Dermatological manifestations relating to nutritional deficiencies after bariatric surgery: case report and integrative literature review

ABSTRACT BACKGROUND: The number of bariatric surgeries performed worldwide is growing. Among the main short, medium or long-term complications after surgery are nutritional deficiencies. Many of these, such as those of Zn, Cu and vitamins A, B1, B3, B6 and B12, are manifested by dermatological lesions before potentially fatal systemic disorders occur. OBJECTIVE: To identify the main dermatological manifestations associated with nutritional deficiencies after bariatric surgery, and the associated variables. DESIGN AND SETTING: Integrative literature review carried out at a public university in Brazil. METHODS: This was a case report and a review of health research portals and databases of national and international biomedical journals, without publication date limitation. The descriptors used for searches followed the ideal methodology for each database/search portal: “bariatric surgery”, “skin”, “skin disease”, “skin manifestation”, “deficiency disease” and “malnutrition”. RESULTS: A total of 59 articles were selected, among which 23 were review articles or articles that addressed specific dermatological manifestations. The other 36 articles described 41 cases, which were organized into a table with the clinical variables. CONCLUSIONS: Although nutritional deficiencies are expected as complications after bariatric surgery, few articles relating them to their dermatological manifestations were found. It is important to recognize skin changes caused by nutritional deficiencies in patients treated via bariatric surgery, as these may occur before systemic complications appear and are easier to diagnose when the patient does not have any systemic symptoms yet. However, there is generally a delay between the appearance of skin lesions and making the diagnosis of nutritional deficiency.


INTRODUCTION
Obesity is associated with decreased quality of life, 1 comorbidities and increased mortality. 2 Cancer is also associated with obesity, particularly in the breast, endometrium, colon and prostate. 3 Obesity is probably an independent risk factor for greater severity of COVID-19 4 and decreases protection in immunization against influenza. 5 The growing incidence of obesity and overweight is among the biggest public health problems worldwide. 6 As a result, the number of bariatric surgeries, which are considered to be an effective treatment for obesity (and diseases resulting from it), 7 is growing.
Nonsurgical treatment modalities may promote some weight loss, but it is usually not maintained over the long term because patient compliance is generally not adequate. Surgical treatment is attractive for patients because it enables a more pronounced weight loss that can be sustained over the long term, in addition to having a positive impact on comorbidities associated with obesity, thereby reducing mortality and improving quality of life. However, like any treatment, bariatric surgery is not without complications, whether perioperative (such as bleeding, infection or thrombotic events) or malabsorptive (which would lead to or worsen vitamin and mineral deficiencies). The indications for surgery need to be individualized for each patient's condition; rigid criteria do not apply, and risk/benefit ratios should always be considered. 8 There are three main categories of bariatric surgery: 9  gastric bypass, with or without retention ring; and 3 -predominantly malabsorptive: biliopancreatic shunt with sleeve gastrectomy, with or without distal gastric preservation, and biliopancreatic shunt with sleeve gastrectomy and pyloric preservation. Roux-en-Y is the type of surgery most performed, followed by sleeve gastrectomy and gastric banding (these three procedures make up 92.2% of those performed worldwide). 10 (Figure 2).  (Figures 1B and 1C). Lifetime monitoring was instituted to prevent recurrent nutrient deficiency conditions. This impressive case raised the issues of postoperative vitamin and mineral deficiencies and of patient compliance, which will be discussed in this paper. However, it was also a sad reminder of patients' and their parents' expectations and the ethics regarding bariatric surgery in the pediatric population; issues that will not be tackled here. 12 webofknowledge.com) and SciELO (https://scielo.org/en/). The following descriptors were used: "bariatric surgery", "skin", "skin disease", "skin manifestation", "deficiency disease", "malnutrition" and "undernutrition"; and, for EMBASE, equivalent descriptors.

METHODS
The eligibility criteria were the following: (a) systematic reviews, meta-analyses, case reports and case series among post-bariatric patients of any sex and age who presented dermatological manifestations resulting from nutritional deficiencies; (b) the languages English, French, Italian, Portuguese and Spanish. The information contained in each text was synthetized and recorded on protocol sheets, so that the team members could verify their validity and applicability and, possibly, find elements to support the discussion that would lead to interpretation of the data. These data were manually collected and stored in spreadsheet format, using the A C B maximum, frequency and percentage). To assess associations between the variables, a meta-analysis was performed on individual participant data (IPD meta-analysis) using logistic regression models with mixed effects, through the Laplace method. The significance level adopted was 5%. The patient's mother was shown the pictures included in this article and consented, in writing, to their publication. This document is in our custody and can be produced for perusal. The institutional Ethics Committee deemed further approval unnecessary, considering that that the main content of the manuscript is a review of the literature.

RESULTS
Fifty-nine of the 138 articles retrieved were selected, after applying the inclusion and exclusion criteria described above. Among these 59 articles, 23  consisted of literature reviews, topic discussions or research focusing on specific dermatological manifestations, which were used to support the introduction and discussion of the present article (Figure 3). The remaining 36 articles 35-68 referred to 41 case reports on patients with cutaneous manifestations secondary to nutritional deficiencies after bariatric surgery, whose data are compiled in Table 1. Five of them were papers presented at two congresses and were referenced together. 25, 47 The mean age was 44 years (range 29-66). The mean time between the day of surgery and the dermatological manifestation was 6.4 years (range 3-16).
The most frequent type of bariatric surgery among the patients who developed dermatological manifestations was Roux-en-Y gastric bypass (70%), followed by biliopancreatic bypass (14%).

DISCUSSION
After bariatric surgery, regular multidisciplinary follow-up of the patients must be maintained for many years. It includes adoption of a balanced diet, supplementation with minerals and vitamins and periodic laboratory evaluations. However, despite the recommendations, studies 69 have shown that these patients are often monitored irregularly and that their adherence to vitamin and mineral supplementation is low.
Our search in the literature showed that only 61% of the patients who developed dermatological signs of nutritional deficiencies adhered to supplementation. Sunil et al. 70 found that being female, not having a full-time job and having symptoms of attachment anxiety were factors that related to lower adherence to post-surgical recommendations. Mahawar et al. 71 reported that the main reasons given by patients for non-adherence to supplementation were: 1 -difficulty remembering to take the pills; 2 -high number of pills; 3 -the advent of side effects; and 4 -financial cost. In addition, it needs to be considered that patients can present nutritional deficiencies even before being treated through bariatric surgery and that these conditions are worsened in the postoperative period, over both the short and the long term. 72 This review showed that most nutritional deficiencies present with dermatological manifestations at a relatively early stage (53% within five years or less after the date of surgery). The most common manifestation was acquired acrodermatitis enteropathica. 73  Zn binds to approximately 10% of human proteins. Therefore, this metal is associated with many organic activities, such as cell development, differentiation and growth, and Zn deficiency manifests itself in several ways, in all organs. 74 It should be noted that zinc supplementation may impair copper absorption, and in bariatric surgery patients with low zinc levels it is recommended that oral copper should be administered separately. 75 The second most-common manifestation was pellagra-like lesions, which manifest as symmetrical erythematous plaques that can be accompanied by edema and sometimes blisters, located on sun-exposed areas of the skin. 76 Pellagra is caused by a deficiency of niacin also known as nicotinic acid, a form of vitamin B3. Niacin     is absorbed from the diet, or synthesized from the amino acid tryptophan, and is important for synthesis of NAD and NADP: coenzymes that generate high-energy phosphate bonds that are essential for the metabolism of glucose, amino acids and proteins.
Niacin deficiency will be felt first in tissues with a high cell turnover, such as the intestines (manifesting as diarrhea) and the skin, and in organs with high energy demands, such as the brain (causing insomnia, fatigue, nervousness, irritability and depression). 77 The next most-common complaints were xerosis and hair thinning, which have been correlated with deficiencies of various nutrients, particularly fat-soluble vitamins, given that malabsorptive surgery impairs the absorption of lipids. 78  Another important element for skin health is vitamin E, which is not synthesized by humans and must be consumed in the diet.
There are eight types of vitamin E, and γ-tocopherol is the most abundant type found in foods, while α-tocopherol is the most abundant type found in human tissues and serum. In human skin, vitamin E inhibits production of prostaglandin E2 and nitric oxide and prevents oxidative stress from ultraviolet (UV) radiation, manifested through formation of sunburn cells, lipid peroxidation and edema.
Vitamin E has a protective role against cancer because it reduces formation of UV-induced photo adducts and immunosuppression. 84 Vitamin B12 deficiency was also commonly detected ( Table 1) and presented in the forms of angular cheilitis, glossitis, hair depigmentation and mucocutaneous hyperpigmentation. Methylcobalamin and adenosylcobalamin are two biologically active forms of vitamin B12. Methylcobalamin is a coenzyme with methionine synthase that is essential for synthesis of pyrimidines and purines, while adenosylcobalamin degrades fatty acids. Excess or deficiency of cobalamin can lead to dermatological manifestations, due to changes in the complex biochemistry and metabolism of this vitamin. 85 Excess B12 can produce acneiform reactions, as it modulates the transcriptional activities of Propionibacterium acnes. This is an indication that development of the disease depends on the interaction mediated by metabolites between the host and the skin flora. 86 If untreated, patients with this deficiency may present with megaloblastic anemia and even neurological manifestations such as paresthesia, loss of positional awareness and cognitive impairment. 77,87 As demonstrated in Table 1, among the 41 patients selected, 27 had systemic manifestations and these were potentially fatal or fatal in 11 patients. 37,41,43,[46][47]49,50,61,65,67 Although not the purpose of this review, it is also necessary to consider that there are cutaneous manifestations that occur after bariatric surgery, which are not due to nutritional deficiency. On the contrary, these are due to excessive replacement of micronutrients, a situation seen with relative frequency in patients in the late postoperative period of bariatric surgery. 86 Discussion of the clinical guidelines for nutrition and metabolic support for patients under follow-up after bariatric surgery was beyond the scope of the present study. 88 Ha et al. 89 published a systematic review and meta-analysis of longitudinal studies on bariatric surgery patients who received postoperative supplementation in accordance with the guidelines.
They found that despite adequate monitoring and treatment, there were significant reductions in micronutrient levels at 11 postoperative time points, with a moderate level of evidence (vitamin A at 12-23 months, vitamin E at ≥ 24 months after Roux-en-Y gastric bypass and ferritin at ≥ 24 months after sleeve gastrectomy). Their results help in understanding the optimal micronutrient monitoring times for these patients. They stated limitations to their study, which were identical to ours: few studies included detailed information on patients' adherence to the recommended treatment, and most articles did not describe the dietary modifications after surgery. The latter is an important point to be considered, as micronutrient absorption is affected by food intake.
In our series, none of the articles described the prescribed supplementation regimens and there was no information on the preoperative nutritional status of the patients. Further studies that are prospective and well-controlled should be conducted to generate more accurate data, so that the consequences of bariatric surgery on the skin can be properly evaluated.

CONCLUSION
Patients who underwent bariatric surgery must be monitored frequently for mineral and vitamin deficiencies. Skin diseases can be a manifestation of such conditions and should prompt immediate investigation of the patient's nutritional status.