been macrocytic as in our case, but both normocytic and microcytic anemia have also been reported [6]. Pancytopenia has been observed in approximately 10% of copper-deficient blood disorders [12].

Zinc is essential for erythropoiesis and can be associated with anemia in both deficient and excess conditions. GATA-1, a GATA family of transcription factor possessing zinc finger domains that requires zinc to form critical tertiary structures, plays an essential role in promoting erythroid differentiation (Fig. 2) [13, 14]. Therefore, zinc deficiency can lead to functional GATA-1 loss and cause anemia due to the maturation failure of bone marrow stem cells to erythrocytes together with iron deficiency status [15, 16].

Fig. 2.

Role of zinc, copper, and iron in the red blood cell differentiation process. At first, erythropoietin (Epo) binds to the Epo receptor expressed on proerythroblast in the bone marrow, leading to the release of GATA-1 that initiates erythroid differentiation. GATA-1 requires zinc for establishing a tertiary structure called a zinc finger. GATA-1 works as a differentiation driver from proerythroblast, basophilic erythroblast, polychromatophilic erythroblast, to orthochromatophilic erythroblast. Thus, zinc deficiency may cause differentiation failure from multipotent stem cells toward the erythroid lineage

In contrast, zinc excess can cause anemia due to copper deficiency. Divalent copper is absorbed through divalent metal transporter 1 (DMT1) that mainly works as a transporter of iron from the intestine, and monovalent copper is absorbed though the copper transporter 1 (CTR1) (Fig. 3) [17, 18]. Copper is absorbed through enterocytes with the ATPase copper transporting alpha, ATP7A [19]. Both zinc and copper can bind metallothionein, which functions to maintain the homeostasis of essential trace elements or the detoxification of excess heavy m [20, 21]. Excess zinc could cause copper deficiency through metallothionein unintendedly induced by zinc [16]. Since copper is a pivotal element in the ferroxidase enzymes, hephaestin, copper deficiency may cause a decrease in the trivalent iron (Fig. 3) [10, 22]. Ceruloplasmin works as a copper transporter and controller of iron efflux via oxidation, which is required for binding to transferrin [23]. Therefore, zinc excess causes anemia by interfering with iron utilization via copper deficiency. We did not use either oral or intravenous iron supplementation during copper therapy because oral iron may compete with the absorption of dietary copper through DMT1 and intravenous iron, such as saccharated ferric oxide containing trivalent iron that effectively supply iron without the complex mechanism though enterocytes even under copper deficiency, may induce an unpredictable increase in the Hb level. Indeed, serum iron, transferrin saturation, and ferritin decreased after copper supplementation, indicating an improvement in the iron utilization rate (Fig. 3). The exact mechanism by which granulocytopenia is induced by copper deficiency remains elusive [6].

Fig. 3.

Absorption mechanism of zinc, copper, and iron in intestinal epithelium. Iron (Fe²⁺) is absorbed through the divalent metal transport 1 (DMT1) expressed on the luminal side of enterocytes. Copper is essential for the oxidase activity of hephaestin that converts the divalent (Fe²⁺) to the trivalent (Fe³⁺) form. This oxidation step is crucial for dynamic iron mobilization after enteral absorption. Zinc (Zn²⁺) and copper (Cu²⁺) are also competitively absorbed from DMT1. Luminal zinc is transported via the other zinc-specific transmembrane transporter, Zrt/Irt-like protein 4 (ZIP4), and excreted through another zinc-specific transporter, zinc transporter 1 (ZnT1), into the bloodstream. Monovalent copper (Cu⁺) is alternatively absorbed through the copper-specific transmembrane transporter, CTR1, and released via another copper-specific transporter, ATPase copper-transporting alpha, ATP7A, into the bloodstream. Metallothionein, a metal-binding protein in the Golgi apparatus, plays a protective role against metal toxicity and oxidative stress in the enterocytes. When excessive zinc reaches the enterocytes, metallothionein induced by zinc binds to intracellular zinc and copper. Enterocytes possessing metallothionein rich in zinc and copper are exfoliated into the intestinal lumen for detoxication, leading to copper loss. Thus, zinc, copper, and iron function co-operatively as important elements for erythropoiesis

Since the patient’s anemia and granulocytopenia improved after the discontinuation of zinc and copper supplementation, we diagnosed her with copper deficiency anemia caused by zinc administration, although we did not perform bone marrow examination. As serum copper might decrease below the reference level when serum zinc levels increase to more than 120 μg/dL in hemodialysis patients, dose reduction or the cessation of zinc supplementation might be recommended, targeting a serum zinc level from 80 to 120 μg/dL [24]. The Japanese Society of Clinical Nutrition defines the normal range of serum zinc as 80–130 µg/dL. Our patient had a relatively high level of serum zinc (125 μg/dL) that resulted in copper deficiency, despite receiving the standard dose. When zinc supplementation is started, serum levels of both zinc and copper should be measured every 3 or 4 months [25]. In addition, if copper deficiency existed before zinc supplementation, zinc may worsen the copper deficiency. Therefore, it is important to ensure that no copper deficiency is present before administering zinc.

We reported a case of macrocytic anemia and granulocytopenia due to copper deficiency caused by standard zinc supplementation in a chronic hemodialysis patient. Copper monitoring is necessary during zinc supplementation, because copper deficiency can occur even when zinc levels are within the normal range.

Abbreviations

ESA

Erythropoiesis-stimulating agent

CRP

C-reactive protein

DMT1

Divalent metal transporter 1

CTR1

Copper transporter 1

ATP7A

ATPase copper transporting alpha

ZIP4

Zrt/Irt-like protein 4

ZnT1

Zinc transporter 1

Author contributions

TW wrote the manuscript with the support of TT. SY, HI, and KK treated the patient while being supported by TT. TW presented this case at the Sixty-eighth Japanese Society of Dialysis Therapy meeting.

Funding

No funding was obtained for this case report.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval and consent to participate

The ethical committee of Kitano Hospital approved this case report.

Consent for publication

Informed consent was obtained from the patient in this case report.