Introduction
Taste distortion or dysgeusia is a common symptom among cancer patients, with prevalence ranging from 22% to 85% of cancer patients receiving chemotherapy (Di Meglio et al. Reference Di Meglio, Dinu and Doni2022; Ito et al. Reference Ito, Yuki and Nakatsumi2022). Chemotherapy may have neurotoxic effects or inhibit the differentiation or proliferation of taste buds, impacting taste and smell (Henkin Reference Henkin1994). Sustained inflammatory state, disruptions in the gut microbiota, radiation to the head and neck causing damage to taste cells, xerostomia, and oral mucositis may be other causes (Murtaza et al. Reference Murtaza, Hichami and Khan2017). Dysgeusia can have many negative downstream effects such as decreased appetite, malnutrition, weight loss, cachexia, and worsened quality of life (Holmes Reference Holmes1993; Rosati et al. Reference Rosati, Mastino and Romeo2024; Suka et al. Reference Suka, Katsube and Fujimoto2024; Liang et al. Reference Liang, Yang and Yin2025).
Zinc is a micronutrient essential for taste perception. Some studies have associated zinc deficiency with dysgeusia in cancer patients (Heyneman Reference Heyneman1996; Yamagata et al. Reference Yamagata, Nakamura and Yamagata2003), with cancer treatment drugs theorized to affect the binding and chelation of zinc (Comeau et al. Reference Comeau, Epstein and Migas2001). Daily zinc supplementation ranging from 25 to 100 mg have been suggested to treat dysgeusia for patients who may have zinc deficiency (Heyneman Reference Heyneman1996).
The effects of zinc overconsumption should be considered, however, for clinicians who are inclined to prescribe zinc empirically for dysgeusia in cancer patients. Short-term effects include gastrointestinal symptoms such as nausea, vomiting, abdominal pain, diarrhea, as well as fatigue, weakness, and dizziness (Fosmire Reference Fosmire1990). Long-term effects include copper deficiency, anemia and neutropenia, impaired immune function, hepatic dysfunction, and neuronal damage (Lemire et al. Reference Lemire, Mailloux and Appanna2008; Morris and Levenson Reference Morris and Levenson2017). This case report describes a cancer patient receiving prolonged zinc supplementation who developed worsening symptoms and was later found to have copper deficiency requiring immediate treatment.
Case presentation
Initial presentation
A patient in his 70s with multiple myeloma being treated with chemotherapy and prior auto-stem cell transplant was seen in the hematology clinic for evaluation of neutropenia. Other past medical history included gastroesophageal reflux disease, Barrett’s esophagus, gastroparesis, and benign prostatic hyperplasia (BPH). White blood cell count at the time of hematology referral was 1.5 K/µL (neutrophil 29.2%), not fully attributable to his multiple myeloma or treatment-related effects, and hemoglobin ranging from 7.7 to 8.6 g/dL. As for symptoms, he reported progressive fatigue, nausea, and poor appetite for the past few weeks. He also stated having worsening numbness and tingling pain extending from the bilateral lower extremities to the thighs and new onset tingling in the bilateral hands for the past few weeks, in the background of known chemotherapy-induced peripheral neuropathy. His home medications included acyclovir 800 mg twice a day and sulfamethoxazole-trimethoprim 800 mg-160 mg three times a week for infection prophylaxis, amoxicillin-clavulanate 875 mg-125 mg twice a day following a recent hospitalization for fever, morphine sulfate immediate release 7.5 mg every 4 h as needed for cancer-related pain, alfuzosin 10 mg daily and finasteride 5 mg daily for BPH, and zinc sulfate 220 mg twice a day for dysgeusia initially prescribed approximately 2 years ago.
For the neutropenia, lab tests to investigate autoimmune etiologies (rheumatoid factor [RF], anti-neutrophil antibody [ANA]) and a copper level were ordered. The patient’s ANA and RF factors were undetectable. However, he was found to have a very low copper level of < 10 mcg/dL. Due to worsening lightheadedness, nausea, fatigue, and the finding of hypocupremia, he was instructed to present to the acute care center.
Hospital course
The patient was admitted to the hospital for further management. Zinc was discontinued. IV cupric chloride infusion of 4 mg daily was initiated with the plan to administer for a total of 10 days.
The supportive and palliative care team was consulted to assist with symptom management. The patient reported painful neuropathy with tingling and numbness in the bilateral lower extremities extending to the upper thighs and bilateral hands. He declined gabapentin or duloxetine; gabapentin had been ineffective, and he had discontinued duloxetine due to side effect concerns. He also reported increase in his chronic lower back pain related to vertebral compression fractures and lumbar facet arthropathy. Morphine immediate release oral solution 5 mg every 4 h as needed was prescribed to treat lower back pain and severe pain from neuropathy. Abdominal imaging revealed constipation, which was treated with senna tablets and polyethylene glycol daily. He reported that dysgeusia was no longer an issue.
For nausea with history of gastroparesis, gastroesophageal reflux disease, and Barrett’s esophagus, the gastrointestinal medicine team was consulted. It was determined that nausea was likely multifactorial due to severe copper deficiency exacerbating the known gastroparesis. He was given erythromycin three times a day for 3 days.
The neurology team was also consulted to assess the peripheral neuropathy. On further neurologic exam, he was found to have impaired gait, decreased vibration sense in the anterior superior iliac spine and ankles bilaterally, as well as a positive Romberg test. The findings were concerning for subacute combined degeneration of the spinal cord related to copper deficiency. Additional lab work to check a vitamin B12 level found this to be within normal range at 945 pg/mL. The neurology team recommended further copper repletion.
Outcome
The patient reported improvement in fatigue, nausea, and pain by hospital day 3, as seen in his Edmonton Symptom Assessment System (ESAS) scores (Table 1). He also reported mild improvement in paresthesia of the lower extremities during his hospital course. He received 5 days of IV cupric chloride inpatient. He was discharged with the plan to continue additional copper infusions in the outpatient setting for 5 more days.
Table 1. Edmonton Symptom Assessment System (ESAS) scores
He was seen in the supportive care clinic 39 days post-discharge and reported some symptom improvement. Fatigue and pain remained improved overall from his hospital admission. He was not using any medications for pain or neuropathy. He reported the numbness and tingling in his lower extremities had diminished to the knee level. He denied dysgeusia but did report persistent issues with early satiety, nausea, and constipation. He was advised to increase laxatives and take metoclopramide 5 mg three times daily for nausea and early satiety.
Discussion
Copper is an essential mineral for cellular processes including energy production, red blood cell formation, neurological, and immune system functions (Scheiber et al. Reference Scheiber, Dringen and Mercer2013). Copper deficiency caused by zinc supplementation has been described in prior literature (Gupta and Carmichael Reference Gupta and Carmichael2023; Magham et al. Reference Magham, Han and Eilbert2023). Both copper and zinc are absorbed in the gastrointestinal tract, primarily in the stomach and small intestine. Excess zinc increases copper-binding protein metallothionein in the enterocytes, causing copper to be bound and eliminated with sloughing of intestinal cells; this ultimately leads to copper depletion (Halfdanarson et al. Reference Halfdanarson, Kumar and Li2008).
The evidence for zinc supplementation to treat dysgeusia in cancer patients has been mixed. Some studies have found zinc can improve dysgeusia, especially in head and neck cancer patients (Silverman and Thompson Reference Silverman and Thompson1984; Ripamonti et al. Reference Ripamonti, Zecca and Brunelli1998; Najafizade et al. Reference Najafizade, Hemati and Gookizade2013), while others have shown no benefit (Halyard et al. Reference Halyard, Jatoi and Sloan2007; Lyckholm et al. Reference Lyckholm, Heddinger and Parker2012; Khan et al. Reference Khan, Safdar and Siddiqui2019). Polaprezinc, a chelated compound combining zinc and L-carnosine, was found to improve dysgeusia in pancreatic cancer (Fujii et al. Reference Fujii, Hirose and Ishihara2018) and head and neck cancer patients (Watanabe et al. Reference Watanabe, Ishihara and Matsuura2010), while no significant difference in xerostomia or taste was found for patients with hematologic malignancy (Hayashi et al. Reference Hayashi, Kobayashi and Suzuki2014).
Clinicians should be aware of additional limitations to zinc supplementation for dysgeusia. First, it is challenging to detect a deficiency in zinc, as serum zinc concentration is not a reliable indicator of insufficiency (King Reference King1990). Therefore, zinc supplementation is usually initiated on an empiric basis. Second, the serum zinc level has not been found to be associated with taste acuity (Bales et al. Reference Bales, Steinman and Freeland-Graves1986), and it is difficult to determine when zinc has been adequately supplemented. Therefore, it may be prudent for clinicians to prescribe zinc supplementation with a predetermined endpoint in mind, such as 2 months of total treatment to reduce the risk for copper deficiency.
Non-pharmacologic strategies for dysgeusia have a low risk to benefit ratio for cancer patients and should also be discussed. For example, oral care with chlorohexidine and sodium bicarbonate mouthwashes can help with dysgeusia (Magnani et al. Reference Magnani, Mastroianni and Giannarelli2019). Nutritional counseling, flavor enhancement, and chemosensory education may also improve nutritional intake and taste perception (Schiffman et al. Reference Schiffman, Sattely-Miller and Taylor2007; Rehwaldt et al. Reference Rehwaldt, Wickham and Purl2009). Clinicians may also provide counseling that some taste and smell alterations can recover months after completion of cancer treatment (de Vries et al. Reference de Vries, Boesveldt and Kelfkens2018).
Copper deficiency may be easily overlooked, especially in cancer patients who often have high symptom burden due to multiple factors such as chemotherapy or the cancer itself. It is an under-recognized cause for cytopenias and myelopathy that is similar in presentation and imaging as vitamin B12 deficiency (Kumar Reference Kumar2006). Timely recognition and treatment with copper repletion are critical; while cytopenia may be reversible with treatment, neurological deficits to the spinal cord and peripheral nerves may become permanent (Gabreyes et al. Reference Gabreyes, Abbasi and Forbes2013). This case further highlights the importance of recognizing zinc supplementation as a cause for copper deficiency. Clinicians should screen for signs of hypocupremia in patients who are taking zinc for dysgeusia and be mindful of overprescribing or prolonged use.
Funding statement
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Competing interests
The authors declare none.
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