Dysgeusia Due to Zinc De ciency After Pancreaticoduodenectomy Requiring Continuous Intravenous Zinc Supplementation: a Case Report and Literature Review

Hironobu Hata (  hatabooh@gmail.com ) National Hospital Organization Hokkaido Cancer Center https://orcid.org/0000-0002-0077-7026 Yojiro Ota Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center Katsuhiko Uesaka Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center Yutaka Yamazaki Hokkaido University Tsubasa Murata Tomakomai City Hospital Chika Murai Hokkaido University Kazuhito Yoshikawa Hokkaido University Kenji Imamachi National Hospital Organisation Hokkaido Cancer Center: Hokkaido Gan Center Takashi Yurikusa Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center Yoshimasa Kitagawa Hokkaido University


Background
Zinc is an essential trace element for humans, which when de cient can cause various pathological conditions, such as dermatitis, hair loss, anemia, dysgeusia, impaired development, gonadal dysfunction, and wound healing disorders. The role of zinc in taste functions is appreciable at various levels of body organization, such as taste buds and the taste sensation transmission [1]. Zinc de ciency secondary to any etiology leads to taste disturbances; thus, zinc depletion is corrected for patients presenting with taste imbalances [2]. It has been observed in vivo that zinc administration improves decreased taste bud cell proliferation caused by zinc de ciency [3]. Zinc administration improves taste in 50-82% of patients suffering from taste disorders [4]. Dysgeusia during cancer treatment is mainly reported in systemic chemotherapy and in surgery and radiation therapy for head and neck cancer [5]. However, there are a few reports of taste disorders secondary to zinc de ciency associated with surgery in other regions of the body.
Pancreaticoduodenectomy (PD) is the standard operation for periampullary cancers. Zinc is primarily absorbed in the duodenum and proximal jejunum, which are mostly resected during PD [6,7] and may result in nutritional sequelae due to zinc de ciency [8]. Armstrong et al. reported that the incidence of zinc de ciency after PD is 50% [9]. Yu et al. reported that 68% of the patients in their study had low serum zinc levels, and 43% exhibited clinical symptoms related to zinc de ciency following PD [10]. However, the frequency of taste disorders was not described in either study. The incidence of zinc de ciency with acrodermatitis enteropathica after PD is approximately 0.3% in a high-volume hospital [8].
Little is known about the adverse oral events and skin disorders caused by zinc de ciency after PD. Therefore, we describe the case of a patient who experienced zinc de ciency with dysgeusia, glossitis, and acrodermatitis enteropathica-like eruption after PD.

Case Presentation
A 73-year-old woman who had pancreatic head adenocarcinoma underwent pancreatoduodenectomy (PD) at the Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, in July 2005. The patient's height, body weight, and body mass index were 154 cm, 56 kg, and 23.6 kg/m 2 , respectively. The patient was discharged 40 days after surgery; however, about a month after discharge, she visited the hospital's Division of Dentistry and Oral Surgery with a chief complaint of tongue pain with dysgeusia. The rst intraoral examination revealed complete atrophy of the lingual papillae, which became erythematous; this is a symptom of glossitis (Fig. 1a). Furthermore, remarkable taste disorder (hypogeusia) and oral pain were reported. The angle of the mouth had stomatitis with erosive changes. The extremities showed acrodermatitis enteropathica-like eruption and abnormal keratinization (Fig. 1b).
Blood test results showed hypoproteinemia (total protein (TP) 5.1 g/dL, albumin (ALB) 2.4 g/dL) ( Table  1). Examination of trace elements showed remarkably lower serum zinc and copper levels (30 µg/dL, 40 µg/dL, respectively) ( Table 1). We diagnosed malnutrition, dysgeusia, glossitis, angular cheilitis, and acrodermatitis enteropathica due to zinc de ciency. µmol, manganese (Mn) 1 µmol, zinc (Zn) 60 µmol (= 4 mg), copper (Cu) 5 µmol, and iodine (I) 1 µmol; this was administered twice a week for two weeks as an outpatient treatment. However, the intravenous replacement therapy was similarly inadequate at this dosing interval and did not provide su cient improvement in the serum copper and zinc values. repeatedly to monitor serum zinc levels to ensure that they were within the normal range (Fig. 2). Despite continuing intravenous zinc replacement therapy, serum zinc levels decreased when additional oral zinc was discontinued in May 2007. After resuming the oral administration of Promac® due to the recurrence of dysgeusia, both the serum zinc level and dysgeusia improved. Since 2008, Pancreatin® (pancreatic enzyme, Mylan Co Inc, USA) 3 g/day had been administered alongside conventional zinc administration for this patient.
As of January 2012, she continued using Elemenmic® intermittently while her serum zinc values were monitored; however, slight angular cheilitis was observed, and she exhibited no signs of glossitis and dysgeusia (Fig. 1c). Moreover, recurrence and metastasis of the primary tumor were not observed. She subsequently died of lung cancer in May 2020.

Discussion And Conclusion
There are few reports on postoperative taste loss in gastrointestinal cancer, and the involvement of zinc de ciency has not been investigated [11]. Since its introduction in 2002 at the Shizuoka Cancer Center Hospital, PD had been performed in approximately 45 patients per year until 2007; however, only the patient in this study experienced severe dysgeusia caused by zinc de ciency. In fact, dysgeusia and skin lesions caused by zinc de ciency following PD have not been assessed in quality-of-life studies [12][13][14][15].
The most common technique for PD consists of the en-bloc removal of the distal segment (antrum) of the stomach, the duodenum, the proximal part of the jejunum, the head of the pancreas, the common bile duct, and the gallbladder. Zinc is mainly absorbed in the duodenum and proximal jejunum, which are resected during PD, subsequently causing zinc de ciency. In the study by Yu  protein absorption after PD; and 3) impaired fractional absorption of zinc due to pancreatic insu ciency, which is improved by exocrine pancreatic replacement [17]. Insu cient protein absorption after PD is because zinc is transported in the serum via carrier proteins, namely ALB (57% of serum zinc), alpha-2macroglobin (40%), and amino acids, such as histidine and cysteine (< 3%) [8]. Consequently, poor protein absorption may cause low zinc availability. Moreover, de ciencies in branched-chain amino acids and essential fatty acids may contribute to the formation of skin lesions similar to those of acrodermatitis enteropathica observed in patients with zinc de ciency [18,19]. From a therapeutic viewpoint, the clinical manifestation of zinc de ciency in PD might be improved not only by supplementation with zinc but also by the administration of pancreatic enzyme formulations and adequate intake of protein and essential fatty acids [8].
In 2017, Nobelzin® tablet 50 mg (zinc acetate hydrate 167.84 mg, Nobelpharma Co. Ltd., Tokyo, Japan), which had been proven to be safe and effective for the long-term treatment of Wilson disease [20], was approved for the additional indication of hypozincemia in Japan [21]. The gastric ulcer healing agent Promac® 150 mg could be supplemented with 34 mg of zinc daily, while zinc replacement was an offlabel use. Now, for zinc replacement therapy, 3 tablets of Nobelzin® could be supplemented with at most 150 mg of zinc, which is more than four times as much zinc supplement as the standard dose of 150 mg of Promac® daily. The difference in bioavailability between zinc acetate hydrate and polaprezinc is unclear; however, in a study of zinc supplement for hemodialysis maintenance patients, 50 mg of zinc per day administered in the zinc acetate hydrate group was superior to 34 mg of zinc per day administered in the polaprezinc group in increasing and maintaining serum zinc levels [22]. It is unclear whether higher oral zinc supplementation with zinc acetate hydrate could replace intravenous zinc supplementation in Page 7/11 our case. A limitation of this study is that the ndings are not generalizable. Further research elucidating the probable causes of zinc de ciency after PD is required to improve the generalizability of our study ndings.
Zinc de ciency after PD rarely occurs, and the mechanism has not been fully elucidated; the clinical oncologist community, including dentists responsible for the oral care of cancer patients, should be aware of dysgeusia associated with zinc de ciency after cancer surgery, as well as that induced by chemotherapy or head and neck radiation therapy.  Transition of zinc supplementation and serum zinc level. Approximately one month after discharge following pancreaticoduodenectomy performed in July 2005, the patient experienced oral pain and dysgeusia caused by zinc de ciency (serum zinc level, 30 μg/dL). Oral zinc supplementation was inadequate, and dietary intake decreased; therefore, she was admitted to the hospital in November 2005

List Of Abbreviations
and administered intravenous supplementation of multi-trace elements (MTEs), including zinc and highcalorie infusion. Serum zinc level increased to 99 μg/dL, and food intake improved; hence, she was discharged 20 days after admission following intravenous zinc supplementation. However, after discharge from the hospital, intravenous zinc supplementation was discontinued, and she became hypozincemic again within a month; therefore, she was readmitted to the hospital at the end of December 2005. At the second discharge in January 2006, a central venous port was indwelled, and home selfinjection of MTEs was performed to maintain zinc levels.